Davidsons new

Ch02-1 Fundamentals of Medicine

Ch02-1 Fundamentals of Medicine

01-1 Clinical decision-making

1 Clinical decision-making

Clinical decision-making N Cooper AL Cracknell Introduction 2 The problem of diagnostic error 2 Clinical reasoning: definitions 2 Clinical skills and decision-making 3 Use and interpretation of diagnostic tests 3 Normal values 3 Factors other than disease that influence test results 4 Operating characteristics 4 Sensitivity and specificity 4 Prevalence of disease 5 Dealing with uncertainty 5 Cognitive biases 6 Type 1 and type 2 thinking 7 Common cognitive biases in medicine 7 Human factors 9 Reducing errors in clinical decision-making 9 Cognitive debiasing strategies 9 Using clinical prediction rules and other decision aids 10 Effective team communication 10 Patient-centred evidence-based medicine and shared decision-making 10 Clinical decision-making: putting it all together 10 Answers to problems 12

2 • CLINICAL DECISION-MAKING Diagnostic error has been defined as ‘a situation in which the clinician has all the information necessary to make the diagnosis but then makes the wrong diagnosis’. Why does this happen? Studies reveal three main reasons: • knowledge gaps • misinterpretation of diagnostic tests • cognitive biases. Examples of errors in these three categories are shown in Box 1.2. Clearly, clinical knowledge is required for sound clinical reasoning, and an incomplete knowledge base or inadequate experience can lead to diagnostic error. However, this chapter focuses on other elements of clinical reasoning: namely, the interpretation of diagnostic tests, cognitive biases and human factors. Clinical reasoning: definitions ‘Clinical reasoning’ describes the thinking and decision-making processes associated with clinical practice. It is a clinician’s ability to make decisions (often with others) based on all the available clinical information, starting with the history and physical examination. Our understanding of clinical reasoning derives from the fields of education, cognitive psychology and studies of expertise. Figure 1.1 shows the different elements involved in clinical reasoning. Good clinical skills are fundamental, followed by understanding how to use and interpret diagnostic tests. Other essential elements include an understanding of cognitive biases and human factors, and the ability to think about one’s own thinking (which is explained in more detail later). Other key elements of clinical reasoning include patient-centred evidencebased medicine (EBM) and shared decision-making with patients and/or carers. Introduction A great deal of knowledge and skill is required to practise as a doctor. Physicians in the 21st century need to have a comprehensive knowledge of basic and clinical sciences, have good communication skills, be able to perform procedures, work effectively in a team and demonstrate professional and ethical behaviour. But how doctors think, reason and make decisions is arguably their most critical skill. Knowledge is necessary, but not sufficient on its own for good performance and safe care. This chapter describes the principles of clinical decision-making, or clinical reasoning. The problem of diagnostic error It is estimated that diagnosis is wrong 10–15% of the time in specialties such as emergency medicine, internal medicine and general practice. Diagnostic error is associated with greater morbidity than other types of medical error, and the majority is considered to be preventable. For every diagnostic error there are a number of root causes. Studies of misdiagnosis assign three main categories, shown in Box 1.1; however, errors in clinical reasoning play a significant role in the majority of diagnostic adverse events. Fig. 1.1 Elements of clinical reasoning. (EBM = evidence-based medicine) Clinical reasoning Clinical skills (history and physical examination) Thinking about thinking Patient-centred EBM Shared decision-making Using and interpreting diagnostic tests Understanding cognitive biases and human factors Adapted from Graber M, Gordon R, Franklin N. Reducing diagnostic errors in medicine: what’s the goal? Acad Med 2002; 77:981–992. 1.1 Root causes of diagnostic error in studies Error category Examples No fault Unusual presentation of a disease Missing information System error Inadequate diagnostic support Results not available Error-prone processes Poor supervision of inexperienced staff Poor team communication Human cognitive error Inadequate data-gathering Errors in reasoning 1.2 Reasons for errors in clinical reasoning Source of error Examples Knowledge gaps Telling a patient she cannot have biliary colic because she has had her gallbladder removed – gallstones can form in the bile ducts in patients who have had a cholecystectomy Misinterpretation of diagnostic tests Deciding a patient has not had a stroke because his brain scan is normal – computed tomography and even magnetic resonance imaging, especially when performed early, may not identify an infarct Cognitive biases Accepting a diagnosis handed over to you without question (the ‘framing effect’) instead of asking yourself ‘What is the evidence that supports this diagnosis?’

Use and interpretation of diagnostic tests • 3

value, the greater the probability). Similarly, an LR of less than 1 decreases the probability of disease. LRs are developed against a diagnostic standard (e.g. in the case of meningitis, lumbar puncture results), so do not exist for all clinical findings. LRs illustrate how an individual clinical finding changes the probability of a disease. For example, in a person presenting with headache and fever, the clinical finding of nuchal rigidity (neck stiffness) may carry little weight in deciding whether to perform a lumbar puncture because LRs do not determine the prior probability of disease; they reflect only how a single clinical finding changes it. Clinicians have to take all the available information from the history and physical examination into account. If the overall clinical probability is high to begin with, a clinical finding with an LR of around 1 does not change this. ‘Evidence-based history and examination’ is a term used to describe how clinicians incorporate knowledge about the prevalence and diagnostic weight of clinical findings into their history and physical examination. This is important because an estimate of clinical probability is vital in decision-making and the interpretation of diagnostic tests. Use and interpretation of diagnostic tests There is no such thing as a perfect diagnostic test. Test results give us test probabilities, not real probabilities. Test results have to be interpreted because they are affected by the following: • how ‘normal’ is defined • factors other than disease • operating characteristics • sensitivity and specificity • prevalence of disease in the population. Normal values Most tests provide quantitative results (i.e. a value on a continuous numerical scale). In order to classify quantitative results as normal or abnormal, it is necessary to define a cut-off point. Many quantitative measurements in populations have a Gaussian or ‘normal’ distribution. By convention, the normal range is defined as those values that encompass 95% of the population, or 2 standard deviations above and below the mean. This means that 2.5% of the normal population will have values above, and 2.5% will have values below the normal range. For this reason, it is more appropriate to talk about the ‘reference range’ rather than the ‘normal range’ (Fig. 1.3). Test results in abnormal populations also have a Gaussian distribution, with a different mean and standard deviation. In some diseases there is no overlap between results from the abnormal and normal population. However, in many diseases there is overlap; in these circumstances, the greater the difference between the test result and the limits of the reference range, the higher the chance that the person has a disease. However, there are also situations in medicine when ‘normal’ is abnormal and ‘abnormal’ is normal. For example, a normal PaCO2 in the context of a severe asthma attack is abnormal and means the patient has life-threatening asthma. A low ferritin in a young menstruating woman is not considered to be a disease at all. Normal, to some extent, is therefore arbitrary. Clinical skills and decision-making Even with major advances in medical technology, the history remains the most important part of the clinical decision-making process. Studies show that physicians make a diagnosis in 70–90% of cases from the history alone. It is important to remember that a good history is gathered not only from the patient but also, if necessary (and with consent if required), from all available sources: for example, paramedic and emergency department notes, eye-witnesses, relatives and/or carers. Clinicians need to be aware of the diagnostic usefulness of clinical features in the history and examination. For example, students are taught that meningitis presents with the following features: • headache • fever • meningism (photophobia, nuchal rigidity). However, the frequency with which patients present with certain features and the diagnostic weight of each feature are important in clinical reasoning. For example, many patients with meningitis do not have classical signs of meningeal irritation (Kernig’s sign, Brudzinski’s sign and nuchal rigidity). In one prospective study, they had likelihood ratios of around 1, meaning they carried little diagnostic weight (Fig. 1.2). Likelihood ratios (LR) are clinical diagnostic weights. An LR of greater than 1 increases the probability of disease (the higher the Fig. 1.2 Likelihood ratio (LR) of Kernig’s sign, Brudzinski’s sign and nuchal rigidity in the clinical diagnosis of meningitis. LR probability of finding in patients disease probabilit

with y of finding in patients disease without LRs are also used for diagnostic tests; here a physical examination finding can be considered a diagnostic test. Data from Thomas KE, Hasbun R, Jekel J, Quagliarello VJ. The diagnostic accuracy of Kernig’s sign, Brudzinski’s sign, and nuchal rigidity in adults with suspected meningitis. Clin Infect Dis 2002; 35:46–52. Change in probability of disease

Infinity Zero

0.5 0.2 0.1

4 • CLINICAL DECISION-MAKING Sensitivity and specificity Diagnostic tests have characteristics termed ‘sensitivity’ and ‘specificity’. Sensitivity is the ability to detect true positives; specificity is the ability to detect true negatives. Even a very good test, with 95% sensitivity, will miss 1 in 20 people with the disease. Every test therefore has ‘false positives’ and ‘false negatives’ (Box 1.4). A very sensitive test will detect most disease but generate abnormal findings in healthy people. A negative result will therefore reliably exclude disease but a positive result does not mean the disease is present – it means further evaluation is required. On the other hand, a very specific test may miss significant pathology but is likely to establish the diagnosis beyond doubt when the result is positive. All tests differ in their sensitivity and specificity, and clinicians require a working knowledge of the tests they use in this respect. In choosing how a test is used to guide decision-making there is a trade-off between sensitivity versus specificity. For example, defining an exercise electrocardiogram (p. 449) as abnormal if there is at least 0.5 mm of ST depression would ensure that very few cases of coronary artery disease are missed but would generate many false-positive results (high sensitivity, low specificity). On the other hand, a cut-off point of 2.0 mm of ST depression would detect most cases of important coronary artery disease with far fewer false positives. This trade-off is illustrated by the receiver operating characteristic curve of the test (Fig. 1.4). An extremely important concept is this: the probability that a person has a disease depends on the pre-test probability, and the sensitivity and specificity of the test. For example, imagine that an elderly lady has fallen and hurt her left hip. On examination, Factors other than disease that influence test results A number of factors other than disease influence test results: • age • ethnicity • pregnancy • sex • spurious (in vitro) results. Box 1.3 gives some examples. Operating characteristics Tests are also subject to operating characteristics. This refers to the way the test is performed. Patients need to be able to comply fully with some tests, such as spirometry (p. 569), and if they cannot, then the test result will be affected. Some tests are very dependent on the skill of the operator and are also affected by the patient’s body habitus and clinical state; ultrasound of the heart and abdomen are examples. A common mistake is when doctors refer to a test result as ‘no abnormality detected’ when, in fact, the report describes a technically difficult and incomplete scan that should more accurately be described as ‘non-diagnostic’. Some conditions are paroxysmal. For example, around half of patients with epilepsy have a normal standard electroencephalogram (EEG). A normal EEG therefore does not exclude epilepsy. On the other hand, around 10% of patients who do not have epilepsy have epileptiform discharges on their EEG. This is referred to as an ‘incidental finding’. Incidental findings are common in medicine, and are increasing in incidence with the greater availability of more sensitive tests. Test results should always be interpreted in the light of the patient’s history and physical examination. Fig. 1.3 Normal distribution and reference range. For many tests, the frequency distribution of results in the normal healthy population (red line) is a symmetrical bell-shaped curve. The mean ± 2 standard deviations (SD) encompasses 95% of the normal population and usually defines the ‘reference range’; 2.5% of the normal population have values above, and 2.5% below, this range (shaded areas). For some diseases (blue line), test results overlap with the normal population or even with the reference range. For other diseases (green line), tests may be more reliable because there is no overlap between the normal and abnormal population. Normal population Number of people having each value Abnormal populations Mean – 2SD Mean

Dealing with uncertainty • 5

new information depends on what you believed beforehand. In other words, the interpretation of a test result depends on the probability of disease before the test. Prevalence of disease Consider this problem that was posed to a group of Harvard doctors: if a test to detect a disease whose prevalence is 1 : 1000 has a false-positive rate of 5%, what is the chance that a person found to have a positive result actually has the disease, assuming you know nothing about the person’s symptoms and signs? Take a moment to work this out. In this problem, we have removed clinical probability and are only considering prevalence. The answer is at the end of the chapter. Predictive values combine sensitivity, specificity and prevalence. Sensitivity and specificity are characteristics of the test; the population does not change this. However, as doctors, we are interested in the question, ‘What is the probability that a person with a positive test actually has the disease?’ This is illustrated in Box 1.5. Post-test probability and predictive values are different. Posttest probability is the probability of a disease after taking into account new information from a test result. Bayes’ Theorem can be used to calculate post-test probability for a patient in any population. The pre-test probability of disease is decided by the doctor; it is a judgement based on information gathered prior to ordering the test. Predictive value is the proportion of patients with a test result who have the disease (or no disease) and is calculated from a table of results in a specific population (see Box 1.5). It is not possible to transfer this value to a different population. This is important to realise because published information about the performance of diagnostic tests may not apply to different populations. In deciding the pre-test probability of disease, clinicians often neglect to take prevalence into account and this distorts their estimate of probability. To estimate the probability of disease in a patient more accurately, clinicians should anchor on the prevalence of disease in the subgroup to which the patient belongs and then adjust to take the individual factors into account. the hip is extremely painful to move and she cannot stand. However, her hip X-rays are normal. Does she have a fracture? The sensitivity of plain X-rays of the hip performed in the emergency department for suspected hip fracture is around 95%. A small percentage of fractures are therefore missed. If our patient has (or is at risk of) osteoporosis, has severe pain on hip movement and cannot bear weight on the affected side, then the clinical probability of hip fracture is high. If, on the other hand, she is unlikely to have osteoporosis, has no pain on hip movement and is able to bear weight, then the clinical probability of hip fracture is low. Doctors are continually making judgements about whether something is true, given that something else is true. This is known as ‘conditional probability’. Bayes’ Theorem (named after English clergyman Thomas Bayes, 1702–1761) is a mathematical way to describe the post-test probability of a disease by combining pre-test probability, sensitivity and specificity. In clinical practice, doctors are not able to make complex mathematical calculations for every decision they make. In practical terms, the answer to the question of whether there is a fracture is that in a high-probability patient a normal test result does not exclude the condition, but in a low-probability patient it makes it very unlikely. This principle is illustrated in Figure 1.5. Sox and colleagues (see ‘Further information’) state a fundamental assertion, which they describe as a profound and subtle principle of clinical medicine: the interpretation of Fig. 1.4 Receiver operating characteristic graph illustrating the trade-off between sensitivity and specificity for a given test. The curve is generated by ‘adjusting’ the cut-off values defining normal and abnormal results, calculating the effect on sensitivity and specificity and then plotting these against each other. The closer the curve lies to the top left-hand corner, the more useful the test. The red line illustrates a test with useful discriminant value and the green line illustrates a less useful, poorly discriminant test. 1.0 0.8 0.6 0.4 0.2 0.01.0 0.8 0.6 Specificity 0.4 0.2

Sensitivity 1.4 Sensitivity and specificity Disease No disease Positive test A B (True positive) (False positive) Negative test C D (False negative) (True negative) Sensitivity = A/(A+C) × 100 Specificity = D/(D+B) × 100 1.5 Predictive values: ‘What is the probability that a person with a positive test actually has the disease?’ Disease No disease Positive test A B (True positive) (False positive) Negative test C D (False negative) (True negative) Positive predictive value = A/(A+B) × 100 Negative predictive value = D/(D+C) × 100 Dealing with uncertainty Clinical findings are imperfect and diagnostic tests are imperfect. It is important to recognise that clinicians frequently deal with uncertainty. By expressing uncertainty as probability, new information from diagnostic tests can be incorporated more accurately. However, subjective estimates of probability can sometimes be unreliable. As the section on cognitive biases will demonstrate (see below), intuition can be a source of error.

6 • CLINICAL DECISION-MAKING an understanding of the prevalence of disease in the particular care setting or the population to which the patient belongs. Cognitive biases Advances in cognitive psychology in recent decades have demonstrated that human thinking and decision-making are prone to error. Cognitive biases are subconscious errors that lead to inaccurate judgement and illogical interpretation of information. They are prevalent in everyday life; as the famous saying goes, ‘to err is human.’ Take a few moments to look at this simple puzzle. Do not try to solve it mathematically but listen to your intuition: A bat and ball cost £1.10. The bat costs £1 more than the ball. How much does the ball cost? The answer is at the end of the chapter. Most people get the answer to this puzzle wrong. Two things are going on: one is that humans have two distinct types of processes when it comes to thinking and decision-making – termed ‘type 1’ and ‘type 2’ thinking. The other is that the human brain is wired to jump to conclusions sometimes or to miss things that are obvious. British psychologist and patient safety pioneer James Knowing the patient’s true state is often unnecessary in clinical decision-making. Sox and colleagues (see ‘Further information’) argue that there is a difference between knowing that a disease is present and acting as if it were present. The requirement for diagnostic certainty depends on the penalty for being wrong. Different situations require different levels of certainty before starting treatment. How we communicate uncertainty to patients will be discussed later in this chapter (p. 10). The treatment threshold combines factors such as the risks of the test, and the risks versus benefits of treatment. The point at which the factors are all evenly weighed is the threshold. If a test or treatment for a disease is effective and low-risk (e.g. giving antibiotics for a suspected urinary tract infection), then there is a lower threshold for going ahead. On the other hand, if a test or treatment is less effective or high-risk (e.g. starting chemotherapy for a malignant brain tumour), then greater confidence is required in the clinical diagnosis and potential benefits of treatment first. In principle, if a diagnostic test will not change the management of the patient, then careful consideration should be given to whether it is necessary to do the test at all. In summary, test results shift our thinking, but rarely give a ‘yes’ or a ‘no’ answer in terms of a diagnosis. Sometimes tests shift the probability of disease by less than we realise. Pre-test probability is key, and this is derived from the history and physical examination, combined with a sound knowledge of medicine and Fig. 1.5 The interpretation of a test result depends on the probability of the disease before the test is carried out. In the example shown, the test being carried out has a sensitivity of 95% and a specificity of 85%. Patient A has very characteristic clinical findings, which make the pre-test probability of the condition for which the test is being used very high – estimated as 90%. Patient B has more equivocal findings, such that the pre-test probability is estimated as only 50%. If the result in Patient A is negative, there is still a significant chance that he has the condition for which he is being tested; in Patient B, however, a negative result makes the diagnosis very unlikely. Patient A 90% chance of having the disease before the test is done 34.6% chance of having the disease if the test is negative

% probability of having the disease

98.3% chance of having the disease if the test is positive Patient B 50% chance of having the disease before the test is done 86.4% chance of having the disease if the test is positive 5.6% chance of having the disease if the test is negative

Cognitive biases • 7

was found beside her at home. Her observations show she has a Glasgow Coma Scale score of 10/15, heart rate 100 beats/ min, blood pressure 100/60 mmHg, respiratory rate 14 breaths/ min, oxygen saturations 98% on air and temperature 37.5°C. Already your mind has reached a working diagnosis. It fits a pattern (type 1 thinking). You think she has taken an overdose. At this point you can stop to think about your thinking (rational override in Fig. 1.6): ‘What is the evidence for this diagnosis? What else could it be?’ On the other hand, imagine being asked to assess a patient who has been admitted with syncope. There are several different causes of syncope and a systematic approach is required to reach a diagnosis (type 2 thinking). However, you recently heard about a case of syncope due to a leaking abdominal aortic aneurysm. At the end of your assessment, following evidence-based guidelines, it is clear the patient can be discharged. Despite this, you decide to observe the patient overnight ‘just in case’ (irrational override in Fig. 1.6). In this example, your intuition is actually availability bias (when things are at the forefront of your mind), which has significantly distorted your estimate of probability. Common cognitive biases in medicine Figure 1.7 illustrates the common cognitive biases prevalent in medical practice. Biases often work together; for example, in Reason said that, ‘Our propensity for certain types of error is the price we pay for the brain’s remarkable ability to think and act intuitively – to sift quickly through the sensory information that constantly bombards us without wasting time trying to work through every situation anew.’ This property of human thinking is highly relevant to clinical decision-making. Type 1 and type 2 thinking Studies of cognitive psychology and functional magnetic resonance imaging demonstrate two distinct types of processes when it comes to decision-making: intuitive (type 1) and analytical (type 2). This has been termed ‘dual process theory’. Box 1.6 explains this in more detail. Psychologists estimate that we spend 95% of our daily lives engaged in type 1 thinking – the intuitive, fast, subconscious mode of decision-making. Imagine driving a car, for example; it would be impossible to function efficiently if every decision and movement were as deliberate, conscious, slow and effortful as in our first driving lesson. With experience, complex procedures become automatic, fast and effortless. The same applies to medical practice. There is evidence that expert decision-making is well served by intuitive thinking. The problem is that although intuitive processing is highly efficient in many circumstances, in others it is prone to error. Clinicians use both type 1 and type 2 thinking, and both types are important in clinical decision-making. When encountering a problem that is familiar, clinicians employ pattern recognition and reach a working diagnosis or differential diagnosis quickly (type 1 thinking). When encountering a problem that is more complicated, they use a slower, systematic approach (type 2 thinking). Both types of thinking interplay – they are not mutually exclusive in the diagnostic process. Figure 1.6 illustrates the interplay between type 1 and type 2 thinking in clinical practice. Errors can occur in both type 1 and type 2 thinking; for example, people can apply the wrong rules or make errors in their application while using type 2 thinking. However, it has been argued that the common cognitive biases encountered in medicine tend to occur when clinicians are engaged in type 1 thinking. For example, imagine being asked to see a young woman who is drowsy. She is handed over to you as a ‘probable overdose’ because she has a history of depression and a packet of painkillers Fig. 1.6 The interplay between type 1 and type 2 thinking in the diagnostic process. Adapted from Croskerry P. A universal model of diagnostic reasoning. Acad Med 2009; 84:1022–1028. Experience Context Ambient conditions Education Training Logical competence Clinical presentation Recognised Not recognised Type 2 processes Type 1 processes Cognitive biases more likely Irrational override Rational override Working diagnosis 1.6 Type 1 and type 2 thinking Type 1 Type 2 Intuitive, heuristic (pattern recognition) Analytical, systematic Automatic, subconscious Deliberate, conscious Fast, effortless Slow, effortful Low/variable reliability High/consistent reliability Vulnerable to error Less prone to error Highly affected by context Less affected by context High emotional involvement Low emotional involvement Low scientific rigour High scientific rigour

8 • CLINICAL DECISION-MAKING Fig. 1.7 Common cognitive biases in medicine. Adapted from Croskerry P. Achieving quality in clinical decision-making: cognitive strategies and detection of bias. Acad Emerg Med 2002; 9:1184–1204. Anchoring The common human tendency to rely too heavily on the first piece of information offered (the ‘anchor’) when making decisions Diagnostic momentum Once a diagnostic label has been attached to a patient (by the patient or other health-care professionals), it can gather momentum with each review, leading others to exclude other possibilities in their thinking Premature closure The tendency to close the decisionmaking process prematurely and accept a diagnosis before it, and other possibilities, have been fully explored Ascertainment bias We sometimes see what we expect to see (‘self-fulfilling prophecy’). For example, a frequent self-harmer attends the emergency department with drowsiness; everyone assumes he has taken another overdose and misses a brain injury Psych-out error Psychiatric patients who present with medical problems are underassessed, under-examined and under-investigated because problems are presumed to be due to, or exacerbated by, their psychiatric condition Framing effect How a case is presented – for example, in handover – can generate bias in the listener. This can be mitigated by always having ‘healthy scepticism’ about other people’s diagnoses Availability bias Things may be at the forefront of your mind because you have seen several cases recently or have been studying that condition in particular. For example, when one of the authors worked in an epilepsy clinic, all blackouts were possible seizures Hindsight bias Knowing the outcome may profoundly influence the perception of past events and decision-making, preventing a realistic appraisal of what actually occurred – a major problem in learning from diagnostic error Search satisficing We may stop searching because we have found something that fits or is convenient, instead of systematically looking for the best alternative, which involves more effort Base rate neglect The tendency to ignore the prevalence of a disease, which then distorts Bayesian reasoning. In some cases, clinicians do this deliberately in order to rule out an unlikely but worst-case scenario Omission bias The tendency towards inaction, rooted in the principle of ‘first do no harm.’ Events that occur through natural progression of disease are more acceptable than those that may be attributed directly to the action of the health-care team Triage-cueing Triage ensures patients are sent to the right department. However, this leads to ‘geography is destiny’. For example, a diabetic ketoacidosis patient with abdominal pain and vomiting is sent to surgery. The wrong location (surgical ward) stops people thinking about medical causes of abdominal pain and vomiting Commission bias The tendency towards action rather than inaction, on the assumption that good can come only from doing something (rather than ‘watching and waiting’) Overconfidence bias The tendency to believe we know more than we actually do, placing too much faith in opinion instead of gathered evidence Unpacking principle Failure to ‘unpack’ all the available information may mean things are missed. For example, if a thorough history is not obtained from either the patient or carers (a common problem in geriatric medicine), diagnostic possibilities may be discounted Confirmation bias The tendency to look for confirming evidence to support a theory rather than looking for disconfirming evidence to refute it, even if the latter is clearly present. Confirmation bias is common when a patient has been seen first by another doctor Posterior probability Our estimate of the likelihood of disease may be unduly influenced by what has gone on before for a particular patient. For example, a patient who has been extensively investigated for headaches presents with a severe headache, and serious causes are discounted Visceral bias The influence of either negative or positive feelings towards patients, which can affect our decisionmaking

Reducing errors in clinical decision-making • 9

• adopting ‘cognitive debiasing strategies’ • using clinical prediction rules and other decision aids • engaging in effective team communication. Cognitive debiasing strategies There are some simple and established techniques that can be used to avoid cognitive biases and errors in clinical decision-making. History and physical examination Taking a history and performing a physical examination may seem obvious, but these are sometimes carried out inadequately. This is the ‘unpacking principle’: failure to unpack all the available information means things can be missed and lead to error. Problem lists and differential diagnosis Once all the available data from history, physical examination and (sometimes) initial test results are available, these need to be synthesised into a problem list. The ability to identify key clinical data and create a problem list is a key step in clinical reasoning. Some problems (e.g. low serum potassium) require action but not necessarily a differential diagnosis. Other problems (e.g. vomiting) require a differential diagnosis. The process of generating a problem list ensures nothing is missed. The process of generating a differential diagnosis works against anchoring on a particular diagnosis too early, thereby avoiding search satisficing and premature closure (see Fig. 1.7). Mnemonics and checklists These are used frequently in medicine in order to reduce reliance on fallible human memory. ABCDE (airway, breathing, circulation, disability, exposure/examination) is probably the most successful checklist in medicine, used during the assessment and treatment of critically ill patients (ABCDE is sometimes prefixed with ‘C’ for ‘control of any obvious problem’; see p. 188). Checklists ensure that important issues have been considered and completed, especially under conditions of complexity, stress or fatigue. Red flags and ROWS (‘rule out worst case scenario’) These are strategies that force doctors to consider serious diseases that can present with common symptoms. Red flags in back pain are listed in Box 24.19 (p. 996). Considering and investigating for possible pulmonary embolism in patients who overconfidence bias (the tendency to believe we know more than we actually do), too much faith is placed in opinion instead of gathered evidence. This bias can be augmented by the availability bias and finally by commission bias (the tendency towards action rather than inaction) – sometimes with disastrous results. The mark of a well-calibrated thinker is the ability to recognise what mode of thinking is being employed and to anticipate and recognise situations in which cognitive biases and errors are more likely to occur. Human factors ‘Human factors’ is the science of the limitations of human performance, and how technology, the work environment and team communication can adapt for this to reduce diagnostic and other types of error. Analysis of serious adverse events in clinical practice shows that human factors and poor team communication play a significant role when things go wrong. Research shows that many errors are beyond an individual’s conscious control and are precipitated by many factors. The discipline of human factors seeks to understand interactions between: • people and tasks or technology • people and their work environment • people in a team. An understanding of these interactions makes it easier for health-care professionals, who are committed to ‘first do no harm,’ to work in the safest way possible. For example, performance is adversely affected by factors such as poorly designed processes and equipment, frequent interruptions and fatigue. The areas of the brain required for type 2 processing are most affected by things like fatigue and cognitive overload, and the brain reverts to type 1 processing to conserve cognitive energy. Figure 1.8 illustrates some of the internal and external factors that affect human judgement and decision-making. Various experiments demonstrate that we focus our attention to filter out distractions. This is advantageous in many situations, but in focusing on what we are trying to see we may not notice the unexpected. In a team context, what is obvious to one person may be completely missed by someone else. Safe and effective team communication therefore requires us never to assume, and to verbalise things, even though they may seem obvious. Reducing errors in clinical decision-making Knowledge and experience do not eliminate errors. Instead, there are a number of ways in which we can act to reduce errors in clinical decision-making. Examples are: Fig. 1.8 Factors that affect our judgement and decision-making. Type 1 thinking = fast, intuitive, subconscious, low-effort. Error Type 1 thinking/ conservation of cognitive effort Cognitive and affective biases Internal factors Knowledge Training Beliefs and values Emotions Sleep/fatigue Stress Physical illness Personality type External factors Interruptions Cognitive overload Time pressure Ambient conditions Insufficient data Team factors Patient factors Poor feedback

10 • CLINICAL DECISION-MAKING with dual antiplatelet therapy and low-molecular-weight heparin as recommended in clinical guidelines? As this chapter has described, clinicians frequently deal with uncertainty/probability. Clinicians need to be able to explain risks and benefits of treatment in an accurate and understandable way. Providing the relevant statistics is seldom sufficient to guide decision-making because a patient’s perception of risk may be influenced by irrational factors as well as individual values. Research evidence provides statistics but these can be confusing. Terms such as ‘common’ and ‘rare’ are nebulous. Whenever possible, clinicians should quote numerical information using consistent denominators (e.g. ‘90 out of 100 patients who have this operation feel much better, 1 will die during the operation and 2 will suffer a stroke’). Visual aids can be used to present complex statistical information (Fig. 1.9). How uncertainty is conveyed to patients is important. Many studies demonstrate a correlation between effective clinician– patient communication and improved health outcomes. If patients feel they have been listened to and understand the problem and proposed treatment plan, they are more likely to follow the plan and less likely to re-attend. Clinical decision-making: putting it all together The following is a practical example that brings together many of the concepts outlined in this chapter: A 25-year-old woman presents with right-sided pleuritic chest pain and breathlessness. She reports that she had an upper present with pleuritic chest pain and breathlessness is a common example of ruling out a worst-case scenario, as pulmonary embolism can be fatal if missed. Red flags and ROWS help to avoid cognitive biases such as the ‘framing effect’ and ‘premature closure’. Newer strategies to avoid cognitive biases and errors in decisionmaking are emerging. These involve explicit training in clinical reasoning and human factors. In theory, if doctors are aware of the science of human thinking and decision-making, then they are more able to think about their thinking, understand situations in which their decision-making may be affected, and take steps to mitigate this. Using clinical prediction rules and other decision aids A clinical prediction rule is a statistical model of the diagnostic process. When clinical prediction rules are matched against the opinion of experts, the model usually outperforms the experts, because it is applied consistently in each case. However, it is important that clinical prediction rules are used correctly – that is, applied to the patient population that was used to create the rule. Clinical prediction rules force a scientific assessment of the patient’s symptoms, signs and other data to develop a numerical probability of a disease or an outcome. They help clinicians to estimate probability more accurately. A good example of a clinical prediction rule to estimate pre-test probability is the Wells score in suspected deep vein thrombosis (see Box 10.15, p. 187). Other commonly used clinical prediction rules predict outcomes and therefore guide the management plan. These include the GRACE score in acute coronary syndromes (see Fig. 16.62, p. 494) and the CURB-65 score in communityacquired pneumonia (see Fig. 17.32, p. 583). Effective team communication Effective team communication and proper handovers are vital for safe clinical care. The SBAR system of communication has been recommended by the UK’s Patient Safety First campaign. It is a structured way to communicate about a patient with another health-care professional (e.g. during handover or when making a referral) and increases the amount of relevant information being communicated in a shorter time. It is illustrated in Box 1.7. In increasingly complex health-care systems, patients are looked after by a wide variety of professionals, each of whom has access to important information required to make clinical decisions. Strict hierarchies are hazardous to patient safety if certain members of the team are not able to speak up. Patient-centred evidence-based medicine and shared decision-making ‘Patient-centred evidence-based medicine’ refers to the application of best-available research evidence while taking individual patient factors into account; these include both clinical and non-clinical factors (e.g. the patient’s social circumstances, values and wishes). For example, a 95-year-old man with dementia and a recent gastrointestinal bleed is admitted with an inferior myocardial infarction. He is clinically well. Should he be treated From Royal College of Physicians of London. National Early Warning Score: standardising the assessment of illness severity in the NHS. Report of a working party. RCP, July 2012; www.rcplondon.ac.uk/projects/outputs/national-earlywarning-score-news (accessed March 2016). 1.7 The SBAR system of communicating SBAR Example (a telephone call to the Intensive Care team) Situation I am [name] calling from [place] about a patient with a NEWS of 10. Background [Patient’s name], 30-year-old woman, no past medical history, was admitted last night with community-acquired pneumonia. Since then her oxygen requirements have been steadily increasing. Assessment Her vital signs are: blood pressure 115/60 mmHg, heart rate 120 beats/min, temperature 38°C, respiratory rate 32 breaths/min, oxygen saturations 89% on 15 L via reservoir bag mask. An arterial blood gas shows pH 7.3 (H+ 50 nmol/L), PaCO2 4.0 kPa (30 mmHg), PaO2 7 kPa (52.5 mmHg), standard bicarbonate 14 mmol/L. Chest X-ray shows extensive right lower zone consolidation. Recommendation Please can you come and see her as soon as possible? I think she needs admission to Intensive Care. (NEWS = National Early Warning Score; a patient with normal vital signs scores 0)

Clinical decision-making: putting it all together • 11

< 500 ng/mL). A normal chest X-ray is a common finding in pulmonary embolism. Several studies have shown that the D-dimer assay has at least 95% sensitivity in acute pulmonary embolism but it has a low specificity. A very sensitive test will detect most disease but generate abnormal findings in healthy people. On the other hand, a negative result virtually, but not completely, excludes the disease. It is important at this point to realise that a raised D-dimer result does not mean this patient has a pulmonary embolism; it just means that we have not been able to exclude it. Since pulmonary embolism is a potentially fatal condition we need to rule out the worst-case scenario (ROWS), and the next step is therefore to arrange further imaging. What kind of imaging depends on individual patient characteristics and what is available. Treatment threshold The treatment threshold combines factors such as the risks of the test, and the risks versus benefits of treatment. A CT pulmonary angiogram (CTPA) could be requested for this patient, although in some circumstances ventilation–perfusion single-photon emission computed tomography (Vࡆ/Qࡆ SPECT, p. 620) may be a more suitable alternative. However, what if the scan cannot be performed until the next day? Because pulmonary embolism is potentially fatal and the risks of treatment in this case are low, the patient should be started on treatment while awaiting the scan. Post-test probability The patient’s scan result is subsequently reported as ‘no pulmonary embolism’. Combined with the low pre-test probability, this scan result reliably excludes pulmonary embolism. Cognitive biases Imagine during this case that the patient had been handed over to you as ‘nothing wrong – probably a pulled muscle’. Cognitive biases (subconscious tendencies to respond in a certain way) would come into play, such as the ‘framing effect’, ‘confirmation bias’ and ‘search satisficing’. The normal clinical examination might confirm the diagnosis of musculoskeletal pain in your mind, despite the examination being entirely consistent with pulmonary embolism and despite the lack of history and examination findings (e.g. chest wall tenderness) to support the diagnosis of musculoskeletal chest pain. Human factors Imagine that, after you have seen the patient, a nurse hands you some blood forms and asks you what tests you would like to request on ‘this lady’. You request blood tests including a D-dimer on the wrong patient. Luckily, this error is intercepted. Reducing cognitive error The diagnosis of pulmonary embolism can be difficult. Clinical prediction rules (e.g. modified Wells score), guidelines (e.g. from the UK’s National Institute for Health and Care Excellence, or NICE) and decision aids (e.g. simplified pulmonary embolism severity index, or PESI) are frequently used in combination with the doctor’s opinion, derived from information gathered in the history and physical examination. respiratory tract infection a week ago and was almost back to normal when the symptoms started. The patient has no past medical history and no family history, and her only medication is the combined oral contraceptive pill. On examination, her vital signs are normal (respiratory rate 19 breaths/min, oxygen saturations 98% on air, blood pressure 115/60 mmHg, heart rate 90 beats/min, temperature 37.5°C) and the physical examination is also normal. You have been asked to assess her for the possibility of a pulmonary embolism. (More information on pulmonary embolism can be found on page 619.) Evidence-based history and examination Information from the history and physical examination is vital in deciding whether this could be a pulmonary embolism. Pleurisy and breathlessness are common presenting features of this disease but are also common presenting features in other diseases. There is nothing in the history to suggest an alternative diagnosis (e.g. high fever, productive cough, recent chest trauma). The patient’s vital signs are normal, as is the physical examination. However, the only feature in the history and examination that has a negative likelihood ratio in the diagnosis of pulmonary embolism is a heart rate of less than 90 beats/min. In other words, the normal physical examination findings (including normal oxygen saturations) carry very little diagnostic weight. Deciding pre-test probability The prevalence of pulmonary embolism in 25-year-old women is low. We anchor on this prevalence and then adjust for individual patient factors. This patient has no major risk factors for pulmonary embolism. To assist our estimate of pre-test probability, we could use a clinical prediction rule: in this case, the modified Wells score for pulmonary embolism, which would give a score of 3 (low probability – answering yes only to the criterion ‘PE is the number one diagnosis, an alternative is less likely’). Interpreting test results Imagine the patient went on to have a normal chest X-ray and blood results, apart from a raised D-dimer of 900 (normal Fig. 1.9 Visual portrayal of benefits and risks. The image refers to an operation that is expected to relieve symptoms in 90% of patients, but cause stroke in 2% and death in 1%. From Edwards A, Elwyn G, Mulley A. Explaining risks: turning numerical data into meaningful pictures. BMJ 2002; 324:827–830, reproduced with permission from the BMJ Publishing Group. Feel better No difference Stroke Dead

12 • CLINICAL DECISION-MAKING The distinctive mark of this easy puzzle is that it evokes an answer that is intuitive, appealing – and wrong. Do the math, and you will see.’ The correct answer is 5p. Further information Books and journal articles Cooper N, Frain J (eds). ABC of clinical reasoning. Oxford: Wiley–Blackwell; 2016. Kahneman D. Thinking, fast and slow. Harmondsworth: Penguin; 2012. McGee S. Evidence-based physical diagnosis, 3rd edn. Philadelphia: Saunders; 2012. Scott IA. Errors in clinical reasoning: causes and remedial strategies. BMJ 2009; 338:b186. Sox H, Higgins MC, Owens DK. Medical decision making, 2nd edn. Chichester: Wiley–Blackwell; 2013. Trowbridge RL, Rencic JJ, Durning SJ. Teaching clinical reasoning. Philadelphia: American College of Physicians; 2015. Vincent C. Patient safety. Edinburgh: Churchill Livingstone; 2006. Websites chfg.org UK Clinical Human Factors Group. clinical-reasoning.org Clinical reasoning resources. creme.org.uk UK Clinical Reasoning in Medical Education group. improvediagnosis.org Society to Improve Diagnosis in Medicine. vassarstats.net/index.html Suite of calculators for statistical computation (Calculator 2 is a calculator for predictive values and likelihood ratios). Person-centred EBM and information given to patient The patient is treated according to evidence-based guidelines that apply to her particular situation. Tests alone do not make a diagnosis and at the end of this process the patient is told that the combination of history, examination and test results mean she is extremely unlikely to have a pulmonary embolism. Viral pleurisy is offered as an alternative diagnosis and she is reassured that her symptoms are expected to settle over the coming days with analgesia. She is advised to re-present to hospital if her symptoms suddenly get worse. Answers to problems Harvard problem (p. 5) Almost half of doctors surveyed said 95%, but they neglected to take prevalence into account. If 1000 people are tested, there will be 51 positive results: 50 false positives and 1 true positive. The chance that a person found to have a positive result actually has the disease is 1/51 or 2%. Bat and ball problem (p. 6) This puzzle is from the book, Thinking, Fast and Slow, by Nobel laureate Daniel Kahneman (see ‘Further information’). He writes, ‘A number came to your mind. The number, of course, is 10p.

Ch02-1 Fundamentals of Medicine

02-2 Clinical therapeutics and good prescribing

2 Clinical therapeutics and good prescribing

Clinical therapeutics and good prescribing SRJ Maxwell Principles of clinical pharmacology 14 Pharmacodynamics 14 Pharmacokinetics 17 Inter-individual variation in drug responses 19 Adverse outcomes of drug therapy 21 Adverse drug reactions 21 Drug interactions 23 Medication errors 24 Drug regulation and management 26 Drug development and marketing 26 Managing the use of medicines 27 Prescribing in practice 28 Decision-making in prescribing 28 Prescribing in special circumstances 31 Writing prescriptions 33 Monitoring drug therapy 34

14 • CLINICAL THERAPEUTICS AND GOOD PRESCRIBING strength of the chemical bond. Some drug–receptor interactions are irreversible, either because the affinity is so strong or because the drug modifies the structure of its molecular target. • Selectivity describes the propensity for a drug to bind to one target rather than another. Selectivity is a relative term, not to be confused with absolute specificity. It is common for drugs targeted at a particular subtype of receptor to exhibit some effect at other subtypes. For example, β-adrenoceptors can be subtyped on the basis of their responsiveness to the endogenous agonist noradrenaline (norepinephrine): the concentration of noradrenaline required to cause bronchodilatation (via β2-adrenoceptors) is ten times higher than that required to cause tachycardia (via β1-adrenoceptors). ‘Cardioselective’ β-blockers have anti-anginal effects on the heart (β1) but may still cause bronchospasm in the lung (β2) and are contraindicated for asthmatic patients. • Agonists bind to a receptor to produce a conformational change that is coupled to a biological response. As agonist concentration increases, so does the proportion of receptors occupied, and hence the biological effect. Partial agonists activate the receptor but cannot produce a maximal signalling effect equivalent to that of a full agonist, even when all available receptors are occupied. • Antagonists bind to a receptor but do not produce the conformational change that initiates an intracellular signal. A competitive antagonist competes with endogenous ligands to occupy receptor-binding sites, with the resulting antagonism depending on the relative affinities and concentrations of drug and ligand. Non-competitive antagonists inhibit the effect of an agonist by mechanisms other than direct competition for receptor binding with the agonist (e.g. by affecting post-receptor signalling). Dose–response relationships Plotting the logarithm of drug dose against drug response typically produces a sigmoidal dose–response curve (Fig. 2.2). Progressive increases in drug dose (which, for most drugs, is proportional to the plasma drug concentration) produce increasing Prescribing medicines is the major tool used by doctors to restore or preserve the health of patients. Medicines contain drugs (the specific chemical substances with pharmacological effects), either alone or in combination with additional drugs, in a formulation mixed with other ingredients. The beneficial effects of medicines must be weighed against their cost and potential adverse drug reactions and interactions. The latter two factors are sometimes caused by injudicious prescribing decisions and by prescribing errors. The modern prescriber must meet the challenges posed by the increasing number of drugs and formulations available and of indications for prescribing them, and the greater complexity of treatment regimens followed by individual patients (‘polypharmacy’, a particular challenge in the ageing population). The purpose of this chapter is to elaborate on the principles and practice that underpin good prescribing (Box 2.1). Fig. 2.1 Pharmacokinetics and pharmacodynamics. Dosage regimen Plasma concentration Concentration at the site of action Pharmacological effects Pharmacokinetics ‘what the body does to a drug’ Monitoring Measure plasma drug concentration ‘what a drug does to the body’ Monitoring Measure clinical effects Time Concentration Pharmacodynamics Concentration Effect These steps in particular take the patient’s views into consideration to establish a therapeutic partnership (shared decision-making to achieve ‘concordance’). 2.1 Steps in good prescribing • Make a diagnosis • Consider factors that might influence the patient’s response to therapy (age, concomitant drug therapy, renal and liver function etc.) • Establish the therapeutic goal • Choose the therapeutic approach* • Choose the drug and its formulation (the ‘medicine’) • Choose the dose, route and frequency • Choose the duration of therapy • Write an unambiguous prescription (or ‘medication order’) • Inform the patient about the treatment and its likely effects • Monitor treatment effects, both beneficial and harmful • Review/alter the prescription Principles of clinical pharmacology Prescribers need to understand what the drug does to the body (pharmacodynamics) and what the body does to the drug (pharmacokinetics) (Fig. 2.1). Although this chapter is focused on the most common drugs, which are synthetic small molecules, the same principles apply to the increasingly numerous ‘biological’ therapies (sometimes abbreviated to ‘biologics’) now in use, which include peptides, proteins, enzymes and monoclonal antibodies (see Box 4.2, p. 65). Pharmacodynamics Drug targets and mechanisms of action Modern drugs are usually discovered by screening compounds for activity either to stimulate or to block the function of a specific molecular target, which is predicted to have a beneficial effect in a particular disease (Box 2.2). Other drugs have useful but less selective chemical properties, such as chelators (e.g. for treatment of iron or copper overload), osmotic agents (used as diuretics in cerebral oedema) or general anaesthetics (that alter the biophysical properties of lipid membranes). The following characteristics of the interaction of drugs with receptors illustrate some of the important determinants of the effects of drugs: • Affinity describes the propensity for a drug to bind to a receptor and is related to the ‘molecular fit’ and the

Principles of clinical pharmacology • 15

Fig. 2.2 Dose–response curve. The green curve represents the beneficial effect of the drug. The maximum response on the curve is the Emax and the dose (or concentration) producing half this value (Emax/2) is the ED50 (or EC50). The red curve illustrates the dose–response relationship for the most important adverse effect of this drug. This occurs at much higher doses; the ratio between the ED50 for the adverse effect and that for the beneficial effect is the ‘therapeutic index’, which indicates how much margin there is for prescribers when choosing a dose that will provide beneficial effects without also causing this adverse effect. Adverse effects that occur at doses above the therapeutic range are normally called ‘toxic effects’, while those occurring within the therapeutic range are ‘side-effects’ and those below it are ‘hyper-susceptibility effects’. Hypersusceptibility Side-effects

0.0001 0.001 0.01 0.1

Therapeutic index 100/0.1 = 1000 Drug dose (mg) Response (% of maximum) Toxic effects Adverse effect ED50 =100 mg Beneficial effect ED50 =0.1 mg Emax ED50 ED50 2.2 Examples of target molecules for drugs Drug target Description Examples Receptors Channel-linked receptors Ligand binding controls a linked ion channel, known as ‘ligand-gated’ (in contrast to ‘voltage-gated’ channels that respond to changes in membrane potential) Nicotinic acetylcholine receptor GABA receptor Sulphonylurea receptor G-protein-coupled receptors (GPCRs) Ligand binding affects one of a family of ‘G-proteins’ that mediate signal transduction either by activating intracellular enzymes (such as adenylate or guanylate cyclase, producing cyclic AMP or GMP, respectively) or by controlling ion channels Muscarinic acetylcholine receptor β-adrenoceptors Dopamine receptors 5-Hydroxytryptamine (5-HT, serotonin) receptors Opioid receptors Kinase-linked receptors Ligand binding activates an intracellular protein kinase that triggers a cascade of phosphorylation reactions Insulin receptor Cytokine receptors Transcription factor receptors Intracellular and also known as ‘nuclear receptors’; ligand binding promotes or inhibits gene transcription and hence synthesis of new proteins Steroid receptors Thyroid hormone receptors Vitamin D receptors Retinoid receptors PPARγ and α receptors Other targets Voltage-gated ion channels Mediate electrical signalling in excitable tissues (muscle and nervous system) Na+ channels Ca2+ channels Enzymes Catalyse biochemical reactions. Drugs interfere with binding of substrate to the active site or of co-factors Cyclo-oxygenase ACE Xanthine oxidase Transporter proteins Carry ions or molecules across cell membranes 5-HT re-uptake transporter Na+/K+ ATPase Cytokines and other signalling molecules Small proteins that are important in cell signalling (autocrine, paracrine and endocrine), especially affecting the immune response Tumour necrosis factors Interleukins Cell surface antigens Block the recognition of cell surface molecules that modulate cellular responses Cluster of differentiation molecules (e.g. CD20, CD80) (ACE = angiotensin-converting enzyme; AMP = adenosine monophosphate; ATPase = adenosine triphosphatase; GABA = γ-aminobutyric acid; GMP = guanosine monophosphate; PPAR = peroxisome proliferator-activated receptor)

16 • CLINICAL THERAPEUTICS AND GOOD PRESCRIBING therapeutic index is usually based on adverse effects that might require dose reduction or discontinuation. For most drugs, the therapeutic index is greater than 100 but there are some notable exceptions with therapeutic indices of less than 10 (e.g. digoxin, warfarin, insulin, phenytoin, opioids). The doses of such drugs have to be titrated carefully for individual patients to maximise benefits but avoid adverse effects. Desensitisation and withdrawal effects Desensitisation refers to the common situation in which the biological response to a drug diminishes when it is given continuously or repeatedly. It may be possible to restore the response by increasing the dose of the drug but, in some cases, the tissues may become completely refractory to its effect. • Tachyphylaxis describes desensitisation that occurs very rapidly, sometimes with the initial dose. This rapid loss of response implies depletion of chemicals that may be necessary for the pharmacological actions of the drug (e.g. a stored neurotransmitter released from a nerve terminal) or receptor phosphorylation. • Tolerance describes a more gradual loss of response to a drug that occurs over days or weeks. This slower change implies changes in receptor numbers or the development of counter-regulatory physiological changes that offset the actions of the drug (e.g. accumulation of salt and water in response to vasodilator therapy). • Drug resistance is a term normally reserved for describing the loss of effectiveness of an antimicrobial (p. 116) or cancer chemotherapy drug. • In addition to these pharmacodynamic causes of desensitisation, reduced response may be the consequence of lower plasma and tissue drug concentrations as a result of altered pharmacokinetics (see below). When drugs induce chemical, hormonal and physiological changes that offset their actions, discontinuation may allow these changes to cause ‘rebound’ withdrawal effects (Box 2.3). response but only within a relatively narrow range of dose; further increases in dose beyond this range produce little extra effect. The following characteristics of the drug response are useful in comparing different drugs: • Efficacy describes the extent to which a drug can produce a target-specific response when all available receptors or binding sites are occupied (i.e. Emax on the dose–response curve). A full agonist can produce the maximum response of which the receptor is capable, while a partial agonist at the same receptor will have lower efficacy. Therapeutic efficacy describes the effect of the drug on a desired biological endpoint and can be used to compare drugs that act via different pharmacological mechanisms (e.g. loop diuretics induce a greater diuresis than thiazide diuretics and therefore have greater therapeutic efficacy). • Potency describes the amount of drug required for a given response. More potent drugs produce biological effects at lower doses, so they have a lower ED50. A less potent drug can still have an equivalent efficacy if it is given in higher doses. The dose–response relationship varies between patients because of variations in the many determinants of pharmacokinetics and pharmacodynamics. In clinical practice, the prescriber is unable to construct a dose–response curve for each individual patient. Therefore, most drugs are licensed for use within a recommended range of doses that is expected to reach close to the top of the dose–response curve for most patients. However, it is sometimes possible to achieve the desired therapeutic efficacy at doses towards the lower end of, or even below, the recommended range. Therapeutic index The adverse effects of drugs are often dose-related in a similar way to the beneficial effects, although the dose–response curve for these adverse effects is normally shifted to the right (Fig. 2.2). The ratio of the ED50 for therapeutic efficacy and for a major adverse effect is known as the ‘therapeutic index’. In reality, drugs have multiple potential adverse effects, but the concept of 2.3 Examples of drugs associated with withdrawal effects Drug Symptoms Signs Treatment Alcohol Anxiety, panic, paranoid delusions, visual and auditory hallucinations Agitation, restlessness, delirium, tremor, tachycardia, ataxia, disorientation, seizures Treat immediate withdrawal syndrome with benzodiazepines Barbiturates, benzodiazepines Similar to alcohol Similar to alcohol Transfer to long-acting benzodiazepine then gradually reduce dosage Glucocorticoids Weakness, fatigue, decreased appetite, weight loss, nausea, vomiting, diarrhoea, abdominal pain Hypotension, hypoglycaemia Prolonged therapy suppresses the hypothalamic–pituitary–adrenal axis and causes adrenal insufficiency requiring glucocorticoid replacement. Withdrawal should be gradual after prolonged therapy (p. 670) Opioids Rhinorrhoea, sneezing, yawning, lacrimation, abdominal and leg cramping, nausea, vomiting, diarrhoea Dilated pupils Transfer addicts to long-acting agonist methadone Selective serotonin re-uptake inhibitors (SSRIs) Dizziness, sweating, nausea, insomnia, tremor, delirium, nightmares Tremor Reduce SSRIs slowly to avoid withdrawal effects

Principles of clinical pharmacology • 17

Parenteral administration These routes avoid absorption via the gastrointestinal tract and first-pass metabolism in the liver: • Intravenous (IV). The IV route enables all of a dose to enter the systemic circulation reliably, without any concerns about absorption or first-pass metabolism (i.e. the dose is 100% bioavailable), and rapidly achieve a high plasma concentration. It is ideal for very ill patients when a rapid, certain effect is critical to outcome (e.g. benzathine benzylpenicillin for meningococcal meningitis). • Intramuscular (IM). IM administration is easier to achieve than the IV route (e.g. adrenaline (epinephrine) for acute anaphylaxis) but absorption is less predictable and depends on muscle blood flow. • Subcutaneous (SC). The SC route is ideal for drugs that have to be administered parenterally because of low oral bioavailability, are absorbed well from subcutaneous fat, and might ideally be injected by patients themselves (e.g. insulin, heparin). • Transdermal. A transdermal patch can enable a drug to be absorbed through the skin and into the circulation (e.g. oestrogens, nicotine, nitrates). Other routes of administration • Topical application of a drug involves direct administration to the site of action (e.g. skin, eye, ear). This has the advantage of achieving sufficient concentration at this site while minimising systemic exposure and the risk of adverse effects elsewhere. • Inhaled (INH) administration allows drugs to be delivered directly to a target in the respiratory tree, usually the small airways (e.g. salbutamol, beclometasone). However, a significant proportion of the inhaled dose may be absorbed from the lung or is swallowed and can reach the systemic circulation. The most common mode of delivery is the metered-dose inhaler but its success depends on some degree of manual dexterity and timing (see Fig. 17.23, p. 571). Patients who find these difficult may use a ‘spacer’ device to improve drug delivery. A special mode Pharmacokinetics Understanding ‘what the body does to the drug’ (Fig. 2.3) is extremely important for prescribers because this forms the basis on which the optimal route of administration and dose regimen are chosen and explains the majority of inter-individual variation in the response to drug therapy. Drug absorption and routes of administration Absorption is the process by which drug molecules gain access to the blood stream. The rate and extent of drug absorption depend on the route of administration (Fig. 2.3). Enteral administration These routes involve administration via the gastrointestinal tract: • Oral. This is the most common route of administration because it is simple, convenient and readily used by patients to self-administer their medicines. Absorption after an oral dose is a complex process that depends on the drug being swallowed, surviving exposure to gastric acid, avoiding unacceptable food binding, being absorbed across the small bowel mucosa into the portal venous system, and surviving metabolism by gut wall or liver enzymes (‘first-pass metabolism’). As a consequence, absorption is frequently incomplete following oral administration. The term ‘bioavailability’ describes the proportion of the dose that reaches the systemic circulation intact. • Buccal, intranasal and sublingual (SL). These routes have the advantage of enabling rapid absorption into the systemic circulation without the uncertainties associated with oral administration (e.g. organic nitrates for angina pectoris, triptans for migraine, opioid analgesics). • Rectal (PR). The rectal mucosa is occasionally used as a site of drug administration when the oral route is compromised because of nausea and vomiting or unconsciousness (e.g. diazepam in status epilepticus). Fig. 2.3 Pharmacokinetics summary. Most drugs are taken orally, are absorbed from the intestinal lumen and enter the portal venous system to be conveyed to the liver, where they may be subject to first-pass metabolism and/or excretion in bile. Active drugs then enter the systemic circulation, from which they may diffuse (or sometimes be actively transported) in and out of the interstitial and intracellular fluid compartments. Drug that remains in circulating plasma is subject to liver metabolism and renal excretion. Drugs excreted in bile may be reabsorbed, creating an enterohepatic circulation. First-pass metabolism in the liver is avoided if drugs are administered via the buccal or rectal mucosa, or parenterally (e.g. by intravenous injection). I n t e r s t i t i a l

f l u i d Intracellular fluid Kidney Liver Parenteral Mouth Stomach Small intestine Large intestine Rectum Buccal Excretion in urine Excretion in faeces Portal venous system Intestinal wall enzymes Liver enzymes Metabolism Circulating plasma Rectal Oral

18 • CLINICAL THERAPEUTICS AND GOOD PRESCRIBING Drug excretion Excretion is the process by which drugs and their metabolites are removed from the body. Renal excretion is the usual route of elimination for drugs or their metabolites that are of low molecular weight and sufficiently water-soluble to avoid reabsorption from the renal tubule. Drugs bound to plasma proteins are not filtered by the glomeruli. The pH of the urine is more acidic than that of plasma, so that some drugs (e.g. salicylates) become un-ionised and tend to of inhaled delivery is via a nebulised solution created by using pressurised oxygen or air to break up solutions and suspensions into small aerosol droplets that can be directly inhaled from the mouthpiece of the device. Drug distribution Distribution is the process by which drug molecules transfer into and out of the blood stream. This is influenced by the drug’s molecular size and lipid solubility, the extent to which it binds to proteins in plasma, its susceptibility to drug transporters expressed on cell surfaces, and its binding to its molecular target and to other cellular proteins (which can be irreversible). Most drugs diffuse passively across capillary walls down a concentration gradient into the interstitial fluid until the concentration of free drug molecules in the interstitial fluid is equal to that in the plasma. As drug molecules in the blood are removed by metabolism or excretion, the plasma concentration falls, drug molecules diffuse back from the tissue compartment into the blood and eventually all will be eliminated. Note that this reverse movement of drug away from the tissues will be prevented if further drug doses are administered and absorbed into the plasma. Volume of distribution The apparent volume of distribution (Vd) is the volume into which a drug appears to have distributed following intravenous injection. It is calculated from the equation Vd D C

where D is the amount of drug given and C0 is the initial plasma concentration (Fig. 2.4A). Drugs that are highly bound to plasma proteins may have a Vd below 10 L (e.g. warfarin, aspirin), while those that diffuse into the interstitial fluid but do not enter cells because they have low lipid solubility may have a Vd between 10 and 30 L (e.g. gentamicin, amoxicillin). It is an ‘apparent’ volume because those drugs that are lipid-soluble and highly tissue-bound may have a Vd of greater than 100 L (e.g. digoxin, amitriptyline). Drugs with a larger Vd have longer half-lives (see below), take longer to reach steady state on repeated administration and are eliminated more slowly from the body following discontinuation. Drug elimination Drug metabolism Metabolism is the process by which drugs are chemically altered from a lipid-soluble form suitable for absorption and distribution to a more water-soluble form that is necessary for excretion. Some drugs, known as ‘prodrugs’, are inactive in the form in which they are administered but are converted to an active metabolite in vivo. Phase I metabolism involves oxidation, reduction or hydrolysis to make drug molecules suitable for phase II reactions or for excretion. Oxidation is by far the most common form of phase I reaction and chiefly involves members of the cytochrome P450 family of membrane-bound enzymes in the endoplasmic reticulum of hepatocytes. Phase II metabolism involves combining phase I metabolites with an endogenous substrate to form an inactive conjugate that is much more water-soluble. Reactions include glucuronidation, sulphation, acetylation, methylation and conjugation with glutathione. This is necessary to enable renal excretion, because lipid-soluble metabolites will simply diffuse back into the body after glomerular filtration (p. 349). Fig. 2.4 Drug concentrations in plasma following single and multiple drug dosing. A In this example of first-order kinetics following a single intravenous dose, the time period required for the plasma drug concentration to halve (half-life, t1/2) remains constant throughout the elimination process. B After multiple dosing, the plasma drug concentration rises if each dose is administered before the previous dose has been entirely cleared. In this example, the drug’s half-life is 30 hours, so that with daily dosing the peak, average and trough concentrations steadily increase as drug accumulates in the body (black line). Steady state is reached after approximately 5 half-lives, when the rate of elimination (the product of concentration and clearance) is equal to the rate of drug absorption (the product of rate of administration and bioavailability). The long half-life in this example means that it takes 6 days for steady state to be achieved and, for most of the first 3 days of treatment, plasma drug concentrations are below the therapeutic range. This problem can be overcome if a larger loading dose (red line) is used to achieve steady-state drug concentrations more rapidly. Time (hours) A constant fraction of drug is cleared in unit time t1/2= 8 hours C0 Plasma drug concentration

A Loading dose Dose Dose Dose Dose Dose Dose Dose Subtherapeutic Dose interval = 24 hours Time (days) Plasma drug concentration

Therapeutic range Adverse effects t1/2= 30 hours B

Principles of clinical pharmacology • 19

means that the effects of a new prescription, or dose titration, for a drug with a long half-life (e.g. digoxin – 36 hours) may not be known for a few days. In contrast, drugs with a very short half-life (e.g. dobutamine – 2 minutes) have to be given continuously by infusion but reach a new steady state within minutes. For drugs with a long half-life, if it is unacceptable to wait for 5 half-lives until concentrations within the therapeutic range are achieved, then an initial ‘loading dose’ can be given that is much larger than the maintenance dose and equivalent to the amount of drug required in the body at steady state. This achieves a peak plasma concentration close to the plateau concentration, which can then be maintained by successive maintenance doses. ‘Steady state’ actually involves fluctuations in drug concentrations, with peaks just after administration followed by troughs just prior to the next administration. The manufacturers of medicines recommend dosing regimens that predict that, for most patients, these oscillations result in troughs within the therapeutic range and peaks that are not high enough to cause adverse effects. The optimal dose interval is a compromise between convenience for the patient and a constant level of drug exposure. More frequent administration (e.g. 25 mg 4 times daily) achieves a smoother plasma concentration profile than 100 mg once daily but is much more difficult for patients to sustain. A solution to this need for compromise in dosing frequency for drugs with half-lives of less than 24 hours is the use of ‘modified-release’ formulations. These allow drugs to be absorbed more slowly from the gastrointestinal tract and reduce the oscillation in plasma drug concentration profile, which is especially important for drugs with a low therapeutic index (e.g. levodopa). Inter-individual variation in drug responses Prescribers have numerous sources of guidance about how to use drugs appropriately (e.g. dose, route, frequency, duration) for many conditions. However, this advice is based on average dose–response data derived from observations in many individuals. When applying this information to an individual patient, prescribers must take account of inter-individual variability in response. Some of this variability is predictable and good prescribers are able to anticipate it and adjust their prescriptions accordingly to maximise the chances of benefit and minimise harm. Inter-individual variation in responses also mandates that effects of treatment should be monitored (p. 34). Some inter-individual variation in drug response is accounted for by differences in pharmacodynamics. For example, the beneficial natriuresis produced by the loop diuretic furosemide is often significantly reduced at a given dose in patients with renal impairment, while delirium caused by opioid analgesics is more likely in the elderly. Differences in pharmacokinetics more commonly account for different drug responses, however. Examples of factors influencing the absorption, metabolism and excretion of drugs are shown in Box 2.4. It is hoped that a significant proportion of the inter-individual variation in drug responses can be explained by studying genetic differences in single genes (‘pharmacogenetics’; Box 2.5) or the effects of multiple gene variants (‘pharmacogenomics’). The aim is to identify those patients most likely to benefit from specific treatments and those most susceptible to adverse effects. In this way, it may be possible to select drugs and dose regimens for individual patients to maximise the benefit-to-hazard ratio (‘personalised medicine’). be reabsorbed. Alkalination of the urine can hasten excretion (e.g. after a salicylate overdose; p. 138). For some drugs, active secretion into the proximal tubule lumen, rather than glomerular filtration, is the predominant mechanism of excretion (e.g. methotrexate, penicillin). Faecal excretion is the predominant route of elimination for drugs with high molecular weight, including those that are excreted in the bile after conjugation with glucuronide in the liver, and any drugs that are not absorbed after enteral administration. Molecules of drug or metabolite that are excreted in the bile enter the small intestine, where they may, if they are sufficiently lipid-soluble, be reabsorbed through the gut wall and return to the liver via the portal vein (see Fig. 2.3). This recycling between the liver, bile, gut and portal vein is known as ‘enterohepatic circulation’ and can significantly prolong the residence of drugs in the body. Elimination kinetics The net removal of drug from the circulation results from a combination of drug metabolism and excretion, and is usually described as ‘clearance’, i.e. the volume of plasma that is completely cleared of drug per unit time. For most drugs, elimination is a high-capacity process that does not become saturated, even at high dosage. The rate of elimination is therefore directly proportional to the drug concentration because of the ‘law of mass action’, whereby higher drug concentrations will drive faster metabolic reactions and support higher renal filtration rates. This results in ‘first-order’ kinetics, when a constant fraction of the drug remaining in the circulation is eliminated in a given time and the decline in concentration over time is exponential (Fig. 2.4A). This elimination can be described by the drug’s half-life (t1/2), i.e. the time taken for the plasma drug concentration to halve, which remains constant throughout the period of drug elimination. The significance of this phenomenon for prescribers is that the effect of increasing doses on plasma concentration is predictable – a doubled dose leads to a doubled concentration at all time points. For a few drugs in common use (e.g. phenytoin, alcohol), elimination capacity is exceeded (saturated) within the usual dose range. This is called ‘zero-order’ kinetics. Its significance for prescribers is that, if the rate of administration exceeds the maximum rate of elimination, the drug will accumulate progressively, leading to serious toxicity. Repeated dose regimens The goal of therapy is usually to maintain drug concentrations within the therapeutic range (see Fig. 2.2) over several days (e.g. antibiotics) or even for months or years (e.g. antihypertensives, lipid-lowering drugs, thyroid hormone replacement therapy). This goal is rarely achieved with single doses, so prescribers have to plan a regimen of repeated doses. This involves choosing the size of each individual dose and the frequency of dose administration. As illustrated in Figure 2.4B, the time taken to reach drug concentrations within the therapeutic range depends on the half-life of the drug. Typically, with doses administered regularly, it takes approximately 5 half-lives to reach a ‘steady state’ in which the rate of drug elimination is equal to the rate of drug administration. This applies when starting new drugs and when adjusting doses of current drugs. With appropriate dose selection, steady-state drug concentrations will be maintained within the therapeutic range. This is important for prescribers because it

20 • CLINICAL THERAPEUTICS AND GOOD PRESCRIBING 2.5 Examples of pharmacogenetic variations that influence drug response Genetic variant Drug affected Clinical outcome Pharmacokinetic Aldehyde dehydrogenase-2 deficiency Ethanol Elevated blood acetaldehyde causes facial flushing and increased heart rate in ~50% of Japanese, Chinese and other Asian populations Acetylation Isoniazid, hydralazine, procainamide Increased responses in slow acetylators, up to 50% of some populations Oxidation (CYP2D6) Nortriptyline Increased risk of toxicity in poor metabolisers Codeine Reduced responses with slower conversion of codeine to more active morphine in poor metabolisers, 10% of European populations Increased risk of toxicity in ultra-fast metabolisers, 3% of Europeans but 40% of North Africans Oxidation (CYP2C18) Proguanil Reduced efficacy with slower conversion to active cycloguanil in poor metabolisers Oxidation (CYP2C9) Warfarin Polymorphisms known to influence dosages Oxidation (CYP2C19) Clopidogrel Reduced enzymatic activation results in reduced antiplatelet effect Sulphoxidation Penicillamine Increased risk of toxicity in poor metabolisers Human leucocyte antigen (HLA)-B1502 Carbamazepine Increased risk of serious dermatological reactions (e.g. Stevens–Johnson syndrome) for 1 in 2000 in Caucasian populations (much higher in some Asian countries) Pseudocholinesterase deficiency Suxamethonium (succinylcholine) Decreased drug inactivation leads to prolonged paralysis and sometimes persistent apnoea requiring mechanical ventilation until the drug can be eliminated by alternate pathways; occurs in 1 in 1500 people Pharmacodynamic Glucose-6-phosphate dehydrogenase (G6PD) deficiency Oxidant drugs, including antimalarials (e.g. chloroquine, primaquine) Risk of haemolysis in G6PD deficiency Acute intermittent porphyria Enzyme-inducing drugs Increased risk of an acute attack SLC01B1 polymorphism Statins Increased risk of rhabdomyolysis HLA-B5701 polymorphism Abacavir Increased risk of skin hypersensitivity reactions HLA-B5801 polymorphism Allopurinol Increased risk of rashes in Han Chinese HLA-B1502 polymorphism Carbamazepine Increased risk of skin hypersensitivity reactions in Han Chinese Hepatic nuclear factor 1 alpha (HNF1A) polymorphism Sulphonylureas Increased sensitivity to the blood glucose-lowering effects Human epidermal growth factor receptor 2 (HER2)-positive breast cancer cells Trastuzumab Increased sensitivity to the inhibitory effects on growth and division of the target cancer cells Age • Drug metabolism is low in the fetus and newborn, may be enhanced in young children, and becomes less effective with age • Drug excretion falls with the age-related decline in renal function Sex • Women have a greater proportion of body fat than men, increasing the volume of distribution and half-life of lipid-soluble drugs Body weight • Obesity increases volume of distribution and half-life of lipid-soluble drugs • Patients with higher lean body mass have larger body compartments into which drugs are distributed and may require higher doses Liver function • Metabolism of most drugs depends on several cytochrome P450 enzymes that are impaired in patients with advanced liver disease • Hypoalbuminaemia influences the distribution of drugs that are highly protein-bound Kidney function • Renal disease and the decline in renal function with ageing may lead to drug accumulation Gastrointestinal function • Small intestinal absorption of oral drugs may be delayed by reduced gastric motility • Absorptive capacity of the intestinal mucosa may be reduced in disease (e.g. Crohn’s or coeliac disease) or after surgical resection Food • Food in the stomach delays gastric emptying and reduces the rate (but not usually the extent) of drug absorption • Some food constituents bind to certain drugs and prevent their absorption Smoking • Tar in tobacco smoke stimulates the oxidation of certain drugs Alcohol • Regular alcohol consumption stimulates liver enzyme synthesis, while binge drinking may temporarily inhibit drug metabolism Drugs • Drug–drug interactions cause marked variation in pharmacokinetics (see Box 2.11) 2.4 Patient-specific factors that influence pharmacokinetics

Adverse outcomes of drug therapy • 21

Adverse outcomes of drug therapy The decision to prescribe a drug always involves a judgement of the balance between therapeutic benefits and risk of an adverse outcome. Both prescribers and patients tend to be more focused on the former but a truly informed decision requires consideration of both. Adverse drug reactions Some important definitions for the adverse effects of drugs are: • Adverse event. A harmful event that occurs while a patient is taking a drug, irrespective of whether the drug is suspected of being the cause. • Adverse drug reaction (ADR). An unwanted or harmful reaction that is experienced following the administration of a drug or combination of drugs under normal conditions of use and is suspected to be related to the drug. An ADR will usually require the drug to be discontinued or the dose reduced. • Side-effect. Any effect caused by a drug other than the intended therapeutic effect, whether beneficial, neutral or harmful. The term ‘side-effect’ is often used interchangeably with ‘ADR’, although the former usually implies an ADR that occurs during exposure to normal therapeutic drug concentrations (e.g. vasodilator-induced ankle oedema). • Hypersensitivity reaction. An ADR that occurs as a result of an immunological reaction and often at exposure to subtherapeutic drug concentrations. Some of these reactions are immediate and result from the interaction of drug antigens with immunoglobulin E (IgE) on mast cells and basophils, which causes a release of vasoactive biomolecules (e.g. penicillin-related anaphylaxis). ‘Anaphylactoid’ reactions present similarly but occur through a direct non-immune-mediated release of the same mediators or result from direct complement activation (p. 75). Hypersensitivity reactions may occur via other mechanisms such as antibody-dependent (IgM or IgG), immune complex-mediated or cell-mediated pathways. • Drug toxicity. Adverse effects of a drug that occur because the dose or plasma concentration has risen above the therapeutic range, either unintentionally or intentionally (drug overdose; see Fig. 2.2 and p. 137). • Drug abuse. The misuse of recreational or therapeutic drugs that may lead to addiction or dependence, serious physiological injury (such as liver damage), psychological harm (abnormal behaviour patterns, hallucinations, memory loss) or death (p. 1184). Prevalence of ADRs ADRs are a common cause of illness, accounting in the UK for approximately 3% of consultations in primary care and 7% of emergency admissions to hospital, and affecting around 15% of hospital inpatients. Many ‘disease’ presentations are eventually attributed to ADRs, emphasising the importance of always taking a careful drug history (Box 2.6). Factors accounting for the rising prevalence of ADRs are the increasing age of patients, polypharmacy (higher risk of drug interactions), increasing availability of over-the-counter medicines, increasing use of herbal or traditional medicines, and the increase in medicines available via the Internet that can be purchased without a prescription from a health-care professional. Risk factors for ADRs are shown in Box 2.7. 2.7 Risk factors for adverse drug reactions Patient factors • Elderly age (e.g. low physiological reserve) • Gender (e.g. ACE inhibitor-induced cough in women) • Polypharmacy (e.g. drug interactions) • Genetic predisposition (see Box 2.5) • Hypersensitivity/allergy (e.g. β-lactam antibiotics) • Diseases altering pharmacokinetics (e.g. hepatic or renal impairment) or pharmacodynamic responses (e.g. bladder instability) • Adherence problems (e.g. cognitive impairment) Drug factors • Steep dose–response curve (e.g. insulin) • Low therapeutic index (e.g. digoxin, cytotoxic drugs) Prescriber factors • Inadequate understanding of principles of clinical pharmacology • Inadequate knowledge of the patient • Inadequate knowledge of the prescribed drug • Inadequate instructions and warnings provided to patients • Inadequate monitoring arrangements planned (ACE = angiotensin-converting enzyme) 2.6 How to take a drug history Information from the patient (or carer) Use language that patients will understand (e.g. ‘medicines’ rather than ‘drugs’, which may be mistaken for drugs of abuse) while gathering the following information: • Current prescribed drugs, including formulations (e.g. modifiedrelease tablets), doses, routes of administration, frequency and timing, duration of treatment • Other medications that are often forgotten (e.g. contraceptives, over-the-counter drugs, herbal remedies, vitamins) • Drugs that have been taken in the recent past and reasons for stopping them • Previous drug hypersensitivity reactions, their nature and time course (e.g. rash, anaphylaxis) • Previous ADRs, their nature and time course (e.g. ankle oedema with amlodipine) • Adherence to therapy (e.g. ‘Are you taking your medication regularly?’) Information from GP medical records and/or pharmacist • Up-to-date list of medications • Previous ADRs • Last order dates for each medication Inspection of medicines • Drugs and their containers (e.g. blister packs, bottles, vials) should be inspected for name, dosage, and the number of dosage forms taken since dispensed (ADR = adverse drug reaction)

22 • CLINICAL THERAPEUTICS AND GOOD PRESCRIBING 2.9 DoTS classification of adverse drug reactions Category Example Dose Below therapeutic dose Anaphylaxis with penicillin In the therapeutic dose range Nausea with morphine At high doses Hepatotoxicity with paracetamol Timing With the first dose Anaphylaxis with penicillin Early stages of treatment Hyponatraemia with diuretics On stopping treatment Benzodiazepine withdrawal syndrome Significantly delayed Clear-cell cancer with diethylstilboestrol Susceptibility See patient factors in Box 2.7 (INR = international normalised ratio) 2.8 Drugs that are common causes of adverse drug reactions Drug or drug class Common adverse drug reactions ACE inhibitors (e.g. lisinopril) Renal impairment Hyperkalaemia Antibiotics (e.g. amoxicillin) Nausea Diarrhoea Anticoagulants (e.g. warfarin, heparin) Bleeding Antipsychotics (e.g. haloperidol) Falls Sedation Delirium Aspirin Gastrotoxicity (dyspepsia, gastrointestinal bleeding) Benzodiazepines (e.g. diazepam) Drowsiness Falls β-blockers (e.g. atenolol) Cold peripheries Bradycardia Calcium channel blockers (e.g. amlodipine) Ankle oedema Digoxin Nausea and anorexia Bradycardia Diuretics (e.g. furosemide, bendroflumethiazide) Dehydration Electrolyte disturbance (hypokalaemia, hyponatraemia) Hypotension Renal impairment Insulin Hypoglycaemia NSAIDs (e.g. ibuprofen) Gastrotoxicity (dyspepsia, gastrointestinal bleeding) Renal impairment Opioid analgesics (e.g. morphine) Nausea and vomiting Delirium Constipation (ACE = angiotensin-converting enzyme; NSAID = non-steroidal anti-inflammatory drug) ADRs are important because they reduce quality of life for patients, reduce adherence to and therefore efficacy of beneficial treatments, cause diagnostic confusion, undermine the confidence of patients in their health-care professional(s) and consume health-care resources. Retrospective analysis of ADRs has shown that more than half could have been avoided if the prescriber had taken more care in anticipating the potential hazards of drug therapy. For example, non-steroidal anti-inflammatory drug (NSAID) use accounts for many thousands of emergency admissions, gastrointestinal bleeding episodes and a significant number of deaths. In many cases, the patients are at increased risk due to their age, interacting drugs (e.g. aspirin, warfarin) or a past history of peptic ulcer disease. Drugs that commonly cause ADRs are listed in Box 2.8. Prescribers and their patients ideally want to know the frequency with which ADRs occur for a specific drug. Although this may be well characterised for more common ADRs observed in clinical trials, it is less clear for rarely reported ADRs when the total numbers of reactions and patients exposed are not known. The words used to describe frequency can be misinterpreted by patients but widely accepted meanings include: very common (10% or more), common (1–10%), uncommon (0.1–1%), rare (0.01–0.1%) and very rare (0.01% or less). Classification of ADRs ADRs have traditionally been classified into two major groups: • Type A (‘augmented’) ADRs. These are predictable from the known pharmacodynamic effects of the drug and are dose-dependent, common (detected early in drug development) and usually mild. Examples include constipation caused by opioids, hypotension caused by antihypertensives and dehydration caused by diuretics. • Type B (‘bizarre’) ADRs. These are not predictable, are not obviously dose-dependent in the therapeutic range, are rare (remaining undiscovered until the drug is marketed) and often severe. Patients who experience type B reactions are generally ‘hyper-susceptible’ because of unpredictable immunological or genetic factors (e.g. anaphylaxis caused by penicillin, peripheral neuropathy caused by isoniazid in poor acetylators). This simple classification has shortcomings, and a more detailed classification based on dose (see Fig. 2.2), timing and susceptibility (DoTS) is now used by those analysing ADRs in greater depth (Box 2.9). The AB classification can be extended as a reminder of some other types of ADR: • Type C (‘chronic/continuous’) ADRs. These occur only after prolonged continuous exposure to a drug. Examples include osteoporosis caused by glucocorticoids, retinopathy caused by chloroquine, and tardive dyskinesia caused by phenothiazines. • Type D (‘delayed’) ADRs. These are delayed until long after drug exposure, making diagnosis difficult. Examples include malignancies that may emerge after immunosuppressive treatment post-transplantation (e.g. azathioprine, tacrolimus) and vaginal cancer occurring many years after exposure to diethylstilboestrol. • Type E (‘end-of-treatment’) ADRs. These occur after abrupt drug withdrawal (see Box 2.3). A teratogen is a drug with the potential to affect the development of the fetus in the first 10 weeks of intrauterine life (e.g. phenytoin, warfarin). The thalidomide disaster in the early 1960s highlighted the risk of teratogenicity and led to mandatory testing of all new drugs. Congenital defects in a live infant or aborted fetus should

Adverse outcomes of drug therapy • 23

of prescribers of a particular drug are issued with questionnaires concerning the clinical outcome for their patients, and the collection of population statistics. Many health-care systems routinely collect patient-identifiable data on prescriptions (a surrogate marker of exposure to a drug), health-care events (e.g. hospitalisation, operations, new clinical diagnoses) and other clinical data (e.g. haematology, biochemistry). As these records are linked, with appropriate safeguards for confidentiality and data protection, they are providing a much more powerful mechanism for assessing both the harms and benefits of drugs. All prescribers will inevitably see patients experiencing ADRs caused by prescriptions written by themselves or their colleagues. It is important that these are recognised early. In addition to the features in Box 2.10, features that should raise suspicion of an ADR and the need to respond (by drug withdrawal, dosage reduction or reporting to the regulatory authorities) include: • concern expressed by a patient that a drug has harmed them • abnormal clinical measurements (e.g. blood pressure, temperature, pulse, blood glucose and weight) or laboratory results (e.g. abnormal liver or renal function, low haemoglobin or white cell count) while on drug therapy • new therapy started that could be in response to an ADR (e.g. omeprazole, allopurinol, naloxone) • the presence of risk factors for ADRs (see Box 2.7). Drug interactions A drug interaction has occurred when the administration of one drug increases or decreases the beneficial or adverse responses to another drug. Although the number of potential interacting drug combinations is very large, only a small number are common in clinical practice. Important drug interactions are most likely to occur when the affected drug has a low therapeutic index, steep dose–response curve, high first-pass or saturable metabolism, or a single mechanism of elimination. Mechanisms of drug interactions Pharmacodynamic interactions occur when two drugs produce additive, synergistic or antagonistic effects at the same drug target (e.g. receptor, enzyme) or physiological system (e.g. electrolyte excretion, heart rate). These are the most common interactions in clinical practice and some important examples are given in Box 2.11. Pharmacokinetic interactions occur when the administration of a second drug alters the concentration of the first at its site of action. There are numerous potential mechanisms: • Absorption interactions. Drugs that either delay (e.g. anticholinergic drugs) or enhance (e.g. prokinetic drugs) gastric emptying influence the rate of rise in plasma concentration of other drugs but not the total amount of drug absorbed. Drugs that bind to form insoluble complexes or chelates (e.g. aluminium-containing antacids binding with ciprofloxacin) can reduce drug absorption. • Distribution interactions. Co-administration of drugs that compete for protein binding in plasma (e.g. phenytoin and diazepam) can increase the unbound drug concentration, but the effect is usually short-lived due to increased elimination and hence restoration of the pre-interaction equilibrium. provoke suspicion of an ADR and a careful exploration of drug exposures (including self-medication and herbal remedies). Detecting ADRs – pharmacovigilance Type A ADRs become apparent early in the development of a new drug. By the time a new drug is licensed and launched on to a possible worldwide market, however, a relatively small number of patients (just several hundred) may have been exposed to it, meaning that rarer but potentially serious type B ADRs may remain undiscovered. Pharmacovigilance is the process of detecting (‘signal generation’) and evaluating ADRs in order to help prescribers and patients to be better informed about the risks of drug therapy. Drug regulatory agencies may respond to this information by placing restrictions on the licensed indications, reducing the recommended dose range, adding special warnings and precautions for prescribers in the product literature, writing to all health-care professionals or withdrawing the product from the market. Voluntary reporting systems allow health-care professionals and patients to report suspected ADRs to the regulatory authorities. A good example is the ‘Yellow Card’ scheme that was set up in the UK in response to the thalidomide tragedy. Reports are analysed to assess the likelihood that they represent a true ADR (Box 2.10). Although voluntary reporting is a continuously operating and effective early-warning system for previously unrecognised rare ADRs, its weaknesses include low reporting rates (only 3% of all ADRs and 10% of serious ADRs are ever reported), an inability to quantify risk (because the ratio of ADRs to prescriptions is unknown), and the influence of prescriber awareness on likelihood of reporting (reporting rates rise rapidly following publicity about potential ADRs). More systematic approaches to collecting information on ADRs include ‘prescription event monitoring’, in which a sample 2.10 TREND analysis of suspected adverse drug reactions Factor Key question Comment Temporal relationship What is the time interval between the start of drug therapy and the reaction? Most ADRs occur soon after starting treatment and within hours in the case of anaphylactic reactions Re-challenge What happens when the patient is re-challenged with the drug? Re-challenge is rarely possible because of the need to avoid exposing patients to unnecessary risk Exclusion Have concomitant drugs and other non-drug causes been excluded? ADR is a diagnosis of exclusion following clinical assessment and relevant investigations for non-drug causes Novelty Has the reaction been reported before? The suspected ADR may already be recognised and mentioned in the SPC approved by the regulatory authorities De-challenge Does the reaction improve when the drug is withdrawn or the dose is reduced? Most, but not all, ADRs improve on drug withdrawal, although recovery may be slow (SPC = summary of product characteristics)

24 • CLINICAL THERAPEUTICS AND GOOD PRESCRIBING consequences of drug–drug interactions by taking a careful drug history (see Box 2.6) before prescribing additional drugs, only prescribing for clear indications, and taking special care when prescribing drugs with a narrow therapeutic index (e.g. warfarin). When prescribing an interacting drug is unavoidable, good prescribers will seek further information and anticipate the potential risk. This will allow them to provide special warnings for the patient and arrange for monitoring, either of the clinical effects (e.g. coagulation tests for warfarin) or of plasma concentration (e.g. digoxin). Medication errors A medication error is any preventable event that may lead to inappropriate medication use or patient harm while the medication is in the control of the health-care professional or patient. Errors may occur in prescribing, dispensing, preparing solutions, administration or monitoring. Many ADRs are considered in retrospect to have been ‘avoidable’ with more care or forethought; in other words, an adverse event considered by one prescriber to be an unfortunate ADR might be considered by another to be a prescribing error. Medication errors are very common. Several thousand medication orders are dispensed and administered each day in a medium-sized hospital. Recent UK studies suggest that • Metabolism interactions. Many drugs rely on metabolism by different isoenzymes of cytochrome P450 (CYP) in the liver. CYP enzyme inducers (e.g. phenytoin, rifampicin) generally reduce plasma concentrations of other drugs, although they may enhance activation of prodrugs. CYP enzyme inhibitors (e.g. clarithromycin, cimetidine, grapefruit juice) have the opposite effect. Enzyme induction effects usually take a few days to manifest because of the need to synthesise new CYP enzyme, in contrast to the rapid effects of enzyme inhibition. • Excretion interactions. These primarily affect renal excretion. For example, drug-induced reduction in glomerular filtration rate (e.g. diuretic-induced dehydration, angiotensin-converting enzyme (ACE) inhibitors, NSAIDs) can reduce the clearance and increase the plasma concentration of many drugs, including some with a low therapeutic index (e.g. digoxin, lithium, aminoglycoside antibiotics). Less commonly, interactions may be due to competition for a common tubular organic anion transporter (e.g. methotrexate excretion may be inhibited by competition with NSAIDs). Avoiding drug interactions Drug interactions are increasing as patients are prescribed more medicines (polypharmacy). Prescribers can avoid the adverse 2.11 Common drug interactions Mechanism Object drug Precipitant drug Result Pharmaceutical* Chemical reaction Sodium bicarbonate Calcium gluconate Precipitation of insoluble calcium carbonate Pharmacokinetic Reduced absorption Tetracyclines Calcium, aluminium, and magnesium salts Reduced tetracycline absorption Reduced protein binding Phenytoin Aspirin Increased unbound and reduced total phenytoin plasma concentration Reduced metabolism: CYP3A4 Amiodarone Grapefruit juice Cardiac arrhythmias because of prolonged QT interval (p. 476) Warfarin Clarithromycin Enhanced anticoagulation CYP2C19 Phenytoin Omeprazole Phenytoin toxicity CYP2D6 Clozapine Paroxetine Clozapine toxicity Xanthine oxidase Azathioprine Allopurinol Azathioprine toxicity Monoamine oxidase Catecholamines Monoamine oxidase inhibitors Hypertensive crisis due to monoamine toxicity Increased metabolism (enzyme induction) Ciclosporin St John’s wort Loss of immunosuppression Reduced renal elimination Lithium Diuretics Lithium toxicity Methotrexate NSAIDs Methotrexate toxicity Pharmacodynamic Direct antagonism at same receptor Opioids Naloxone Reversal of opioid effects used therapeutically Salbutamol Atenolol Inhibits bronchodilator effect Direct potentiation in same organ system Benzodiazepines Alcohol Increased sedation ACE inhibitors NSAIDs Increased risk of renal impairment Indirect potentiation by actions in different organ systems Digoxin Diuretics Digoxin toxicity enhanced because of hypokalaemia Warfarin Aspirin, NSAIDs Increased risk of bleeding because of gastrotoxicity and antiplatelet effects Diuretics ACE inhibitors Blood pressure reduction (may be therapeutically advantageous) because of the increased activity of the renin–angiotensin system in response to diuresis *Pharmaceutical interactions are related to the formulation of the drugs and occur before drug absorption. (ACE = angiotensin-converting enzyme; NSAID = non-steroidal anti-inflammatory drug)

Adverse outcomes of drug therapy • 25

7–9% of hospital prescriptions contain an error, and most are written by junior doctors. Common prescribing errors in hospitals include omission of medicines (especially failure to prescribe regular medicines at the point of admission or discharge, i.e. ‘medicines reconciliation’), dosing errors, unintentional prescribing and poor use of documentation (Box 2.12). Most prescription errors result from a combination of failures by the individual prescriber and the health-service systems in which they work (Box 2.13). Health-care organisations increasingly encourage reporting of errors within a ‘no-blame culture’ so that they can be subject to ‘root cause analysis’ using human error theory (Fig. 2.5). Prevention is targeted at the factors in Box 2.13, and can be supported by prescribers communicating and cross-checking with colleagues (e.g. when calculating doses adjusted for body weight, or planning appropriate monitoring after drug administration), and by health-care systems providing clinical pharmacist support (e.g. for checking the patient’s previous medications and current prescriptions) and electronic prescribing (which avoids errors due to illegibility or serious dosing mistakes, and may be combined with a clinical decision support system to take account of patient characteristics and drug history, and provide warnings of potential contraindications and drug interactions). 2.13 Causes of prescribing errors Systems factors • Working hours of prescribers (and others) • Patient throughput • Professional support and supervision by colleagues • Availability of information (medical records) • Design of prescription forms • Distractions • Availability of decision support • Checking routines (e.g. clinical pharmacy) • Reporting and reviewing of incidents Prescriber factors Knowledge • Clinical pharmacology principles • Drugs in common use • Therapeutic problems commonly encountered • Knowledge of workplace systems Skills • Taking a good drug history • Obtaining information to support prescribing • Communicating with patients • Numeracy and calculations • Prescription writing Attitudes • Coping with risk and uncertainty • Monitoring of prescribing • Checking routines 2.12 Hospital prescribing errors Error type Approximate % of total Omission on admission

Underdose

Overdose

Strength/dose missing

Omission on discharge

Administration times incorrect/missing

Duplication

Product or formulation not specified

Incorrect formulation

No maximum dose

Unintentional prescribing

No signature

Clinical contraindication

Incorrect route

No indication

Intravenous instructions incorrect/missing

Drug not prescribed but indicated

Drug continued for longer than needed

Route of administration missing

Start date incorrect/missing

Risk of drug interaction < 0.5 Controlled drug requirements incorrect/missing < 0.5 Daily dose divided incorrectly < 0.5 Significant allergy < 0.5 Drug continued in spite of adverse effects < 0.5 Premature discontinuation < 0.5 Failure to respond to out-of-range drug level < 0.5 Fig. 2.5 Human error theory. Unintended errors may occur because the prescriber fails to complete the prescription correctly (a slip; e.g. writes the dose in ‘mg’ not ‘micrograms’) or forgets part of the action that is important for success (a lapse; e.g. forgets to co-prescribe folic acid with methotrexate); prevention requires the system to provide appropriate checking routines. Intended errors occur when the prescriber acts incorrectly due to lack of knowledge (a mistake; e.g. prescribes atenolol for a patient with known severe asthma because of ignorance about the contraindication); prevention must focus on training the prescriber. Planned action Prescribing Intended action Correct action Intended outcome Unintended action Lapse Slip Wrong plan selected (Causes include poor training and lack of experience) Correct plan known but not executed (Causes include workload, time pressures, distractions) Prescription not as intended Prescriber unaware Prescription incomplete or forgotten Prescriber may remember Violation Mistake Prescription as intended but written based on the wrong principles or lack of knowledge Prescriber unaware Deliberate deviations from standard practice Prescriber aware

26 • CLINICAL THERAPEUTICS AND GOOD PRESCRIBING cell lines, molecular cloning and purification processes. After the patent for the originator product expires, other manufacturers may develop similar products (‘biosimilars’) that share similar pharmacological actions but are not completely identical. ‘Biosimilars’ are considered distinct from ‘generic’ medications, as complex biological molecules are more susceptible to differences in manufacturing processes than conventional small-molecule-type pharmaceuticals. The number of new drugs produced by the pharmaceutical industry has declined in recent years. The traditional approach of targeting membrane-bound receptors and enzymes with small molecules (see Box 2.2) is now giving way to new targets, such as complex second-messenger systems, cytokines, nucleic acids and cellular networks. These require novel therapeutic agents, which present new challenges for ‘translational medicine’, the discipline of converting scientific discoveries into a useful medicine with a well-defined benefit–risk profile (Box 2.15). Licensing new medicines New drugs are given a ‘market authorisation’, based on the evidence of quality, safety and efficacy presented by the manufacturer. The regulator not only will approve the drug but also will take great care to ensure that the accompanying information reflects the evidence that has been presented. The summary of product characteristics (SPC), or ‘label’, provides detailed information about indications, dosage, adverse effects, warnings, monitoring and so on. If approved, drugs can be made available with different levels of restriction: • Controlled drug (CD). These drugs are subject to strict legal controls on supply and possession, usually due to their abuse potential (e.g. opioid analgesics). 2.14 Clinical development of new drugs Phase I • Healthy volunteers (20–80) • These involve initial single-dose, ‘first-into-man’ studies, followed by repeated-dose studies. They aim to establish the basic pharmacokinetic and pharmacodynamic properties, and short-term safety • Duration: 6–12 months Phase II • Patients (100–200) • These investigate clinical effectiveness (‘proof of concept’), safety and dose–response relationship, often with a surrogate clinical endpoint, in the target patient group to determine the optimal dosing regimen for larger confirmatory studies • Duration: 1–2 years Phase III • Patients (100s–1000s) • These are large, expensive clinical trials that confirm safety and efficacy in the target patient population, using relevant clinical endpoints. They may be placebo-controlled studies or comparisons with other active compounds • Duration: 1–2 years Phase IV • Patients (100s–1000s) • These are undertaken after the medicine has been marketed for its first indication to evaluate new indications, new doses or formulations, long-term safety or cost-effectiveness Responding when an error is discovered All prescribers will make errors. When they do, their first duty is to protect the patient’s safety. This will involve a clinical review and the taking of any steps that will reduce harm (e.g. remedial treatment, monitoring, recording the event in the notes, informing colleagues). Patients should be informed if they have been exposed to potential harm. For errors that do not reach the patient, it is the prescriber’s duty to report them, so that others can learn from the experience and take the opportunity to reflect on how a similar incident might be avoided in the future. Drug regulation and management Given the powerful beneficial and potentially adverse effects of drugs, the production and use of medicines are strictly regulated (e.g. by the Food and Drug Administration in the USA, Medicines and Healthcare Products Regulatory Agency in the UK, and Central Drugs Standard Control Organisation in India). Regulators are responsible for licensing medicines, monitoring their safety (pharmacovigilance; p. 23), approving clinical trials, and inspecting and maintaining standards of drug development and manufacture. In addition, because of the high costs of drugs and their adverse effects, health-care services must prioritise their use in light of the evidence of their benefit and harm, a process referred to as ‘medicines management’. Drug development and marketing Naturally occurring products have been used to treat illnesses for thousands of years and some remain in common use today. Examples include morphine from the opium poppy (Papaver somniferum), digitalis from the foxglove (Digitalis purpurea), curare from the bark of a variety of species of South American trees, and quinine from the bark of the Cinchona species. Although plants and animals remain a source of discovery, the majority of new drugs come from drug discovery programmes that aim to identify small-molecule compounds with specific interactions with a molecular target that will induce a predicted biological effect. The usual pathway for development of these small molecules includes: identifying a plausible molecular target by investigating pathways in disease; screening a large library of compounds for those that interact with the molecular target in vitro; conducting extensive medicinal chemistry to optimise the properties of lead compounds; testing efficacy and toxicity of these compounds in vitro and in animals; and undertaking a clinical development programme (Box 2.14). This process typically takes longer than 10 years and may cost up to US$1 billion. Manufacturers have a defined period of exclusive marketing of the drug while it remains protected by an original patent, typically 10–15 years, during which time they must recoup the costs of developing the drug. Meanwhile, competitor companies will often produce similar ‘me too’ drugs of the same class. Once the drug’s patent has expired, ‘generic’ manufacturers may step in to produce cheaper formulations of the drug. Paradoxically, if a generic drug is produced by only one manufacturer, the price may actually rise, sometimes substantially. Newer ‘biological’ products are based on large molecules (e.g. human recombinant antibodies) derived from complex manufacturing processes involving specific

Drug regulation and management • 27

Managing the use of medicines Many medicines meet the three key regulatory requirements of quality, safety and efficacy. Although prescribers are legally entitled to prescribe any of them, it is desirable to limit the choice so that treatments for specific diseases can be focused on the most effective and cost-effective options, prescribers (and patients) gain familiarity with a smaller number of medicines, and pharmacies can concentrate stocks on them. The process of ensuring optimal use of available medicines is known as ‘medicines management’ or ‘quality use of medicines’. It involves careful evaluation of the evidence of benefit and harm from using the medicine, an assessment of cost-effectiveness, and support for processes to implement the resulting recommendations. These activities usually involve both national (e.g. National Institute for Health and Care Excellence (NICE) in the UK) and local organisations (e.g. drug and therapeutics committees). Evaluating evidence The principles of evidence-based medicine are described on page 10. Drugs are often evaluated in high-quality randomised controlled trials, the results of which can be considered by systematic review (Fig. 2.6). Ideally, data are available not only for comparison with placebo but also for ‘head-to-head’ comparison with alternative therapies. Trials are conducted in selected patient populations, however, and are not representative of every clinical scenario, so extrapolation to individual patients is not always straightforward. Other subtle bias may be introduced because of the sources of funding (e.g. pharmaceutical industry) and the interests of the investigators in being involved in research that has a ‘positive’ impact. These biases may be manifest in the way the trials are conducted or in how they are interpreted or reported. A common example of the latter is the difference between relative and absolute risk of clinical events reported in prevention trials. If a clinical event is encountered in the placebo arm at a rate of 1 in 50 patients (2%) but only 1 in 100 patients (1%) in the active treatment arm, then the impact of treatment can be described as either a 50% relative risk reduction or 1% absolute risk reduction. Although the former sounds more impressive, it is the latter that is of more importance to the • Prescription-only medicine (PoM). These are available only from a pharmacist and can be supplied only if prescribed by an appropriate practitioner. • Pharmacy (P). These are available only from a pharmacist but can be supplied without a prescription. • General sales list (GSL). These medicines may be bought ‘over the counter’ (OTC) from any shop and without a prescription. Although the regulators take great care to agree the exact indications for prescribing a medicine, based on the evidence provided by the manufacturer, there are some circumstances in which prescribers may direct its use outside the terms stated in the SPC (‘off-label’ prescribing). Common situations where this might occur include prescribing outside the approved age group (e.g. prescribing for children) or using an alternative formulation (e.g. administering a medicine provided in a solid form as an oral solution). Other important examples might include prescribing for an indication for which there are no approved medicines or where all of the approved medicines have caused unacceptable adverse effects. Occasionally, medicines may be prescribed when there is no marketing authorisation in the country of use. Examples include when a medicine licensed in another country is imported for use for an individual patient (‘unlicensed import’) or when a patient requires a specific preparation of a medicine to be manufactured (‘unlicensed special’). When prescribing is ‘off-label’ or ‘unlicensed’, there is an increased requirement for prescribers to be able to justify their actions and to inform and agree the decision with the patient. Drug marketing The marketing activities of the pharmaceutical industry are well resourced and are important in the process of recouping the massive costs of drug development. In some countries, such as the USA, it is possible to promote a new drug by direct-toconsumer advertising, although this is illegal in the countries of the European Union. A major focus is on promotion to prescribers via educational events, sponsorship of meetings, advertisements in journals, involvement with opinion leaders, and direct contact by company representatives. Such largesse has the potential to cause significant conflicts of interest and might tempt prescribers to favour one drug over another, even in the face of evidence on effectiveness or cost-effectiveness. 2.15 Novel therapeutic alternatives to conventional small-molecule drugs Approaches Therapeutic indications Challenges Monoclonal antibodies Targeting of receptors or other molecules with relatively specific antibodies Cancer Chronic inflammatory diseases (e.g. rheumatoid arthritis, inflammatory bowel disease) Selectivity of action Complex manufacturing process Small interfering RNA (siRNA) Inhibition of gene expression Macular degeneration Delivery to target Gene therapy Delivery of modified genes that supplement or alter host DNA Cystic fibrosis Cancer Cardiovascular disease Delivery to target Adverse effects of delivery vector (e.g. virus) Stem cell therapy Stem cells differentiate and replace damaged host cells Parkinson’s disease Spinal cord injury Ischaemic heart disease Delivery to target Immunological compatibility Long-term effects unknown

28 • CLINICAL THERAPEUTICS AND GOOD PRESCRIBING Implementing recommendations Many recommendations about drug therapy are included in clinical guidelines written by an expert group after systematic review of the evidence. Guidelines provide recommendations rather than obligations for prescribers and are helpful in promoting more consistent and higher-quality prescribing. They are often written without concern for cost-effectiveness, however, and may be limited by the quality of available evidence. Guidelines cannot anticipate the extent of the variation between individual patients who may, for example, have unexpected contraindications to recommended drugs or choose different priorities for treatment. When deviating from respected national guidance, prescribers should be able to justify their practice. Additional recommendations for prescribing are often implemented locally or imposed by bodies responsible for paying for health care. Most health-care units have a drug and therapeutics committee (or equivalent) comprised of senior and junior medical staff, pharmacists and nurses, as well as managers (because of the implications of the committee’s work for governance and resources). This group typically develops local prescribing policy and guidelines, maintains a local drug formulary and evaluates requests to use new drugs. The local formulary contains a more limited list than any national formulary (e.g. British National Formulary) because the latter lists all licensed medicines that can be prescribed legally, while the former contains only those that the health-care organisation has approved for local use. The local committee may also be involved, with local specialists, in providing explicit protocols for management of clinical scenarios. Prescribing in practice Decision-making in prescribing Prescribing should be based on a rational approach to a series of challenges (see Box 2.1). individual patient. It means that the number of patients that needed to be treated (NNT) for 1 to benefit (compared to placebo) was 100. This illustrates how large clinical trials of new medicines can produce highly statistically significant and impressive relative risk reductions and still predict a very modest clinical impact. Evaluating cost-effectiveness New drugs often represent an incremental improvement over the current standard of care but are usually more expensive. Health-care budgets are limited in every country and so it is impossible to fund all new medicines. This means that very difficult financial decisions have to be taken with due regard to the principles of ethical justice. The main approach taken is cost-effectiveness analysis (CEA), where a comparison is made between the relative costs and outcomes of different courses of action. CEA is usually expressed as a ratio where the denominator is a gain in health and the numerator is the cost associated with the health gain. A major challenge is to compare the value of interventions for different clinical outcomes. One method is to calculate the quality-adjusted life years (QALYs) gained if the new drug is used rather than standard treatment. This analysis involves estimating the ‘utility’ of various health states between 1 (perfect health) and 0 (dead). If the additional costs and any savings are known, then it is possible to derive the incremental cost-effectiveness ratio (ICER) in terms of cost/QALY. These principles are exemplified in Box 2.16. There are, however, inherent weaknesses in this kind of analysis: it usually depends on modelling future outcomes well beyond the duration of the clinical trial data that are available; it assumes that QALYs gained at all ages are of equivalent value; and the appropriate standard care against which the new drug should be compared is often uncertain. These pharmacoeconomic assessments are challenging and resource-intensive, and are undertaken at national level in most countries, e.g. in the UK by NICE. Fig. 2.6 Systematic review of the evidence from randomised controlled clinical trials. This forest plot shows the effect of warfarin compared with placebo on the likelihood of stroke in patients with atrial fibrillation in five randomised controlled trials that passed the quality criteria required for inclusion in a meta-analysis. For each trial, the purple box is proportionate to the number of participants. The tick marks show the mean odds ratio and the black lines indicate its 95% confidence intervals. Note that not all the trials showed statistically significant effects (i.e. the confidence intervals cross 1.0). However, the meta-analysis, represented by the black diamond, confirms a highly significant statistical benefit. The overall odds ratio is approximately 0.4, indicating a mean 60% risk reduction with warfarin treatment in patients with the characteristics of the participants in these trials. Odds ratio Favours treatment 0.1 0.2 0.5

Favours placebo 2.16 Cost-effectiveness analysis A clinical trial lasting 2 years compares two interventions for the treatment of colon cancer: • Treatment A: standard treatment, cost £1000/year, oral therapy • Treatment B: new treatment, cost £6000/year, monthly intravenous infusions, often followed by a week of nausea. The new treatment (B) significantly increases the average time to progression (18 months versus 12 months) and reduces overall mortality (40% versus 60%). The health economist models the survival curves from the trial in order to undertake a cost–utility analysis and concludes that: • Intervention A: allows an average patient to live for 2 extra years at a utility 0.7 = 1.4 QALYs (cost £2000) • Intervention B: allows an average patient to live for 3 extra years at a utility 0.6 = 1.8 QALYs (cost £18 000). The health economists conclude that treatment B provides an extra 0.4 QALYs at an extra cost of £16 000, meaning that the ICER = £40 000/QALY. They recommend that the new treatment should not be funded on the basis that their threshold for cost acceptability is £30 000/QALY. (ICER = incremental cost-effectiveness ratio; QALY = quality-adjusted life year)

Prescribing in practice • 29

Excretion Drugs that depend on renal excretion for elimination (e.g. digoxin, aminoglycoside antibiotics) should be avoided in patients with impaired renal function if suitable alternatives exist. Efficacy Prescribers normally choose drugs with the greatest efficacy in achieving the goals of therapy (e.g. proton pump inhibitors rather than H2-receptor antagonists). It may be appropriate, however, to compromise on efficacy if other drugs are more convenient, safer to use or less expensive. Avoiding adverse effects Prescribers should be wary of choosing drugs that are more likely to cause adverse effects (e.g. cephalosporins rather than alternatives for patients allergic to penicillin) or worsen coexisting conditions (e.g. β-blockers as treatment for angina in patients with asthma). Features of the disease This is most obvious when choosing antibiotic therapy, which should be based on the known or suspected sensitivity of the infective organism (p. 116). Severity of disease The choice of drug should be appropriate to disease severity (e.g. paracetamol for mild pain, morphine for severe pain). Coexisting disease This may be either an indication or a contraindication to therapy. Hypertensive patients might be prescribed a β-blocker if they also have left ventricular impairment but not if they have asthma. Avoiding adverse drug interactions Prescribers should avoid giving combinations of drugs that might interact, either directly or indirectly (see Box 2.11). Patient adherence to therapy Prescribers should choose drugs with a simple dosing schedule or easier administration (e.g. the ACE inhibitor lisinopril once daily rather than captopril 3 times daily for hypertension). Cost Prescribers should choose the cheaper drug (e.g. a generic or biosimilar) if two drugs are of equal efficacy and safety. Even if cost is not a concern for the individual patient, it is important to remember that unnecessary expenditure will ultimately limit choices for other prescribers and patients. Sometimes a more costly drug may be appropriate (e.g. if it yields improved adherence). Genetic factors There are already a small number of examples where genotype influences the choice of drug therapy (see Box 2.5). Choosing a dosage regimen Prescribers have to choose a dose, route and frequency of administration (dosage regimen) to achieve a steady-state drug concentration that provides sufficient exposure of the target tissue without producing toxic effects. Manufacturers draw up dosage recommendations based on average observations in many patients but the optimal regimen that will maximise the benefit to harm ratio for an individual patient is never certain. Making a diagnosis Ideally, prescribing should be based on a confirmed diagnosis but, in reality, many prescriptions are based on the balance of probability, taking into account the differential diagnosis (e.g. proton pump inhibitors for post-prandial retrosternal discomfort). Establishing the therapeutic goal The goals of treatment are usually clear, particularly when relieving symptoms (e.g. pain, nausea, constipation). Sometimes the goal is less obvious to the patient, especially when aiming to prevent future events (e.g. ACE inhibitors to prevent hospitalisation and extend life in chronic heart failure). Prescribers should be clear about the therapeutic goal against which they will judge success or failure of treatment. It is also important to establish that the value placed on this goal by the prescriber is shared by the patient (concordance). Choosing the therapeutic approach For many clinical problems, drug therapy is not absolutely mandated. Having taken the potential benefits and harms into account, prescribers must consider whether drug therapy is in the patient’s interest and is preferred to no treatment or one of a range of alternatives (e.g. physiotherapy, psychotherapy, surgery). Assessing the balance of benefit and harm is often complicated and depends on various features associated with the patient, disease and drug (Box 2.17). Choosing a drug For most common clinical indications (e.g. type 2 diabetes, depression), more than one drug is available, often from more than one drug class. Although prescribers often have guidance about which represents the rational choice for the average patient, they still need to consider whether this is the optimal choice for the individual patient. Certain factors may influence the choice of drug: Absorption Patients may find some formulations easier to swallow than others or may be vomiting and require a drug available for parenteral administration. Distribution Distribution of a drug to a particular tissue sometimes dictates choice (e.g. tetracyclines and rifampicin are concentrated in the bile, and lincomycin and clindamycin in bones). Metabolism Drugs that are extensively metabolised should be avoided in severe liver disease (e.g. opioid analgesics). 2.17 Factors to consider when balancing benefits and harms of drug therapy • Seriousness of the disease or symptom • Efficacy of the drug • Seriousness of potential adverse effects • Likelihood of adverse effects • Efficacy of alternative drugs or non-drug therapies • Safety of alternative drugs or non-drug therapies

30 • CLINICAL THERAPEUTICS AND GOOD PRESCRIBING Duration Some drugs require a single dose (e.g. thrombolysis post myocardial infarction), while for others the duration of the course of treatment is certain at the outset (e.g. antibiotics). For most, the duration will be largely at the prescriber’s discretion and will depend on response and disease progression (e.g. analgesics, antidepressants). For many, the treatment will be long-term (e.g. insulin, antihypertensives, levothyroxine). Involving the patient Patients should, whenever possible, be engaged in making choices about drug therapy. Their beliefs and expectations affect the goals of therapy and help in judging the acceptable benefit/ harm balance when selecting treatments. Very often, patients may wish to defer to the professional expertise of the prescriber. Nevertheless, they play key roles in adherence to therapy and in monitoring treatment, not least by providing early warning of adverse events. It is important for them to be provided with the necessary information to understand the choice that has been made, what to expect from the treatment, and any measurements that must be undertaken (Box 2.20). A major drive to include patients has been the recognition that up to half of the drug doses for chronic preventative therapy are not taken. This is often termed ‘non-compliance’ but is more appropriately called ‘non-adherence’, to reflect a less paternalistic view of the doctor–patient relationship; it may or may not be intentional. Non-adherence to the dose regimen reduces the likelihood of benefits to the patient and can be costly in terms Rational prescribing involves treating each prescription as an experiment and gathering sufficient information to amend it if necessary. There are some general principles that should be followed, as described below. Dose titration Prescribers should generally start with a low dose and titrate this slowly upwards as necessary. This cautious approach is particularly important if the patient is likely to be more sensitive to adverse pharmacodynamic effects (e.g. delirium or postural hypotension in the elderly) or have altered pharmacokinetic handling (e.g. renal or hepatic impairment), and when using drugs with a low therapeutic index (e.g. benzodiazepines, lithium, digoxin). There are some exceptions, however. Some drugs must achieve therapeutic concentration quickly because of the clinical circumstance (e.g. antibiotics, glucocorticoids, carbimazole). When early effect is important but there may be a delay in achieving steady state because of a drug’s long half-life (e.g. digoxin, warfarin, amiodarone), an initial loading dose is given prior to establishing the appropriate maintenance dose (see Fig. 2.4). If adverse effects occur, the dose should be reduced or an alternative drug prescribed; in some cases, a lower dose may suffice if it can be combined with another synergistic drug (e.g. the immunosuppressant azathioprine reduces glucocorticoid requirements in patients with inflammatory disease). It is important to remember that the shape of the dose–response curve (see Fig. 2.2) means that higher doses may produce little added therapeutic effect and might increase the chances of toxicity. Route There are many reasons for choosing a particular route of administration (Box 2.18). Frequency Frequency of doses is usually dictated by a manufacturer’s recommendation. Less frequent doses are more convenient for patients but result in greater fluctuation between peaks and troughs in drug concentration (see Fig. 2.4). This is relevant if the peaks are associated with adverse effects (e.g. dizziness with antihypertensives) or the troughs are associated with troublesome loss of effect (e.g. anti-Parkinsonian drugs). These problems can be tackled either by splitting the dose or by employing a modified-release formulation, if available. Timing For many drugs the time of administration is unimportant. There are occasionally pharmacokinetic or therapeutic reasons, however, for giving drugs at particular times (Box 2.19). Formulation For some drugs there is a choice of formulation, some for use by different routes. Some are easier to ingest, particularly by children (e.g. elixirs). The formulation is important when writing repeat prescriptions for drugs with a low therapeutic index that come in different formulations (e.g. lithium, phenytoin, theophylline). Even if the prescribed dose remains constant, an alternative formulation may differ in its absorption and bioavailability, and hence plasma drug concentration. These are examples of the small number of drugs that should be prescribed by specific brand name rather than ‘generic’ international non-proprietary name (INN). 2.18 Factors influencing the route of drug administration Reason Example Only one route possible Dobutamine (IV) Gliclazide (oral) Patient adherence Phenothiazines and thioxanthenes (2 weekly IM depot injections rather than daily tablets, in schizophrenia) Poor absorption Furosemide (IV rather than oral, in severe heart failure) Rapid action Haloperidol (IM rather than oral, in acute behavioural disturbance) Vomiting Phenothiazines (PR or buccal rather than oral, in nausea) Avoidance of first-pass metabolism Glyceryl trinitrate (SL, in angina pectoris) Certainty of effect Amoxicillin (IV rather than oral, in acute chest infection) Direct access to the site of action (avoiding unnecessary systemic exposure) Bronchodilators (INH rather than oral, in asthma) Local application of drugs to skin, eyes etc. Ease of access Diazepam (PR, if IV access is difficult in status epilepticus) Adrenaline (epinephrine) (IM, if IV access is difficult in acute anaphylaxis) Comfort Morphine (SC rather than IV in terminal care) (IM = intramuscular; INH = by inhalation; IV = intravenous; PR = per rectum; SC = subcutaneous; SL = sublingual)

Prescribing in practice • 31

Stopping drug therapy It is also important to review long-term treatment at regular intervals to assess whether continued treatment is required. Elderly patients are keen to reduce their medication burden and are often prepared to compromise on the original goals of long-term preventative therapy to achieve this. Prescribing in special circumstances Prescribing for patients with renal disease Patients with renal impairment are readily identified by having a low estimated glomerular filtration rate (eGFR < 60 mL/min) based on their serum creatinine, age, sex and ethnic group (p. 386). This group includes a large proportion of elderly patients. If a drug (or its active metabolites) is eliminated predominantly by the kidneys, it will tend to accumulate and so the maintenance dose must be reduced. For some drugs, renal impairment makes patients more sensitive to their adverse pharmacodynamic effects. of wasted medicines and unnecessary health-care episodes. An important reason may be lack of concordance with the prescriber about the goals of treatment. A more open and shared decisionmaking process might resolve any misunderstandings at the outset and foster improved adherence, as well as improved satisfaction with health-care services and confidence in prescribers. Fully engaging patients in shared decision-making is sometimes constrained by various factors, such as limited consultation time and challenges in communicating complex numerical data. Writing the prescription The culmination of the planning described above is writing an accurate and legible prescription so that the drug will be dispensed and administered as planned (see ‘Writing prescriptions’ below). Monitoring treatment effects Rational prescribing involves monitoring for the beneficial and adverse effects of treatment so that the balance remains in favour of a positive outcome (see ‘Monitoring drug therapy’ below). 2.19 Factors influencing the timing of drug therapy Drug Recommended timing Reasons Diuretics (e.g. furosemide) Once in the morning Night-time diuresis undesirable Statins (e.g. simvastatin) Once at night HMG CoA reductase activity is greater at night Antidepressants (e.g. amitriptyline) Once at night Allows adverse effects to occur during sleep Salbutamol Before exercise Reduces symptoms in exercise-induced asthma Glyceryl trinitrate Paracetamol When required Relief of acute symptoms only Regular nitrate therapy (e.g. isosorbide mononitrate) Eccentric dosing regimen (e.g. twice daily at 8 a.m. and 2 p.m.) Reduces development of nitrate tolerance by allowing drug-free period each night Aspirin With food Minimises gastrotoxic effects Alendronate Once in the morning before breakfast, sitting upright Minimises risk of oesophageal irritation Tetracyclines 2 hours before or after food or antacids Divalent and trivalent cations chelate tetracyclines, preventing absorption Hypnotics (e.g. temazepam) Once at night Maximises therapeutic effect and minimises daytime sedation Antihypertensive drugs (e.g. amlodipine) Once in the morning Blood pressure is higher during the daytime (HMG CoA = 3-hydroxy-3-methylglutaryl-coenzyme A) 2.20 What patients need to know about their medicines* Knowledge Comment The reason for taking the medicine How the medicine works Reinforces the goals of therapy How to take the medicine May be important for the effectiveness (e.g. inhaled salbutamol in asthma) and safety (e.g. alendronate for osteoporosis) of treatment What benefits to expect May help to support adherence or prompt review because of treatment failure What adverse effects might occur Discuss common and mild effects that may be transient and might not require discontinuation Mention rare but serious effects that might influence the patient’s consent Precautions that improve safety Explain symptoms to report that might allow serious adverse effects to be averted, monitoring that will be required and potentially important drug–drug interactions When to return for review This will be important to enable monitoring *Many medicines are provided with patient information leaflets, which the patient should be encouraged to read.

32 • CLINICAL THERAPEUTICS AND GOOD PRESCRIBING Examples of drugs that require extra caution in patients with renal disease are listed in Box 2.21. Prescribing for patients with hepatic disease The liver has a large capacity for drug metabolism and hepatic insufficiency has to be advanced before drug dosages need to be modified. Patients who may have impaired metabolism include those with jaundice, ascites, hypoalbuminaemia, malnutrition or encephalopathy. Hepatic drug clearance may also be reduced in acute hepatitis, in hepatic congestion due to cardiac failure, and in the presence of intrahepatic arteriovenous shunting (e.g. in hepatic cirrhosis). There are no good tests of hepatic drugmetabolising capacity or of biliary excretion, so dosage should be guided by the therapeutic response and careful monitoring for adverse effects. The presence of liver disease also increases the susceptibility to adverse pharmacological effects of drugs. Some drugs that require extra caution in patients with hepatic disease are listed in Box 2.21. Prescribing for elderly patients The issues around prescribing in the elderly are discussed in Box 2.22. Prescribing for women who are pregnant or breastfeeding Prescribing in pregnancy should be avoided if possible to minimise the risk of adverse effects in the fetus. Drug therapy in pregnancy may, however, be required either for a pre-existing problem (e.g. epilepsy, asthma, hypothyroidism) or for problems that arise during pregnancy (e.g. morning sickness, anaemia, prevention of neural tube defects, gestational diabetes, hypertension). About 35% of women take drug therapy at least once during 2.23 Prescribing in pregnancy • Teratogenesis: a potential risk, especially when drugs are taken between 2 and 8 weeks of gestation (4–10 weeks from last menstrual period). Common teratogens include retinoids (e.g. isotretinoin), cytotoxic drugs, angiotensin-converting enzyme inhibitors, antiepileptics and warfarin. If there is inadvertent exposure, then the timing of conception should be established, counselling given and investigations undertaken for fetal abnormalities. • Adverse fetal effects in late gestation: e.g. tetracyclines may stain growing teeth and bones; sulphonamides displace fetal bilirubin from plasma proteins, potentially causing kernicterus; opioids given during delivery may be associated with respiratory depression in the neonate. • Altered maternal pharmacokinetics: extracellular fluid volume and Vd increase. Plasma albumin falls but other binding globulins (e.g. for thyroid and steroid hormones) increase. Glomerular filtration increases by approximately 70%, enhancing renal clearance. Placental metabolism contributes to increased clearance, e.g. of levothyroxine and glucocorticoids. The overall effect is a fall in plasma levels of many drugs. • In practice: Avoid any drugs unless the risk:benefit analysis is in favour of treating (usually the mother). Use drugs for which there is some record of safety in humans. Use the lowest dose for the shortest time possible. Choose the least harmful drug if alternatives are available. 2.22 Prescribing in old age • Reduced drug elimination: partly due to impaired renal function. • Increased sensitivity to drug effects: notably in the brain (leading to sedation or delirium) and as a result of comorbidities. • More drug interactions: largely as a result of polypharmacy. • Lower starting doses and slower dose titration: often required, with careful monitoring of drug effects. • Drug adherence: may be poor because of cognitive impairment, difficulty swallowing (dry mouth) and complex polypharmacy regimens. Supplying medicines in pill organisers (e.g. dosette boxes or calendar blister packs), providing automatic reminders, and regularly reviewing and simplifying the drug regimen can help. • Some drugs that require extra caution, and their mechanisms: Digoxin: increased sensitivity of Na+/K+ pump; hypokalaemia due to diuretics; renal impairment favours accumulation → increased risk of toxicity. Antihypertensive drugs: reduced baroreceptor function → increased risk of postural hypotension. Antidepressants, hypnotics, sedatives, tranquillisers: increased sensitivity of the brain; reduced metabolism → increased risk of toxicity. Warfarin: increased tendency to falls and injury and to bleeding from intra- and extracranial sites; increased sensitivity to inhibition of clotting factor synthesis → increased risk of bleeding. Clomethiazole, lidocaine, nifedipine, phenobarbital, propranolol, theophylline: metabolism reduced → increased risk of toxicity. Non-steroidal anti-inflammatory drugs: poor renal function → increased risk of renal impairment; susceptibility to gastrotoxicity → increased risk of upper gastrointestinal bleeding. 2.21 Some drugs that require extra caution in patients with renal or hepatic disease Kidney disease Liver disease Pharmacodynamic effects enhanced ACE inhibitors and ARBs (renal impairment, hyperkalaemia) Metformin (lactic acidosis) Spironolactone (hyperkalaemia) NSAIDs (impaired renal function) Sulphonylureas (hypoglycaemia) Insulin (hypoglycaemia) Warfarin (increased anticoagulation because of reduced clotting factor synthesis) Metformin (lactic acidosis) Chloramphenicol (bone marrow suppression) NSAIDs (gastrointestinal bleeding, fluid retention) Sulphonylureas (hypoglycaemia) Benzodiazepines (coma) Pharmacokinetic handling altered (reduced clearance) Aminoglycosides (e.g. gentamicin) Vancomycin Digoxin Lithium Other antibiotics (e.g. ciprofloxacin) Atenolol Allopurinol Cephalosporins Methotrexate Opioids (e.g. morphine) Phenytoin Rifampicin Propranolol Warfarin Diazepam Lidocaine Opioids (e.g. morphine) (ACE = angiotensin-converting enzyme; ARB = angiotensin receptor blocker; NSAID = non-steroidal anti-inflammatory drug) pregnancy and 6% take drug therapy during the first trimester (excluding iron, folic acid and vitamins). The most commonly used drugs are simple analgesics, antibacterial drugs and antacids. Some considerations when prescribing in pregnancy are listed in Box 2.23.

Prescribing in practice • 33

Hospital discharge (‘to take out’) medicines Most patients will be prescribed a short course of their medicines at discharge. This prescription is particularly important because it usually informs future therapy at the point of transfer of prescribing responsibility to primary care. Great care is required to ensure that this list is accurate. It is particularly important to ensure that any hospital medicines that should be stopped are not included and that those intended to be administered for a short duration only are clearly identified. It is also important for any significant ADRs experienced in hospital to be recorded and any specific monitoring or review identified. Prescribing in primary care Most of the considerations above are equally applicable to primary care (GP) prescriptions. In many health-care systems, community prescribing is electronic, making issues of legibility irrelevant and often providing basic decision support to limit the range of doses that can be written and highlight potential drug interactions. Important additional issues more relevant to GP prescribing are: • Formulation. The prescription needs to carry information about the formulation for the dispensing pharmacist (e.g. tablets or oral suspension). • Amount to be supplied. In the hospital the pharmacist will organise this. Elsewhere it must be specified either as the precise number of tablets or as the duration of treatment. Creams and ointments should be specified in grams and lotions in mL. • Controlled drugs. Prescriptions for ‘controlled’ drugs (e.g. opioid analgesics, with potential for drug abuse) are subject to additional legal requirements. In the UK, they Drugs that are excreted in breast milk may cause adverse effects in the baby. Prescribers should always consult the summary of product characteristics for each drug or a reliable formulary when treating a pregnant woman or breastfeeding mother. Writing prescriptions A prescription is a means by which a prescriber communicates the intended plan of treatment to the pharmacist who dispenses a medicine and to a nurse or patient who administers it. It should be precise, accurate, clear and legible. The two main kinds of prescription are those written, dispensed and administered in hospital and those written in primary care (in the UK by a GP), dispensed at a community pharmacy and self-administered by the patient. The information supplied must include: • the date • the identification details of the patient • the name of the drug • the formulation • the dose • the frequency of administration • the route and method of administration • the amount to be supplied (primary care only) • instructions for labelling (primary care only) • the prescriber’s signature. Prescribing in hospital Although GP prescribing is increasingly electronic, most hospital prescribing continues to be based around the prescription and administration record (the ‘drug chart’) (Fig. 2.7). A variety of charts are in use and prescribers must familiarise themselves with the local version. Most contain the following sections: • Basic patient information: will usually include name, age, date of birth, hospital number and address. These details are often ‘filled in’ using a sticky addressograph label but this increases the risk of serious error. • Previous adverse reactions/allergies: communicates important patient safety information based on a careful drug history and/or the medical record. • Other medicines charts: notes any other hospital prescription documents that contain current prescriptions being received by the patient (e.g. anticoagulants, insulin, oxygen, fluids). • Once-only medications: for prescribing medicines to be used infrequently, such as single-dose prophylactic antibiotics and other pre-operative medications. • Regular medications: for prescribing medicines to be taken for a number of days or continuously, such as a course of antibiotics, antihypertensive drugs and so on. • ‘As required’ medications: for prescribing for symptomatic relief, usually to be administered at the discretion of the nursing staff (e.g. antiemetics, analgesics). Prescribers should be aware of the risks of prescription error (Box 2.24 and see Box 2.13), ensure they have considered the rational basis for their prescribing decision described above, and then follow the guidance illustrated in Figure 2.7 in order to write the prescription. It is a basic principle that a prescription will be followed by a judgement as to its success or failure and any appropriate changes made (e.g. altered dosage, discontinuation or substitution). 2.24 High-risk prescribing moments • Trying to amend an active prescription (e.g. altering the dose/ timing) – always avoid and start again • Writing up drugs in the immediate presence of more than one prescription chart or set of notes – avoid • Allowing one’s attention to be diverted in the middle of completing a prescription – avoid • Prescribing ‘high-risk’ drugs (e.g. anticoagulants, opioids, insulin, sedatives) – ask for help if necessary • Prescribing parenteral drugs – take care • Rushing prescribing (e.g. in the midst of a busy ward round) – avoid • Prescribing unfamiliar drugs – consult the formulary and ask for help if necessary • Transcribing multiple prescriptions from an expired chart to a new one – take care to review the rationale for each medicine • Writing prescriptions based on information from another source such as a referral letter (the list may contain errors and some of the medicines may be the cause of the patient’s illness) – review the justification for each as if it is a new prescription • Writing up ‘to take out’ drugs (because these will become the patient’s regular medication for the immediate future) – take care and seek advice if necessary • Calculating drug doses – ask a colleague to perform an independent calculation or use approved electronic dose calculators • Prescribing sound-alike or look-alike drugs (e.g. chlorphenamine and chlorpromazine) – take care

34 • CLINICAL THERAPEUTICS AND GOOD PRESCRIBING Fig. 2.7 Example of a hospital prescription and administration record (‘drug chart’). A Front page. The correct identification of the patient is critical to reducing the risk of an administration error. This page also clearly identifies other prescriptions charts in use and previous adverse reactions to drugs to minimise the risk of repeated exposure. Note also the codes employed by the nursing staff to indicate reasons why drugs may not have been administered. The patient’s name and date of birth should be written on each page of the chart. The patient’s weight and height may be required to calculate safe doses for many drugs with narrow therapeutic indices. B ‘Once-only medicines’. This area is used for prescribing medicines that are unlikely to be repeated on a regular basis. Note that the prescriber has written the names of all drugs legibly in block capitals. The generic international non-proprietary name (INN) should be used in preference to the brand name (e.g. write ‘SIMVASTATIN’, not ‘ZOCOR’). The only exceptions are when variation occurs in the properties of alternative branded formulations (e.g. modified-release preparations of drugs such as lithium, theophylline, phenytoin and nifedipine) or when the drug is a combination product with no generic name (e.g. Kliovance). The only acceptable abbreviations for drug dose units are ‘g’ and ‘mg’. ‘Units’ (e.g. of insulin or heparin) and ‘micrograms’ must always be written in full, never as ‘U’ or ‘μg’ (nor ‘mcg’, nor ‘ug’). For liquid preparations write the dose in mg; ‘mL’ can be written only for a combination product (e.g. Gaviscon liquid) or if the strength is not expressed in weight (e.g. adrenaline (epinephrine) 1 in 1000). Use numbers/figures (e.g. 1 or ‘one’) to denote use of a sachet/enema but avoid prescribing numbers of tablets without specifying their strength. Always include the dose of inhaled drugs in addition to stating numbers of ‘puffs’, as strengths can vary. Widely accepted abbreviations for route of administration are: intravenous – ‘IV’; intramuscular – ‘IM’; subcutaneous – ‘SC’; sublingual – ‘SL’; per rectum – ‘PR’; per vaginam – ‘PV’; nasogastric – ‘NG’; inhaled – ‘INH’; and topical – ‘TOP’. ‘ORAL’ is preferred to per oram – ‘PO’. Care should be taken in specifying ‘RIGHT’ or ‘LEFT’ for eye and ear drops. The prescriber should sign and print their name clearly so that they can be identified by colleagues. The prescription should be dated and have an administration time. The nurse who administered the prescription has signed to confirm that the dose has been administered. OTHER MEDICINES CHARTS CODES FOR NON-ADMINISTRATION OF PRESCRIBED MEDICINE PREVIOUS ADVERSE REACTIONS (This must be completed before prescribing on this chart) Hospital/Ward: Consultant: Name of patient: Hospital number: (Attach printed label here) D.O.B.: Weight: Date Date Time Medicine (approved name) Dose Route Time given Given by Prescriber – sign and print If a dose is not administered as prescribed, intial and enter a code in the column with a circle drawn round the code according to the reason as shown below. Inform the responsible doctor of the appropriate timescale.

  1. Patient refuses
  2. Patient not present
  3. Medicines not available – CHECK ORDERED
  4. Asleep/drowsy
  5. Administration route not available – CHECK FOR ALTERNATIVE
  6. Vomiting/nausea
  7. Time varied on doctor’s instructions
  8. Once-only/as-required medicine given
  9. Dose withheld on doctor’s instructions
  10. Possible adverse reaction/side-effect Type of chart Medicine Description of reaction Completed by Date Height: If rewritten, date: DISCHARGE PRESCRIPTION PRESCRIPTION AND ADMINISTRATION RECORD Standard Chart ONCE-ONLY MEDICINES Date completed:– Completed by:– A B must contain the address of the patient and prescriber (not necessary on most hospital forms), the form and the strength of the preparation, and the total quantity of the preparation/number of dose units in both words and figures. • ‘Repeat prescriptions’. A large proportion of GP prescribing involves ‘repeat prescriptions’ for chronic medication. These are often generated automatically, although the prescriber remains responsible for regular review and for ensuring that the benefit-to-harm ratio remains favourable. Monitoring drug therapy Prescribers should measure the effects of the drug, both beneficial and harmful, to inform decisions about dose titration (up or down), discontinuation or substitution of treatment. Monitoring can be achieved subjectively by asking the patient about symptoms or, more objectively, by measuring a clinical effect. Alternatively, if the pharmacodynamic effects of the drug are difficult to assess, the plasma drug concentration may be measured, on the basis that it will be closely related to the effect of the drug (see Fig. 2.2).

Prescribing in practice • 35

REGULAR MEDICINES AS-REQUIRED THERAPY C D Drug (approved name) Dose Date Time

Prescriber–sign and print Notes Start date Pharmacy Route Drug (approved name) Dose Prescriber–sign and print Notes Start date Pharmacy Route Drug (approved name) Dose and frequency Prescriber–sign and print Start date Indication/notes Pharmacy Route Date Time Dose Initials Date Time Dose Initials Drug (approved name) Dose and frequency Prescriber–sign and print Start date Indication/notes Pharmacy Route Date Time Dose Initials Date Time Dose Initials Drug (approved name) Dose Prescriber–sign and print Notes Start date Pharmacy Route C ‘Regular medicines’. This area is used for prescribing medicines that are going to be given regularly. In addition to the name, dose and route, a frequency of administration is required for each medicine. Widely accepted Latin abbreviations for dose frequency are: once daily – ‘OD’; twice daily – ‘BD’; 3 times daily – ‘TDS’; 4 times daily – ‘QDS’; as required – ‘PRN’; in the morning – ‘OM’ (omni mane); at night – ‘ON’ (omni nocte); and immediately – ‘stat’. The hospital chart usually requires specific times to be identified for regular medicines that coincide with nursing drug rounds and these can be circled. If treatment is for a known time period, cross off subsequent days when the medicine is not required. The ‘notes’ box can be used to communicate additional important information (e.g. whether a medicine should be taken with food, type of inhaler device used, and anything else that the drug dispenser should know). State here the times for peak/trough plasma levels for drugs requiring therapeutic monitoring. Prescriptions should be discontinued by drawing a vertical line at the point of discontinuation, horizontal lines through the remaining days on the chart, and diagonal lines through the drug details and administration boxes. This action should be signed and dated and a supplementary note written to explain it (e.g. describing any adverse effect). In this example, amlodipine has been discontinued because of ankle oedema. There is room for the ward pharmacist to sign to indicate that the prescription has been reviewed and that a supply of the medicine is available. The administration boxes allow the nurse to sign to confirm that the dose has been given. Note that these boxes also allow for recording of reasons for non-administration (in this example ‘2’ indicates that the patient was not present on the ward at the time) and the prevention of future administration by placing an ‘X’ in the box. D ‘As-required medicines’. These prescriptions leave the administration of the drug to the discretion of the nursing staff. The prescription must describe clearly the indication, frequency, minimal time interval between doses, and maximum dose in any 24-hour period (in this case, the maximum daily dose of paracetamol is 4 g). Fig. 2.7, cont’d Clinical and surrogate endpoints Ideally, clinical endpoints are measured directly and the drug dosage titrated to achieve the therapeutic goal and avoid toxicity (e.g. control of ventricular rate in a patient with atrial fibrillation). Sometimes this is impractical because the clinical endpoint is a future event (e.g. prevention of myocardial infarction by statins or resolution of a chest infection with antibiotics); in these circumstances, it may be possible to select a ‘surrogate’ endpoint that will predict success or failure. This may be an intermediate step in the pathophysiological process (e.g. serum cholesterol as a surrogate for risk of myocardial infarction) or a

36 • CLINICAL THERAPEUTICS AND GOOD PRESCRIBING Interpreting the result A target range is provided for many drugs, based on average thresholds for therapeutic benefit and toxicity. Inter-individual variability means that these can be used only as a guide. For instance, in a patient who describes symptoms that could be consistent with toxicity but has a drug concentration in the top half of the target range, toxic effects should still be suspected. Another important consideration is that some drugs are heavily protein-bound (e.g. phenytoin) but only the unbound drug is pharmacologically active. Patients with hypoalbuminaemia may therefore have a therapeutic or even toxic concentration of unbound drug, despite a low ‘total’ concentration. Further information Websites bnf.org The British National Formulary (BNF) is a key reference resource for UK NHS prescribers, with a list of licensed drugs, chapters on prescribing in renal failure, liver disease, pregnancy and during breastfeeding, and appendices on drug interactions. cochrane.org The Cochrane Collaboration is a leading international body that provides evidence-based reviews (around 7000 so far). evidence.nhs.uk NHS Evidence provides a wide range of health information relevant to delivering quality patient care. icp.org.nz The Interactive Clinical Pharmacology site is designed to increase understanding of principles in clinical pharmacology. medicines.org.uk/emc/ The electronic Medicines Compendium (eMC) contains up-to-date, easily accessible information about medicines licensed by the UK Medicines and Healthcare Products Regulatory Agency (MHRA) and the European Medicines Agency (EMA). nice.org.uk The UK National Institute for Health and Care Excellence makes recommendations to the UK NHS on new and existing medicines, treatments and procedures. who.int/medicines/en/ The World Health Organisation Essential Medicines and Pharmaceutical Policies. measurement that follows the pathophysiology, even if it is not a key factor in its progression (e.g. serum C-reactive protein as a surrogate for resolution of inflammation in chest infection). Such surrogates are sometimes termed ‘biomarkers’. Plasma drug concentration The following criteria must be met to justify routine monitoring by plasma drug concentration: • Clinical endpoints and other pharmacodynamic (surrogate) effects are difficult to monitor. • The relationship between plasma concentration and clinical effects is predictable. • The therapeutic index is low. For drugs with a high therapeutic index, any variability in plasma concentrations is likely to be irrelevant clinically. Some examples of drugs that fulfil these criteria are listed in Box 2.25. Measurement of plasma concentration may be useful in planning adjustments of drug dose and frequency of administration; to explain an inadequate therapeutic response (by identifying subtherapeutic concentration or incomplete adherence); to establish whether a suspected ADR is likely to be caused by the drug; and to assess and avoid potential drug interactions. Timing of samples in relation to doses The concentration of drug rises and falls during the dosage interval (see Fig. 2.4B). Measurements made during the initial absorption and distribution phases are unpredictable because of the rapidly changing concentration, so samples are usually taken at the end of the dosage interval (a ‘trough’ or ‘pre-dose’ concentration). This measurement is normally made in steady state, which usually takes five half-lives to achieve after the drug is introduced or the dose changed (unless a loading dose has been given). 2.25 Drugs commonly monitored by plasma drug concentration Drug Half-life (hrs)* Comment Digoxin

Steady state takes several days to achieve. Samples should be taken 6 hrs post dose. Measurement is useful to confirm the clinical impression of toxicity or non-adherence but clinical effectiveness is better assessed by ventricular heart rate. Risk of toxicity increases progressively at concentrations > 1.5 μg/L, and is likely at concentrations > 3.0 μg/L (toxicity is more likely in the presence of hypokalaemia) Gentamicin

Measure pre-dose trough concentration (should be < 1 μg/mL) to ensure that accumulation (and the risk of nephrotoxicity and ototoxicity) is avoided; see Fig. 6.18 (p. 122) Levothyroxine

120 Steady state may take up to 6 weeks to achieve (p. 640) Lithium

Steady state takes several days to achieve. Samples should be taken 12 hrs post dose. Target range 0.4–1 mmol/L Phenytoin

Measure pre-dose trough concentration (should be 10–20 mg/L) to ensure that accumulation is avoided. Good correlation between concentration and toxicity. Concentration may be misleading in the presence of hypoalbuminaemia Theophylline (oral)

Steady state takes 2–3 days to achieve. Samples should be taken 6 hrs post dose. Target concentration is 10–20 mg/L but its relationship with bronchodilator effect and adverse effects is variable Vancomycin

Measure pre-dose trough concentration (should be 10–15 mg/L) to ensure clinical efficacy and that accumulation and the risk of nephrotoxicity are avoided (p. 123) *Half-lives vary considerably with different formulations and between patients.

Ch02-1 Fundamentals of Medicine

03-3 Clinical genetics

3 Clinical genetics

Clinical genetics K Tatton-Brown DR FitzPatrick The fundamental principles of genomics 38 The packaging of genes: DNA, chromatin and chromosomes 38 From DNA to protein 38 Non-coding RNA 40 Cell division, differentiation and migration 40 Cell death, apoptosis and senescence 41 Genomics, health and disease 42 Classes of genetic variant 42 Consequences of genomic variation 44 Normal genomic variation 45 Constitutional genetic disease 46 Somatic genetic disease 50 Interrogating the genome: the changing landscape of genomic technologies 51 Looking at chromosomes 51 Looking at genes 52 Genomics and clinical practice 56 Genomics and health care 56 Treatment of genetic disease 58 Ethics in a genomic age 59

38 • CLINICAL GENETICS via the production of messenger ribonucleic acid (mRNA) to the production of proteins. The human genome contains over 20 000 genes, although many of these are inactive or silenced in different cell types, reflecting the variable gene expression responsible for cell-specific characteristics. The central dogma is the pathway describing the basic steps of protein production: transcription, splicing, translation and protein modification (Fig. 3.2). Although this is now recognised as an over-simplification (contrary to this linear relationship, a single gene will often encode many different proteins), it remains a useful starting point to explore protein production. Transcription: DNA to messenger RNA Transcription describes the production of ribonucleic acid (RNA) from the DNA template. For transcription to commence, an enzyme called RNA polymerase binds to a segment of DNA at the start of the gene: the promoter. Once bound, RNA polymerase moves along one strand of DNA, producing an RNA molecule complementary to the DNA template. In protein-coding genes this is known as messenger RNA (mRNA). A DNA sequence close to the end of the gene, called the polyadenylation signal, acts as a signal for termination of the RNA transcript (Fig. 3.3). We have entered a genomic era. Powerful new technologies are driving forward transformational change in health care. Genetic sequencing has evolved from the targeted sequencing of a single gene to the parallel sequencing of multiple genes. In addition to improving the chances of identifying a genetic cause of rare diseases, these technologies are increasingly directing therapies and, in the future, are likely to be used in the diagnosis and prevention of common diseases such as diabetes. In this chapter we explore the fundamentals of genomics, the basic principles underlying these new genomic technologies and how the data generated can be applied safely for patient benefit. We will review the use of genomic technology across a breadth of medical specialties, including obstetrics, paediatrics, oncology and infectious disease, and consider how health care is likely to be transformed by technology over the coming decade. Finally, we will consider the ethical impact that these technologies are likely to have, both for the individual and for their wider family. The fundamental principles of genomics The packaging of genes: DNA, chromatin and chromosomes Genes are functional units encoded in double-stranded deoxyribonucleic acid (DNA), packaged as chromosomes and located in the nucleus of the cell: a membrane-bound compartment found in all cells except erythrocytes and platelets (Fig. 3.1). DNA consists of a linear sequence of just four bases: adenine (A,) cytosine (C), thymine (T) and guanine (G.) It forms a ‘double helix’, a twisted ladder-like structure formed from two complementary strands of DNA joined by hydrogen bonds between bases on the opposite strand that can form only between a C and a G base and an A and a T base. It is this feature of DNA that enables faithful DNA replication and is the basis for many of the technologies designed to interrogate the genome: when the DNA double helix ‘unzips’, one strand can act as a template for the creation of an identical strand. A single copy of the human genome comprises approximately 3.1 billion base pairs of DNA, wound around proteins called histones. The unit consisting of 147 base pairs wrapped around four different histone proteins is called the nucleosome. Sequences of nucleosomes (resembling a string of beads) are wound and packaged to form chromatin: tightly wound, densely packed chromatin is called heterochromatin and open, less tightly wound chromatin is called euchromatin. The chromatin is finally packaged into the chromosomes. Humans are diploid organisms: the nucleus contains two copies of the genome, visible microscopically as 23 chromosome pairs (known as the karyotype). Chromosomes 1 through to 22 are known as the autosomes and consist of identical chromosomal pairs. The 23rd ‘pair’ of chromosomes are the two sex chromosomes: females have two X chromosomes and males an X and Y chromosome. A normal female karyotype is therefore written as 46,XX and a normal male is 46,XY. From DNA to protein Genes are functional elements on the chromosome that are capable of transmitting information from the DNA template Fig. 3.1 The packaging of DNA, genes and chromosomes. From bottom to top: the double helix and the complementary DNA bases; chromatin; and a normal female chromosome pattern – the karyotype. DNA helix Histones Chromatin Chromosome Normal female karyotype Nucleosome A T G A C G G A T T A C T G C C T A

The fundamental principles of genomics • 39

Fig. 3.2 The central dogma of protein production. Double-stranded DNA as a template for single-stranded RNA, which codes for the production of a peptide chain of amino acids. Each of these chains has an orientation. For DNA and RNA, this is 5′ to 3′. For peptides, this is N-terminus to C-terminus. DNA 5’CGATTC3’ 3’GCTAAG5’ 5’CGAUUC3’ N_ArgPhe_C RNA Protein Transcription Translation Fig. 3.3 RNA synthesis and its translation into protein. Gene transcription involves binding of RNA polymerase II to the promoter of genes being transcribed with other proteins (transcription factors) that regulate the transcription rate. The primary RNA transcript is a copy of the whole gene and includes both introns and exons, but the introns are removed within the nucleus by splicing and the exons are joined to form the messenger RNA (mRNA). Prior to export from the nucleus, a methylated guanosine nucleotide is added to the 5′ end of the RNA (‘cap’) and a string of adenine nucleotides is added to the 3′ (‘polyA tail’). This protects the RNA from degradation and facilitates transport into the cytoplasm. In the cytoplasm, the mRNA binds to ribosomes and forms a template for protein production. (tRNA = transfer RNA; UTR = untranslated region) Protein product N-term C-term cap Messenger RNA (mRNA) Messenger RNA (mRNA) AAAAA tRNAs Ribosome Nuclear membrane Primary RNA transcript Spliceosome RNA export to cytoplasm cap cap AAAAA PolyA tail 3'UTR 5'UTR Nuclear pore AAAAA Splicing Transcription 3' 5' 3' Sense strand Enhancer Transcription factors RNA polymerase II Exon 1 Intron 2 Intron 1 Exon 2 Exon 3 Exon 1 Exon 2 Exon 3 Promoter Nucleolus Nuclear membrane Gene A Gene B Gene C Active gene RNA Nucleus Translation RNA differs from DNA in three main ways: • RNA is single-stranded. • The sugar residue within the nucleotide is ribose, rather than deoxyribose. • It contains uracil (U) in place of thymine (T). The activity of RNA polymerase is regulated by transcription factors. These proteins bind to specific DNA sequences at the promoter or to enhancer elements that may be many thousands of base pairs away from the promoter; a loop in the chromosomal DNA brings the enhancer close to the promoter, enabling the bound proteins to interact. The human genome encodes more than 1200 different transcription factors. Mutations within transcription factors, promoters and enhancers can cause disease. For example, the blood disorder alpha-thalassaemia is usually caused by gene deletions (see p. 954 and Box 3.4). However, it can also result from a mutation in an enhancer located more than 100 000 base pairs (bp) from the α-globin gene promoter, leading to greatly reduced transcription. Gene activity, or expression, is influenced by a number of complex interacting factors, including the accessibility of the gene promoter to transcription factors. DNA can be modified by the addition of a methyl group to cytosine molecules (methylation). If DNA methylation occurs in promoter regions, transcription is silenced, as methyl cytosines are usually not available for transcription factor binding. A second mechanism determining promoter accessibility is the structural configuration of chromatin. In open chromatin, called euchromatin, gene promoters are accessible to RNA polymerase and transcription factors; therefore it is transcriptionally active. This contrasts with heterochromatin, which is densely packed and transcriptionally silent. The chromatin configuration is determined by modifications (such as methylation or acetylation) of specific amino acid residues of histone protein tails. Modifications of DNA and histones are termed epigenetic (‘epi-’ meaning ‘above’ the genome), as they do not alter the primary sequence of the DNA code but have biological significance in chromosomal function. Abnormal epigenetic changes are increasingly recognised as important events in the progression of cancer, allowing expression of normally silenced genes that result in cancer cell de-differentiation and proliferation. They also afford therapeutic targets. For instance, the histone deacetylase inhibitor vorinostat has been successfully used to treat cutaneous T-cell lymphoma, due to the re-expression of genes that had

40 • CLINICAL GENETICS into the cytoplasm or packaged into vesicles for secretion. The clinical importance of post-translational modification of proteins is shown by the severe developmental, neurological, haemostatic and soft tissue abnormalities that are associated with the many different congenital disorders of glycosylation. Post-translational modifications can also be disrupted by the synthesis of proteins with abnormal amino acid sequences. For example, the most common mutation in cystic fibrosis (ΔF508) results in an abnormal protein that cannot be exported from the ER and Golgi (see Box 3.4). Non-coding RNA Approximately 4500 genes in humans encode non-coding RNAs (ncRNA) rather than proteins. There are various categories of ncRNA, including transfer RNA (tRNA), ribosomal RNA (rRNA), ribozymes and microRNA (miRNA). The miRNAs, which number over 1000, have a role in post-translational gene expression: they bind to mRNAs, typically in the 3′UTR, promoting target mRNA degradation and gene silencing. Together, miRNAs affect over half of all human genes and have important roles in normal development, cancer and common degenerative disorders. This is the subject of considerable research interest at present. Cell division, differentiation and migration In normal tissues, molecules such as hormones, growth factors and cytokines provide the signal to activate the cell cycle: a controlled programme of biochemical events that culminates in cell division. In all cells of the body, except the gametes (the sperm and egg cells, also known as the germ line), mitosis completes cell division, resulting in two diploid daughter cells. In contrast, the sperm and eggs cells complete cell division with meiosis, resulting in four haploid daughter cells (Fig. 3.4). The stages of cell division in the non-germ-line, somatic cells are shown below: • Cells not committed to mitosis are said to be in G0. • Cells committed to mitosis must go through the preparatory phase of interphase consisting of G1, S and G2: • G1 (first gap): synthesis of the cellular components necessary to complete cell division • S (synthesis): DNA replication producing identical copies of each chromosome called the sister chromatids • G2 (second gap): repair of any errors in the replicated DNA before proceeding to mitosis. • Mitosis (M) consists of four phases: • Prophase: the chromosomes condense and become visible, the centrioles move to opposite ends of the cell and the nuclear membrane disappears. • Metaphase: the centrioles complete their migration to opposite ends of the cell and the chromosomes – consisting of two identical sister chromatids – line up at the equator of the cell. • Anaphase: spindle fibres attach to the chromosome and pull the sister chromatids apart. • Telophase: the chromosomes decondense, the nuclear membrane reforms and two daughter cells – each with 46 chromosomes – are formed. The progression from one phase to the next is tightly controlled by cell-cycle checkpoints. For example, the checkpoint between previously been silenced in the tumour. These genes encode transcription factors that promote T-cell differentiation as opposed to proliferation, thereby causing tumour regression. RNA splicing, editing and degradation Transcription produces an RNA molecule that is a copy of the whole gene, termed the primary or nascent transcript. This nascent transcript then undergoes splicing, whereby regions not required to make protein (the intronic regions) are removed while those segments that are necessary for protein production (the exonic regions) are retained and rejoined. Splicing is a highly regulated process that is carried out by a multimeric protein complex called the spliceosome. Following splicing, the mRNA molecule is exported from the nucleus and used as a template for protein synthesis. Many genes produce more than one form of mRNA (and thus protein) by a process termed alternative splicing, in which different combinations of exons are joined together. Different proteins from the same gene can have entirely distinct functions. For example, in thyroid C cells the calcitonin gene produces mRNA encoding the osteoclast inhibitor calcitonin (p. 634), but in neurons the same gene produces an mRNA with a different complement of exons via alternative splicing that encodes a neurotransmitter, calcitonin-gene-related peptide (p. 772). Translation and protein production Following splicing, the segment of mRNA containing the code that directs synthesis of a protein product is called the open reading frame (ORF). The inclusion of a particular amino acid in the protein is specified by a codon composed of three contiguous bases. There are 64 different codons with some redundancy in the system: 61 codons encode one of the 20 amino acids, and the remaining three codons – UAA, UAG and UGA (known as stop codons) – cause termination of the growing polypeptide chain. ORFs in humans most commonly start with the amino acid methionine. All mRNA molecules have domains before and after the ORF called the 5′ untranslated region (UTR) and 3′UTR, respectively. The start of the 5′UTR contains a cap structure that protects mRNA from enzymatic degradation, and other elements within the 5′UTR are required for efficient translation. The 3′UTR also contains elements that regulate efficiency of translation and mRNA stability, including a stretch of adenine bases known as a polyA tail (see Fig. 3.3). The mRNAs then leave the nucleus via nuclear pores and associate with ribosomes, the sites of protein production (see Fig. 3.3). Each ribosome consists of two subunits (40S and 60S), which comprise non-coding rRNA molecules (see Fig. 3.9, p. 50) complexed with proteins. During translation, a different RNA molecule known as transfer RNA (tRNA) binds to the ribosome. The tRNAs deliver amino acids to the ribosome so that the newly synthesised protein can be assembled in a stepwise fashion. Individual tRNA molecules bind a specific amino acid and ‘read’ the mRNA ORF via an ‘anticodon’ of three nucleotides that is complementary to the codon in mRNA (see Fig. 3.3). A proportion of ribosomes is bound to the membrane of the endoplasmic reticulum (ER), a complex tubular structure that surrounds the nucleus. Proteins synthesised on these ribosomes are translocated into the lumen of the ER, where they undergo folding and processing. From here, the protein may be transferred to the Golgi apparatus, where it undergoes post-translational modifications, such as glycosylation (covalent attachment of sugar moieties), to form the mature protein that can be exported

The fundamental principles of genomics • 41

(prophase, metaphase, anaphase and telophase) but differs from mitosis in the following ways: • It consists of two separate cell divisions known as meiosis I and meiosis II. • It reduces the chromosome number from the diploid to the haploid number via a tetraploid stage, i.e. from 46 to 92 (MI S) to 46 (MI M) to 23 (MII M) chromosomes, so that when a sperm cell fertilises the egg, the resulting zygote will return to a diploid, 46, chromosome complement. This reduction to the haploid number occurs at the end of meiosis II. • The 92 chromosome stage consists of 23 homologous pairs of sister chromatids, which then swap genetic material, a process known as recombination. This occurs at the end of MI prophase and ensures that the chromosome that a parent passes to his or her offspring is a mix of the chromosomes that the parent inherited from his or her own mother and father. The individual steps in meiotic cell division are similar in males and females. However, the timing of the cell divisions is very different. In females, meiosis begins in fetal life but does not complete until after ovulation. A single meiotic cell division can thus take more than 40 years to complete. As women become older, the separation of chromosomes at meiosis II becomes less efficient. That is why the risk of trisomies (p. 44) due to non-disjunction grows greater with increasing maternal age. In males, meiotic division does not begin until puberty and continues throughout life. In the testes, both meiotic divisions are completed in a matter of days. Cell death, apoptosis and senescence With the exception of stem cells, human cells have only a limited capacity for cell division. The Hayflick limit is the number of divisions a cell population can go through in culture before division stops and enters a state known as senescence. This ‘biological clock’ is of great interest in the study of the normal ageing process. Rare human diseases associated with premature ageing, called progeric syndromes, have been very helpful in identifying the importance of DNA repair mechanisms in senescence (p. 1034). For example, in Werner’s syndrome, a DNA helicase (an enzyme that separates the two DNA strands) is mutated, leading to failure of DNA repair and premature ageing. A distinct mechanism of cell death is seen in apoptosis, or programmed cell death. Apoptosis is an active process that occurs in normal tissues and plays an important role in development, tissue remodelling and the immune response. The signal that triggers apoptosis is specific to each tissue or cell type. This signal activates enzymes, called caspases, which actively destroy cellular components, including chromosomal DNA. This degradation results in cell death, but the cellular corpse contains characteristic vesicles called apoptotic bodies. The corpse is then recognised and removed by phagocytic cells of the immune system, such as macrophages, in a manner that does not provoke an inflammatory response. A third mechanism of cell death is necrosis. This is a pathological process in which the cellular environment loses one or more of the components necessary for cell viability. Hypoxia is probably the most common cause of necrosis. Fig. 3.4 Meiosis and gametogenesis: the main chromosomal stages of meiosis in both males and females. A single homologous pair of chromosomes is represented in different colours. The final step is the production of haploid germ cells. Each round of meiosis in the male results in four sperm cells; in the female, however, only one egg cell is produced, as the other divisions are sequestered on the periphery of the mature egg as peripheral polar bodies. Egg Sperm Father Mother Meiotic cell divisions 1st polar bodies 2nd polar body DNA replication Sister chromatids Homologous pairing Swapping of genetic material between homologues: Recombination Individual chromosome pair (homologues) Non-disjunction of chromosomes is a common error in human meiosis, resulting in trisomy of individual chromosomes or uniparental disomy (both chromosomes from single parent) G2 and mitosis ensures that all damaged DNA is repaired prior to segregation of the chromosomes. Failure of these control processes is a crucial driver in the pathogenesis of cancer, as discussed on page 1316. • Meiosis is a special, gamete-specific, form of cell division (Fig. 3.4). Like mitosis, meiosis consists of four phases

42 • CLINICAL GENETICS mutation (Box 3.1 and Fig. 3.5). If a multiple of three nucleotides is involved, this is in-frame. If an indel change affects one or two nucleotides within the ORF of a protein-coding gene, this can have serious consequences because the triple nucleotide sequence of the codons is disrupted, resulting in a frameshift mutation. The effect on the gene is typically severe because the amino acid sequence is totally disrupted. Fig. 3.5 Different types of mutation affecting coding exons. A Normal sequence. B A synonymous nucleotide substitution changing the third base of a codon; the resulting amino acid sequence is unchanged. C A missense mutation in which the nucleotide substitution results in a change in a single amino acid from the normal sequence (AAG) encoding lysine to glutamine (CAG). D Insertion of a G residue (boxed) causes a frameshift mutation, completely altering the amino acid sequence downstream. This usually results in a loss-of-function mutation. E A nonsense mutation resulting in a single nucleotide change from a lysine codon (AAG) to a premature stop codon (TAG). Normal Silent polymorphism (no amino acid change) Missense mutation causing Lys–Gln amino acid change ‘G’ insertion causing frameshift mutation Nonsense mutation causing premature termination codon A B C D E 3.1 Classes of genetics variant The classes of genetic variant can be illustrated using the sentence ‘THE FAT FOX WAS ILL COS SHE ATE THE OLD CAT’ Synonymous Silent polymorphism with no amino acid change THE FAT FOX WAS ILL COS SHE ATE THE OLD KAT where the C is replaced with a K but the meaning remains the same Non-synonymous Causing an amino acid change THE FAT BOX WAS ILL COS SHE ATE THE OLD CAT where the F of FOX is replaced by a B and the original meaning of the sentence is lost Stop gain (also called a nonsense mutation) Causing the generation of a premature stop codon THE CAT where the F of FAT is replaced by a C generating a premature stop codon Indel Where bases are either inserted or deleted; disruption of the reading frame is dependent on the number of bases inserted or deleted THE FAT FOX WAS ILL ILL COS SHE ATE THE OLD CAT where the insertion of three bases results in maintenance of the reading frame THE FAT FOX WAW ASI LLC OSS HEA TET HEO LDC AT where the insertion of two bases results in disruption of the reading frame Genomics, health and disease Classes of genetic variant There are many different classes of variation in the human genome, categorised by the size of the DNA segment involved and/or by the mechanism giving rise to the variation. Nucleotide substitutions The substitution of one nucleotide for another is the most common type of genomic variation. Depending on their frequency and functional consequences, these changes are known as point mutations or single nucleotide polymorphisms (SNPs). They occur by misincorporation of a nucleotide during DNA synthesis or by chemical modification of the base. When these substitutions occur within ORFs of a protein-coding gene, they are further classified into: • synonymous – resulting in a change in the codon without altering the amino acid • non-synonymous (also known as a missense mutation) – resulting in a change in the codon and the encoded amino acid • stop gain (or nonsense mutation) – introducing a premature stop codon and resulting in truncation of the protein • splicing – taking place at splice sites that most frequently occur at the junction between an intron and an exon. These different types of mutation are illustrated in Box 3.1 and examples are shown in Figures 3.5 and 3.6. Insertions and deletions One or more nucleotides may be inserted or lost in a DNA sequence, resulting in an insertion/deletion (indel) polymorphism or

Genomics, health and disease • 43

size of the original repeat, in that longer repeats tend to be more unstable. Many microsatellites and minisatellites occur in introns or in chromosomal regions between genes and have no obvious adverse effects. However, some genetic diseases are caused by microsatellite repeats that result in duplication of amino acids within the affected gene product or affect gene expression (Box 3.2). Simple tandem repeat mutations Variations in the length of simple tandem repeats of DNA are thought to arise as the result of slippage of DNA during meiosis and are termed microsatellite (small) or minisatellite (larger) repeats. These repeats are unstable and can expand or contract in different generations. This instability is proportional to the Fig. 3.6 Splice site mutations. A The normal sequence is shown, illustrating two exons, and intervening intron (blue) with splice donor (AG) and splice acceptor sites (GT) underlined. Normally, the intron is removed by splicing to give the mature messenger RNA that encodes the protein. B In a splice site mutation the donor site is mutated. As a result, splicing no longer occurs, leading to read-through of the mRNA into the intron, which contains a premature termination codon downstream of the mutation. Normal Splice site mutation Splice donor site Exon Exon Intron Exon Exon Intron Intron removed by splicing Splice acceptor site mRNA ‘reads through’ intron Abnormal protein with premature stop codon A B 3.2 Diseases associated with triplet and other repeat expansions* Repeat No. of repeats Gene Gene location Inheritance Normal Mutant Coding repeat expansion Huntington’s disease [CAG] 6–34

35 Huntingtin 4p16 AD Spinocerebellar ataxia (type 1) [CAG] 6–39 40 Ataxin 6p22–23 AD Spinocerebellar ataxia (types 2, 3, 6, 7) [CAG] Various Various Various Various AD Dentatorubral-pallidoluysian atrophy [CAG] 7–25 49 Atrophin 12p12–13 AD Machado–Joseph disease [CAG] 12–40 67 MJD 14q32 AD Spinobulbar muscular atrophy [CAG] 11–34 40 Androgen receptor Xq11–12 XL recessive Non-coding repeat expansion Myotonic dystrophy [CTG] 5–37 50 DMPK-3′UTR 19q13 AD Friedreich’s ataxia [GAA] 7–22 200 Frataxin-intronic 9q13 AR Progressive myoclonic epilepsy [CCCCGCCCCGCG]4–8 2–3 25 Cystatin B-5′UTR 21q AR Fragile X mental retardation [CGG] 5–52 200 FMR1–5′UTR Xq27 XL dominant Fragile site mental retardation 2 (FRAXE) [GCC] 6–35 200 FMR2 Xq28 XL, probably recessive *The triplet repeat diseases fall into two major groups: those with disease stemming from expansion of [CAG]n repeats in coding DNA, resulting in multiple adjacent glutamine residues (polyglutamine tracts), and those with non-coding repeats. The latter tend to be longer. Unaffected parents usually display ‘pre-mutation’ allele lengths that are just above the normal range. (AD/AR = autosomal dominant/recessive; UTR = untranslated region; XL = X-linked)

44 • CLINICAL GENETICS Copy number variations Variation in the number of copies of an individual segment of the genome from the usual diploid (two copies) content can be categorised by the size of the segment involved. Rarely, individuals may gain (trisomy) or lose (monosomy) a whole chromosome. Such numerical chromosome anomalies most commonly occur by a process known as non-disjunction, where pairs of homologous chromosomes do not separate at meiosis II (p. 40). Common trisomies include Down’s syndrome (trisomy 21), Edward’s syndrome (trisomy 18) and Patau’s syndrome (trisomy 13). Monosomy of the autosomes (present in all the cells, as opposed to in a mosaic distribution) does not occur but Turner’s syndrome, in which there is monosomy for the X chromosome, affects approximately 1 in 2500 live births (Box 3.3). Large insertions or deletions of chromosomal DNA also occur and are usually associated with a learning disability and/or congenital malformations. Such structural chromosomal anomalies usually arise as the result of one of two different processes: • non-homologous end-joining • non-allelic homologous recombination. Random double-stranded breaks in DNA are a necessary process in meiotic recombination and also occur during mitosis at a predictable rate. The rate of these breaks is dramatically increased by exposure to ionising radiation. When such breaks take place, they are usually repaired accurately by DNA repair mechanisms within the cell. However, in a proportion of breaks, segments of DNA that are not normally contiguous will be joined (‘non-homologous end-joining’). If the joined fragments are from different chromosomes, this results in a translocation. If they are 3.3 Chromosome and contiguous gene disorders Disease Locus Incidence Clinical features Numerical chromosomal abnormalities Down’s syndrome (trisomy 21) 47,XY,+21 or 47,XX+21 1 in 800 Characteristic facies, IQ usually < 50, congenital heart disease, reduced life expectancy Edwards’ syndrome (trisomy 18) 47,XY,+18 or 47,XX,+18 1 in 6000 Early lethality, characteristic skull and facies, frequent malformations of heart, kidney and other organs Patau’s syndrome (trisomy 13) 47,XY,+13 or 47, XX,+13 1 in 15 000 Early lethality, cleft lip and palate, polydactyly, small head, frequent congenital heart disease Klinefelter’s syndrome 47,XXY 1 in 1000 Phenotypic male, infertility, gynaecomastia, small testes (p. 660) XYY 47,XYY 1 in 1000 Usually asymptomatic, some impulse control problems Triple X syndrome 47,XXX 1 in 1000 Usually asymptomatic, may have reduced IQ Turner’s syndrome 45,X 1 in 5000 Phenotypic female, short stature, webbed neck, coarctation of the aorta, primary amenorrhoea (p. 659) Recurrent deletions, microdeletions and contiguous gene defects Di George/velocardiofacial syndrome 22q11.2 1 in 4000 Cardiac outflow tract defects, distinctive facial appearance, thymic hypoplasia, cleft palate and hypocalcaemia. Major gene seems to be TBX1 (cardiac defects and cleft palate) Prader–Willi syndrome 15q11–q13 1 in 15 000 Distinctive facial appearance, hyperphagia, small hands and feet, distinct behavioural phenotype. Imprinted region, deletions on paternal allele in 70% of cases Angelman’s syndrome 15q11–q13 1 in 15 000 Distinctive facial appearance, absent speech, electroencephalogram (EEG) abnormality, characteristic gait. Imprinted region, deletions on maternal allele encompassing UBE3A Williams’ syndrome 7q11.23 1 in 10 000 Distinctive facial appearance, supravalvular aortic stenosis, learning disability and infantile hypercalcaemia. Major gene for supravalvular aortic stenosis is elastin Smith–Magenis syndrome 17p11.2 1 in 25 000 Distinctive facial appearance and behavioural phenotype, self-injury and rapid eye movement (REM) sleep abnormalities. Major gene seems to be RAI1 from the same chromosome, this will result in either inversion, duplication or deletion of a chromosomal fragment (Fig. 3.7). Large insertions and deletions may be cytogenetically visible as chromosomal deletions or duplications. If the anomalies are too small to be detected by microscopy, they are termed microdeletions and microduplications. Many microdeletion syndromes have been described and most result from nonallelic homologous recombination between repeats of highly similar DNA sequences, which leads to recurrent chromosome anomalies – and clinical syndromes – occurring in unrelated individuals (Fig. 3.7 and Box 3.3). Consequences of genomic variation The consequence of an individual mutation depends on many factors, including the mutation type, the nature of the gene product and the position of the variant in the protein. Mutations can have profound or subtle effects on gene and cell function. Variations that have profound effects are responsible for ‘classical’ genetic diseases, whereas those with subtle effects may contribute to the pathogenesis of common disease where there is a genetic component, such as diabetes. • Neutral variants have no effect on quality or type of protein produced. • Loss-of-function mutations result in loss or reduction in the normal protein function. Whole-gene deletions are the archetypal loss-of-function variants but stop-gain or indel mutations (early in the ORF), missense mutations affecting a critical domain and splice-site mutations can also result in loss of protein function.

Genomics, health and disease • 45

as a common polymorphism. However, the most frequent is the single nucleotide polymorphism, or SNP (pronounced ‘snip’), describing the substitution of a single base. Polymorphisms and common disease The protective and detrimental polymorphisms associated with common disease have been identified primarily through genome-wide association studies (GWAS, p. 56) and are the basis for many direct-to-consumer tests that purport to determine individual risk profiles for common diseases or traits such as cardiovascular disease, diabetes and even male-pattern baldness! An example is the polymorphism in the gene SLC2A9 that not only explains a significant proportion of the normal population variation in serum urate concentration but also predisposes ‘high-risk’ allele carriers to the development of gout. However, the current reality is that, until we have a more comprehensive understanding of the full genomic landscape and knowledge of the complete set of detrimental and protective polymorphisms, we cannot accurately assess risk. Evolutionary selection Genetic variants play an important role in evolutionary selection, with advantageous variants resulting in positive selection via improved reproductive fitness, and variations that decrease • Gain-of-function mutations result in a gain of protein function. They are typically non-synonymous mutations that alter the protein structure, leading to activation/ alteration of its normal function through causing either an interaction with a novel substrate or a change in its normal function. • Dominant negative mutations are the result of nonsynonymous mutations or in-frame deletions/duplications but may also, less frequently, be caused by triplet repeat expansion mutations. Dominant negative mutations are heterozygous changes that result in the production of an abnormal protein that interferes with the normal functioning of the wild-type protein. Normal genomic variation We each have 5–50 million variants in our genome, occurring approximately every 300 bases. These variants are mostly polymorphisms, arising in more than 1% of the population; they have no or subtle effects on gene and cell function, and are not associated with a high risk of disease. Polymorphisms can occur within exons, introns or the intergenic regions that comprise 98–99% of the human genome. Each of the classes of genetic variant discussed on page 42 is present in the genome Fig. 3.7 Chromosomal analysis and structural chromosomal disorders. A Human chromosomes can be classed as metacentric if the centromere is near the middle, or acrocentric if the centromere is at the end. The bands of each chromosome are given a number, starting at the centromere and working out along the short (p) arm and long (q) arm. Translocations and inversions are balanced structural chromosome anomalies where no genetic material is missing but it is in the wrong order. Translocations can be divided into reciprocal (direct swap of chromosomal material between nonhomologous chromosomes) and Robertsonian (fusion of acrocentric chromosomes). Deletions and duplications can also occur due to non-allelic homologous recombination (illustrated in part B). Deletions are classified as interstitial if they lie within a chromosome, and terminal if the terminal region of the chromosome is affected. Duplications can be either in tandem (where the duplicated fragment is inserted next to the region that is duplicated and orientated in the correct direction) or inverted (where the duplicated fragment is in the wrong direction). (N = normal; A = abnormal) B A common error of meiotic recombination, known as non-allelic homologous recombination, can occur (right panel), resulting in a deletion on one chromosome and a duplication in the homologous chromosome. The error is induced by tandem repeats in the DNA sequences (green), which can misalign and bind to each other, thereby ‘fooling’ the DNA into thinking the pairing prior to recombination is correct. Chromosome

Cen p

21.1 21.3 21.2

34.2 q Cen p N N A N A N A N A N A N A A 13 (sa) (st) 11.2

24.2

32.2 q Metacentric Acrocentric Chromosome

Reciprocal translocation Robertsonian translocation Inversions Interstitial Terminal Tandem Inverted Mechanism underlying recurrent deletions and duplication: non-allelic homologous recombination How structural chromosomal anomalies are described Deletions Duplications B A Recombination Normal pairing Abnormal pairing between DNA repeats Deletion Duplication

DNA repeat Maternal chromosome Paternal chromosome

46 • CLINICAL GENETICS history, on both sides of the family, enquiring about details of all medical conditions in family members, consanguinity, dates of birth and death, and any history of pregnancy loss or infant death. The basic symbols and nomenclature used in drawing a pedigree are shown in Figure 3.8. Patterns of disease inheritance Autosomal dominant inheritance Take some time to draw out the following pedigree: Anne is referred to Clinical Genetics to discuss her personal history of colon cancer (she was diagnosed at the age of 46 years) and family history of colon/endometrial cancer: her mother was diagnosed with endometrial cancer at the age of 60 years and her cousin through her healthy maternal aunt was diagnosed with colon cancer in her fifties. Both her maternal grandmother and grandfather died of ‘old age’. There is no family history of note on her father’s side of the family. He has one brother and both his parents died of old age, in their eighties. Anne has two healthy daughters, aged 12 and 14 years, and a healthy full sister. This family history is typical of an autosomal dominant condition (Fig. 3.8): in this case, a colon/endometrial cancer susceptibility syndrome known as Lynch’s syndrome, associated with disruption of one of the mismatch repair genes: MSH2, MSH6, MLH1 and PMS2 (see p. 830 and Box 3.11, p. 57). reproductive fitness becoming excluded through evolution. Given this simple paradigm, it would be tempting to assume that common mutations are all advantageous and all rare mutations are pathogenic. Unfortunately, it is often difficult to classify any common mutation as either advantageous or deleterious – or, indeed, neutral. Mutations that are advantageous in early life and thus enhance reproductive fitness may be deleterious in later life. There may be mutations that are advantageous for survival in particular conditions (e.g. famine or pandemic) that may be disadvantageous in more benign circumstances by causing a predisposition to obesity or autoimmune disorders. Constitutional genetic disease Familial genetic disease is caused by constitutional mutations, which are inherited through the germ line. However, different mutations in the same gene can have different consequences, depending on the genetic mechanism underlying that disease. About 1% of the human population carries constitutional mutations that cause disease. Constructing a family tree The family tree – or pedigree – is a fundamental tool of the clinical geneticist, who will routinely take a three-generation family Fig. 3.8 Drawing a pedigree and patterns of inheritance. A The main symbols used to represent pedigrees in diagrammatic form. B The main modes of disease inheritance (see text for details). SB Male Clinically affected Deceased individual (with age at death) Separated Consanguinity Clinically affected, several diagnoses Carrier Positive presymptomatic test Monozygotic twins Dizygotic twins Stillbirth (with gestation) Termination Miscarriage (with gestation) Unknown sex Female Partners Recessive inheritance Dominant inheritance Mitochondrial DNA disorder X-linked recessive inheritance Transmission to 50% of offspring independent of gender Consanguinity Affected males related through unaffected females Both sexes affected but only inherited through female meiosis I II III IV I II III IV I II III IV V I II III IV

d. 50 y 30 wk SB 39 wk 16 wk A B

Genomics, health and disease • 47

• Males and females are usually affected in roughly equal numbers (unless the clinical presentation of the condition is gender-specific, such as an inherited susceptibility to breast and/or ovarian cancer). The offspring risk for an individual affected with an autosomal dominant condition is 1 in 2 (or 50%). This offspring risk is true for each pregnancy, since half the affected individual gametes (sperm or egg cells) will contain the affected chromosome/gene and half will contain the normal chromosome/gene. There is a long list of autosomal dominant conditions, some of which are shown in Box 3.4. Features of an autosomal dominant pedigree include: • There are affected individuals in each generation (unless the mutation has arisen de novo, i.e. for the first time in an affected individual). However, variable penetrance and expressivity can influence the number of affected individuals and the severity of disease in each generation. Penetrance is defined as the proportion of individuals bearing a mutated allele who develop the disease phenotype. The mutation is said to be fully penetrant if all individuals who inherit a mutation develop the disease. Expressivity describes the level of severity of each aspect of the disease phenotype. 3.4 Genetic conditions dealt with by clinicians in other specialties Name of condition Gene Reference Autosomal dominant conditions Autosomal dominant polycystic kidney disease (ADPKD) PKD1 (85%), PKD2 (15%) p. 405 Box 15.28, p. 415 Tuberous sclerosis TSC1 TSC2 p. 1264 p. 1264 Marfan’s syndrome FBN1 p. 508 Long QT syndrome KCNQ1 p. 476 Brugada’s syndrome SCN5A p. 477 Neurofibromatosis type 1 NF1 p. 1131 Box 25.77, p. 1132 Neurofibromatosis type 2 NF2 p. 1131 Box 25.77, p. 1132 Hereditary spherocytosis ANK1 p. 947 Vascular Ehlers–Danlos syndrome (EDS type 4) COL3A1 p. 970 Hereditary haemorrhagic telangiectasia ENG, ALK1, GDF2 p. 970 Osteogenesis imperfecta COL1A1, COL1A2 p. 1055 Charcot–Marie–Tooth disease PMP22, MPZ, GJB1 p. 1140 Hereditary neuropathy with liability to pressure palsies PMP22 Autosomal recessive conditions Familial Mediterranean fever MEFV p. 81 Mevalonic aciduria (mevalonate kinase deficiency) MVK p. 81 Autosomal recessive polycystic kidney disease (ARPKD) PKHD1 Box 15.28, p. 415 Kartagener’s syndrome (primary ciliary dyskinesia) DNAI1 Box 17.30, p. 578 Cystic fibrosis CFTR1 p. 580 Box 17.30, p. 578 p. 842 Pendred’s syndrome SLC26A4 p. 650 Congenital adrenal hyperplasia-21 hydroxylase deficiency CYP21A p. 676 Box 18.27, p. 658 Haemochromatosis HFE p. 895 Wilson’s disease ATP7B p. 896 Alpha1-antitrypsin deficiency SERPINA1 p. 897 Gilbert’s syndrome UGT1A1 p. 897 Benign recurrent intrahepatic cholestasis ATP8B1 p. 902 Alpha-thalassaemia HBA1, HBA2 p. 951 p. 954 Beta-thalassaemia HBB p. 951 p. 953 Sickle cell disease HBB p. 951 Spinal muscular atrophy SMN1 p. 1117 X-linked conditions Alport’s syndrome COL4A5 Box 15.28, p. 415 p. 403 Primary agammaglobulinaemia BTK p. 78 Haemophilia A (factor VIII deficiency) F8 p. 971 Haemophilia B (factor IX deficiency) F9 p. 973 Duchenne muscular dystrophy DMD p. 1143 and Box 25.91

48 • CLINICAL GENETICS Autosomal recessive inheritance As above, take some time to draw a pedigree representing the following: Mr and Mrs Kent, a non-consanguineous couple, are referred because their son, Jamie, had severe neonatal liver disease. Included among the many investigations that the paediatric hepatologist undertook was testing for α1-antitrypsin deficiency (Box 3.5). Jamie was shown to have the PiZZ phenotype. Testing confirmed both parents as carriers with PiMZ phenotypes. In the family, Jamie has an older sister who has no medical problems. Mr Kent is one of four children with two brothers and a sister and Mrs Kent has a younger brother. Both sets of grandparents are alive and well. There is no family history of α1-antitrypsin deficiency. This family history is characteristic of an autosomal recessive disorder (Fig. 3.8), where both alleles of a gene must be mutated before the disease is manifest in an individual; an affected individual inherits one mutant allele from each of their parents, who are therefore healthy carriers for the condition. An autosomal recessive condition might be suspected in a family where: • Males and females are affected in roughly equal proportions. • Parents are blood related; this is known as consanguinity. Where there is consanguinity, the mutations are usually homozygous, i.e. the same mutant allele is inherited from both parents. • Individuals within one sibship in one generation are affected and so the condition can appear to have arisen ‘out of the blue’. Approximately 1 in 4 children born to carriers of an autosomal recessive condition will be affected. The offspring risk for carrier parents is therefore 25% and the chances of an unaffected child, with an affected sibling, being a carrier is 2/3. Examples of some autosomal recessive conditions, discussed elsewhere in this book, are shown in Box 3.4. X-linked inheritance The following is an exemplar of an X-linked recessive pedigree (Fig. 3.8): Edward has a diagnosis of Duchenne muscular dystrophy (DMD, Box 3.6). His parents had suspected the diagnosis when he was 3 years old because he was not yet walking and there was a family history of DMD: Edward’s maternal uncle had been affected and died at the age of 24 years. Edward’s mother has no additional siblings. After Edward demonstrated a very high creatinine kinase level, the paediatrician also requested genetic testing, which identified a deletion of exons 2–8 of the dystrophin gene. Edward has a younger, healthy sister and grandparents on both sides of the family are well, although the maternal grandmother has recently developed a cardiomyopathy. Edward’s father has an older sister and an older brother who are both well. Genetic diseases caused by mutations on the X chromosome have specific characteristics: • X-linked diseases are mostly recessive and restricted to males who carry the mutant allele. This is because males 3.5 Alpha1-antitrypsin deficiency Inheritance pattern • Autosomal recessive Genetic cause • Two common mutations in the SERPINA1 gene: p.Glu342Lys and p.Glu264Val Prevalence • 1 in 1500–3000 of European ancestry Clinical presentation • Variable presentation from neonatal period through to adulthood • Neonatal period: prolonged jaundice with conjugated hyperbilirubinaemia or (rarely) liver disease • Adulthood: pulmonary emphysema and/or cirrhosis. Rarely, the skin disease, panniculitis, develops Disease mechanism • SERPINA1 encodes α1-antitrypsin, which protects the body from the effects of neutrophil elastase. The symptoms of α1-antitrypsin deficiency result from the effects of this enzyme attacking normal tissue Disease variants • M variant: if an individual has normal SERPINA1 genes and produces normal levels of α1-antitrypsin, they are said to have an M variant • S variant: p.Glu264Val mutation results in α1-antitrypsin levels reduced to about 40% of normal • Z variant: p.Glu342Lys mutation results in very little α1-antitrypsin • PiZZ: individuals who are homozygous for the p.Glu342Lys mutation are likely to have α1-antitrypsin deficiency and the associated symptoms • PiZS: individuals who are compound heterozygous for p.Glu342Lys and p.Glu264Val are likely to be affected, especially if they smoke, but usually to a milder degree 3.6 Duchenne muscular dystrophy* Inheritance pattern • X-linked recessive Genetic cause • Mutations or deletions encompassing/within the DMD (dystrophin) gene located at Xp21 Prevalence • 1 in 3000–4000 live male births Clinical presentation • Delayed motor milestones • Speech delay • Grossly elevated creatine kinase (CK) levels (in the thousands) • Ambulation is usually lost between the ages of 7 and 13 years • Lifespan is reduced with a mean age of death, usually from respiratory failure, in the mid-twenties • Cardiomyopathy affects almost all boys with Duchenne muscular dystrophy and some female carriers Disease mechanism • DMD encodes dystrophin, a major structural component of muscle • Dystrophin links the internal cytoskeleton to the extracellular matrix Disease variants • Becker muscular dystrophy, although a separate disease, is also caused by mutations in the dystrophin gene • In Duchenne muscular dystrophy, there is no dystrophin protein, whereas in Becker muscular dystrophy there is a reduction in the amount or alteration in the size of the dystrophin protein *See also page 1143.

Genomics, health and disease • 49

dinucleotide (NADH) and the reduced form of flavine adenine dinucleotide (FADH2). Both NADH and FADH2 then donate electrons to the respiratory chain. Here these elections are transferred via a complex series of reactions, resulting in the formation of a proton gradient across the inner mitochondrial membrane. The gradient is used by an inner mitochondrial membrane protein, ATP synthase, to produce ATP, which is then transported to other parts of the cell. Dephosphorylation of ATP is used to produce the energy required for many cellular processes. Each mitochondrion contains 2–10 copies of a 16-kilobase (kB) double-stranded circular DNA molecule (mtRNA). This mtDNA contains 13 protein-coding genes, all involved in the respiratory chain, and the ncRNA genes required for protein synthesis within the mitochondria (Fig. 3.9). The mutational rate of mtDNA is relatively high due to the lack of protection by chromatin. Several mtDNA diseases characterised by defects in ATP production have been described. Mitochondria are most numerous in cells with high metabolic demands, such as muscle, retina and the basal ganglia, and these tissues tend to be the ones most severely affected in mitochondrial diseases (Box 3.7). There are many other mitochondrial diseases that are caused by mutations in nuclear genes, which encode proteins that are then imported into the mitochondrion and are critical for energy production, e.g. most forms of Leigh’s syndrome (although Leigh’s syndrome may also be caused by a mitochondrial gene mutation). The inheritance of mtDNA disorders is characterised by transmission from females, but males and females generally are equally affected (see Fig. 3.8). Unlike the other inheritance patterns mentioned above, mitochondrial inheritance has nothing to do with meiosis but reflects the fact that mitochondrial DNA is transmitted by oöcytes: sperm do not contribute mitochondria to the zygote. Mitochondrial disorders tend to be variable in penetrance and expressivity within families, and this is mostly accounted for by the fact that only a proportion of multiple mtDNA molecules within mitochondria contain the causal mutation (the degree of mtDNA heteroplasmy). Imprinting Several chromosomal regions (loci) have been identified where gene expression is inherited in a parent-of-origin-specific manner; have only one X chromosome, whereas females have two (see Fig. 3.1). However, occasionally, female carriers may exhibit signs of an X-linked disease due to a phenomenon called skewed X-inactivation. All female embryos, at about 100 cells in size, stably inactivate one of their two X chromosomes in each cell. Where this inactivation is random, approximately 50% of the cells will express the genes from one X chromosome and 50% of cells will express genes from the other. Where there is a mutant gene, there is often skewing away from the associated X chromosome, resulting in an unaffected female carrier. However, if, by chance, there is a disproportionate inactivation of the normal X chromosome with skewing towards the mutant allele, then an affected female carrier may be affected (albeit more mildly than males). • The gene can be transmitted from female carriers to their sons: in families with an X-linked recessive condition, there are often a number of affected males related through unaffected females. • Affected males cannot transmit the condition to their sons (but all their daughters would be carriers). The risk of a female carrier having an affected child is 25% or half of her male offspring. Mitochondrial inheritance The mitochondrion is the main site of energy production within the cell. Mitochondria arose during evolution via the symbiotic association with an intracellular bacterium. They have a distinctive structure with functionally distinct inner and outer membranes. Mitochondria produce energy in the form of adenosine triphosphate (ATP). ATP is mostly derived from the metabolism of glucose and fat (Fig. 3.9). Glucose cannot enter mitochondria directly but is first metabolised to pyruvate via glycolysis. Pyruvate is then imported into the mitochondrion and metabolised to acetyl-co-enzyme A (acetyl-CoA). Fatty acids are transported into the mitochondria following conjugation with carnitine and are sequentially catabolised by a process called β-oxidation to produce acetyl-CoA. The acetyl-CoA from both pyruvate and fatty acid oxidation is used in the citric acid (Krebs) cycle – a series of enzymatic reactions that produces CO2, the reduced form of nicotinamide adenine 3.7 The structure of the respiratory chain complexes and the diseases associated with their dysfunction Complex Enzyme nDNA subunits1 mtDNA subunits2 Diseases I NADH dehydrogenase

MELAS, MERRF bilateral striatal necrosis, LHON, myopathy and exercise intolerance, Parkinsonism, Leigh’s syndrome, exercise myoglobinuria, leucodystrophy/myoclonic epilepsy II Succinate dehydrogenase

Phaeochromocytoma, Leigh’s syndrome III Cytochrome bc1 complex

Parkinsonism/MELAS, cardiomyopathy, myopathy, exercise myoglobinuria, Leigh’s syndrome IV Cytochrome c oxidase

Sideroblastic anaemia, myoclonic ataxia, deafness, myopathy, MELAS, MERRF mitochondrial encephalomyopathy, motor neuron disease-like, exercise myoglobinuria, Leigh’s syndrome V ATP synthase

Leigh’s syndrome, NARP, bilateral striatal necrosis 1nDNA subunits. 2mtDNA subunits = number of different protein subunits in each complex that are encoded in the nDNA and mtDNA, respectively. (ATP = adenosine triphosphate; LHON = Leber hereditary optic neuropathy; MELAS = myopathy, encephalopathy, lactic acidosis and stroke-like episodes; MERRF = myoclonic epilepsy and ragged red fibres; mtDNA = mitochondrial DNA; NADH = the reduced form of nicotinamide adenine dinucleotide; NARP = neuropathy, ataxia and retinitis pigmentosa; nDNA = nuclear DNA)

50 • CLINICAL GENETICS Somatic genetic disease Somatic mutations are not inherited but instead occur during post-zygotic mitotic cell divisions at any point from embryonic development to late adult life. An example of this phenomenon is polyostotic fibrous dysplasia (McCune–Albright syndrome), in Fig. 3.9 Mitochondria. A Mitochondrial structure. There is a smooth outer membrane surrounding a convoluted inner membrane, which has inward projections called cristae. The membranes create two compartments: the inter-membrane compartment, which plays a crucial role in the electron transport chain, and the inner compartment (or matrix), which contains mitochondrial DNA and the enzymes responsible for the citric acid (Krebs) cycle and the fatty acid β-oxidation cycle. B Mitochondrial DNA. The mitochondrion contains several copies of a circular double-stranded DNA molecule, which has a non-coding region, and a coding region that encodes the genes responsible for energy production, mitochondrial transfer RNA (tRNA) molecules and mitochondrial ribosomal RNA (rRNA) molecules. (ATP = adenosine triphosphate; NADH = the reduced form of nicotinamide adenine dinucleotide) C Mitochondrial energy production. Fatty acids enter the mitochondrion conjugated to carnitine by carnitine-palmityl transferase type 1 (CPT I) and, once inside the matrix, are unconjugated by CPT II to release free fatty acids (FFA). These are broken down by the β-oxidation cycle to produce acetyl-co-enzyme A (acetyl-CoA). Pyruvate can enter the mitochondrion directly and is metabolised by pyruvate dehydrogenase (PDH) to produce acetyl-CoA. The acetyl-CoA enters the Krebs cycle, leading to the production of NADH and flavine adenine dinucleotide (reduced form) (FADH2), which are used by proteins in the electron transport chain to generate a hydrogen ion gradient across the inter-membrane compartment. Reduction of NADH and FADH2 by proteins I and II, respectively, releases electrons (e), and the energy released is used to pump protons into the inter-membrane compartment. Coenzyme Q10/ubiquinone (Q) is an intensely hydrophobic electron carrier that is mobile within the inner membrane. As electrons are exchanged between proteins in the chain, more protons are pumped across the membrane, until the electrons reach complex IV (cytochrome oxidase), which uses the energy to reduce oxygen to water. The hydrogen ion gradient is used to produce ATP by the enzyme ATP synthase, which consists of a proton channel and catalytic sites for the synthesis of ATP from ADP. When the channel opens, hydrogen ions enter the matrix down the concentration gradient, and energy is released that is used to make ATP. L

s t r a n d H

s t r a n d Outer membrane Inner membrane NADH NAD I II III Q Cyt C IV NADH FADH2 Fatty acid β-oxidation cycle Citric acid (Krebs) cycle H+ e 2e FADH2 FADH2 Lactate Pyruvate PDH Acetyl-CoA Glucose 22 tRNAs NADH dehydrogenase 7 subunits Cytochrome B/C oxidase 4 subunits 2 ribosomal RNA subunits 2 ATP synthase subunits Intragenic DNA Inner membrane Cristae Matrix Outer membrane FFA CPT I CPT II Carnitine Carnitine-FA ester C A B FFA FAD 2H+ H2O O2 ATP ADP

Interrogating the genome: the changing landscape of genomic technologies • 51

light or cigarette smoke, or if the cell has defects in DNA repair systems. Cancer is thus a disease that affects the fundamental processes of molecular and cell biology. Interrogating the genome: the changing landscape of genomic technologies Looking at chromosomes The analysis of metaphase chromosomes by light microscopy was the mainstay of clinical cytogenetic analysis for decades, the aim being to detect gain or loss of whole chromosomes (aneuploidy) or large chromosomal segments (> 4 million bp). More recently, genome-wide microarrays (array comparative genomic hybridisation or array CGH) have replaced chromosome analysis, allowing rapid and precise detection of segmental gain or loss of DNA throughout the genome (see Box 3.3). Microarrays consist of grids of multiple wells containing short DNA sequences (reference DNA) that are complementary to known sequences in the genome. Patient and reference DNA are each labelled with a coloured fluorescent dye (generally, patient DNA is labelled with a green fluorescent dye and reference DNA with a red fluorescent dye) and added to the microarray grid. Where there is an equal quantity of patient and reference DNA bound to the spot, this results in yellow fluorescence. Where there is too much patient DNA (representing a duplication of a chromosome region), the spot will be greener; it will be more red (appears orange) where there is 2 : 1 ratio of the control:patient DNA (representing heterozygous deletion of a chromosome region; Fig. 3.10). Array CGH and other array-based approaches can detect small chromosomal deletions and duplications. They are also generally more sensitive than conventional karyotyping at detecting mosaicism (where there are two or more populations of cells, derived from a single fertilised egg, with different genotypes). which a somatic mutation in the GS alpha gene causes constitutive activation of downstream signalling, resulting in focal lesions in the skeleton and endocrine dysfunction (p. 1055). The most important example of human disease caused by somatic mutations is cancer (see Ch. 33). Here, ‘driver’ mutations occur within genes that are involved in regulating cell division or apoptosis, resulting in abnormal cell growth and tumour formation. The two general categories of cancer-causing mutation are gain-of-function mutations in growth-promoting genes (oncogenes) and loss-of-function mutations in growth-suppressing genes (tumour suppressor genes). Whichever mechanism is acting, most tumours require an initiating mutation in a single cell that can then escape from normal growth controls. This cell replicates more frequently or fails to undergo programmed death, resulting in clonal expansion. As the size of the clone increases, one or more cells may acquire additional mutations that confer a further growth advantage, leading to proliferation of these subclones, which may ultimately result in aggressive metastatic cancer. The cell’s complex self-regulating machinery means that more than one mutation is usually required to produce a malignant tumour (see Fig. 33.3, p. 1318). For example, if a mutation results in activation of a growth factor gene or receptor, then that cell will replicate more frequently as a result of autocrine stimulation. However, this mutant cell will still be subject to normal cell-cycle checkpoints to promote DNA integrity in its progeny. If additional mutations in the same cell result in defective cell-cycle checkpoints, however, it will rapidly accumulate further mutations, which may allow completely unregulated growth and/ or separation from its matrix and cellular attachments and/or resistance to apoptosis. As cell growth becomes increasingly dysregulated, cells de-differentiate, lose their response to normal tissue environment and cease to ensure appropriate mitotic chromosomal segregation. These processes combine to generate the classical malignant characteristics of disorganised growth, variable levels of differentiation, and numerical and structural chromosome abnormalities. An increase in somatic mutation rate can occur on exposure to external mutagens, such as ultraviolet 3.8 Imprinting disorders Disorder Locus Genes Notes Beckwith–Wiedemann syndrome 11p15 CDKN1C, IGF2, H19 Increased growth, macroglossia, hemihypertrophy, abdominal wall defects, ear lobe pits/creases and increased susceptibility to developing childhood tumours Prader–Willi syndrome 15q11–q13 SNRPN, Necdin and others Obesity, hypogonadism and learning disability. Lack of paternal contribution (due to deletion of paternal 15q11–q13, or inheritance of both chromosome 15q11–q13 regions from the mother) Angelman’s syndrome (AS) 15q11–q13 UBE3A Severe mental retardation, ataxia, epilepsy and inappropriate laughing bouts. Due to loss-of-function mutations in the maternal UBE3A gene. The neurological phenotype results because most tissues express both maternal and paternal alleles of UBE3A, whereas the brain expresses predominantly the maternal allele Pseudohypoparathyroidism (p. 664) 20q13 GNAS1 Inheritance of the mutation from the mother results in hypocalcaemia, hyperphosphataemia, raised parathyroid hormone (PTH) levels, ectopic calcification, obesity, delayed puberty and shortened 4th and 5th metacarpals (the syndrome known as Albright’s hereditary osteodystrophy, AHO). When the mutation is inherited from the father, PTH, calcium and phosphate levels are normal but the other features are present (pseudopseudohypoparathyroidism, p. 664). These differences are due to the fact that, in the kidney (the main target organ through which PTH regulates serum calcium and phosphate), the paternal allele is silenced and the maternal allele is expressed, whereas both alleles are expressed in other tissues.

52 • CLINICAL GENETICS cycle of heating/cooling and denaturation/replication is repeated many times, resulting in the exponential amplification of DNA between primer sites (Fig. 3.11). Gene sequencing In the mid-1970s, a scientist called Fred Sanger pioneered a DNA sequencing technique (‘Sanger sequencing’) that determined the precise order and nucleotide type (thymine, cytosine, adenine and guanine) in a molecule of DNA. Modern Sanger sequencing uses fluorescently labelled, chain-terminating nucleotides that are sequentially incorporated into the newly synthesised DNA, generating multiple DNA chains of differing lengths. These DNA chains are subject to capillary electrophoresis, which separates them by size, allowing the fragments to be ‘read’ by a laser and producing a sequence chromatogram that corresponds to the target sequence (Fig. 3.12). Although transformative, Sanger sequencing was difficult and costly to scale, as exemplified by the Human Genome Project, which took 12 years to sequence the entire human genome at a cost approaching 3 billion dollars. Recently, DNA sequencing has been transformed again by a group of technologies collectively known as ‘next-generation sequencing’ (NGS; Fig. 3.13). This refers to a family of postSanger sequencing technologies that utilise the same five basic principles: • Library preparation: DNA samples are fragmented (by enzyme cleavage or ultrasound) and then modified with a custom adapter sequence. • Amplification: the library fragment is amplified to produce DNA clusters, each originating from a single DNA fragment. Each cluster will act as a single sequencing reaction. • Capture: if an entire genome is being sequenced, this step will not be included. The capture step is required if targeted resequencing is necessary, such as for a panel gene test or an exome (Box 3.9). • Sequencing: each DNA cluster is simultaneously sequenced and the data from each captured; this is known as a ‘read’ and is usually between 50 and 300 bases long sequenced (see Box 3.10 for a detailed description of the three most commonly used sequencing methods: synthesis, ligation and ion semiconductor sequencing). • Alignment and variant identification: specialised software analyses read sequences and compares the data to a reference template. This is known as ‘alignment’ or ‘mapping’ and, although there are 3 billion bases in the However, array-based approaches will not detect balanced chromosome rearrangements where there is no loss or gain of genes/chromosome material, such as balanced reciprocal translocations, or a global increase in copy number, such as triploidy. The widespread use of array-based approaches has brought a number of challenges for clinical interpretation, including the identification of copy number variants (CNVs) of uncertain clinical significance, CNVs of variable penetrance and incidental findings. A CNV of uncertain clinical significance describes a loss or gain of chromosome material where there are insufficient data to conclude whether or not it is associated with a learning disability and/or medical problems. While this uncertainty can be difficult to prepare families for and can be associated with considerable anxiety, it is likely that there will be greater clarity in the future as we generate larger CNV datasets. A CNV of variable penetrance, also known as a neurosusceptibility locus, describes a chromosome deletion or duplication associated with a lower threshold for manifesting a learning disability or autistic spectrum disorder. CNVs of variable penetrance are therefore identified at greater frequencies among individuals with a learning disability and/or autistic spectrum disorder than in the general population. The current understanding is that additional modifying factors (genetic, environmental or stochastic) must influence the phenotypic expression of these neurosusceptibility loci. Finally, an incidental CNV finding describes a deletion or duplication encompassing a gene or genes that are causative of a phenotype or risk unrelated to the presenting complaint. For instance, if, through the array CGH investigation for an intellectual disability, a deletion encompassing the BRCA1 gene were identified, this would be considered an incidental finding. Looking at genes Gene amplification: polymerase chain reaction The polymerase chain reaction (PCR) is a fundamental laboratory technique that amplifies targeted sections of the human genome for further analyses – most commonly, DNA sequencing. The method utilises thermal cycling: repeated cycles of heating and cooling allow the initial separation of double-stranded DNA into two single strands (known as denaturation), each of which serves as a template during the subsequent replication step, guided by primers designed to anneal to a specific genomic region. This Fig. 3.10 Detection of chromosome abnormalities by comparative genomic hybridisation (CGH). Deletions and duplications are detected by looking for deviation from the 1 : 1 ratio of patient and control DNA in a microarray. Ratios in excess of 1 indicate duplications, whereas ratios below 1 indicate deletions. CGH Patient DNA Label DNA with different fluorescent dyes Mix equimolar amounts of labelled DNA Apply DNA mix to glass slide with high-density array of different DNA probes with known location in the human genome Patient/control ratio = 0.5:1 → deletion of patient DNA Patient/control ratio = 1.5:1 → duplication of patient DNA Patient/control ratio = 1:1 → normal Normal control DNA

Interrogating the genome: the changing landscape of genomic technologies • 53

human genome, allows the remarkably accurate determination of the genomic origin where a read consists of 25 nucleotides or more. Variants are identified as differences between the read and the reference genome. For instance, if there is a different nucleotide in half the reads at a given position compared to the reference genome, this is likely to represent a heterozygous base substitution. The number of reads that align at a given point is called the ‘depth’ or ‘coverage’. The higher the read depth, the more accurate the variant call. However, in general, a depth of 30 or more reads is generally accepted as producing diagnostic-grade results. Rather than sequencing only one small section of DNA at a time, NGS allows the analysis of many hundreds of thousands of DNA strands in a single experiment and so is also commonly referred to as multiple parallel sequencing technology. Today’s NGS machines can sequence the entire human genome in a single day at a cost approaching 1000 US dollars. NGS capture Although we now have the capability to sequence the entire genome in a single experiment, whole-genome sequencing is not always the optimal use of NGS. NGS capture refers to the ‘pull-down’ of a targeted region of the genome and may constitute several to several hundred genes associated with a given phenotype (a gene panel), the exons of all known coding genes (an exome), or the exons of all coding genes known to be associated with disease (a clinical exome). Each of these targeted resequencing approaches is associated with a number of advantages and disadvantages (see Box 3.9). In order for NGS to be used for optimal patient benefit, it is essential for the clinician to have a good understanding of which test is the best one to request in any given clinical presentation. Challenges of NGS technologies Genomic technologies have the potential to transform the way that we practise medicine, and ever faster and cheaper DNA sequencing offers increasing opportunities to prevent, diagnose and treat disease. However, genomic technologies are not without their challenges: for instance, storing the enormous quantities of data generated by NGS. While the A, C, T and G of our genomic code could be stored on the memory of a smartphone, huge computers, able to store several petabytes of data (where 1 petabyte is 1 million gigabytes of data), are required to store the information needed to generate each individual’s genome. Even if we can store and handle these huge datasets successfully, we then need to be able to sift through the millions of Fig. 3.11 The polymerase chain reaction (PCR). PCR involves adding a tiny amount of the patient’s DNA to a reaction containing primers (short oligonucleotides 18–21 bp in length, which bind to the DNA flanking the region of interest) and deoxynucleotide phosphates (dATP, dCTP, dGTP, dTTP), which are used to synthesise new DNA and a heat-stable polymerase. The reaction mix is first heated to 95°C, which causes the double-stranded DNA molecules to separate. The reaction is then cooled to 50–60°C, which allows the primers to bind to the target DNA. The reaction is then heated to 72°C, at which point the polymerase starts making new DNA strands. These cycles are repeated 20–30 times, resulting in exponential amplification of the DNA fragment between the primer sites. The resulting PCR products can then be used for further analysis – most commonly, DNA sequencing (see Fig. 3.12). Cool ~60°C DNA sample DNA strands separate Primers bind to DNA DNA replicated Heat 95°C Heat 95°C Cool ~60°C Repeat cycles 20–30 times

PCR cycles Exponential amplification of DNA between primer sites DNA molecules

DNA strands separate Primers bind to DNA Cycle no. 1 DNA replicated Heat ~72°C Heat ~72°C Polymerase

54 • CLINICAL GENETICS their interpretation will require input from a genetics expert in the context of the clinical presentation, where an ‘innocent until proven guilty’ approach is often adopted. Finally, if we are to interrogate the entire genome or even the exome, it is foreseeable that we will routinely identify ‘incidental’ or secondary findings – in other words, findings not related to the initial diagnostic question. The UK has so far advocated a conservative approach to incidental findings. Uses of NGS NGS is now frequently used, within diagnostic laboratories, to identify base substitutions and indels (although the latter were Fig. 3.12 Sanger sequencing of DNA, which is very widely used in DNA diagnostics. This is performed using PCR-amplified fragments of DNA corresponding to the gene of interest. The sequencing reaction is carried out with a combination dNTP and fluorescently labelled di-deoxy-dNTP (ddATP, ddTTP, ddCTP and ddGTP), which become incorporated into the newly synthesised DNA, causing termination of the chain at that point. The reaction products are then subject to capillary electrophoresis and the different-sized fragments are detected by a laser, producing a sequence chromatogram that corresponds to the target DNA sequence. Capillary electrophoresis Largest fragments migrate slowest Smallest fastest Laser fluorescence detector ddTTP ddCTP ddATP ddGTP DNA sample PCR DNA sequence chromatogram Key Fragments detected by laser fluorescence New DNA molecules terminated by incorporation of ddNTP Polymerase

Interrogating the genome: the changing landscape of genomic technologies • 55

Fig. 3.13 Sequencing by synthesis as used in the Illumina system. (1) Library preparation: DNA is fragmented and specialist adapters are ligated to the fragmented ends. (2) Cluster amplification: the library is loaded to a flow cell and the adapters hybridise to the flow-cell surface. Each bound fragment is hybridised. (3) Sequencing. (4) Alignment and variant interpretation: reads are aligned to a reference sequence using complex software and differences between reference and case genomes are identified. CCGATATCTAGCTTA ATATCTAGC CG TAGC TATCTAGC CCG TAGCTAGCTTA 1 Library preparation 2 Cluster amplification Genomic DNA Fragmentation Adapter ligation Flow cell Amplification 3 Sequencing Reads Reference genome 4 Alignment and variant interpretation G T A C A A 3.10 Next-generation sequencing methods Sequencing by synthesis (Fig. 3.13) • The most frequently used NGS method • Used in Illumina systems (commonly used in diagnostic laboratories) • Uses fluorescently labelled, terminator nucleotides that are sequentially incorporated into a growing DNA chain • Library DNA samples (fragmented DNA flanked by DNA adapter sequences) are anchored to a flow cell by hybridisation of the DNA adapter sequence to probes on the flow-cell surface • Amplification occurs by washing the flow cell in a mixture containing all four fluorescently labelled terminator nucleotides: A, C, T and G • Once the nucleotide, complementary to the first base of the DNA template, is incorporated, no further nucleotides can be added until the mixture is washed away • The nucleotide terminator is shed and the newly incorporated nucleotide reverts to a regular, non-fluorescent nucleotide that can be extended • The process is then repeated with the incorporation of a second base etc. • Sequencing by synthesis is therefore space- and time-dependent: a sensor will detect the order of fluorescent emissions for each spot on the plate (representing the cluster) and determine the sequence for that read Sequencing by ligation • Used in SOLiD systems • Uses DNA ligase rather than DNA polymerase (as is used in sequencing by synthesis) and short oligonucleotides (as opposed to single nucleotides) • Library DNA samples are washed in a mixture containing oligonucleotide probes representing 4–16 dinucleotide sequences. Only one nucleotide in the probe is fluorescently labelled • The complementary oligo probes will hybridise, using DNA ligase, to the target sequence, initially at a primer annealed to the anchor site and then progressively along the DNA strand • After incorporation of each probe, fluorescence is measured and the dye is cleaved off • Eventually, a new strand is synthesised (composed of a series of the oligo probes) • A new strand is then synthesised but is offset by one nucleotide • The process is repeated a number of times (5 rounds in the SOLiD system), providing overlapping templates that are analysed and a composite of the target sequence determined Ion semiconductor sequencing • When a nucleotide is incorporated into a growing DNA strand, a hydrogen ion is released that can be detected by an alteration in the pH of the solution. This hydrogen ion release forms the basis of ion semiconductor sequencing • Each amplified DNA cluster is located above a semiconductor transistor, capable of detecting differences in the pH of the solution • The DNA cluster is washed in a mixture containing only one type of nucleotide • If the correct nucleotide, complementary to the next base on the DNA template, is in the mixture and incorporated, a hydrogen ion is released and detected • If a homopolymer (sequence of two or more identical nucleotides) is present, this will be detected as a decrease in pH proportionate to the number of identical nucleotides in the sequence initially problematic). The current NGS challenge is to detect large deletions or duplications spanning several hundreds or thousands of bases and therefore exceeding any single read. Increasingly, however, this dosage analysis is being achieved using sophisticated computational methods, negating the need for more traditional technologies such as array CGH. Additional potential uses of NGS include detection of balanced and unbalanced translocations and mosaicism: NGS has proved remarkably sensitive at detecting the latter when there is high read coverage for a given region. Of note, however, NGS is still not able to interrogate the epigenome (and so will not identify conditions caused by a disruption of imprinting, such as Beckwith–Wiedemann, Silver–Russell, Angelman’s and Prader–Willi syndromes) and will not detect triplet repeat expansions such as those that cause Huntington’s disease,

56 • CLINICAL GENETICS regions of the genome, and therefore genes, more strongly associated with a given SNP profile and therefore more likely to contribute to the disease under study. Genomics and obstetrics Prenatal genetic testing may be performed where a pregnancy is considered at increased risk of being affected with a genetic condition, either because of the ultrasound/biochemical screening results or because of the family history. While invasive tests, such as amniocentesis and chorionic villus sampling, have been the mainstay of prenatal diagnosis for many years, they are increasingly being superseded by non-invasive testing of cell-free fetal DNA (cffDNA), originating from placental trophoblasts and detectable in the maternal circulation from 4–5 weeks’ gestation; it is present in sufficient quantities for testing by 9 weeks. • Non-invasive prenatal testing (NIPT): the sequencing and quantification, using NGS, of cffDNA chromosome-specific DNA sequences to identify trisomy 13, 18 or 21. The accuracy of NIPT in detecting pregnancy-specific aneuploidy approaches 98%. A false-negative result can occur when there is too little cffDNA (possibly due to early gestation or high maternal body mass index) or when aneuploidy has arisen later in development and is confined to the embryo and not represented in the placenta. False positives can occur with confined placental mosaicism (describing aneuploidy in the placenta, not the fetus) or with an alternative cause of aneuploidy in the maternal circulation, such a cell-free tumour DNA. • Non-invasive prenatal diagnosis (NIPD): the identification of a fetal single-gene defect that either has been paternally inherited or has arisen de novo and so is not identifiable in the maternal genome. Examples of conditions that are currently amenable to NIPD include achondroplasia and the craniosynostoses. Increasingly, however, NIPD is being used for autosomal recessive conditions such as cystic fibrosis, where parents are carriers for different mutations. The free fetal DNA is tested to see whether the paternal mutation is identified and, if absent, the fetus is not affected. If the paternal mutation is identified, however, a definitive invasive test is required to determine whether the maternal mutation has also been inherited and the fetus is affected. Where a genetic diagnosis is known in a family, a couple may opt to undertake pre-implantation genetic diagnosis (PGD). PGD is used as an adjunct to in vitro fertilisation and involves the genetic testing of a single cell from a developing embryo, prior to implantation. Genomics and oncology Until recently, individuals were stratified to genetic testing if they presented with a personal and/or family history suggestive of an inherited cancer predisposition syndrome (Box 3.11). Relevant clinical information included the age of cancer diagnosis and number/type of tumours. For example, the diagnosis of bilateral breast cancer in a woman in her thirties with a mother who had ovarian cancer in her forties is suggestive of BRCA1/2-associated familial breast/ovarian cancer. In many familial cancer syndromes, somatic mutations act together with an inherited mutation to cause specific cancers (p. 50). Familial cancer syndromes may be due to germ-line loss-of-function mutations in tumour suppressor genes encoding DNA repair enzymes or proto-oncogenes. At the cellular level, loss of one copy of a tumour suppressor myotonic dystrophy and fragile X syndrome (see Boxes 3.8 and 3.2). Third-generation sequencing Increasingly, third-generation or single-molecule sequencing is entering the diagnostic arena. As with next- or second-generation sequencing, a number of different platforms are commercially available. One of the most successful is SMRT technology (single-molecule sequencing in real time), developed by Pacific Biosciences. This system utilises a single-stranded DNA molecule (as compared to the amplified clusters used in NGS), which acts as a template for the sequential incorporation, using a polymerase, of fluorescently labelled nucleotides. As each complementary nucleotide is added, the fluorescence (and therefore the identity of the nucleotide) is recorded before it is removed and another nucleotide is added. A key advantage of third-generation sequencing is the long length of the read it generates: in the region of 10–15 kilobases. It is also cheaper than NGS, as fewer reagents are required. Given these inherent advantages, third-generation sequencing is likely to supersede NGS in the near future. Given the confusion surrounding the terminology of NGS and third-generation sequencing, these technologies are increasingly referred to as ‘massively parallel sequencing’. Genomics and clinical practice Genomics and health care Genomics in rare neurodevelopmental disorders Although, by definition, the diagnosis of a rare disorder is made infrequently, rare diseases, when considered together, affect about 3 million people in the UK, the majority of whom are children. NGS has transformed the ability to diagnose individuals affected by a rare disease. Whereas previously, when we were restricted to the sequential analysis of single genes, a clinician would need to make a clinical diagnosis in order to target testing, NGS allows the interrogation of multiple genes in a single experiment. This might be done through a gene panel, a clinical exome or an exome (see Box 3.9 and p. 53), and has increased the diagnostic yield in neurodevelopmental disorders to approximately 30%. Not only does the identification of the genetic cause of a rare disorder potentially provide families with answers, prognostic information and the opportunity to meet and derive support from other affected families but also it can provide valuable information for those couples planning further children and wishing to consider prenatal testing in the future. Genomics and common disease Most common disorders are determined by interactions between a number of genes and the environment. In this situation, the genetic contribution to disease is termed polygenic. Until recently, very little progress had been made in identifying the genetic variants that predispose to common disorders, but this has been changed by the advent of genome-wide association studies. A GWAS typically involves genotyping many (> 500 000) genetic markers (SNPs) spread across the genome in a large group of individuals with the disease and in controls. By comparing the SNP genotypes in cases and controls, it is possible to identify

Genomics and clinical practice • 57

ever) in some members of these cancer-prone families. In DNA repair diseases, the inherited mutations increase the somatic mutation rate. Autosomal dominant mutations in genes encoding components of specific DNA repair systems are relatively common causes of familial colon cancer and breast cancer (e.g. BRCA1). Increasingly, genetics is moving into the mainstream, becoming integrated into routine oncological care as new gene-specific treatments are introduced. Testing for a genetic predisposition gene does not have any functional consequences, as the cell is protected by the remaining normal copy. However, a somatic mutation affecting the normal allele is likely to occur in one cell at some point during life, resulting in complete loss of tumour suppressor activity and a tumour developing by clonal expansion of that cell. This two-hit mechanism (one inherited, one somatic) for cancer development is known as the Knudson hypothesis. It explains why tumours may not develop for many years (or 3.11 Inherited cancer predisposition syndromes Syndrome name Gene Associated cancers Additional clinical features Birt–Hogg–Dubé syndrome FLCN Renal tumour (oncocytoma, chromophobe (and mixed), renal cell carcinoma) Fibrofolliculoma Trichodiscoma Pulmonary cysts Breast/ovarian hereditary susceptibility BRCA1 BRCA2 Breast carcinoma Ovarian carcinoma Pancreatic carcinoma Prostate carcinoma Cowden’s syndrome PTEN Breast carcinoma Thyroid carcinoma Endometrial carcinoma Macrocephaly Intellectual disability/autistic spectrum disorder Trichilemmoma Acral keratosis Papillomatous papule Thyroid cyst Lipoma Haemangioma Intestinal hamartoma Gorlin’s syndrome/basal cell naevus syndrome PTCH1 Basal cell carcinoma Medulloblastoma Odontogenic keratocyst Palmar or plantar pits Falx calcification Rib abnormalities (e.g. bifid, fused or missing ribs) Macrocephaly Cleft lip/palate Li–Fraumeni syndrome TP53 Sarcoma (e.g. osteosarcoma, chondrosarcoma, rhabdomyosarcoma) Breast carcinoma Brain cancer (esp. glioblastoma) Adrenocortical carcinoma Brain Lynch’s syndrome/ hereditary non-polyposis colon cancer MLH1 MSH2 MSH6 PMS2 Colorectal carcinoma (majority right-sided) Endometrial carcinoma Gastric carcinoma Cholangiocarcinoma Ovarian carcinoma (esp. mucinous) Multiple endocrine neoplasia 1 MEN1 Parathyroid tumour Endocrine pancreatic tumour Anterior pituitary tumour Lipoma Facial angiofibroma Multiple endocrine neoplasia 2 and 3 (also known as 2a and 2b, respectively) RET Medullary thyroid tumour Phaeochromocytoma Parathyroid tumour Polyposis, familial adenomatous (FAP) APC Colorectal adenocarcinoma (FAP is characterised by thousands of polyps from the second decade; without colectomy, malignant transformation of at least one of these polyps is inevitable) Duodenal carcinoma Hepatoblastoma Desmoid tumour Congenital hypertrophy of the retinal pigment epithelium (CHRPE) Polyposis, MYH-associated MYH (MUTYH) Colorectal adenocarcinoma Duodenal adenocarcinoma Retinoblastoma, familial RB1 Retinoblastoma Osteosarcoma

58 • CLINICAL GENETICS azathioprine, a drug that is used in the treatment of autoimmune diseases and in cancer chemotherapy. Genetic screening for polymorphic variants of TPMT can be useful in identifying patients who have increased sensitivity to the effects of azathioprine and who can be treated with lower doses than normal. Gene therapy and genome editing Replacing or repairing mutated genes (gene therapy) is challenging in humans. Retroviral-mediated ex vivo replacement of the defective gene in bone marrow cells for the treatment of severe combined immune deficiency syndrome (p. 79) has been successful. The major problems with clinical use of virally delivered gene therapy have been oncogenic integration of the exogenous DNA into the genome and severe immune response to the virus. Other therapies for genetic disease include PTC124, a compound that can ‘force’ cells to read through a mutation that results in a premature termination codon in an ORF with the aim of producing a near-normal protein product. This therapeutic approach could be applied to any genetic disease caused by nonsense mutations. The most exciting development in genetics for a generation has been the discovery of accurate, efficient and specific techniques to enable editing of the genome in cells and organisms. This technology is known as CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats and CRISPR-associated) genome editing. It is likely that ex vivo correction of genetic disease will become commonplace over the next few years. In vivo correction is not yet possible and will take much longer to become part of clinical practice. Induced pluripotent stem cells and regenerative medicine Adult stem-cell therapy has been in wide use for decades in the form of bone marrow transplantation. The identification of adult stem cells for other tissues, coupled with the ability to purify and maintain such cells in vitro, now offers exciting therapeutic potential for other diseases. It was recently discovered that many different adult cell types can be trans-differentiated to form cells (induced pluripotent stem cells or iPS cells) with almost all the characteristics of embryonal stem cells derived from the early blastocyst. In mammalian model species, such cells can be taken and used to regenerate differentiated tissue cells, such as in heart and brain. They have great potential both for the development of tissue models of human disease and for regenerative medicine. Pathway medicine The ability to manipulate pathways that have been altered in genetic disease has tremendous therapeutic potential for Mendelian disease, but a firm understanding of both disease pathogenesis and drug action at a biochemical level is required. An exciting example has been the discovery that the vascular pathology associated with Marfan’s syndrome is due to the defective fibrillin molecules causing up-regulation of transforming growth factor (TGF)-β signalling in the vessel wall. Losartan is an antihypertensive drug that is marketed as an angiotensin II receptor antagonist. However, it also acts as a partial antagonist of TGF-β signalling and is effective in preventing aortic dilatation in a mouse model of Marfan’s syndrome, showing promising effects in early human clinical trials. to cancer is therefore moving from the domain of clinical genetics, where it has informed diagnosis, cascade treatment and screening/prophylactic management, to oncology, where it is informing the immediate management of the patient following cancer diagnosis. This is exemplified by BRCA1 and BRCA2 (BRCA1/2)-related breast cancer. Previously, women with a mutation in either the BRCA1 or BRCA2 gene would have received similar first-line chemotherapy to women with a sporadic breast cancer without a known genetic association. More recently, it has been shown that BRCA1/2 mutation-positive tumours are sensitive to poly ADP ribose polymerase (PARP) inhibitors. PARP inhibitors block the single-strand break-repair pathway. In a BRCA1/2 mutation-positive tumour – with compromised double-strand break repair – the additional loss of the singlestrand break-repair pathway will drive the cell towards apoptosis. Indeed, PARP inhibitors have been shown to be so effective at destroying BRCA1/2 mutation-positive tumour cells, and with such minimal side-effects, that BRCA1/2 gene testing is increasingly determining patient management. It is likely, with a growing understanding of the genomic architecture of tumours, increasing accessibility of NGS and an expanding portfolio of gene-directed therapies, that testing for many of the other inherited cancer susceptibility genes will, in time, move into the mainstream. Genomics in infectious disease NGS technologies are also transforming infectious disease. Given that a microbial genome can be sequenced within a single day at a current cost of less than 100 US dollars, microbiologists are able to identify a causative microorganism and target effective treatment rapidly and accurately. Moreover, microbial genome sequencing enables the effective surveillance of infections to reduce and prevent transmission. Finally, an understanding of the microbial genome will drive the development of vaccines and antibiotics, essential in an era characterised by increasing microbial resistance to established antibiotic agents. Treatment of genetic disease Pharmacogenomics Pharmacogenomics is the science of dissecting the genetic determinants of drug kinetics and effects using information from the human genome. For more than 50 years, it has been appreciated that polymorphic mutations within genes can affect individual responses to some drugs, such as loss-of-function mutations in CYP2D6 that cause hypersensitivity to debrisoquine, an adrenergic-blocking medication formerly used for the treatment of hypertension, in 3% of the population. This gene is part of a large family of highly polymorphic genes encoding cytochrome P450 proteins, mostly expressed in the liver, which determine the metabolism of a host of specific drugs. Polymorphisms in the CYP2D6 gene also determine codeine activation, while those in the CYP2C9 gene affect warfarin inactivation. Polymorphisms in these and other drug metabolic genes determine the persistence of drugs and, therefore, should provide information about dosages and toxicity. With the increasing use of NGS, genetic testing for assessment of drug response is seldom employed routinely, but in the future it may be possible to predict the best specific drugs and dosages for individual patients based on genetic profiling: so-called ‘personalised medicine’. An example is the enzyme thiopurine methyltransferase (TPMT), which catabolises

Further information • 59

BRCA1/2 mutations), DCT is undertaken in isolation with no direct access to professional support. Furthermore, in addition to some (common) single-gene mutations, such as the founder BRCA1/2 mutations frequently identified in the Ashkenazi Jewish population and discussed in this example, current DCT packages utilise a series of SNPs to determine an overall risk profile; they evaluate the number of detrimental and protective SNPs for a given disease. However, given that only a minority of the risk SNPs have so far been characterised, this is often inaccurate. Individuals may be falsely reassured that they are not at increased risk of a genetic condition despite a family history suggesting otherwise, resulting in inadequate surveillance and/or management. The ethical considerations listed in this clinical scenario give just a flavour of some of the issues frequently encountered in clinical genetics. They are not meant to be an exhaustive summary and whole textbooks and meetings are devoted to the discussion of hugely complex ethical issues in genetics. However, a guiding principle is that, although each counselling situation will be unique with specific communication and ethical challenges, a genetic result is permanent and has implications for the whole family, not just the individual. Where possible, therefore, an informed decision regarding genetic testing should be taken by a competent adult following counselling by an experienced and appropriately trained clinician. Further information Books and journal articles Alberts B, Bray D, Hopkin K et al. Essential cell biology, 4th edn. New York: Garland Science; 2013. Firth H, Hurst JA. Oxford desk reference: clinical genetics. Oxford: Oxford University Press; 2005. Read A, Donnai D. New clinical genetics, 2nd edn. Banbury: Scion; 2010. Strachan T, Read A. Human molecular genetics, 4th edn. New York: Garland Science; 2010. Websites bsgm.org.uk British Society for Genetic Medicine; has a report on genetic testing of children. decipher.sanger.ac.uk Excellent, comprehensive genomic database. ensembl.org Annotated genome databases from multiple organisms. futurelearn.com/courses/the-genomics-era Has a Massive Open Online Course on genomics, for which one of the authors of the current chapter is the lead educator. genome.ucsc.edu Excellent source of genomic information. ncbi.nlm.nih.gov Online Mendelian Inheritance in Man (OMIM). ncbi.nlm.nih.gov/books/NBK1116/ Gene Reviews: excellent US-based source of information about many rare genetic diseases. orpha.net/consor/cgi-bin/index.php Orphanet: European-based database on rare disease. Ethics in a genomic age As genomic technology is increasingly moving into mainstream clinical practice, it is essential for clinicians from all specialties to appreciate the complexities of genetic testing and consider whether genetic testing is the right thing to do in a given clinical scenario. To exemplify the ethical considerations associated with genetic testing, it may be helpful to think about them in the context of a clinical scenario. As you read the scenario, try to think what counselling/ethical issues might arise. A 32-year-old woman is referred to discuss BRCA2 testing; she is currently pregnant with her second child (she already has a 2-year-old daughter) and has an identical twin sister. Her mother, a healthy 65-year-old with Ashkenazi Jewish ancestry, participated in direct-to-consumer testing (DCT) for ‘a bit of fun’ and a BRCA2 mutation – common in the Ashkenazi Jewish population – was identified. There is no significant cancer family history of note. Consider the following issues: • Pre-symptomatic/predictive testing: this describes testing for a known familial gene mutation in an unaffected individual (compared with diagnostic testing, where genetic testing is undertaken in an affected individual). Although this could be considered for the unaffected patient, in the current scenario any testing would also have implications for her identical twin sister. This needs to be fully explored with the patient and her sister prior to testing. There is also the potential issue of predictive testing in the patient’s first child. A fundamental tenet in clinical genetics is that predictive genetic testing should be avoided in childhood for adult-onset conditions. This is because, if no benefit to the patient is accrued through childhood testing, it is better to retain the child’s right to decide for herself, when she is old enough, whether she wishes to participate in genetic testing or not. • Prenatal testing: the principles behind predictive genetic testing in childhood can be extended to prenatal testing, i.e. if a pregnancy is being continued, a baby should not be tested for an adult-onset condition that cannot be prevented or treated in childhood. However, prenatal testing itself is hugely controversial and there is much debate as to how severe a condition should be to justify prenatal diagnosis, which would determine ongoing pregnancy decisions. • DCT: while DCT can be interesting and empowering for individuals wishing to find out more about their genetic backgrounds, it also has several drawbacks. Perhaps the main one is that, unlike face-to-face genetic counselling (which usually precedes any genetic testing, certainly where there are serious health implications for the individual and their family, such as is associated with

7KLVSDJHLQWHQWLRQDOO\OHIWEODQN

Ch02-1 Fundamentals of Medicine

04-4 Clinical immunology

4 Clinical immunology

Clinical immunology SE Marshall SL Johnston Functional anatomy and physiology 62 The innate immune system 62 The adaptive immune system 67 The inflammatory response 70 Acute inflammation 70 Chronic inflammation 71 Laboratory features of inflammation 71 Presenting problems in immune disorders 73 Recurrent infections 73 Intermittent fever 74 Anaphylaxis 75 Immune deficiency 77 Primary phagocyte deficiencies 77 Complement pathway deficiencies 78 Primary antibody deficiencies 78 Primary T-lymphocyte deficiencies 79 Secondary immune deficiencies 80 Periodic fever syndromes 81 Amyloidosis 81 Autoimmune disease 81 Allergy 84 Angioedema 87 Transplantation and graft rejection 88 Transplant rejection 88 Complications of transplant immunosuppression 89 Organ donation 90 Tumour immunology 90

62 • CLINICAL IMMUNOLOGY to protect against infection (Fig. 4.1). Immune defences are normally categorised into the innate immune response, which provides immediate protection against an invading pathogen, and the adaptive or acquired immune response, which takes more time to develop but confers exquisite specificity and long-lasting protection. The innate immune system Innate defences against infection include anatomical barriers, phagocytic cells, soluble molecules such as complement and acute phase proteins, and natural killer cells. The innate immune system recognises generic microbial structures present on non-mammalian tissue and can be mobilised within minutes. A specific stimulus will elicit essentially identical responses in different individuals, in contrast with adaptive antibody and T-cell responses, which vary greatly between individuals. Physical barriers The tightly packed keratinised cells of the skin physically limit colonisation by microorganisms. The hydrophobic oils that are secreted by sebaceous glands further repel water and microorganisms, and microbial growth is inhibited by the skin’s low pH and low oxygen tension. Sweat also contains lysozyme, an enzyme that destroys the structural integrity of bacterial cell walls; ammonia, which has antibacterial properties; and several The immune system has evolved to identify and destroy pathogens while minimising damage to host tissue. Despite the ancient observation that recovery from an infectious disease frequently results in protection against that condition, the existence of the immune system as a functional entity was not recognised until the end of the 19th century. More recently, it has become clear that the immune system not only protects against infection but also regulates tissue repair following injury, and when dysregulated, governs the responses that can lead to autoimmune and auto-inflammatory diseases. Dysfunction or deficiency of the immune response can lead to a wide variety of diseases that may potentially involve every organ system in the body. The aim of this chapter is to provide a general understanding of the immune system, how it contributes to human disease and how manipulation of the immune system can be put to therapeutic use. A review of the key components of the immune response is followed by sections that illustrate the clinical presentation of the most common forms of immune dysfunction: immune deficiency, inflammation, autoimmunity and allergy. More detailed discussion of individual conditions can be found in the relevant organ-specific chapters of this book. Functional anatomy and physiology The immune system consists of an intricately linked network of lymphoid organs, cells and proteins that are strategically placed Fig. 4.1 Anatomy of the immune system. Adenoids Lymph nodes Tonsils Thoracic duct Spleen Bone marrow Liver Appendix Germinal centre Proliferating B cells after antigen exposure Afferent lymph Paracortex T cells Dendritic cells Cortex B cells in primary lymphoid follicles Efferent lymph Medulla Plasma cells Sinuses with macrophages Blood vessels Capsule Lymph node section Lymphatics Neutrophil Eosinophil Cells of the innate immune system Natural killer cell Basophil Mast cell Monocyte Macrophage T lymphocyte Cells of the adaptive immune system Antigen-presenting cell B lymphocyte Thymus Peyer’s patches in small intestine

Functional anatomy and physiology • 63

the specific soluble proteins and cells of the innate immune system are activated. Phagocytes Phagocytes (‘eating cells’) are specialised cells that ingest and kill microorganisms, scavenge cellular and infectious debris, and produce inflammatory molecules that regulate other components of the immune system. They include neutrophils, monocytes and macrophages, and are particularly important for defence against bacterial and fungal infections. Phagocytes express a wide range of surface receptors, including pattern recognition receptors (PRRs), which recognise pathogen-associated molecular patterns (PAMPs) on invading microorganisms, allowing their identification. The PRRs include Toll-like receptors, nucleotide oligomerisation domain (NOD) protein-like receptors and mannose receptors, whereas the PAMPs they recognise are molecular motifs not present on mammalian cells, including bacterial cell wall components, bacterial DNA and viral double-stranded RNA. While phagocytes can recognise microorganisms through PRRs alone, engulfment of microorganisms is greatly enhanced by opsonisation. Opsonins include acute phase proteins produced by the liver, such as C-reactive protein and complement. Antibodies generated by the adaptive immune system also act as opsonins. They bind both to the pathogen and to phagocyte receptors, acting as a bridge between the two to facilitate phagocytosis (Fig. 4.2). This is followed by intracellular pathogen destruction and downstream activation of pro-inflammatory genes, resulting in the generation of pro-inflammatory cytokines as discussed below. antimicrobial peptides such as defensins. Similarly, the mucous membranes of the respiratory, gastrointestinal and genitourinary tracts provide a physical barrier to infection. Secreted mucus traps invading pathogens, and immunoglobulin A (IgA), generated by the adaptive immune system, prevents bacteria and viruses attaching to and penetrating epithelial cells. As in the skin, lysozyme and antimicrobial peptides within mucosal membranes directly kill invading pathogens, and lactoferrin acts to starve invading bacteria of iron. Within the respiratory tract, cilia directly trap pathogens and contribute to removal of mucus, assisted by physical manœuvres such as sneezing and coughing. In the gastrointestinal tract, hydrochloric acid and salivary amylase chemically destroy bacteria, while normal peristalsis and induced vomiting or diarrhoea assist clearance of invading organisms. The microbiome, which is made up of endogenous commensal bacteria, provides an additional constitutive defence against infection. Approximately 1014 bacteria normally reside at epithelial surfaces in symbiosis with the human host (p. 102). They compete with pathogenic microorganisms for scarce resources, including space and nutrients, and produce fatty acids and bactericidins that inhibit the growth of many pathogens. In addition, recent research has demonstrated that commensal bacteria help to shape the immune response by inducing specific regulatory T cells within the intestine. Eradication of the normal flora with broad-spectrum antibiotics commonly results in opportunistic infection by organisms such as Clostridium difficile, which rapidly colonise an undefended ecological niche. These constitutive barriers are highly effective, but if external defences are breached by a wound or pathogenic organism, Fig. 4.2 Phagocytosis and opsonisation. Phagocytosis of microbes can be augmented by several opsonins, such as C-reactive protein, antibodies and complement fragments like C3b, which enhance the ability of phagocytic cells to engulf microorganisms and destroy them. Phagocytes also recognise components of microbes, such as lipopolysaccharide, peptidoglycans, DNA and RNA, collectively as pathogen-associated molecular patterns (PAMPs). These activate pattern recognition receptors (PRRs), such as Toll-like receptors and nucleotide oligomerisation domain (NOD)-like receptors, which promote inflammatory gene expression through the nuclear factor kappa beta (NFκB) pathway. Uric acid and other crystals can also promote inflammation through the NOD pathway. Microbes C3b Antibody C-reactive protein Fc receptor Toll-like receptors NOD-like receptors Lipopolysaccharide Bacterial DNA Bacterial RNA Peptidoglycans Crystals NFκB NFκB Lysosome C3b receptor Phagocytic cell Pro-inflammatory gene expression Response genes

64 • CLINICAL IMMUNOLOGY constitute about 5% of leucocytes. From the blood stream they migrate to peripheral tissues, where they differentiate into tissue macrophages and reside for long periods. Specialised populations of tissue macrophages include Kupffer cells in the liver, alveolar macrophages in the lung, mesangial cells in the kidney, and microglial cells in the brain. Macrophages, like neutrophils, are capable of phagocytosis and killing of microorganisms but also play an important role in the amplification and regulation of the inflammatory response (Box 4.1). They are particularly important in tissue surveillance and constantly survey their immediate surroundings for signs of tissue damage or invading organisms. Dendritic cells Dendritic cells are specialised antigen-presenting cells that are present in tissues in contact with the external environment, such as the skin and mucosal membranes. They can also be found in an immature state in the blood. They sample the environment for foreign particles and, once activated, carry microbial antigens to regional lymph nodes, where they interact with T cells and B cells to initiate and shape the adaptive immune response. Cytokines Cytokines are signalling proteins produced by cells of the immune system and a variety of other cell types. More than 100 have been identified. Cytokines have complex and overlapping roles in cellular communication and regulation of the immune response. Subtle differences in cytokine production, particularly at the initiation of an immune response, can have a major impact on outcome. Cytokines bind to specific receptors on target cells and activate downstream intracellular signalling pathways, ultimately leading to changes in gene transcription and cellular function. Two important signalling pathways are illustrated in Figure 4.3. The nuclear factor kappa B (NFκB) pathway is activated by tumour necrosis factor (TNF), by other members of the TNF superfamily such as receptor activator of nuclear kappa B ligand Neutrophils Neutrophils, also known as polymorphonuclear leucocytes, are derived from the bone marrow and circulate freely in the blood. They are short-lived cells with a half-life of 6 hours, and are produced at the rate of 1011 cells daily. Their functions are to kill microorganisms, to facilitate rapid transit of cells through tissues, and to amplify the immune response non-specifically. These functions are mediated by enzymes contained in granules, which also provide an intracellular milieu for the killing and degradation of microorganisms. Two main types of granule are recognised: primary or azurophil granules, and the more numerous secondary or specific granules. Primary granules contain myeloperoxidase and other enzymes important for intracellular killing and digestion of ingested microbes. Secondary granules are smaller and contain lysozyme, collagenase and lactoferrin, which can be released into the extracellular space. Enzyme production is increased in response to infection, which is reflected by more intense granule staining on microscopy, known as ‘toxic granulation’. Changes in damaged or infected cells trigger local production of inflammatory molecules and cytokines. These cytokines stimulate the production and maturation of neutrophils in the bone marrow, and their release into the circulation. Neutrophils are recruited to specific sites of infection by chemotactic agents, such as interleukin 8 (IL-8), and by activation of local endothelium. Up-regulation of cellular adhesion molecules on neutrophils and the endothelium also facilitates neutrophil migration. The transit of neutrophils through the blood stream is responsible for the rise in neutrophil count that occurs in early infection. Once present within infected tissue, activated neutrophils seek out and engulf invading microorganisms. These are initially enclosed within membrane-bound vesicles, which fuse with cytoplasmic granules to form the phagolysosome. Within this protected compartment, killing of the organism occurs through a combination of oxidative and non-oxidative killing. Oxidative killing, also known as the respiratory burst, is mediated by the nicotinamide adenine dinucleotide phosphate (NADPH)–oxidase enzyme complex, which converts oxygen into reactive oxygen species such as hydrogen peroxide and superoxide that are lethal to microorganisms. The myeloperoxidase enzyme within neutrophils produces hypochlorous acid, which is a powerful oxidant and antimicrobial agent. Non-oxidative (oxygen-independent) killing occurs through the release of bactericidal enzymes into the phagolysosome. Each enzyme has a distinct antimicrobial spectrum, providing broad coverage against bacteria and fungi. An additional, recently identified form of neutrophil-mediated killing is neutrophil extracellular trap (NET) formation. Activated neutrophils can release chromatin with granule proteins such as elastase to form an extracellular matrix that binds to microbial proteins. This can immobilise or kill microorganisms without requiring phagocytosis. The process of phagocytosis and NET formation (NETosis) depletes neutrophil glycogen reserves and is followed by neutrophil death. As the cells die, their contents are released and lysosomal enzymes degrade collagen and other components of the interstitium, causing liquefaction of closely adjacent tissue. The accumulation of dead and dying neutrophils results in the formation of pus, which, if extensive, may lead to abscess formation. Monocytes and macrophages Monocytes are the precursors of tissue macrophages. They are produced in the bone marrow and enter the circulation, where they 4.1 Functions of macrophages Amplification of the inflammatory response • Stimulate the acute phase response (through production of IL-1 and IL-6) • Activate vascular endothelium (IL-1, TNF-α) • Stimulate neutrophil maturation and chemotaxis (IL-1, IL-8) • Stimulate monocyte chemotaxis Killing of microorganisms • Phagocytosis • Microbial killing through oxidative and non-oxidative mechanisms Clearance, resolution and repair • Scavenging of necrotic and apoptotic cells • Clearance of toxins and other inorganic debris • Tissue remodelling (elastase, collagenase, matrix proteins) • Down-regulation of inflammatory cytokines • Wound healing and scar formation (IL-1, platelet-derived growth factor, fibroblast growth factor) Link between innate and adaptive immune systems • Activate T cells by presenting antigen in a recognisable form • T cell-derived cytokines increase phagocytosis and microbicidal activity of macrophages in a positive feedback loop (IL = interleukin; TNF = tumour necrosis factor)

Functional anatomy and physiology • 65

IKK, which in turn leads to phosphorylation of the inhibitor of nuclear factor kappa B protein (IκB), causing it to be degraded, and allowing NFκB to translocate to the nucleus and activate gene transcription. The Janus kinase/signal transducers and activators of transcription (JAK-STAT) pathway is involved in (RANKL; p. 985), and by the Toll-like receptors and NOD-like receptors (see Fig. 4.2). In the case of TNF superfamily members, receptor binding causes the inhibitor of kappa B kinase (IKK) complex of three proteins to be recruited to the receptor by binding TNF receptor-associated proteins (TRAF). This activates Fig. 4.3 Cytokines signalling pathways and the immune response. Cytokines regulate the immune response through binding to specific receptors that activate a variety of intracellular signalling pathways, two of which are shown. Members of the tumour necrosis factor (TNF) superfamily and the Toll-like receptors and NOD-like receptors (Fig. 4.2) signal through the nuclear factor kappa B (NFκB) pathway. Several other cytokines, including interleukin-2 (IL-2), IL-6 and interferons, employ the Janus kinase/ signal transducer and activator of transcription (JAK-STAT) pathway to regulate cellular function (see text for more details). (IκB = inhibitor of kappa B; IKK = I kappa B kinase; P = phosphorylation of the signalling protein; TRAF = tumour necrosis factor receptorassociated factor) JAK JAK inhibitor Response genes Response genes JAK Cytokines Cytokine receptor P P P P P STAT STAT P P STAT STAT DNA TNF TNF receptor TRAF IκB P IκB NFκB NFκB IKKκ IKKα IKKβ IFN-γ IL-6 IL-2 4.2 Important cytokines in the regulation of the immune response Cytokine Source Actions Biologic therapies Interferon-alpha (IFN-α) T cells and macrophages Antiviral activity Activates NK cells, CD8+ T cells and macrophages Recombinant IFN-α used in hepatitis C and some malignancies Interferon-gamma (IFN-γ) T cells and NK cells Increases antimicrobial activity of macrophages Regulates cytokine production by T cells and macrophages Used in chronic granulomatous disease Tumour necrosis factor alpha (TNF-α) Macrophages, NK cells and others, including T cells Pro-inflammatory Increases expression of other cytokines and adhesion molecules Causes apoptosis of some target cells Directly cytotoxic TNF-α inhibitors used in rheumatoid arthritis, inflammatory bowel disease, psoriasis and many other inflammatory conditions Interleukin-1 (IL-1) Macrophages and neutrophils Stimulates neutrophil recruitment, fever, and T-cell and macrophage activation as part of the inflammatory response IL-1 inhibitors used in systemic juvenile rheumatoid arthritis, periodic fever syndromes and acute gout Interleukin-2 (IL-2) CD4+ T cells Stimulates proliferation and differentiation of antigenspecific T lymphocytes Interleukin-4 (IL-4) CD4+ T cells Stimulates maturation of B and T cells, and production of IgE antibody Antibodies to IL-4 receptor used in severe atopic dermatitis Interleukin-6 (IL-6) Monocytes and macrophages Stimulates neutrophil recruitment, fever, and T-cell and macrophage activation as part of the inflammatory response, stimulates maturation of B cells into plasma cells Antibodies to IL-6 receptor used in rheumatoid arthritis Interleukin-12 (IL-12) Monocytes and macrophages Stimulates IFN-γ and TNF-α release by T cells Activates NK cells Antibody to p40 subunit of IL-12 used in psoriasis and psoriatic arthritis Interleukin-17 (IL-17) Th17 cells (T helper), NK cells, NK-T cells Pro-inflammatory cytokine Involved in mucosal immunity and control of extracellular pathogens, synergy with IL-1 and TNF Antibody to IL-17 used in psoriasis, psoriatic arthritis and ankylosing spondylitis Interleukin-22 (IL-22) Th17 cells Induction of epithelial cell proliferation and antimicrobial proteins in keratinocytes (IgE = immunoglobulin E; NK = natural killer)

66 • CLINICAL IMMUNOLOGY important in the defence against encapsulated bacteria such as Neisseria spp. and Haemophilus influenzae. Complement fragments generated by activation of the cascade can also act as opsonins, rendering microorganisms more susceptible to phagocytosis by macrophages and neutrophils (see Fig. 4.2). In addition, they are chemotactic agents, promoting leucocyte trafficking to sites of inflammation. Some fragments act as anaphylotoxins, binding to complement receptors on mast cells and triggering release of histamine, which increases vascular permeability. The products of complement activation also help to target immune complexes to antigen-presenting cells, providing a link between the innate and the acquired immune systems. Finally, activated complement products dissolve the immune complexes that triggered the cascade, minimising bystander damage to surrounding tissues. A monoclonal antibody directed against the central complement molecule C5, eculizumab, has been developed for therapeutic use in paroxysmal nocturnal haemoglobinuria and atypical haemolytic uraemic syndromes (p. 408). Invasive infection, including meningococcal sepsis, has been reported with eculizumab therapy, highlighting the importance of the complement system in preventing such infections. Mast cells and basophils Mast cells and basophils are bone marrow-derived cells that play a central role in allergic disorders. Mast cells reside predominantly in tissues exposed to the external environment, such as the skin and gut, while basophils circulate in peripheral blood and are recruited into tissues in response to inflammation. Both contain large cytoplasmic granules that enclose vasoactive substances such as histamine (see Fig. 4.14). Mast cells and Fig. 4.4 The complement pathway. The classical pathway is activated by binding of antigen–antibody complexes to C1 but is blocked by C1 inhibitor (C1inh), whereas mannose-binding lectins, which are macromolecules that bind to various microorganisms, activate the pathway by binding C4. Bacteria can directly activate the pathway through C3, which plays a pivotal role in complement activation through all three pathways. Smooth muscle contraction Activation of cells Vascular permeability Lysis of bacteria Membrane attack complex (MAC) Opsonisation of bacteria Direct activation Lectin pathway Mannosebinding lectin Classical pathway Antibody–antigen complexes Alternate pathway C4 C2 C3 C3a C1inh C5a C5 C3b C5b C6 C7 C8 C1 C9 transducing signals downstream of many cytokine receptors, including those for IL-2, IL-6 and interferon-gamma (IFN-γ). On receptor binding, JAK proteins are recruited to the intracellular portion of the receptor and are phosphorylated. These in turn phosphorylate STAT proteins, which translocate to the nucleus and activate gene transcription, altering cellular function. The function and disease associations of several important cytokines are shown in Box 4.2. Cytokine inhibitors are now routinely used in the treatment of autoimmune diseases, most of which are monoclonal antibodies to cytokines or their receptors. In addition, small-molecule inhibitors have been developed that inhibit the intracellular signalling pathways used by cytokines. These include the Janus kinase inhibitors tofacitinib and baracitinib, which are used in rheumatoid arthritis (p. 1026), and the tyrosine kinase inhibitor imatinib, which is used in chronic myeloid leukaemia (p. 959). Integrins Integrins are transmembrane proteins that play important roles in cell–cell and cell–matrix interactions. They mediate attachment of the cell to the extracellular matrix, signal transduction and cell migration. Their role in autoimmune disease has been extensively studied. Targeted therapy with a recombinant humanised anti-α4 integrin antibody, natalizumab, is an effective treatment for multiple sclerosis, which works by preventing immune cells from traversing the vascular endothelium and entering the central nervous system (p. 1109). Complement The complement system comprises a group of more than 20 tightly regulated, functionally linked proteins that act to promote inflammation and eliminate invading pathogens. Complement proteins are produced in the liver and are present in inactive form in the circulation. When the complement system is activated, it sets in motion a rapidly amplified biological cascade analogous to the coagulation cascade (p. 918). There are three mechanisms by which the complement cascade can be activated (Fig. 4.4): • The alternate pathway is triggered directly by binding of C3 to bacterial cell-wall components, such as lipopolysaccharide of Gram-negative bacteria and teichoic acid of Gram-positive bacteria. • The classical pathway is initiated when two or more IgM or IgG antibody molecules bind to antigen. The associated conformational change exposes binding sites on the antibodies for the first protein in the classical pathway, C1, which is a multiheaded molecule that can bind up to six antibody molecules. Once two or more ‘heads’ of a C1 molecule are bound to antibody, the classical cascade is triggered. An important inhibitor of the classical pathway is C1 inhibitor (C1inh), as illustrated in Figure 4.4. • The lectin pathway is activated by the direct binding of mannose-binding lectin to microbial cell surface carbohydrates. This mimics the binding of C1 to immune complexes and directly stimulates the classical pathway, bypassing the need for immune complex formation. Activation of complement by any of these pathways results in activation of C3. This in turn activates the final common pathway, in which the complement proteins C5–C9 assemble to form the membrane attack complex (MAC). This can puncture the cell wall, leading to osmotic lysis of target cells. This step is particularly

Functional anatomy and physiology • 67

Lymphoid organs The primary lymphoid organs are involved in lymphocyte development. They include the bone marrow, where T and B lymphocytes differentiate from haematopoietic stem cells (p. 914) and where B lymphocytes also mature, and the thymus, the site of T-cell maturation (see Fig. 4.1). After maturation, lymphocytes migrate to the secondary lymphoid organs. These include the spleen, lymph nodes and mucosa-associated lymphoid tissue. These trap and concentrate foreign substances and are the major sites of interaction between naïve lymphocytes and microorganisms. The thymus The thymus is a bi-lobed structure in the anterior mediastinum, and is organised into cortical and medullary areas. The cortex is densely populated with immature T cells, which migrate to the medulla to undergo selection and maturation. The thymus is most active in the fetal and neonatal period, and involutes after puberty. Failure of thymic development is associated with profound T-cell immune deficiency (p. 79) but surgical removal of the thymus in childhood (usually during major cardiac surgery) is not associated with significant immune dysfunction. The spleen The spleen is the largest of the secondary lymphoid organs. It is highly effective at filtering blood and is an important site of phagocytosis of senescent erythrocytes, bacteria, immune complexes and other debris, and of antibody synthesis. It is important for defence against encapsulated bacteria, and asplenic individuals are at risk of overwhelming Streptococcus pneumoniae and H. influenzae infection (see Box 4.5). Lymph nodes These are positioned to maximise exposure to lymph draining from sites of external contact, and are highly organised (Fig. 4.1) • The cortex contains primary lymphoid follicles, which are the site of B-lymphocyte interactions. When B cells encounter antigen, they undergo intense proliferation, forming germinal centres. • The paracortex is rich in T lymphocytes and dendritic cells. • The medulla is the major site of antibody-secreting plasma cells. • Within the medulla there are many sinuses, which contain large numbers of macrophages. Mucosa-associated lymphoid tissue Mucosa-associated lymphoid tissue (MALT) consists of diffusely distributed lymphoid cells and follicles present along mucosal surfaces. It has a similar function to the more organised, encapsulated lymph nodes. They include the tonsils, adenoids and Peyer’s patches in the small intestine. Lymphatics Lymphoid tissue is connected by a network of lymphatics, with three major functions: it provides access to lymph nodes, returns interstitial fluid to the venous system, and transports fat from the small intestine to the blood stream (see Fig. 14.13, p. 372). The lymphatics begin as blind-ending capillaries, which come together to form lymphatic ducts, entering and leaving regional lymph nodes as afferent and efferent ducts, respectively. They eventually coalesce and drain into the thoracic duct and left subclavian vein. Lymphatics may be either deep or superficial, and follow the distribution of major blood vessels. basophils express IgE receptors on their cell surface, which bind IgE antibody. On encounter with specific antigen, the cell is triggered to release histamine and other mediators present within the granules and to synthesise additional mediators, including leukotrienes, prostaglandins and cytokines. An inflammatory cascade is initiated that increases local blood flow and vascular permeability, stimulates smooth muscle contraction, and increases secretion at mucosal surfaces. Natural killer cells Natural killer (NK) cells are large granular lymphocytes that play a major role in defence against tumours and viruses. They exhibit features of both the adaptive and the innate immune systems in that they are morphologically similar to lymphocytes and recognise similar ligands, but they are not antigen-specific and cannot generate immunological memory. NK cells express a variety of cell surface receptors, some of which are stimulatory and others inhibitory. The effects of inhibitory receptors normally predominate. These recognise human leucocyte antigen (HLA) molecules that are expressed on normal nucleated cells, preventing NK cell-mediated attack, whereas the stimulatory receptors recognise molecules that are expressed primarily when cells are damaged. This allows NK cells to remain tolerant to healthy cells but not to damaged ones. When cells become infected by viruses or undergo malignant change, expression of HLA class I molecules on the cell surface can be down-regulated. This is an important mechanism by which these cells then evade adaptive T-lymphocyte responses. In this circumstance, however, NK cell defences becomes important, as down-regulation of HLA class I abrogates the inhibitory signals that normally prevent NK activation. The net result is NK attack on the abnormal target cell. NK cells can also be activated by binding of antigen–antibody complexes to surface receptors. This physically links the NK cell to its target in a manner analogous to opsonisation and is known as antibody-dependent cellular cytotoxicity (ADCC). Activated NK cells can kill their targets in various ways. They secrete pore-forming proteins such as perforin into the membrane of the target cell, and proteolytic enzymes called granzymes into the target cell, which cause apoptosis. In addition, NK cells produce a variety of cytokines such as TNF-α and IFN-γ, which have direct antiviral and anti-tumour effects. The adaptive immune system If the innate immune system fails to provide effective protection against an invading pathogen, the adaptive immune system is mobilised (see Fig. 4.1). This has three key characteristics: • It has exquisite specificity and can discriminate between very small differences in molecular structure. • It is highly adaptive and can respond to an almost unlimited number of molecules. • It possesses immunological memory, and changes consequent to initial activation by an antigen allow a more effective immune response on subsequent encounters. There are two major arms of the adaptive immune response. Humoral immunity involves the production of antibodies by B lymphocytes, and cellular immunity involves the activation of T lymphocytes, which synthesise and release cytokines that affect other cells, as well as directly killing target cells. These interact closely with each other and with the components of the innate immune system to maximise effectiveness of the immune response.

68 • CLINICAL IMMUNOLOGY Humoral immunity Humoral immunity is mediated by B lymphocytes, which differentiate from haematopoietic stem cells in the bone marrow. Their major functions are to produce antibody and interact with T cells, but they are also involved in antigen presentation. Mature B lymphocytes can be found in the bone marrow, lymphoid tissue, spleen and, to a lesser extent, the blood stream. They Fig. 4.5 B-cell activation. Activation of B cells is initiated through binding of an antigen with the immunoglobulin receptor on the cell surface. For activation to proceed, an interaction with T-helper cells is also required, providing additional signals through binding of CD40 ligand (CD40L) to CD40; an interaction between the T-cell receptor (TCR) and processed antigenic peptides presented by human leucocyte antigen (HLA) molecules on the B-cell surface; and cytokines released by the T-helper cells. Fully activated B cells undergo clonal expansion with differentiation towards plasma cells that produce antibody. Following activation, memory cells are generated that allow rapid antibody responses when the same antigen is encountered on a second occasion. (CD = cluster of differentiation; IL = interleukin) T-helper cell Immunoglobulin receptor Antigen CD40L CD40 TCR HLA B-cell activation B cell Clonal expansion Plasma cells Antibodies Memory B cells IL-4 IL-5 Fig. 4.6 The structure of an immunoglobulin (antibody) molecule. The variable region is responsible for antigen binding, whereas the constant region can interact with immunoglobulin receptors expressed on immune cells. Variable region (Fab) Constant region (Fc) Light chain Heavy chain 4.3 Classes and properties of antibody Antibody Concentration in adult serum Complement activation* Opsonisation Presence in external secretions Other properties IgG 6.0–16.0 g/L IgG1 +++ IgG2 + IgG3 +++ IgG1 ++ IgG3 ++ ++ Four subclasses: IgG1, IgG2, IgG3, IgG4 Distributed equally between blood and extracellular fluid, and transported across placenta IgG2 is particularly important in defence against polysaccharides antigens IgA 1.5–4.0 g/L – – ++++ Two subclasses: IgA1, IgA2 Highly effective at neutralising toxins Particularly important at mucosal surfaces IgM 0.5–2.0 g/L ++++ – + Highly effective at agglutinating pathogens IgE 0.003–0.04 g/L – – – Majority of IgE is bound to mast cells, basophils and eosinophils Important in allergic disease and defence against parasite infection IgD Not detected – – – Function in B-cell development *Activation of the classical pathway, also called ‘complement fixation’. express a unique immunoglobulin receptor on their cell surface, the B-cell receptor, which binds to soluble antigen targets (Fig. 4.5). Encounters with antigen usually occur within lymph nodes. If provided with appropriate cytokines and other signals from nearby T lymphocytes, antigen-specific B cells respond by rapidly proliferating in a process known as clonal expansion (Fig. 4.5). This is accompanied by a highly complex series of genetic rearrangements known as somatic hypermutation, which generates B-cell populations that express receptors with greater affinity for antigen than the original. These cells differentiate into either long-lived memory cells, which reside in the lymph nodes, or plasma cells, which produce antibody. Memory cells allow production of a more rapid and more effective response on subsequent exposure to that pathogen. Immunoglobulins Immunoglobulins (Ig) play a central role in humoral immunity. They are soluble proteins produced by plasma cells and are made up of two heavy and two light chains (Fig. 4.6). The heavy chain determines the antibody class or isotype, such as IgG, IgA, IgM, IgE or IgD. Subclasses of IgG and IgA also occur. The antigen is recognised by the antigen-binding regions (Fab) of both heavy and light chains, while the consequences of antibody binding are determined by the constant region of the heavy chain (Fc) (Box 4.3). Antibodies have several functions.

Functional anatomy and physiology • 69

and production of antibody is decreased to 2–3 days, the amount of antibody produced is increased, and the response is dominated by IgG antibodies of high affinity. Furthermore, in contrast to the initial antibody response, secondary antibody responses do not require additional input from T lymphocytes. This allows the rapid generation of highly specific responses on re-exposure to a pathogen and is an important mechanism in vaccine efficacy. Cellular immunity Cellular immunity is mediated by T lymphocytes, which play important roles in defence against viruses, fungi and intracellular bacteria. They also play an important immunoregulatory role, by orchestrating and regulating the responses of other components of the immune system. T-lymphocyte precursors differentiate from haematopoietic stem cells in the bone marrow and are exported to the thymus when they are still immature (see Fig. 4.1). Individual T cells express a unique receptor that is highly Fig. 4.7 T-cell activation. Activation of T cells is initiated when an antigenic peptide bound to a human leucocyte antigen (HLA) molecule on antigenpresenting cells interacts with the T-cell receptor expressed by T lymphocytes. Additional signals are required for T-cell activation, however. These include binding of the co-stimulatory molecules CD80 and CD86 with CD28 on the T cell, and interleukin 2 (IL-2), which is produced in an autocrine manner by T cells that are undergoing activation. Other molecules are present that can inhibit T-cell activation, however, including cytotoxic T-lymphocyte-associated protein 4 (CTLA4), which competes with CD28 for binding to CD80 and CD86; and PD1, which, by binding PDL1, is also inhibitory. Following activation, T cells proliferate and, depending on their subtype, have various functions with distinct patterns of cytokine production, as indicated. Memory cells are also generated that can mount a rapid immune response on encountering the same antigen. (CD = cluster of differentiation; CD40L = CD40 ligand; IFN-γ = interferon-gamma; IL = interleukin; PD1 = programmed cell death 1; PDL1 = programmed death ligand 1; TGF-β = transforming growth factor beta; TNF-α = tumour necrosis factor alpha) CD80 CD86 CD4+ T cells Th2 cells Cytokines IL-4, IL-5, IL-10, IL-13 Function B-cell activation Eosinophil activation Th1 cells Cytokines TNF-α, IFN-γ, IL-2 Function Pro-inflammatory Th17 cells Cytokines IL-17 Function Mucosal immunity Pro-inflammatory Regulatory T cells Memory T cells Memory T cells Cytokines Fas ligand TNF-α, IFN-γ Function Direct cell killing CD8+ T cells Cytokines IL-10, TGF-β Function Anti-inflammatory PDL1 HLA T-cell receptor T-cell activation Antigenic peptide PD1 CTLA4 CD28 Antigen-presenting cell IL-2 They facilitate phagocytosis by acting as opsonins (see Fig. 4.2) and facilitate cell killing by cytotoxic cells, particularly NK cells by antibody-dependent cellular cytotoxicity. Binding of antibodies to antigen can trigger activation of the classical complement pathway (see Fig. 4.4). In addition, antibodies can directly neutralise the biological activity of their antigen target. This is a particularly important feature of IgA antibodies, which act predominantly at mucosal surfaces. The humoral immune response is characterised by immunological memory, in which the antibody response to successive exposures to an antigen is qualitatively and quantitatively improved from the first exposure. When a previously unstimulated or ‘naïve’ B lymphocyte is activated by antigen, the first antibody to be produced is IgM, which appears in the serum after 5–10 days. Depending on additional stimuli provided by T lymphocytes, other antibody classes (IgG, IgA and IgE) are produced 1–2 weeks later. If the memory B cell is subsequently re-exposed to the same antigen, the lag time between exposure

70 • CLINICAL IMMUNOLOGY molecules that down-regulate T-cell activity. One such inhibitory molecule, CTLA4, has been harnessed therapeutically in the form of abatacept, which is a fusion protein comprised of the Fc fragment of immunoglobulin linked to CTLA4. This is used to inhibit T-cell activation in rheumatoid arthritis and solid organ transplantation. The inflammatory response Inflammation is the response of tissues to injury or infection, and is necessary for normal repair and healing. This section focuses on the general principles of the inflammatory response and its multisystem manifestations. The role of inflammation in specific diseases is discussed in many other chapters of this book. Acute inflammation Acute inflammation is the result of rapid and complex interplay between the cells and soluble molecules of the innate immune system. The classical external signs include heat, redness, pain and swelling (Fig. 4.8). The inflammatory process is initiated by local tissue injury or infection. Damaged epithelial cells produce cytokines and antimicrobial peptides, causing early infiltration of phagocytic cells. Production of leukotrienes, prostaglandins, histamine, kinins, anaphylotoxins and inducible nitric oxide synthase also occurs within inflamed tissue. These mediators cause vasodilatation and increased vascular permeability, causing trafficking of fluid and cells into the affected tissue. In addition, pro-inflammatory cytokines, such as IL-1, TNF-α and IL-6 produced at the site of injury, are released systemically and act on the hypothalamus to cause fever, and on the liver to stimulate production of acute phase proteins. The acute phase response The acute phase response refers to the production of a variety of proteins by the liver in response to inflammatory stimuli. These proteins have a wide range of activities. Circulating levels of C-reactive protein (CRP) and serum amyloid A may be increased 1000-fold, contributing to host defence and stimulating repair and regeneration. Fibrinogen plays an essential role in wound healing, and α1-antitrypsin and α1-antichymotrypsin control the pro-inflammatory cascade by neutralising the enzymes produced by activated neutrophils, preventing widespread tissue destruction. In addition, antioxidants such as haptoglobin and manganese superoxide dismutase scavenge for oxygen free radicals, while increased levels of iron-binding proteins such as ferritin and lactoferrin decrease the iron available for uptake by bacteria (p. 941). Immunoglobulins are not acute phase proteins but are often increased in chronic inflammation. Septic shock Septic shock is the clinical manifestation of overwhelming inflammation (p. 196). It is characterised by excessive production of pro-inflammatory cytokines by macrophages, causing hypotension, hypovolaemia and tissue oedema. In addition, uncontrolled neutrophil activation causes release of proteases and oxygen free radicals within blood vessels, damaging the vascular endothelium and further increasing capillary permeability. Direct activation of the coagulation pathway combines with endothelial cell disruption to form clots within the damaged vessels. The specific for a single antigen. Within the thymus T cells undergo a process of stringent selection to ensure that autoreactive cells are destroyed. Mature T lymphocytes leave the thymus and expand to populate other organs of the immune system. It has been estimated that an individual possesses 107–109 T-cell clones, each with a unique T-cell receptor, ensuring at least partial coverage for any antigen encountered. Unlike B cells, T cells cannot recognise intact protein antigens in their native form. Instead, the protein must be broken down into component peptides by antigen-presenting cells for presentation to T lymphocytes in association with HLA molecules on the antigen-presenting cell surface. This process is known as antigen processing and presentation, and it is the complex of peptide and HLA together that is recognised by individual T cells (Fig. 4.7). The structure of HLA molecules varies widely between individuals. Since each HLA molecule has the capacity to present a subtly different peptide repertoire to T lymphocytes, this ensures enormous diversity in recognition of antigens by the T-cell population. All nucleated cells have the capacity to process and present antigens, but cells with specialised antigenpresenting functions include dendritic cells, macrophages and B lymphocytes. These carry additional co-stimulatory molecules, such as CD80 and CD86, providing the necessary ‘second signal’ for full T-cell activation. T lymphocytes can be divided into two subgroups on the basis of function and recognition of HLA molecules. These are designated CD4+ and CD8+ T cells, according to the ‘cluster of differentiation’ (CD) antigen number of key proteins expressed on their cell surface. CD8 + T lymphocytes These cells recognise antigenic peptides in association with HLA class I molecules (HLA-A, HLA-B, HLA-C). They kill infected cells directly through the production of pore-forming molecules such as perforin and release of digesting enzymes triggering apoptosis of the target cell, and are particularly important in defence against viral infection. CD4 + T lymphocytes These cells recognise peptides presented on HLA class II molecules (HLA-DR, HLA-DP and HLA-DQ) and have mainly immunoregulatory functions. They produce cytokines and provide co-stimulatory signals that support the activation of CD8+ T lymphocytes and assist the production of mature antibody by B cells. In addition, their close interaction with phagocytes determines cytokine production by both cell types. CD4+ lymphocytes can be further subdivided into subsets on the basis of the cytokines they produce: • Th1 (T helper) cells typically produce IL-2, IFN-γ and TNF-α, and support the development of delayed-type hypersensitivity responses (p. 83). • Th2 cells typically produce IL-4, IL-5, IL-10 and IL-13, and promote allergic responses (p. 84). • T-regulatory cells (T regs) are a further subset of specialised CD4+ lymphocytes that are important in actively suppressing activation of other cells and preventing autoimmune disease. • Th17 cells are pro-inflammatory cells defined by their production of IL-17. They are related to regulatory T cells, and play a role in immune defence at mucosal surfaces T-cell activation is regulated by a balance between co-stimulatory molecules, the second signal required for activation, and inhibitory

The inflammatory response • 71

Chronic inflammation In most instances, the development of an active immune response results in clearance and control of the inflammatory stimulus and resolution of tissue damage. Failure of this process may result in chronic inflammation, with significant associated bystander damage, known as hypersensitivity responses. Persistence of microorganisms can result in ongoing accumulation of neutrophils, macrophages and activated T lymphocytes within the lesion. If this is associated with local deposition of fibrous tissue, a granuloma may form. Granulomas are characteristic of tuberculosis and leprosy (Hansen’s disease), in which the microorganism is protected by a robust cell wall that shields it from killing, despite phagocytosis. Laboratory features of inflammation Inflammation is associated with changes in many laboratory investigations. Leucocytosis is common, and reflects the transit of activated neutrophils and monocytes to the site of infection. The platelet count may also be increased. The most widely used laboratory measure of acute inflammation is CRP. Circulating clinical consequences include cardiovascular collapse, acute respiratory distress syndrome, disseminated intravascular coagulation, multi-organ failure and often death. Septic shock most frequently results from infection with Gram-negative bacteria, because lipopolysaccharide produced by these organisms is particularly effective at activating the inflammatory cascade. Early recognition and appropriate early intervention can improve patient outcome (p. 196). Resolution of inflammation Resolution of an inflammatory response is crucial for normal healing. This involves active down-modulation of inflammatory stimuli and repair of bystander damage to local tissues. Extravasated neutrophils undergo apoptosis and are phagocytosed by macrophages, along with the remains of microorganisms. Macrophages also synthesise collagenase and elastase, which break down local connective tissue and aid in the removal of debris. Normal tissue homeostasis is also associated with reversion of parenchymal cells to a non-inflammatory phenotype. Macrophage-derived cytokines, including transforming growth factor-beta (TGF-β) and platelet-derived growth factor, stimulate fibroblasts and promote the synthesis of new collagen, while angiogenic factors stimulate new vessel formation. Fig. 4.8 Clinical features of acute inflammation. In this example, the response is to a penetrating injury and infection of the foot. Hypothalamus: Change in temperature set point Fever Sweating Neuro-endocrine and autonomic stress responses Flushing ↑Respiratory rate ↑Heart rate, flow murmur Adrenal release of glucocorticoids and catecholamines Release of insulin from pancreas Bone marrow: ↑Production and mobilisation of neutrophils Vasodilatation ↑Local vascular permeability Neutrophils + Macrophages Inflammatory mediators and cytokines Tissue damage Bacteria Local infection Skin rupture Phagocytosis Cytokine production Vasodilatation ↑Local vascular permeability ↑Leucocyte influx Headache Delirium Anorexia Low blood pressure Liver: ↑Synthesis of acute phase proteins Enlarged draining lymph nodes Ascending lymphangitis Local cellulitis Pain Redness Swelling Nail

72 • CLINICAL IMMUNOLOGY by the composition of plasma proteins and the morphology of circulating erythrocytes. These factors govern the propensity of red cells to aggregate, the major determinant of the ESR. Erythrocytes are inherently negatively charged, which prevents them from clumping together in the blood stream. Since plasma proteins are positively charged, an increase in plasma protein concentrations neutralises the negative charge of erythrocytes, overcoming their inherent repulsive forces and causing them aggregate, resulting in rouleaux formation. Rouleaux have a higher mass-to-surface area ratio than single red cells, and therefore sediment faster. The most common reason for an increased ESR is an acute phase response, which causes an increase in the concentration of acute phase proteins, including CRP. However, other conditions that do not affect acute phase proteins may alter the composition and concentration of other plasma protein (Box 4.4). For example, immunoglobulins comprise a significant proportion of plasma proteins but do not participate in the acute phase response. Thus any condition that causes an increase in serum immunoglobulins will increase the ESR without a corresponding increase in CRP. In addition, abnormal red cell morphology can make rouleaux formation impossible. For these reasons, an inappropriately low ESR occurs in spherocytosis and sickle-cell anaemia. Plasma viscosity Plasma viscosity is another surrogate measure of plasma protein concentration. Like the ESR, it is affected by the concentration of large plasma proteins, including fibrinogen and immunoglobulins. It is not affected by properties of erythrocytes and is generally considered to be more reliable than the ESR as a marker of inflammation. levels of many other acute phase reactants, including fibrinogen, ferritin and complement components, are also increased in response to acute inflammation, while albumin levels are reduced. Chronic inflammation is frequently associated with a normocytic normochromic anaemia (p. 943). C-reactive protein C-reactive protein (CRP) is an acute phase reactant synthesised by the liver, which opsonises invading pathogens. Circulating concentrations of CRP increase within 6 hours of the start of an inflammatory stimulus. Serum concentrations of CRP provide a direct biomarker of acute inflammation and, because the serum half-life of CRP is 18 hours, levels fall promptly once the inflammatory stimulus is removed. Sequential measurements are useful in monitoring disease activity (Box 4.4). For reasons that remain unclear, some diseases are associated with only minor elevations of CRP despite unequivocal evidence of active inflammation. These include systemic lupus erythematosus (SLE), systemic sclerosis, ulcerative colitis and leukaemia. An important practical point is that if the CRP is raised in these conditions, it suggests intercurrent infection rather than disease activity. Since the CRP is a more sensitive early indicator of the acute phase response, it is generally used in preference to the erythrocyte sedimentation rate (ESR). If both ESR and CRP are used, any discrepancy should be resolved by assessing the individual determinants of the ESR, which are discussed below. Erythrocyte sedimentation rate The ESR is an indirect measure of inflammation. It measures how fast erythrocytes fall through plasma, which is determined 4.4 Conditions commonly associated with abnormal C-reactive protein (CRP) and/or erythrocyte sedimentation rate (ESR) Condition Consequence Effect on CRP1 Effect on ESR2 Acute bacterial, fungal or viral infection Stimulates acute phase response Increased (range 50–150 mg/L; in severe infections may be

300 mg/L) Increased Necrotising bacterial infection Stimulates profound acute inflammatory response Greatly increased (may be 300 mg/L) Increased Chronic bacterial or fungal infection Localised abscess, bacterial endocarditis or tuberculosis Stimulates acute and chronic inflammatory response with polyclonal increase in immunoglobulins, as well as increased acute phase proteins Increased (range 50–150 mg/L) Increased disproportionately to CRP Acute inflammatory diseases Crohn’s disease, polymyalgia rheumatica, inflammatory arthritis Stimulates acute phase response Increased (range 50–150 mg/L) Increased Systemic lupus erythematosus, Sjögren’s syndrome, ulcerative colitis Chronic inflammatory response Normal Increased Multiple myeloma Monoclonal increase in serum immunoglobulin without acute inflammation Normal Increased Pregnancy, old age, end-stage renal disease Increased fibrinogen Normal Moderately increased 1Reference range < 10 mg/L. 2Reference range: adult males < 10 mm/hr, adult females < 20 mm/hr.

Presenting problems in immune disorders • 73

4.5 Immune deficiencies and common patterns of infection Phagocyte deficiency Complement deficiency Antibody deficiency T-lymphocyte deficiency Bacteria Staphylococcus aureus Pseudomonas aeruginosa Serratia marcescens Burkholderia cenocepacia Nocardia Mycobacterium tuberculosis Atypical mycobacteria Neisseria meningitidis Neisseria gonorrhoeae Haemophilus influenzae Streptococcus pneumoniae Haemophilus influenzae Streptococcus pneumoniae Staphylococcus aureus Mycobacterium tuberculosis Atypical mycobacteria Fungi Candida spp. Aspergillus spp. – – Candida spp. Aspergillus spp. Pneumocystis jirovecii Viruses – – Cytomegalovirus (CMV) Enteroviruses Epstein–Barr virus (EBV) Herpes zoster virus Human papillomavirus Human herpesvirus 8 Protozoa – Giardia lamblia Toxoplasma gondii Cryptosporidia Presenting problems in immune disorders Recurrent infections Infections can occur in otherwise healthy individuals but recurrent infection raises suspicion of an immune deficiency. Depending on the component of the immune system affected, the infections may involve bacteria, viruses, fungi or protozoa, as summarised in Box 4.5. T-cell deficiencies can involve pathogens from all groups. Aetiology Infections secondary to immune deficiency occur because of defects in the number or function of phagocytes, B cells, T cells or complement, as described later in this chapter. Clinical assessment Clinical features that may indicate immune deficiency are listed in Box 4.6. Frequent or severe infections, or ones caused by unusual organisms or at unusual sites are typical of immune deficiency. Investigations Initial investigations should include full blood count and white cell differential, CRP, renal and liver function tests, urine dipstick, serum immunoglobulins with protein electrophoresis, and HIV testing. Additional microbiological tests, virology and imaging are required to identify the causal organism and localise the site of infection, as outlined in Box 4.7. If primary immune deficiency is suspected on the basis of initial investigations, more specialised tests should be considered, as summarised in Box 4.8. Management If an immune deficiency is suspected but has not yet been formally characterised, patients should not receive live vaccines because of the risk of vaccine-induced disease. Further management depends on the underlying cause and details are provided later. 4.6 Warning signs of primary immune deficiency* In children In adults ≥ 4 new ear infections within 1 year ≥ 2 new ear infections within 1 year ≥ 2 serious sinus infections within 1 year ≥ 2 new sinus infections within 1 year, in the absence of allergy ≥ 2 months on antibiotics with little effect Recurrent viral infections ≥ 2 pneumonias within 1 year ≥ 1 pneumonia per year for more than 1 year Failure of an infant to gain weight or grow normally Chronic diarrhoea with weight loss Recurrent deep skin or organ abscesses Recurrent deep skin or organ abscesses Persistent thrush in mouth or elsewhere on skin after infancy Persistent thrush or fungal infection on skin or elsewhere Need for intravenous antibiotics to clear infections Recurrent need for intravenous antibiotics to clear infections ≥ 2 deep-seated infections such as sepsis, meningitis or cellulitis Infection with atypical mycobacteria A family history of primary immune deficiency A family history of primary immune deficiency *The presence of two or more of the above features may indicate the presence of an underlying primary immunodeficiency. © Jeffrey Modell Foundation.

74 • CLINICAL IMMUNOLOGY 4.7 Initial investigations in suspected immune deficiency Test Value Comment Full blood count Full white cell differential May define pathway for further investigation Acute phase reactants Help determine presence of active infection Serum immunoglobulins Detection of antibody deficiency Serum protein electrophoresis Detection of paraprotein May be the cause of immune paresis; paraprotein should be excluded prior to diagnosis of primary antibody deficiency Serum free light chains/Bence Jones proteins Detection of paraprotein Human immunodeficiency virus (HIV) test To exclude HIV as cause of secondary immune deficiency Imaging according to history and examination findings Detection of active infection/end-organ damage May support treatment decisions, e.g. if there is evidence of bronchiectasis 4.8 Specialist investigations in suspected immune deficiency Test Value Comment Complement (C3/C4/CH50/AP50) Investigation of recurrent pyogenic bacterial infection Inherited complement deficiency likely to give low/ absent results on functional assays Test vaccination Determination of functional humoral immune response Helpful in patients with borderline low or normal immunoglobulins but confirmed recurrent infection Neutrophil function Investigation of recurrent invasive bacterial and fungal infection, especially with catalase-positive organisms Respiratory burst low/absent in chronic granulomatous disease Investigation of leucocyte adhesion deficiency Leucocytosis with absent CD11a, b, c expression Lymphocyte immunophenotyping (by flow cytometry) Determination of specific lymphocyte subsets, T cell, B cell, NK cell May define specific primary immune deficiency, e.g. absent B cells in X-linked agammaglobulinaemia Lymphocyte proliferation Determination of lymphocyte proliferation in response to mitogenic stimulation Poor responses seen in certain T-cell immune deficiencies Cytokine production To determine T-cell immune function in response to antigen stimulation; limited availability, not routine Can be helpful, for example, in investigation of atypical mycobacterial infection Genetic testing Under specialist supervision when specific primary immune deficiency suspected May confirm genetic cause, with implications for family members and future antenatal testing (NK = natural killer) Intermittent fever Intermittent fever has a wide differential diagnosis, including recurrent infection, malignancy and certain rheumatic disorders, such as Still’s disease, vasculitis and SLE (pp. 1040 and 1034), but a familial fever syndrome is a potential cause. Aetiology Familial fever syndromes are genetic disorders caused by mutations in genes responsible for regulating the inflammatory response. The symptoms are caused by activation of intracellular signalling pathways involved in the regulation of inflammation, with over-production of pro-inflammatory cytokines such as IL-1. Clinical assessment A full clinical history and physical examination should be performed, paying attention to the patient’s ethnic background and any family history of a similar disorder. If this assessment shows no evidence of underlying infection, malignancy or a rheumatic disorder and there is a positive family history and early age at onset, then the likelihood of a familial fever syndrome is increased. Investigations Blood should be taken for a full blood count, measurement of ESR and CRP, and assessment of renal and liver function. Serum ferritin should be checked, as very high levels support the diagnosis of Still’s disease. Blood and urine cultures should also be performed, along with an autoimmune screen that includes measurement of antinuclear antibodies and consideration of antineutrophil cytoplasmic antibodies to check for evidence of SLE or vasculitis, respectively. Imaging may be required to exclude occult infection. If these investigations provide no evidence of infection or another cause, then genetic analysis should be considered to confirm the diagnosis of a familial fever syndrome (p. 81). Negative genetic testing does not, however, entirely exclude a periodic fever syndrome. Management Symptomatic management with non-steroidal anti-inflammatory drugs (NSAIDs) should be initiated, pending the results of investigations. If the response to NSAIDs is inadequate, glucocorticoids can be tried, provided that infection has been excluded. If a familial fever syndrome is confirmed, then definitive therapy should be initiated, depending on the underlying diagnosis (p. 81).

Presenting problems in immune disorders • 75

leading to hypotension, and bronchoconstriction, as summarised in Box 4.9. It can be difficult to distinguish IgE-mediated anaphylaxis clinically from non-specific degranulation of mast cells on exposure to drugs, chemicals or other triggers where IgE is not involved, previously known as anaphylactoid reactions. Common triggers are shown in Box 4.10. Clinical assessment The clinical features of anaphylaxis and ‘anaphylactoid’ reactions are indistinguishable and are summarised in Figure 4.9. Several other conditions can mimic anaphylaxis and these are listed in Box 4.11. It is important to assess the severity of the reaction, and the time between allergen exposure and onset of symptoms provides Anaphylaxis Anaphylaxis is a potentially life-threatening, systemic allergic reaction characterised by circulatory collapse, bronchospasm, laryngeal stridor, often associated with angioedema, and urticaria. The risk of death is increased in patients with pre-existing asthma, particularly if this is poorly controlled, and in situations where treatment with adrenaline (epinephrine) is delayed. Aetiology Anaphylaxis occurs when an allergen binds to and cross-links membrane-bound IgE on mast cells in a susceptible individual, causing release of histamine, tryptase and other vasoactive mediators from mast cells. These mediators have a variety of effects, including vasodilatation, increased capillary permeability 4.10 Common causes of systemic allergic reactions Anaphylaxis: IgE-mediated mast cell degranulation Foods • Peanuts • Tree nuts • Fish and shellfish • Milk • Eggs • Soy products Insect stings • Bee venom • Wasp venom Chemicals, drugs and other foreign proteins • Intravenous anaesthetic agents (suxamethonium) • Penicillin and other antibiotics • Latex Anaphylactoid: non-lgE-mediated mast cell degranulation Drugs • Aspirin and non-steroidal anti-inflammatory drugs (NSAIDs) • Opiates • Radiocontrast media Physical • Exercise • Cold Idiopathic • No cause is identified in 20% of patients with anaphylaxis 4.9 Clinical features of mast cell degranulation Mediator Biological effects Pre-formed and stored within granules Histamine Vasodilatation, chemotaxis, bronchoconstriction, increased capillary permeability and increased mucus secretion Tryptase Bronchoconstriction, activates complement C3 Eosinophil chemotactic factor Eosinophil chemotaxis Neutrophil chemotactic factor Neutrophil chemotaxis Synthesised on activation of mast cells Leukotrienes Increase vascular permeability, chemotaxis, mucus secretion and smooth muscle contraction Prostaglandins Bronchoconstriction, platelet aggregation and vasodilatation Thromboxanes Bronchoconstriction Platelet-activating factor Bronchoconstriction, chemotaxis of eosinophils and neutrophils Fig. 4.9 Clinical manifestations of anaphylaxis. In this example, the response is to an insect sting containing venom to which the patient is allergic. This causes release of histamine and other vasoactive mediators, which cause the characteristic features of anaphylaxis that are illustrated. Itching of palms, soles of feet and genitalia Feeling of impending doom, loss of consciousness Conjunctival injection Flushing Sweating Hypotension Urticaria Wheeze, bronchoconstriction Angioedema of lips and mucous membrane Abdominal pain Diarrhoea Cardiac arrhythmias Laryngeal obstruction Stridor Wasp sting

76 • CLINICAL IMMUNOLOGY Management The principles of management of the acute event are summarised in Box 4.12. Individuals who have recovered from an anaphylactic event should be referred for specialist assessment. The aim is to identify the trigger factor, to educate the patient regarding avoidance and management of subsequent episodes, and to establish whether specific treatment, such as immunotherapy, is indicated. If the trigger factor cannot be identified or avoided, recurrence is common. Patients who have previously experienced an anaphylactic event should be prescribed self-injectable adrenaline (epinephrine) and they and their families or carers should be instructed in its use (Box 4.13). The use of a MedicAlert (or similar) bracelet will increase the likelihood of the injector being administered in an emergency. Allergy in adolescence requires additional consideration and management, as set out in Box 4.14. a guide. Enquiry should be made about potential triggers. If none is immediately obvious, a detailed history of the previous 24 hours may be helpful. The most common triggers of anaphylaxis are foods, latex, insect venom and drugs (see Box 4.10). A history of previous local allergic responses to the offending agent is common. The route of allergen exposure may influence the principal clinical features of a reaction; for example, if an allergen is inhaled, the major symptom is frequently wheezing. Features of anaphylaxis may overlap with the direct toxic effects of drugs and venoms (Chs 7 and 8). Potentiating factors, such as exercise or alcohol, can lower the threshold for an anaphylactic event. It is important to identify precipitating factors so that appropriate avoidance measures may be taken in the longer term. Investigations Measurement of serum mast cell tryptase concentrations is useful to confirm the diagnosis but cannot distinguish between anaphylaxis and non-IgE-mediated anaphylactoid reactions. Specific IgE tests may be useful in confirming hypersensitivity and may be preferable to skin-prick tests when investigating patients with a history of anaphylaxis. 4.14 Allergy in adolescence • Resolution of childhood allergy: most children affected by allergy to milk, egg, soybean or wheat will grow out of their food allergies by adolescence but allergies to peanuts, tree nuts, fish and shellfish are frequently life-long. • Risk-taking behaviour and fatal anaphylaxis: serious allergy is increasingly common in adolescents and this is the highest risk group for fatal, food-induced anaphylaxis. This is associated with increased risk-taking behaviour, and food-allergic teenagers are more likely than adults to eat unsafe foods, deny reaction symptoms and delay emergency treatment. • Emotional impact of food allergies: some adolescents may neglect to carry a prescribed adrenalin autoinjector because of the associated nuisance and/or stigma. Surveys of food-allergic teens reveal that many take risks because they feel socially isolated by their allergy. 4.13 How to prescribe self-injectable adrenaline (epinephrine) Prescription (normally initiated by an immunologist or allergist) • Specify the brand of autoinjector, as they have different triggering mechanisms • Prescribe two devices Indications • Anaphylaxis to allergens that are difficult to avoid: Insect venom Foods • Idiopathic anaphylactic reactions • History of severe localised reactions with high risk of future anaphylaxis: Reaction to trace allergen Likely repeated exposure to allergen • History of severe localised reactions with high risk of adverse outcome: Poorly controlled asthma Lack of access to emergency care Patient and family education • Know when and how to use the device • Carry the device at all times • Seek medical assistance immediately after use • Wear an alert bracelet or necklace • Include the school in education for young patients (see ‘Further information’) Other considerations • Caution with β-blockers in anaphylactic patients as they may increase the severity of an anaphylactic reaction and reduce the response to adrenaline (epinephrine) 4.12 Emergency management of anaphylaxis Treatment Comment Prevent further contact with allergen Prevents ongoing mast cell activation Ensure airway patency Prevents hypoxia Administer adrenaline (epinephrine) promptly: 0.3–1.0 mL 1 : 1000 solution IM in adults Repeat at 5–10-min intervals if initial response is inadequate Intramuscular route important because of peripheral vasoconstriction Acts within minutes Increases blood pressure Reverses bronchospasm Administer antihistamines: Chlorphenamine 10 mg IM or slow IV injection Blocks effect of histamine on target cells Administer glucocorticoids: Hydrocortisone 200 mg IV Reduces cytokine release Prevents rebound symptoms in severe cases Provide supportive treatment: Nebulised β2-agonists IV fluids Oxygen Reverses bronchospasm Restores plasma volume Reverses hypoxia (IM = intramuscular; IV = intravenous) 4.11 Differential diagnosis of anaphylaxis Causes of hypotension • Vasovagal syncope • Cardiac arrhythmia • Cardiogenic shock Causes of respiratory distress • Status asthmaticus • Pulmonary embolus Causes of laryngeal obstruction • C1 inhibitor deficiency • Idiopathic angioedema Causes of generalised flushing • Systemic mastocytosis • Carcinoid syndrome • Phaeochromocytoma

Immune deficiency • 77

antifungal agents. The most important examples are illustrated in Figure 4.10 and discussed below. Chronic granulomatous disease This is caused by mutations in genes that encode NADPH oxidase enzymes, which results in failure of oxidative killing. The defect leads to susceptibility to catalase-positive organisms such as Staphylococcus aureus, Burkholderia cenocepacia and Aspergillus. Intracellular killing of mycobacteria in macrophages is also impaired. Infections most commonly involve the lungs, lymph nodes, soft tissues, bone, skin and urinary tract, and are characterised histologically by granuloma formation. Most cases are X-linked (p. 48). Leucocyte adhesion deficiencies These very rare disorders of phagocyte migration occur because of failure to express adhesion molecules on the surface of leucocytes, resulting in their inability to exit the blood stream. The most common cause is loss-of-function mutations affecting the ITGB2 gene, which encodes the integrin β-2 chain, a component of the adhesion molecule LFA1. They are characterised by recurrent bacterial infections but sites of infection lack evidence of neutrophil infiltration, such as pus formation. Peripheral blood neutrophil counts may be very high during acute infection because of the failure of mobilised neutrophils to exit blood vessels. Specialised tests show reduced or absent expression of adhesion molecules on neutrophils. Immune deficiency The consequences of immune deficiency include recurrent infection, autoimmunity as a result of immune dysregulation, and increased susceptibility to malignancy, especially malignancy driven by viral infections such as Epstein–Barr virus. Immune deficiency may arise through intrinsic defects in immune function but is much more commonly due to secondary causes, including infection, drug therapy, malignancy and ageing. This section gives an overview of primary immune deficiencies. More than a hundred such deficiencies have been described, most of which are genetically determined and present in childhood or adolescence. The presentation of immune deficiency depends on the component of the immune system that is defective (see Box 4.5). There is considerable overlap and redundancy in the immune network, however, and some diseases do not fall easily into this classification. Primary phagocyte deficiencies Primary phagocyte deficiencies typically present with recurrent bacterial and fungal infections, which may involve unusual sites. Affected patients require aggressive management of infections, including intravenous antibiotics and surgical drainage of abscesses, and long-term prophylaxis with antibacterial and Fig. 4.10 Normal phagocyte function and mechanisms of primary phagocyte deficiency. Under normal circumstances, neutrophils traverse the endothelium to enter tissues by the cell surface molecule lymphocyte function-associated antigen 1 (LFA1), which binds to intercellular adhesion molecule 1 (ICAM1) on endothelium. In order for macrophages to engulf and kill microorganisms, they need to be activated by cytokines and also require nicotinamide adenine dinucleotide phosphate (NADPH) oxidase to generate free radicals. Primary phagocyte deficiencies can occur as the result of leucocytes being unable to traverse endothelium due to defects in LFA1, because of mutations in cytokines or their receptors, or because of defects in NADPH oxidase. (IFN-γ = interferon-gamma; IL = interleukin) Neutrophils traverse endothelium through binding of LFA1 to ICAM1 Normal Primary phagocyte deficiency Leucocyte adhesion deficiency Neutrophils cannot traverse endothelium due to defects in ITGB2, a component of LFA1 Chronic granulomatous disease Cytokines activate macrophages Destruction of microorganisms through NADPH oxidase-mediated killing Cytokine defects LFA1 IL-23 IL-12 IFN-γ Phagocytes cannot be activated due to defects in cytokines or their receptors Microorganisms cannot be destroyed in lysosomes due to NADPH oxidase deficiency IL-23 IL-12 IFN-γ IL-23 IL-12 IFN-γ ICAM1

78 • CLINICAL IMMUNOLOGY Management Patients with complement deficiencies should be vaccinated with meningococcal, pneumococcal and H. influenzae B vaccines to boost their adaptive immune responses. Lifelong prophylactic penicillin to prevent meningococcal infection is recommended, as is early access to acute medical assessment in the event of infection. Patients should also carry a MedicAlert or similar. At-risk family members should be screened for complement deficiencies with functional complement assays. The management of C1 esterase deficiency is discussed elsewhere. Primary antibody deficiencies Primary antibody deficiencies occur as the result of abnormalities in B-cell function, as summarised in Figure 4.11. They are characterised by recurrent bacterial infections, particularly of the respiratory and gastrointestinal tract. The most common causative organisms are encapsulated bacteria such as Streptococcus pneumoniae and H. influenzae. These disorders usually present in infancy, when the protective benefit of placental transfer of maternal immunoglobulin has waned. The most important causes are discussed in more detail below. X-linked agammaglobulinaemia This rare X-linked disorder (p. 48) is caused by mutations in the BTK gene, which encodes Bruton tyrosine kinase, a signalling protein that is required for B-cell development. Affected males present with severe bacterial infections during infancy. There is a marked reduction in B-cell numbers and immunoglobulin levels are low or undetectable. Management is with immunoglobulin replacement therapy and antibiotics to treat infections. Selective IgA deficiency This is the most common primary antibody deficiency, affecting 1 : 600 northern Europeans. Although IgA deficiency is usually asymptomatic with no clinical sequelae, about 30% of individuals experience recurrent mild respiratory and gastrointestinal infections. The diagnosis can be confirmed by measurement of IgA levels, which are low or undetectable (< 0.05 g/L). In some Defects in cytokines and cytokine receptors Mutations of the genes encoding cytokines such as IFN-γ, IL-12, IL-23 or their receptors result in failure of intracellular killing by macrophages, and affected individuals are particularly susceptible to mycobacterial infections. Complement pathway deficiencies Loss-of-function mutations have been identified in almost all the complement pathway proteins (see Fig. 4.4). While most complement deficiencies are rare, mannose-binding lectin deficiency is common and affects about 5% of the northern European population, many of whom are asymptomatic (see below). Clinical features Patients with deficiency in complement proteins can present in different ways. In some cases, the presenting feature is recurrent infection with encapsulated bacteria, particularly Neisseria spp., reflecting the importance of the membrane attack complex in defence against these organisms. However, genetic deficiencies of the classical complement pathway (C1, C2 and C4) also present with an increased risk of autoimmune disease, particularly SLE (p. 1034). Individuals with mannose-binding lectin deficiency have an increased incidence of bacterial infections if subjected to an additional cause of immune compromise, such as premature birth or chemotherapy. The significance of this condition has been debated, however, since population studies have shown no overall increase in infectious disease or mortality in patients with this disorder. Deficiency of the regulatory protein Cl inhibitor is not associated with recurrent infection but causes recurrent angioedema (p. 87). Investigations Screening for complement deficiencies usually involves specialised functional tests of complement-mediated haemolysis. These are known as the CH50 (classical haemolytic pathway 50) and AP50 (alternative pathway 50) tests. If abnormal, haemolytic tests are followed by measurement of individual complement components. Fig. 4.11 B lymphocytes and primary antibody deficiencies (green boxes). (Ig = immunoglobulin) Failure of lymphocyte precursors: Severe combined immune deficiency Stem cells Lymphoid progenitors Bone marrow Failure of production of IgG antibodies: Common variable immune deficiency Specific antibody deficiency IgM-producing B cells Failure of B-cell maturation: X-linked agammaglobulinaemia Immature B cells IgG IgE IgA Plasma cells Failure of IgA production: Selective IgA deficiency

Immune deficiency • 79

IgG level just prior to an infusion) within the normal range. This has been shown to minimise progression of end-organ damage and improve clinical outcome. Treatment may be self-administered and is life-long. Benefits of immunisation are limited because of the defect in IgG antibody production, and as with all primary immune deficiencies, live vaccines should be avoided. Primary T-lymphocyte deficiencies These are a group of diseases characterised by recurrent viral, protozoal and fungal infections (see Box 4.5). Many T-cell deficiencies are also associated with defective antibody production because of the importance of T cells in providing help for B cells. These disorders generally present in childhood. Several causes of T-cell deficiency are recognised. These are summarised in Figure 4.12 and discussed in more detail below. DiGeorge syndrome This results from failure of development of the third and fourth pharyngeal pouches, and is usually caused by a deletion of chromosome 22q11. The immune deficiency is accounted for by failure of thymic development; however, the immune deficiency can be very heterogeneous. Affected patients tend to have very low numbers of circulating T cells despite normal development in the bone marrow. It is associated with multiple developmental anomalies, including congenital heart disease, hypoparathyroidism, tracheo-oesophageal fistulae, cleft lip and palate. Bare lymphocyte syndromes These rare disorders are caused by mutations in a variety of genes that regulate expression of HLA molecules or their transport to the cell surface. If HLA class I molecules are affected, CD8+ lymphocytes fail to develop normally, while absent expression of HLA class II molecules affects CD4+ lymphocyte maturation. In addition to recurrent infections, failure to express HLA class I is associated with systemic vasculitis caused by uncontrolled activation of NK cells. Severe combined immune deficiency Severe combined immune deficiency (SCID) results from mutations in a number of genes that regulate lymphocyte development, with failure of T-cell maturation, with or without accompanying B- and NK-cell maturation. The most common cause is X-linked SCID, resulting from loss-of-function mutations in the interleukin-2 receptor gamma (IL2RG) gene. The gene product is a component of several interleukin receptors, including those for IL-2, IL-7 and IL-15, which are absolutely required for T-cell and NK development. This results in T-cell-negative, NK-cell-negative, patients, there is a compensatory increase in serum IgG levels. Specific treatment is generally not required. Common variable immune deficiency Common variable immune deficiency (CVID) is characterised by low serum IgG levels and failure to make antibody responses to exogenous pathogens. It is a heterogeneous adult-onset primary immune deficiency of unknown cause. The presentation is with recurrent infections, and bronchiectasis is a recognised complication. Paradoxically, antibody-mediated autoimmune diseases, such as idiopathic thrombocytopenic purpura and autoimmune haemolytic anaemia, are common in CVID. It is also associated with an increased risk of malignancy, particularly lymphoproliferative disease. Functional IgG antibody deficiency This is a poorly characterised condition resulting in defective antibody responses to polysaccharide antigens. Some patients are also deficient in the antibody subclasses IgG2 and IgG4, and this condition was previously called IgG subclass deficiency. There is overlap between specific antibody deficiency, IgA deficiency and CVID, and some patients may progress to a more global antibody deficiency over time. Investigations Serum immunoglobulins (Box 4.15) should be measured in conjunction with protein and urine electrophoresis to exclude secondary causes of hypogammaglobulinaemia, and B- and T-lymphocyte subsets should be measured. Specific antibody responses to known pathogens should be assessed by measuring IgG antibodies against tetanus, H. influenzae and S. pneumoniae (most patients will have been exposed to these antigens through infection or immunisation). If specific antibody levels are low, immunisation with the appropriate killed vaccine should be followed by repeat antibody measurement 6–8 weeks later; failure to mount a response indicates a significant defect in antibody production. These functional tests have generally superseded IgG subclass quantitation. Management Patients with antibody deficiencies generally require aggressive treatment of infections and prophylactic antibiotics may be indicated. An exception is deficiency of IgA, which usually does not require treatment. The mainstay of treatment in most patients with antibody deficiency is immunoglobulin replacement therapy. This is derived from plasma from hundreds of donors and contains IgG antibodies to a wide variety of common organisms. Replacement immunoglobulin may be administered either intravenously or subcutaneously, with the aim of maintaining trough IgG levels (the 4.15 Investigation of primary antibody deficiencies Serum immunoglobulin (Ig) concentrations Circulating lymphocyte numbers IgM IgG IgA IgE B cells T cells Test immunisation Selective IgA deficiency Normal Often elevated Absent Normal Normal Normal Not applicable* Common variable immune deficiency Normal or low Low Low or absent Low or absent Variable Variable No antibody response Specific antibody deficiency Normal Normal Normal Normal Normal Normal No antibody response to polysaccharide antigens *Test immunisation is not usually performed in IgA deficiency but some patients may have impaired responses.

80 • CLINICAL IMMUNOLOGY include lymphadenopathy, splenomegaly and a variety of other autoimmune diseases. Susceptibility to infection is increased because of the neutropenia. Secondary immune deficiencies Secondary immune deficiencies are much more common than primary immune deficiencies and occur when the immune system is compromised by external factors (Box 4.16). Common causes include infections, such as HIV and measles, and cytotoxic B-cell-positive SCID. Another cause is deficiency of the enzyme adenosine deaminase (ADA), which causes lymphocyte death due to accumulation of toxic purine metabolites intracellularly, resulting in T-cell-negative, B-cell-negative and NK-cell-negative SCID. The absence of an effective adaptive immune response causes recurrent bacterial, fungal and viral infections soon after birth. Bone marrow transplantation (BMT; p. 936) is the treatment option of first choice. Gene therapy has been approved for treatment of ADA deficiency when there is no suitable donor for BMT and is under investigation for a number of other causes of SCID. Investigations The principal tests for T-lymphocyte deficiencies are a total lymphocyte count and quantitation of individual lymphocyte subpopulations. Serum immunoglobulins should also be measured. Second-line, functional tests of T-cell activation and proliferation may be indicated. Patients in whom T-lymphocyte deficiencies are suspected should be tested for HIV infection (p. 310). Management Patients with T-cell deficiencies should be considered for antiPneumocystis and antifungal prophylaxis, and require aggressive management of infections when they occur. Immunoglobulin replacement is indicated for associated defective antibody production. Stem cell transplantation (p. 936) or gene therapy may be appropriate in some disorders. Where a family history is known and antenatal testing confirms a specific defect, stem cell therapy prior to recurrent invasive infection can improve outcome. Autoimmune lymphoproliferative syndrome This rare disorder is caused by failure of normal lymphocyte apoptosis, most commonly due to mutations in the FAS gene, which encodes Fas, a signalling protein that regulates programmed cell death in lymphocytes. This results in massive accumulation of autoreactive T cells, which cause autoimmune-mediated anaemia, thrombocytopenia and neutropenia. Other features Fig. 4.12 T-lymphocyte function and dysfunction (green boxes). (HLA = human leucocyte antigen) Failure of lymphocyte precursors: Severe combined immune deficiency Stem cells Lymphoid progenitors Bone marrow Failure of expression of HLA molecules: Bare lymphocyte syndromes Failure of thymic development: DiGeorge syndrome Proliferation and maturation of thymocytes Export of mature T lymphocytes to periphery T-lymphocyte activation and effector function Apoptotic cell death Failure of apoptosis: Autoimmune lymphoproliferative syndromes Thymus Failure of cytokine production: Cytokine deficiencies 4.16 Causes of secondary immune deficiency Physiological • Ageing • Prematurity • Pregnancy Infection • HIV infection • Measles • Mycobacterial infection Iatrogenic • Immunosuppressive therapy • Antineoplastic agents • Glucocorticoids • Stem cell transplantation • Radiation injury • Antiepileptic agents Malignancy • B-cell malignancies including leukaemia, lymphoma and myeloma • Solid tumours • Thymoma Biochemical and nutritional disorders • Malnutrition • Renal insufficiency/dialysis • Diabetes mellitus • Specific mineral deficiencies (iron, zinc) Other conditions • Burns • Asplenia/hyposplenism

Autoimmune disease • 81

attacks. Standard anti-inflammatory drugs, including colchicine and glucocorticoids, are ineffective in suppressing the attacks but IL-1 inhibitors, such as anakinra, and TNF inhibitors, such as etanercept, may improve symptoms and can induce complete remission in some patients. TNF receptor-associated periodic syndrome TNF receptor-associated periodic syndrome (TRAPS) also known as Hibernian fever, is an autosomal dominant syndrome caused by mutations in the TNFRSF1A gene. The presentation is with recurrent attacks of fever, arthralgia, myalgia, serositis and rashes. Attacks may be prolonged for 1 week or more. During a typical attack, laboratory findings include neutrophilia, increased CRP and elevated IgA levels. The diagnosis can be confirmed by low serum levels of the soluble type 1 TNF receptor and by mutation screening of the TNFRSF1A gene. As in FMF, the major complication is amyloidosis, and regular screening for proteinuria is advised. Acute episodes respond to systemic glucocorticoids. Therapy with IL-1 inhibitors, such as anakinra, can be effective in preventing attacks. Amyloidosis Amyloidosis is the name given to a group of acquired and hereditary disorders characterised by the extracellular deposition of insoluble proteins. Pathophysiology Amyloidosis is caused by deposits consisting of fibrils of the specific protein involved, linked to glycosaminoglycans, proteoglycans and serum amyloid P. Protein accumulation may be localised or systemic, and the clinical manifestations depend on the organ(s) affected. Amyloid diseases are classified by the aetiology and type of protein deposited (Box 4.18). Clinical features The clinical presentation may be with nephrotic syndrome (p. 395), cardiomyopathy (p. 538) or peripheral neuropathy (p. 1138). Amyloidosis should always be considered as a potential diagnosis in patients with these disorders when the cause is unclear. Investigations The diagnosis is established by biopsy, which may be of an affected organ, rectum or subcutaneous fat. The pathognomonic histological feature is apple-green birefringence of amyloid deposits when stained with Congo red dye and viewed under polarised light. Immunohistochemical staining can identify the type of amyloid fibril present. Quantitative scintigraphy with radiolabelled serum amyloid P is a valuable tool in determining the overall load and distribution of amyloid deposits. Management The aims of treatment are to support the function of affected organs and, in acquired amyloidosis, to prevent further amyloid deposition through treatment of the primary cause. When the latter is possible, regression of existing amyloid deposits may occur. Autoimmune disease Autoimmunity can be defined as the presence of immune responses against self-tissue. This may be a harmless phenomenon, identified and immunosuppressive drugs, particularly those used in the management of transplantation, autoimmunity and cancer. Physiological immune deficiency occurs at the extremes of life; the decline of the immune response in the elderly is known as immune senescence (Box 4.17). Management of secondary immune deficiency is described in the relevant chapters on infectious diseases (Ch. 11), HIV (Ch. 12), haematological disorders (Ch. 23) and oncology (Ch. 33). Periodic fever syndromes These rare disorders are characterised by recurrent episodes of fever and organ inflammation, associated with an elevated acute phase response (p. 74). Familial Mediterranean fever Familial Mediterranean fever (FMF) is the most common of the familial periodic fevers, predominantly affecting Mediterranean people, including Arabs, Turks, Sephardic Jews and Armenians. It results from mutations of the MEFV gene, which encodes a protein called pyrin that regulates neutrophil-mediated inflammation by indirectly suppressing the production of IL-1. FMF is characterised by recurrent painful attacks of fever associated with peritonitis, pleuritis and arthritis, which last for a few hours to 4 days and are associated with markedly increased CRP levels. Symptoms resolve completely between episodes. Most individuals have their first attack before the age of 20. The major complication of FMF is AA amyloidosis (see below). Colchicine significantly reduces the number of febrile episodes in 90% of patients but is ineffective during acute attacks. Mevalonic aciduria (mevalonate kinase deficiency) Mevalonate kinase deficiency, previously known as hyper-IgD syndrome, is an autosomal recessive disorder that causes recurrent attacks of fever, abdominal pain, diarrhoea, lymphadenopathy, arthralgia, skin lesions and aphthous ulceration. Most patients are from Western Europe, particularly the Netherlands and northern France. It is caused by loss-of-function mutations in the gene encoding mevalonate kinase, which is involved in the metabolism of cholesterol. It remains unclear why this causes an inflammatory periodic fever. Serum IgD and IgA levels may be persistently elevated, and CRP levels are increased during acute 4.17 Immune senescence • T-cell responses: decline, with reduced delayed-type hypersensitivity responses. • Antibody production: decreased for many exogenous antigens. Although autoantibodies are frequently detected, autoimmune disease is less common. • Response to vaccination: reduced; 30% of healthy older people may not develop protective immunity after influenza vaccination. • Allergic disorders and transplant rejection: less common. • Susceptibility to infection: increased; community-acquired pneumonia by threefold and urinary tract infection by 20-fold. Latent infections, including tuberculosis and herpes zoster, may be reactivated. • Manifestations of inflammation: may be absent, with lack of pyrexia or leucocytosis. • Secondary immune deficiency: common.

82 • CLINICAL IMMUNOLOGY those determining cytokine activity, co-stimulation (the expression of second signals required for full T-cell activation; see Fig. 4.7) and cell death. Many of the same gene variants underlie multiple autoimmune disorders, reflecting their common pathogenesis (Box 4.19). Even though some of these associations are the strongest that have been identified in complex genetic diseases, only by the presence of low-titre autoantibodies or autoreactive T cells. However, if these responses cause significant organ damage, autoimmune diseases occur. These are a major cause of chronic morbidity and disability, affecting up to 1 in 30 adults at some point during life. Pathophysiology Autoimmune diseases result from the failure of immune tolerance, the process by which the immune system recognises and accepts self-tissue. Central immune tolerance occurs during lymphocyte development, when T and B lymphocytes that recognise self-antigens are eliminated before they develop into fully immunocompetent cells. This process is most active in fetal life but continues throughout life as immature lymphocytes are generated. Some autoreactive cells inevitably evade deletion and escape into the circulation, however, and are controlled through peripheral tolerance mechanisms. Peripheral immune tolerance mechanisms include the suppression of autoreactive cells by regulatory T cells; the generation of functional hyporesponsiveness (anergy) in lymphocytes that encounter antigen in the absence of the co-stimulatory signals that accompany inflammation; and cell death by apoptosis. Autoimmune diseases develop when selfreactive lymphocytes escape from these tolerance mechanisms. Multiple genetic and environmental factors contribute to the development of autoimmune disease. Autoimmune diseases are much more common in women than in men, for reasons that remain unclear. Many are associated with genetic variations in the HLA loci, reflecting the importance of HLA genes in shaping lymphocyte responses. Other important susceptibility genes include 4.19 Association of specific gene polymorphisms with autoimmune diseases Gene Function Diseases HLA complex Key determinants of antigen presentation to T cells Most autoimmune diseases PTPN22 Regulation of T- and B-cell receptor signalling Rheumatoid arthritis, type 1 diabetes, systemic lupus erythematosus CTLA4 Important co-stimulatory molecule that transmits inhibitory signals to T cells Rheumatoid arthritis, type 1 diabetes IL23R Cytokine-mediated control of T cells Inflammatory bowel disease, psoriasis, ankylosing spondylitis TNFRSF1A Control of tumour necrosis factor network Multiple sclerosis ATG5 Autophagy Systemic lupus erythematosus 4.18 Causes of amyloidosis Disorder Pathological basis Predisposing conditions Other features Acquired systemic amyloidosis Reactive (AA) amyloidosis (p. 81) Increased production of serum amyloid A as part of prolonged or recurrent acute inflammatory response Chronic infection (tuberculosis, bronchiectasis, chronic abscess, osteomyelitis) Chronic inflammatory diseases (untreated rheumatoid arthritis, familial Mediterranean fever) 90% of patients present with non-selective proteinuria or nephrotic syndrome Light chain amyloidosis (AL) Increased production of monoclonal light chain Monoclonal gammopathies, including myeloma, benign gammopathies and plasmacytoma Restrictive cardiomyopathy, peripheral and autonomic neuropathy, carpal tunnel syndrome, proteinuria, spontaneous purpura, amyloid nodules and plaques Macroglossia occurs rarely but is pathognomonic Prognosis is poor Dialysis-associated (Aβ2M) amyloidosis Accumulation of circulating β2-microglobulin due to failure of renal catabolism in kidney failure Renal dialysis Carpal tunnel syndrome, chronic arthropathy and pathological fractures secondary to amyloid bone cyst formation Manifestations occur 5–10 years after the start of dialysis Senile systemic amyloidosis Normal transthyretin protein deposited in tissues Age > 70 years Feature of normal ageing (affects

90% of 90-year-olds) Usually asymptomatic Hereditary systemic amyloidosis 20 forms of hereditary systemic amyloidosis Production of protein with an abnormal structure that predisposes to amyloid fibril formation. Most commonly due to mutations in transthyretin gene Autosomal dominant inheritance Peripheral and autonomic neuropathy, cardiomyopathy Renal involvement unusual 10% of gene carriers are asymptomatic throughout life

Autoimmune disease • 83

Investigations Autoantibodies Many autoantibodies have been identified and are used in the diagnosis and monitoring of autoimmune diseases, as discussed elsewhere in this book. Antibodies can be quantified either by titre (the maximum dilution of the serum at which the antibody can be detected) or by concentration in standardised units using an enzyme-linked immunosorbent assay (ELISA) in which the antigen is used to coat microtitre plates to which the patient’s serum is added (Fig. 4.13A). Qualitative tests are also employed for antinuclear antibodies in which the pattern of nuclear staining is recorded (Fig. 4.13B). they have very limited predictive value and are generally not useful in determining management of individual patients. Several environmental factors may be associated with autoimmunity in genetically predisposed individuals, including infection, cigarette smoking and hormone levels. The most widely studied of these is infection, as occurs in acute rheumatic fever following streptococcal infection or reactive arthritis following bacterial infection. Several mechanisms have been invoked to explain the autoimmunity that occurs after an infectious trigger. These include crossreactivity between proteins expressed by the pathogen and the host (molecular mimicry), such as Guillain–Barré syndrome and Campylobacter infection (p. 1140); release of sequestered antigens from tissues that are damaged during infections that are not usually visible to the immune system; and production of inflammatory cytokines that overwhelm the normal control mechanisms that prevent bystander damage. Occasionally, autoimmune disease may be an adverse effect of drug treatment. For example, metabolic products of the anaesthetic agent halothane can bind to liver enzymes, resulting in a structurally novel protein that is recognised as a foreign antigen by the immune system. This can provoke the development of autoantibodies and activated T cells, which can cause hepatic necrosis. Clinical features The clinical presentation of autoimmune disease is highly variable. Autoimmune diseases can be classified by organ involvement or by the predominant mechanism responsible for tissue damage. The Gell and Coombs classification of hypersensitivity is the most widely used, and distinguishes four types of immune response that result in tissue damage (Box 4.20). • Type I hypersensitivity is relevant in allergy but is not associated with autoimmune disease. • Type II hypersensitivity causes injury to a single tissue or organ and is mediated by specific autoantibodies. • Type III hypersensitivity results from deposition of immune complexes, which initiates activation of the classical complement cascade, as well as recruitment and activation of phagocytes and CD4+ lymphocytes. The site of immune complex deposition is determined by the relative amount of antibody, size of the immune complexes, nature of the antigen and local haemodynamics. Generalised deposition of immune complexes gives rise to systemic diseases such as SLE. • Type IV hypersensitivity is mediated by activated T cells and macrophages, which together cause tissue damage. 4.20 Gell and Coombs classification of hypersensitivity diseases Type Mechanism Example of disease in response to exogenous agent Example of autoimmune disease Type I Immediate hypersensitivity IgE-mediated mast cell degranulation Allergic disease None described Type II Antibody-mediated Binding of cytotoxic IgG or IgM antibodies to antigens on cell surface causes cell killing ABO blood transfusion reaction Hyperacute transplant rejection Autoimmune haemolytic anaemia Idiopathic thrombocytopenic purpura Goodpasture’s disease Type III Immune complex-mediated IgG or IgM antibodies bind soluble antigen to form immune complexes that trigger classical complement pathway activation Serum sickness Farmer’s lung Systemic lupus erythematosus Cryoglobulinaemia Type IV Delayed type Activated T cells, and phagocytes Acute cellular transplant rejection Nickel hypersensitivity Type 1 diabetes Hashimoto’s thyroiditis Fig. 4.13 Autoantibody testing. A Measurement of antibody levels by enzyme-linked immunosorbent assay (ELISA). The antigen of interest is used to coat microtitre plates to which patient serum is added. If autoantibodies are present, these bind to the target antigen on the microtitre plate. The amount of bound antibody is quantitated by adding a secondary antibody linked to an enzyme that converts a colourless substrate to a coloured one, which can be detected by a plate reader. B Qualitative analysis of autoantibodies by patterns of nuclear staining. In this assay, patient serum is added to cultured cells and a secondary antibody is added with a fluorescent label to detect any bound antibody. If antinuclear antibodies are present, they are detected as bright green staining. Different antinuclear antibody patterns may be seen in different types of connective tissue disease (Ch. 24). B (Nucleolar and Homogenous), Courtesy of Juliet Dunphy, Biomedical Scientist, Royal United Hospital Bath, previously of Bath Institute of Rheumatic Diseases, UK; (Speckled), Courtesy of Mr Richard Brown, Clinical Scientist in Immunology, Southwest Pathology Services, UK. Antibodies bind to target Target antigen Wash Detection of bound antibody Quantitate on plate reader Target antigen Wash Nucleolar Homogenous Speckled A B

84 • CLINICAL IMMUNOLOGY They comprise a range of disorders from mild to life-threatening and affect many organs. Atopy is the tendency to produce an exaggerated IgE immune response to otherwise harmless environmental substances, while an allergic disease can be defined as the clinical manifestation of this inappropriate IgE immune response. Pathophysiology The immune system does not normally respond to the many environmental substances to which it is exposed on a daily basis. In allergic individuals, however, an initial exposure to a normally harmless exogenous substance (known as an allergen) triggers the production of specific IgE antibodies by activated B cells. These bind to high-affinity IgE receptors on the surface of mast cells, a step that is not itself associated with clinical sequelae. However, re-exposure to the allergen binds to and cross-links membrane-bound IgE, which activates the mast cells, releasing a variety of vasoactive mediators (the early phase response; Fig. 4.14 and see Box 4.9). This type I hypersensitivity reaction forms the basis of an allergic reaction, which can range from sneezing and rhinorrhoea to anaphylaxis (Box 4.22). In some individuals, the early phase response is followed by persistent activation of mast cells, manifest by ongoing swelling and local inflammation. This is known as the late phase reaction and is mediated by mast cell metabolites, basophils, eosinophils and macrophages. Long-standing or recurrent allergic inflammation may give rise to a chronic inflammatory response characterised by a complex infiltrate of macrophages, eosinophils and T lymphocytes, in addition to mast cells and basophils. Once this has been established, inhibition of mast cell mediators with antihistamines is clinically ineffective in isolation. Mast cell activation may also be non-specifically triggered through other signals, such as neuropeptides, anaphylotoxins and bacterial peptides. The increasing incidence of allergic diseases is largely unexplained but one widely held theory is the ‘hygiene hypothesis’. This proposes that infections in early life are critically important in maturation of the immune response and bias the immune system against the development of allergies; the high prevalence Complement Measurement of complement components can be useful in the evaluation of immune complex-mediated diseases. Classical complement pathway activation leads to a decrease in circulating C4 levels and is often also associated with decreased C3 levels. Serial measurement of C3 and C4 is a useful surrogate measure of disease activity in conditions such as SLE. Cryoglobulins Cryoglobulins are antibodies directed against other immunoglobulins, forming immune complexes that precipitate in the cold. They can lead to type III hypersensitivity reactions, with typical clinical manifestations including purpuric rash, often of the lower extremities, arthralgia and peripheral neuropathy. Cryoglobulins are classified into three types, depending on the properties of the immunoglobulin involved (Box 4.21). Testing for cryoglobulins requires the transport of a serum specimen to the laboratory at 37°C. Cryoglobulins should not be confused with cold agglutinins; the latter are autoantibodies specifically directed against the I/i antigen on the surface of red cells, which can cause intravascular haemolysis in the cold (p. 950). Management The management of autoimmune disease depends on the organ system involved and further details are provided elsewhere in this book. In general, treatment of autoimmune diseases involves the use of glucocorticoids and immunosuppressive agents, which are increasingly used in combination with biologic agents targeting disease-specific cytokines and their receptors. Not all conditions require immune suppression, however. For example, the management of coeliac disease involves dietary gluten withdrawal, while autoimmune hypothyroidism requires appropriate thyroxine supplementation. Allergy Allergic diseases are a common and increasing cause of illness, affecting between 15% and 20% of the population at some time. 4.21 Classification of cryoglobulins Type I Type II Type III Immunoglobulin (Ig) isotype and specificity Isolated monoclonal IgM paraprotein with no particular specificity Immune complexes formed by monoclonal IgM paraprotein directed towards constant region of IgG Immune complexes formed by polyclonal IgM or IgG directed towards constant region of IgG Prevalence 25% 25% 50% Disease association Lymphoproliferative disease, especially Waldenström macroglobulinaemia (p. 966) Infection, particularly hepatitis C; lymphoproliferative disease Infection, particularly hepatitis C; autoimmune disease, including rheumatoid arthritis and systemic lupus erythematosus Symptoms Hyperviscosity: Raynaud’s phenomenon Acrocyanosis Retinal vessel occlusion Arterial and venous thrombosis Small-vessel vasculitis: Purpuric rash Arthralgia Neuropathy Cutaneous ulceration, hepatosplenomegaly, glomerulonephritis, Raynaud’s phenomenon Small-vessel vasculitis: Purpuric rash, arthralgia Cutaneous ulceration Hepatosplenomegaly, glomerulonephritis Raynaud’s phenomenon Protein electrophoresis Monoclonal IgM paraprotein Monoclonal IgM paraprotein No monoclonal paraprotein Rheumatoid factor Negative Strongly positive Strongly positive Complement Usually normal Decreased C4 Decreased C4 Serum viscosity Raised Normal Normal

Allergy • 85

of insect venom frequently stimulates the production of IgE antibodies, and thus may be followed by allergic reactions to single stings. Allergic IgE-mediated reactions vary from mild to life-threatening. Antigen-specific immunotherapy (desensitisation; see below) with bee or wasp venom can reduce the incidence of recurrent anaphylaxis from 50–60% to approximately 10% but requires up to 5 years of treatment. Peanut allergy Peanut allergy is the most common food-related allergy. More than 50% of patients present before the age of 3 years and some individuals react to their first known exposure to peanuts, thought to result from sensitisation to arachis oil in topical creams. Peanuts are ubiquitous in the Western diet, and every year up to 25% of peanut-allergic individuals experience a reaction as a result of inadvertent exposure. Birch oral allergy syndrome This syndrome is characterised by the combination of birch pollen hay fever and local oral symptoms, including itch and angioedema, after contact with certain raw fruits, raw vegetables and nuts. Cooked fruits and vegetables are tolerated without difficulty. It is due to shared or cross-reactive allergens that are destroyed by cooking or digestion, and can be confirmed by skin prick testing using fresh fruit. Severe allergic reactions are unusual. Diagnosis When assessing a patient with a complaint of allergy, it is important to identify what the patient means by the term, as up to 20% of the UK population describe themselves as having a food allergy; in fact, less than 1% have true allergy, as defined by an IgE-mediated hypersensitivity reaction confirmed on double-blind challenge. The nature of the symptoms should be established and specific triggers identified, along with the predictability of a reaction, and the time lag between exposure to a potential allergen and onset of symptoms. An allergic reaction usually occurs within minutes of exposure and provokes predictable, reproducible symptoms such as angioedema, urticaria and wheezing. Specific enquiry should be made about other allergic symptoms, past and present, and about a family history of allergic disease. Potential allergens in the home and workplace should be identified. A detailed drug history should always be taken, including details of adherence to medication, possible adverse effects and the use of over-the-counter or complementary therapies. of allergic disease is the penalty for the decreased exposure to infection that has resulted from improvements in sanitation and health care. Genetic factors also contribute strongly to the development of allergic diseases. A positive family history is common in patients with allergy, and genetic association studies have identified a wide variety of predisposing variants in genes controlling innate immune responses, cytokine production, IgE levels and the ability of the epithelial barrier to protect against environmental agents. The expression of a genetic predisposition is complex; it is governed by environmental factors, such as pollutants and cigarette smoke, and the incidence of bacterial and viral infection. Clinical features Common presentations of allergic disease are shown in Box 4.22. Those that affect the respiratory system and skin are discussed in more detail in Chapters 17 and 29, respectively. Here we focus on general principles of the approach to the allergic patient, some specific allergies and anaphylaxis. Insect venom allergy Local non-IgE-mediated reactions to insect stings are common and may cause extensive swelling around the site lasting up to 7 days. These usually do not require specific treatment. Toxic reactions to venom after multiple (50–100) simultaneous stings may mimic anaphylaxis. In addition, exposure to large amounts Fig. 4.14 Type I (immediate) hypersensitivity response. A After an encounter with allergen, B cells produce immunoglobulin E (IgE) antibody against the allergen. B Specific IgE antibodies bind to circulating mast cells via high-affinity IgE cell surface receptors. C On re-encounter with allergen, the allergen binds to the IgE antibody-coated mast cells. This cross-linking of the IgE triggers mast cell activation with release of vasoactive mediators (see Box 4.9). B B B T T B B B B Allergen T and B cells IgE antibody IgE receptor Mast cell Histamine, tryptase and vasoactive peptides A B C 4.22 Clinical manifestations of allergy Dermatological • Urticaria • Atopic eczema if chronic • Allergic contact eczema • Angioedema Respiratory • Asthma • Atopic rhinitis Ophthalmological • Allergic conjunctivitis Gastrointestinal • Food allergy Other • Anaphylaxis • Drug allergy • Allergy to insect venom

86 • CLINICAL IMMUNOLOGY causes, including parasitic and helminth infections (pp. 299 and 288), lymphoma (p. 961), drug reactions and eosinophilic granulomatosis with polyangiitis (previously known as Churg–Strauss vasculitis; p. 1043). Normal total IgE levels do not exclude allergic disease. Eosinophilia Peripheral blood eosinophilia is common in atopic individuals but lacks specificity. Eosinophilia of more than 20% or an absolute eosinophil count over 1.5 × 109/L should initiate a search for a non-atopic cause, such as eosinophilic granulomatosis with polyangiitis or parasitic infection (p. 928). Management Several approaches can be deployed in the management of allergic individuals, as discussed below. Avoidance of the allergen This is indicated in all cases and should be rigorously attempted, with the advice of specialist dietitians and occupational physicians if necessary. Antihistamines Antihistamines are useful in the management of allergy as they inhibit the effects of histamine on tissue H1 receptors. Long-acting, non-sedating preparations are particularly useful for prophylaxis. Glucocorticoids These are highly effective in allergic disease, and if used topically, adverse effects can be minimised. Sodium cromoglicate Sodium cromoglicate stabilises the mast cell membrane, inhibiting release of vasoactive mediators. It is effective as a prophylactic agent in asthma and allergic rhinitis but has no role in management of acute attacks. It is poorly absorbed and therefore ineffective in the management of food allergies. Antigen-specific immunotherapy This involves the sequential administration of increasing doses of allergen extract over a prolonged period of time. The mechanism of action is not fully understood but it is highly effective in the prevention of insect venom anaphylaxis and of allergic rhinitis secondary to grass pollen. The traditional route of administration is by subcutaneous injection, which carries a risk of anaphylaxis and should be performed only in specialised centres. Sublingual immunotherapy is also increasingly used. Clinical studies to date do not support the use of allergen immunotherapy for food hypersensitivity, although this is an area of active investigation. Omalizumab Omalizumab is a monoclonal antibody directed against IgE; it inhibits the binding of IgE to mast cells and basophils. It is licensed for treatment of refractory chronic spontaneous urticaria and also for severe persistent allergic asthma that has failed to respond to standard therapy (p. 572). The dose and frequency are determined by baseline IgE (measured before the start of treatment) and body weight. It is under investigation for allergic rhinitis but not yet approved for this indication. Adrenaline (epinephrine) Adrenaline given by injection in the form of a pre-loaded selfinjectable device can be life-saving in the acute management of anaphylaxis (see Box 4.12). Investigations Skin-prick tests Skin-prick testing is a key investigation in the assessment of patients suspected of having allergy. A droplet of diluted standardised allergen is placed on the forearm and the skin is superficially punctured through the droplet with a sterile lancet. Positive and negative control material must be included in the assessment. After 15 minutes, a positive response is indicated by a local weal and flare response 2 mm or more larger than the negative control. A major advantage of skin-prick testing is that patient can clearly see the results, which may be useful in gaining adherence to avoidance measures. Disadvantages include the remote risk of a severe allergic reaction, so resuscitation facilities should be available. Results are unreliable in patients with extensive skin disease. Antihistamines inhibit the magnitude of the response and should be discontinued for at least 3 days before testing; low-dose glucocorticoids do not influence test results. A number of other prescribed medicines can also lead to false-negative results, including amitriptyline and risperidone. Specific IgE tests An alternative to skin-prick testing is the quantitation of IgE directed against the suspected allergen. The sensitivity and specificity of specific IgE tests (previously known as radioallergosorbent tests, RAST) are lower than those of skin-prick tests. However, IgE tests may be very useful if skin testing is inappropriate, such as in patients taking antihistamines or those with severe skin disease or dermatographism. They can also be used to test for cross-reactivity – for example, with multiple insect venoms, where component-resolved diagnostics, using recombinant allergens, is increasingly used rather than crude allergen extract. Specific IgE tests can also be used post-mortem to identify allergens responsible for lethal anaphylaxis. Supervised exposure to allergen Tests involving supervised exposure to an allergen (allergen challenge) are usually performed in specialist centres on carefully selected patients, and include bronchial provocation testing, nasal challenge, and food or drug challenge. These may be particularly useful in the investigation of occupational asthma or food allergy. Patients can be considered for challenge testing when skin tests and/or IgE tests are negative, as they can be helpful in ruling out allergic disease. Mast cell tryptase Measurement of serum mast cell tryptase is extremely useful in investigating a possible anaphylactic event. Ideally, measurements should be made at the time of the reaction following appropriate resuscitation, and 3 hours and 24 hours later. The basis of the test is the fact that circulating levels of mast cell degranulation products rise dramatically to peak 1–2 hours after a systemic allergic reaction. Tryptase is the most stable of these and is easily measured in serum. Serum total IgE Serum total IgE measurements are not routinely indicated in the investigation of allergic disease, other than to aid in the interpretation of specific IgE results, as false-positive specific IgEs are common in patients with atopy, who often have a high total IgE level. Although atopy is the most common cause of an elevated total IgE in developed countries, there are many other

Angioedema • 87

diagnosis. If no obvious trigger can be identified, measurement of complement C4 is useful in differentiating hereditary and acquired angioedema from other causes. If C4 levels are low, further investigations should be initiated to look for evidence of C1 inhibitor deficiency. Management Management depends on the underlying cause. Angioedema associated with allergen exposure generally responds to antihistamines and glucocorticoids. Following acute management of angioedema secondary to drug therapy, drug withdrawal Angioedema Angioedema is an episodic, localised, non-pitting swelling of submucous or subcutaneous tissues. Pathophysiology The causes of angioedema are summarised in Box 4.23. It may be a manifestation of allergy or non-allergic degranulation of mast cells in response to drugs and toxins. In these conditions the main cause is mast cell degranulation with release of histamine and other vasoactive mediators. In hereditary angioedema, the cause is C1 inhibitor deficiency, which causes increased local release of bradykinin. Angiotensin-converting enzyme (ACE) inhibitor-induced angioedema also occurs as the result of increased bradykinin levels due to inhibition of its breakdown. Clinical features Angioedema is characterised by soft-tissue swelling that most frequently affects the face (Fig. 4.15) but can also affect the extremities and genitalia. Involvement of the larynx or tongue may cause life-threatening respiratory tract obstruction, and oedema of the intestinal mucosa may cause abdominal pain and distension. Investigations Differentiating the mechanism of angioedema is important in determining the most appropriate treatment. A clinical history of allergy or drug exposure can give clues to the underlying 4.23 Types of angioedema Allergic reaction to specific trigger Idiopathic angioedema Hereditary angioedema ACE-inhibitor associated angioedema Pathogenesis IgE-mediated degradation of mast cells Non-IgE-mediated degranulation of mast cells C1 inhibitor deficiency, with resulting increased local bradykinin concentration Inhibition of breakdown of bradykinin Key mediator Histamine Histamine Bradykinin Bradykinin Prevalence Common Common Rare autosomal dominant disorder 0.1–0.2% of patients treated with ACE inhibitors Clinical features Usually associated with urticaria History of other allergies common Follows exposure to specific allergen, in food, animal dander or insect venom Usually associated with urticaria May be triggered by physical stimuli such as heat, pressure or exercise Dermatographism common Occasionally associated with underlying infection or thyroid disease Not associated with urticaria or other features of allergy Does not cause anaphylaxis May cause life-threatening respiratory tract obstruction Can cause severe abdominal pain Not associated with urticaria Does not cause anaphylaxis Usually affects the head and neck, and may cause life-threatening respiratory tract obstruction Can occur years after the start of treatment Investigations Specific IgE tests or skin-prick tests Specific IgE tests and skin-prick tests often negative Hypothyroidism should be excluded Complement C4 (invariably low in acute attacks) C1 inhibitor levels No specific investigations Treatment Allergen avoidance Antihistamines Antihistamines are mainstay of treatment and prophylaxis Unresponsive to antihistamines Anabolic steroids C1 inhibitor concentrate or icatibant for acute attacks ACE inhibitor should be discontinued ARBs should be avoided if possible unless there is a strong indication Associated drug reactions Specific drug allergies NSAIDs Opioids, radiocontrast media ACE inhibitors, ARBs (ACE = angiotensin-converting enzyme; ARBs = angiotensin II receptor blockers; NSAIDs = non-steroidal anti-inflammatory drugs) Fig. 4.15 Angioedema. This young man has hereditary angioedema. A Normal appearance. B During an acute attack. From Helbert M. Flesh and bones of immunology. Edinburgh: Churchill Livingstone, Elsevier Ltd; 2006. B A

88 • CLINICAL IMMUNOLOGY should prevent further attacks, although ACE inhibitor-induced angioedema can continue for a limited period post drug withdrawal. Management of angioedema associated with C1 inhibitor deficiency is discussed below. Hereditary angioedema Hereditary angioedema (HAE), also known as inherited C1 inhibitor deficiency, is an autosomal dominant disorder caused by decreased production or activity of C1 inhibitor protein. This complement regulatory protein inhibits spontaneous activation of the classical complement pathway (see Fig. 4.4). It also acts as an inhibitor of the kinin cascade, activation of which increases local bradykinin levels, giving rise to local pain and swelling. Clinical features The angioedema in HAE may be spontaneous or triggered by local trauma or infection. Multiple parts of the body may be involved, especially the face, extremities, upper airway and gastrointestinal tract. Oedema of the intestinal wall causes severe abdominal pain and many patients with undiagnosed HAE undergo exploratory laparotomy. The most important complication is laryngeal obstruction, often associated with minor dental procedures, which can be fatal. Episodes of angioedema are self-limiting and usually resolve within 48 hours. Patients with HAE generally present in adolescence but may go undiagnosed for many years. A family history can be identified in 80% of cases. HAE is not associated with allergic diseases and is specifically not associated with urticaria. Investigations Acute episodes are accompanied by low C4 levels; a low C4 during an episode of angioedema should therefore trigger further investigation. The diagnosis can be confirmed by measurement of C1 inhibitor levels and function. Management Severe acute attacks should be treated with purified C1 inhibitor concentrate or the bradykinin receptor antagonist icatibant. Anabolic steroids, such as danazol, can be used to prevent attacks and act by increasing endogenous production of complement proteins. Tranexamic acid can be helpful as prophylaxis in some patients. Patients can be taught to self-administer therapy and should be advised to carry a MedicAlert or similar. Acquired C1 inhibitor deficiency This rare disorder is clinically indistinguishable from HAE but presents in late adulthood. It is associated with autoimmune and lymphoproliferative diseases. Most cases are due to the 4.24 Immunological diseases in pregnancy Allergic disease • Maternal dietary restrictions during pregnancy or lactation: current evidence does not support these for prevention of allergic disease. • Breastfeeding for at least 4 months: prevents or delays the occurrence of atopic dermatitis, cow’s milk allergy and wheezing in early childhood, as compared with feeding formula milk containing intact cow’s milk protein. Autoimmune disease • Suppressed T-cell-mediated immune responses in pregnancy: may suddenly reactivate post-partum. Some autoimmune diseases may improve during pregnancy but flare immediately after delivery. Systemic lupus erythematosus (SLE) is an exception, however, as it is prone to exacerbation in pregnancy or the puerperium. • Passive transfer of maternal antibodies: can mediate autoimmune disease in the fetus and newborn, including SLE, Graves’ disease and myasthenia gravis. • Antiphospholipid syndrome (p. 977): an important cause of fetal loss, intrauterine growth restriction and pre-eclampsia. • HIV in pregnancy: see p. 326. 4.25 Classification of transplant rejection Type Time Pathological findings Mechanism Treatment Hyperacute rejection Minutes to hours Thrombosis, necrosis Pre-formed antibody to donor antigens results in complement activation (type II hypersensitivity) None – irreversible graft loss Acute cellular rejection 5–30 days Cellular infiltration CD4+ and CD8+ T cells (type IV hypersensitivity) Increase immunosuppression Acute vascular rejection 5–30 days Vasculitis Antibody and complement activation Increase immunosuppression Chronic allograft failure

30 days Fibrosis, scarring Immune and non-immune mechanisms Minimise drug toxicity, control hypertension and hyperlipidaemia development of autoantibodies to C1 inhibitor, but the condition can also be caused by autoantibodies that activate C1. Treatment of the underlying disorder may induce remission of angioedema. As with HAE, a low C4 is seen during acute episodes. Transplantation and graft rejection Transplantation provides the opportunity for definitive treatment of end-stage organ disease. The major complications are graft rejection, drug toxicity and infection consequent to immunosuppression. Transplant survival continues to improve, as a result of the introduction of less toxic immunosuppressive agents and increased understanding of the processes of transplant rejection. Stem cell transplantation and its complications are discussed on page 936. Transplant rejection Solid organ transplantation inevitably stimulates an aggressive immune response by the recipient, unless the transplant is between monozygotic twins. The type and severity of the rejection response is determined by the genetic disparity between the donor and recipient, the immune status of the host and the nature of the tissue transplanted (Box 4.25). The most important genetic determinant

Transplantation and graft rejection • 89

Investigations Pre-transplantation testing HLA typing determines an individual’s HLA polymorphisms and facilitates donor–recipient matching. Potential transplant recipients are also screened for the presence of anti-HLA antibodies. The recipient is excluded from receiving a transplant that carries these alleles. Donor–recipient cross-matching is a functional assay that directly tests whether serum from a recipient (which potentially contains anti-donor antibodies) is able to bind and/or kill donor lymphocytes. It is specific to a prospective donor–recipient pair and is done immediately prior to transplantation. A positive cross-match is a contraindication to transplantation because of the risk of hyperacute rejection. Post-transplant biopsy: C4d staining C4d is a fragment of the complement protein C4 (see Fig. 4.4). Deposition of C4d in graft capillaries indicates local activation of the classical complement pathway and provides evidence of antibody-mediated damage. This is useful in the early diagnosis of vascular rejection. Complications of transplant immunosuppression Transplant recipients require indefinite treatment with immunosuppressive agents. In general, two or more immunosuppressive drugs are used in synergistic combination in order to minimise adverse effects (Box 4.26). The major complications of long-term immunosuppression are infection and malignancy. The risk of some opportunistic infections may be minimised through the use of prophylactic medication, such as ganciclovir for cytomegalovirus prophylaxis and trimethoprim–sulfamethoxazole for Pneumocystis prophylaxis. Immunisation with killed vaccines is appropriate, although the immune response may be curtailed. Live vaccines should not be given. is the difference between donor and recipient HLA proteins (p. 67). The extensive polymorphism of these proteins means that donor HLA antigens are almost invariably recognised as foreign by the recipient immune system, unless an active attempt has been made to minimise incompatibility. • Hyperacute rejection results in rapid and irreversible destruction of the graft (Box 4.25). It is mediated by pre-existing recipient antibodies against donor HLA antigens, which arise as a result of previous exposure through transplantation, blood transfusion or pregnancy. It is very rarely seen in clinical practice, as the use of screening for anti-HLA antibodies and pre-transplant cross-matching ensures the prior identification of recipient–donor incompatibility. • Acute cellular rejection is the most common form of graft rejection. It is mediated by activated T lymphocytes and results in deterioration in graft function. If allowed to progress, it may cause fever, pain and tenderness over the graft. It is usually amenable to increased immunosuppressive therapy. • Acute vascular rejection is mediated by antibody formed de novo after transplantation. It is more curtailed than the hyperacute response because of the use of intercurrent immunosuppression but it is also associated with reduced graft survival. Aggressive immunosuppressive therapy is indicated and physical removal of antibody through plasmapheresis may be indicated in severe causes. Not all post-transplant anti-donor antibodies cause graft damage; their consequences are determined by specificity and ability to trigger other immune components, such as the complement cascade. • Chronic allograft failure, also known as chronic rejection, is a major cause of graft loss. It is associated with proliferation of transplant vascular smooth muscle, interstitial fibrosis and scarring. The pathogenesis is poorly understood but contributing factors include immunological damage caused by subacute rejection, hypertension, hyperlipidaemia and chronic drug toxicity. 4.26 Immunosuppressive drugs used in transplantation Drug Mechanism of action Major adverse effects Anti-proliferative agents Azathioprine, mycophenolate mofetil Inhibit lymphocyte proliferation by blocking DNA synthesis May be directly cytotoxic at high doses Increased susceptibility to infection Leucopenia Hepatotoxicity Calcineurin inhibitors Ciclosporin, tacrolimus Inhibit T-cell signalling; prevent lymphocyte activation; block cytokine transcription Increased susceptibility to infection Hypertension Nephrotoxicity Diabetogenic (especially tacrolimus) Gingival hypertrophy, hirsutism (ciclosporin) Glucocorticoids Decrease phagocytosis and release of proteolytic enzymes; decrease lymphocyte activation and proliferation; decrease cytokine production; decrease antibody production Increased susceptibility to infection Multiple other complications (p. 670) Anti-thymocyte globulin (ATG) Antibodies to cell surface proteins deplete or block T cells Profound non-specific immunosuppression Increased susceptibility to infection Basiliximab Monoclonal antibody directed against CD25 (IL-2Rα chain), expressed on activated T cells Increased susceptibility to infection Gastrointestinal side-effects Belatacept Selectively inhibits T-cell activation through blockade of CTLA4 Increased susceptibility to infection and malignancy Gastrointestinal side-effects Hypertension Anaemia/leucopenia

90 • CLINICAL IMMUNOLOGY arise. The ability of the immune system to kill cancer cells effectively is influenced by tumour immunogenicity and specificity. Many cancer antigens are poorly expressed and specific antigens can mutate, either spontaneously or in response to treatment, which can result in evasion of immune responses. In addition, the inhibitory pathways that are used to maintain self-tolerance and limit collateral tissue damage during antimicrobial immune responses can be co-opted by cancerous cells to evade immune destruction. Recognition and understanding of these immune checkpoint pathways has led to the development of a number of new treatments for cancers that are otherwise refractory to treatment. For example, antibodies to CTLA4, a co-stimulatory molecule normally involved in down-regulation of immune responses, have been licensed for refractory melanoma, and antibodies to PD1 (programmed cell death protein 1) are used in melanoma, non-small-cell lung cancer and renal cell carcinoma. Potential risks include the development of autoimmunity, reflecting the importance of these pathways in the control of self-tolerance. Further information allergy.org.au An Australasian site providing information on allergy, asthma and immune diseases. allergyuk.org UK site for patients and health-care professionals. anaphylaxis.org.uk Provides information and support for patients with severe allergies. info4pi.org A US site managed by the non-profit Jeffrey Modell Foundation, which provides extensive information about primary immune deficiencies. niaid.nih.gov National Institute of Allergy and Infectious Diseases: provides useful information on a variety of allergic diseases, immune deficiency syndromes and autoimmune diseases. The increased risk of malignancy arises because T-cell suppression results in failure to control viral infections associated with malignant transformation. Virus-associated tumours include lymphoma (associated with Epstein–Barr virus), Kaposi’s sarcoma (associated with human herpesvirus 8) and skin tumours (associated with human papillomavirus). Immunosuppression is also linked with a small increase in the incidence of common cancers not associated with viral infection (such as lung, breast and colon cancer), reflecting the importance of T cells in anticancer surveillance. Organ donation The major problem in transplantation is the shortage of organ donors. Cadaveric organ donors are usually previously healthy individuals who experience brainstem death (p. 211), frequently as a result of road traffic accidents or cerebrovascular events. Even if organs were obtained from all potential cadaveric donors, though, their numbers would be insufficient to meet current needs. An alternative is the use of living donors. Altruistic living donation, usually from close relatives, is widely used in renal transplantation. Living organ donation is inevitably associated with some risk to the donor and it is highly regulated to ensure appropriate appreciation of the risks involved. Because of concerns about coercion and exploitation, non-altruistic organ donation (the sale of organs) is illegal in most countries. Tumour immunology Surveillance by the immune system is critically important in monitoring and removing damaged and mutated cells as they

Ch02-1 Fundamentals of Medicine

05-5 Population health and epidemiology

5 Population health and epidemiology

Population health and epidemiology H Campbell DA McAllister Global burden of disease and underlying risk factors 92 Life expectancy 92 Global causes of death and disability 92 Risk factors underlying disease 93 Social determinants of health 93 The hierarchy of systems – from molecules to ecologies 93 The life course 93 Preventive medicine 93 Principles of screening 94 Epidemiology 95 Understanding causes and effect 95 Health data/informatics 97

92 • POPULATION HEALTH AND EPIDEMIOLOGY the population to older ages, and this is placing an increasing burden on health systems. For a few conditions (e.g. HIV/AIDS, diabetes mellitus and chronic kidney disease), age-standardised death rates continue to rise. Within this overall pattern, significant regional variations exist: for example, communicable, maternal, neonatal and nutritional causes still account for about two-thirds of premature mortality in sub-Saharan Africa. GBD also provides estimates of disability from disease (Box 5.2). This has raised awareness of the importance of conditions like depression, low back and neck pain, and asthma, which account for a relatively large disease burden but relatively few deaths. This, in turn, has resulted in greater health policy priority being given to these conditions. Since the policy focus in national health systems is increasingly on keeping people healthy rather than only on reducing premature deaths, it is important to have measures of these health outcomes. It is also essential to recognise that, although these estimates represent the best overall picture of burden of disease, they are based on imperfect data. Nevertheless, the quality of data underlying the estimates and the modelling processes are The UK Faculty of Public Health defines public health as ‘the science and art of promoting and protecting health and well-being, preventing ill-health and prolonging life through the organised efforts of society’. This definition recognises that there is a collective responsibility for the health of the population that requires partnerships between government, health services and others to promote and protect health and prevent disease. Population health has been defined as ‘the health outcomes of a group of individuals, including the distribution of such outcomes within the group’. Medical doctors can play a role in all these efforts to improve health both through their clinical work and through their support of broader actions to improve public health. Global burden of disease and underlying risk factors The Global Burden of Disease (GBD) exercise was initiated by the World Bank in 1992, with first estimates appearing in 1993. Regular updated figures have been published since, together with projections of future disease burden. The aim was to produce reliable and internally consistent estimates of disease burden for all diseases and injuries, and to assess their physiological, behavioural and social risk factors, so that this information could be made available to health workers, researchers and policy-makers. The GBD exercise adopted the metric ‘disability adjusted life year’ (DALY) to describe population health. This combines information about premature mortality in a population (measured as Years of Life Lost from an ‘expected’ life expectancy) and years of life lived with disability (Years of Life lived with Disability, which is weighted by a severity factor). The International Classification of Disease (ICD) rules, which assign one cause to each death, are followed. All estimates are presented by age and sex groups and by regions of the world. Many countries now also report their own national burden of disease data. Life expectancy Global life expectancy at birth increased from 61.7 years in 1980 to 71.8 years in 2015, an increase of 0.29 years per calendar year. This change is due to a substantial fall in child mortality (mainly caused by common infections), partly offset by rises in mortality from adult conditions such as diabetes and chronic kidney disease. Some areas have not shown these increases in life expectancy in men, often due to war and interpersonal violence. Global causes of death and disability Box 5.1 shows a ranked list of the major causes of global premature deaths in 2015. Communicable, maternal, neonatal and nutritional causes accounted for about one-quarter of deaths worldwide, down from about one-third in 1990. In contrast, deaths from non-communicable diseases are increasing in importance and now account for about two-thirds of all deaths globally, including about 13 million from ischaemic heart disease and stroke, and about 8 million from cancer. The age-standardised death rates for most diseases globally are falling. However, despite this, the numbers of deaths from many diseases are rising due to global population growth and the change in age structure of 5.2 Global disability: top 15 ranked causes, 20151,2

  1. Lower back and neck pain (1)
  2. Sense organ diseases (3)
  3. Depressive disorders (4)
  4. Iron deficiency anaemia (2)
  5. Skin diseases (5)
  6. Diabetes (9)
  7. Migraine (6)
  8. Other musculoskeletal conditions3 (7)
  9. Anxiety disorders (8)
  10. Oral disorders (11)
  11. Asthma (10)
  12. Schizophrenia (13)
  13. Osteoarthritis (19)
  14. Chronic obstructive pulmonary disease (14)
  15. Falls (12) 1By Years of Life lived with Disability (YLD). 2Rank in 1990 is shown in brackets. 3Not otherwise classified as specific conditions such as osteoarthritis. 5.1 Global premature mortality: top 15 ranked causes, 20151,2
  16. Ischaemic heart disease (4)
  17. Cerebrovascular disease (5)
  18. Lower respiratory infections (1)
  19. Neonatal preterm birth complications (2)
  20. Diarrhoeal diseases (3)
  21. Neonatal encephalopathy (6)
  22. HIV/AIDS (29)
  23. Road injuries (10)
  24. Malaria (7)
  25. Chronic obstructive pulmonary disease (12)
  26. Congenital anomalies (9)
  27. Tuberculosis (11)
  28. Lung cancer3 (20)
  29. Self-harm (16)
  30. Diabetes (> 30) 1By Years of Life Lost (YLL). 2Rank in 1990 is shown in brackets. 3‘All cancers combined’ would rank in the top three causes.

Social determinants of health • 93

to higher risk of hypertension and type 2 diabetes in young adults, and of cardiovascular disease in middle age. It has been suggested that under-nutrition during middle to late gestation permanently ‘programs’ cardiovascular and metabolic responses. This ‘life course’ perspective highlights the cumulative effect on health of exposures to illness, adverse environmental conditions and behaviours that damage health. Preventive medicine The complexity of interactions between physical, social and economic determinants of health means successful prevention is often difficult. Moreover, the life-course perspective illustrates that it may be necessary to intervene early in life or even before birth, to prevent important disease later. Successful prevention is likely to require many interventions across the life course and at several levels in the hierarchy of systems. The examples below illustrate this. improving over time and provide an increasingly robust basis for evidence-based health planning and priority setting. Risk factors underlying disease Box 5.3 shows a ranked list of the main risk factors that underlay GBD in 2015 and how this ranking has changed in recent years. Social determinants of health Health emerges from a highly complex interaction between a person’s genetic background and environmental factors (aspects of the physical, biological (microbes), built and social environments, and also distant influences such as the global ecosystem; Fig. 5.1). The hierarchy of systems – from molecules to ecologies Influences on health exist at many levels and extend beyond the individual to include the family, community, population and ecology. Box 5.4 shows an example of this for determinants of coronary heart disease and demonstrates the importance of considering not only the disease process in a patient but also its context. Health care is not the only determinant – and is usually not the major determinant – of health status in the population. The concept of ‘global health’ recognises the global dimension of health problems, whether these be emerging or pandemic infections or global economic influences on health. The life course The determinants of health operate over the whole lifespan. Values and behaviours acquired during childhood and adolescence have a profound influence on educational outcomes, job prospects and risk of disease. These can have a strong influence, for example, on whether a young person takes up damaging behaviour like smoking, risky sexual activity and drug misuse. Influences on health can operate even before birth. Low birth weight can lead Fig. 5.1 Hierarchy of systems that influence population health. Adapted from an original model by Whitehead M, Dahlgren G. What can be done about inequalities in health? Lancet 1991; 338:1059–1063. Macro-economy, politics, culture, global forces Other neighbourhoods, other regions People Age, sex and hereditary factors

L i f e s t y l e

W o r k ,

p l a y D i e t ,

p h y s i c a l

a c t i v i t y

S o c i a l c a p it a l

C o m m u n i t y

N e t w o r k s W e a lt h

c r e a ti o n

L o c a l e c o n o m y

M a r k e t s B ui ld in g s,

pl a c e s

E n vi r o n m e n t

A ir , w at e r, l a n d Cl i m at e c h a n g e

Gl o b al e c o s y st e m

Bi o di v er si ty 5.3 Global risk factors: top 15 ranked causes, 20151–3

  1. High blood pressure (3)
  2. Smoking/second-hand smoke exposure (5)
  3. High fasting blood glucose (10)
  4. High body mass index (13)
  5. Childhood underweight (1)
  6. Ambient particulate matter pollution (6)
  7. High total cholesterol (12)
  8. Household air pollution (4)
  9. Alcohol use (11)
  10. High sodium intake (14)
  11. Low wholegrain intake (15)
  12. Unsafe sex (20)
  13. Low fruit intake (16)
  14. Unsafe water (2)
  15. Low glomerular filtration rate (21) 1By percentage of burden of disease they cause. 2Rank in 1990 is shown in brackets. 3All dietary risk factors and physical inactivity combined accounted for 10% of global burden of disease. Low physical activity was ranked 21, iron deficiency 16 and suboptimal breastfeeding 22 in 2015. 5.4 ‘Hierarchy of systems’ applied to ischaemic heart disease Level in the hierarchy Example of effect Molecular ApoB mutation causing hypercholesterolaemia Cellular Macrophage foam cells accumulate in vessel wall Tissue Atheroma and thrombosis of coronary artery Organ Ischaemia and infarction of myocardium System Cardiac failure Person Limited exercise capacity, impact on employment Family Passive smoking, diet Community Shops and leisure opportunities Population Prevalence of obesity Society Policies on smoking, screening for risk factors Ecology Agriculture influencing fat content in diet

94 • POPULATION HEALTH AND EPIDEMIOLOGY of obesity, therefore, we not only need to help those who are already obese but also develop strategies that impact on the whole population and reverse the obesogenic environment. Poverty and affluence The adverse health and social consequences of poverty are well documented: high birth rates, high death rates and short life expectancy. Typically, with industrialisation, the pattern changes: low birth rates, low death rates and longer life expectancy. Instead of infections, chronic conditions such as heart disease dominate in an older population. Adverse health consequences of excessive affluence are also becoming apparent. Despite experiencing sustained economic growth for the last 50 years, people in many industrialised countries are not growing any happier and the litany of socioeconomic problems – crime, congestion, inequality – persists. Many countries are now experiencing a ‘double burden’. They have large populations still living in poverty who are suffering from problems such as diarrhoea and malnutrition, alongside affluent populations (often in cities) who suffer from chronic illness such as diabetes and heart disease. Atmospheric pollution Emissions from industry, power plants and motor vehicles of sulphur oxides, nitrogen oxides, respirable particles and metals are severely polluting cities and towns in Asia, Africa, Latin America and Eastern Europe. Burning of fossil and biomass fuels, with production of short-lived carbon pollutants (SLCPs – methane, ozone, black carbon and hydrofluorocarbons), contributes to increased death rates from respiratory and cardiovascular disease in vulnerable adults, such as those with established respiratory disease and the elderly, while children experience an increase in bronchitic symptoms. Developing countries also suffer high rates of respiratory disease as a result of indoor pollution caused mainly by heating and cooking using solid biomass fuels. Climate change and global warming Climate change is arguably the world’s most important environmental health issue. A combination of habitat destruction and increased production of carbon dioxide and SLCPs, caused primarily by human activity, seems to be the main cause. The temperature of the globe is rising, and if current trends continue, warming by 4°C is predicted by 2050. The climate is being affected, putting millions of people at risk of rising sea levels, flooding, droughts and failed crops These have already claimed millions of lives during the past 20 years and have adversely affected the lives of many more. The economic costs of property damage and the impact on agriculture, food supplies and prosperity have also been substantial. Global warming will also include changes in the geographical range of some vector-borne infectious diseases. Currently, politicians cannot agree an effective framework of actions to tackle the problem, but reducing emissions of CO2 and SLCPs is essential. Principles of screening Screening is the application of a test to a large number of asymptomatic people with the aim of reducing morbidity or mortality from a disease. The World Health Organisation (WHO) Alcohol Alcohol use is an increasingly important risk factor underlying GBD (see Box 5.3). Reasons for increasing rates of alcohol-related harm vary by place and time but include the falling price of alcohol (in real terms), increased availability and cultural change fostering higher levels of consumption. Public, professional and governmental concern has now led to a minimum price being charged for a unit of alcohol, tightening of licensing regulations and curtailment of some promotional activity in many countries. However, even more aggressive public health measures will be needed to reverse the levels of harm in the population. The approach for individual patients suffering adverse effects of alcohol is described elsewhere (e.g. pp. 1184 and 880). Smoking Smoking is one of the top three risk factors underlying GBD (see Box 5.3). It is responsible for a substantial majority of cases of chronic obstructive pulmonary disease (COPD) and lung cancer (pp. 573 and 598), and most smokers die either from these or from ischaemic heart disease. Smoking also causes cancers of the upper respiratory and gastrointestinal tracts, pancreas, bladder and kidney, and increases risks of peripheral vascular disease, stroke and peptic ulceration. Maternal smoking is an important cause of fetal growth retardation. Moreover, there is evidence that passive (‘second-hand’) smoking has adverse effects on cardiovascular and respiratory health. The decline in smoking in many high-income countries has been achieved not only by warning people of the health risks but also by increasing taxation of tobacco, banning advertising, legislating against smoking in public places and giving support for smoking cessation to maintain this decline. However, smoking rates remain high in many poorer areas and are increasing among young women. In many developing countries, tobacco companies have found new markets and rates are rising. A complex hierarchy of systems interacts to cause smokers to initiate and maintain their habit. At the molecular and cellular levels, nicotine acts on the nervous system to create dependence and maintain the smoking habit. There are also strong influences at the personal and social level, such as young female smokers being motivated to ‘stay thin’ or ‘look cool’ and peer pressure. Other important influences include cigarette advertising, with the advertising budget of the tobacco industry being much greater than that of health services. Strategies to help individuals stop smoking (such as nicotine replacement therapy, anti-smoking advice and behavioural support) are cost-effective and form an important part of the overall strategy. Obesity Obesity is an increasingly important risk factor underlying GBD (see Box 5.3). The weight distribution of almost the whole population is shifting upwards: the slim are becoming less slim while the fat are getting fatter (p. 698). In the UK, this translates into a 1 kg increase in weight per adult per year (on average over the adult population). The current obesity epidemic cannot be explained simply by individual behaviour and poor choice but also requires an understanding of the obesogenic environment that encourages people to eat more and exercise less. This includes the availability of cheap and heavily marketed energy-rich foods, the increase in labour-saving devices (e.g. lifts and remote controls) and the rise in passive transport (cars as opposed to walking, cycling, or walking to public transport hubs). To combat the health impact

Epidemiology • 95

has identified a set of (‘Wilson and Jungner’) criteria to guide health systems in deciding when it is appropriate to implement screening programmes. The essential criteria are: • Is the disease an important public health problem? • Is there a suitable screening test available? • Is there a recognisable latent or early stage? • Is there effective treatment for the disease at this stage that improves prognosis? A suitable screening test is one that is cheap, acceptable, easy to perform and safe, and gives a valid result in terms of sensitivity and specificity (p. 4). Screening programmes should always be evaluated in trials so that robust evidence is provided in favour of their adoption. These evaluations are prone to several biases – self-selection bias, lead-time bias and length bias – and these need to be accounted for in the analysis. Examples of large-scale programmes in the UK include breast, colorectal and cervical cancer national screening programmes and a number of screening tests carried out in pregnancy and in the newborn, such as the: • diabetic eye screening programme • fetal anomaly screening programme • infectious diseases in pregnancy screening programme • newborn and infant physical examination screening programme • newborn blood spot screening programme • newborn hearing screening programme • sickle-cell and thalassaemia screening programme. These are illustrated in Figure 5.2. Problems with screening include: • over-diagnosis (of a disease that would not have come to attention on its own or would not have led to death) • false reassurance • diversion of resources from investments that could control the disease more cost-effectively. An example of these problems is the use of prostate-specific antigen (PSA) testing as a screening test for the diagnosis of prostate cancer (p. 438). Epidemiology Epidemiologists study disease in free-living humans, seeking to describe patterns of health and disease and to understand how different exposures cause or prevent disease (Box 5.5). Chronic diseases and risk factors (e.g. smoking, obesity etc.) are often described in terms of their prevalence. A prevalence is simply a proportion: e.g. the prevalence of diabetes in people aged 80 and older in developed countries is around 10%. Events such as deaths, hospitalisations and first occurrences of a disease are described using incidence rates: e.g. if there are 100 new cases of a disease in a single year in a population of 1000, the incidence rate is 105 per 1000 person-years, not 100, because of the effect of ‘person-time’. Person-time is the sum of the total ‘exposed’ time for the population and in this example is 950 person-years. The reason person-time is less than 1000 is that 100 people experienced the event. These 100 people are assumed to have had an event, on average, halfway through the time period, removing 100 × 0.5 person-years from the exposure time (as it is not possible to have a first occurrence of a disease twice). Hence, the incidence per 1000 person-years is 105, not 100. A similar measure is the cumulative incidence or risk, which is the number of new cases as a proportion of the total people at risk at the beginning of the exposure time. If, in the example above, the same 1000 people were observed for a year (i.e. with no one joining or leaving the group), then the 1-year risk is 10% (100/1000). The time period should always be specified. These rates and proportions are used to describe how diseases (and risk factors) vary according to time, person and place. Temporal variation may occur seasonally (e.g. malaria occurs in the wet season but not the dry) or as longer-term ‘secular’ trends (e.g. malaria may re-emerge due to drug resistance). Person comparisons include age, sex, socioeconomic status, employment, and lifestyle characteristics. Place comparisons include the local environment (e.g. urban versus rural) and international comparisons. Understanding causes and effect Epidemiological research complements that based on animal, cell and tissue models, the findings of which do not always translate to humans. For example, only a minority of drug discoveries from laboratory research are effective when tested in people. However, differentiating causes from mere non-causal associations is a considerable challenge for epidemiology. This is because while laboratory researchers can directly manipulate conditions to isolate and understand causes, such approaches are impossible in free-living populations. Epidemiologists have developed a different approach, based around a number of study designs (Box 5.6). Of these, the clinical trial is closest to the laboratory experiment. An early example of a clinical trial is shown in Figure 5.3, along with ‘effect measures’, which are used to quantify the difference in rates and risks. In clinical trials, patients are usually allocated randomly to treatments so that, on average, groups are similar, apart from the intervention of interest. Nevertheless, for any particular trial, especially a small trial, the laws of probability mean that differences can and do occur by chance. Poorly designed or executed trials can also limit comparability between groups. Allocation may not be truly random (e.g. because of inadequate concealment of the randomisation sequence), and there may 5.5 Calculation of risk using descriptive epidemiology Prevalence • The ratio of the number of people with a longer-term disease or condition, at a specified time, to the number of people in the population Incidence • The number of events (new cases or episodes) occurring in the population at risk during a defined period of time Attributable risk • The difference between the risk (or incidence) of disease in exposed and non-exposed populations Attributable fraction • The ratio of the attributable risk to the incidence Relative risk • The ratio of the risk (or incidence) in the exposed population to the risk (or incidence) in the non-exposed population

96 • POPULATION HEALTH AND EPIDEMIOLOGY Fig. 5.2 UK NHS Pregnancy and Newborn Screening Programmes: optimum times for testing. (GA1 = glutaric aciduria type 1; HCU = homocystinuria; IVA = isovaleric acidaemia; MCADD = medium-chain acyl-CoA dehydrogenase deficiency; MSUD = maple syrup urine disease; PKU = phenylketonuria; T13, 18, 21 = trisomy 13, 18 and 21) Based on Version 8.1, March 2016, Gateway ref: 2014696, Public Health England. Blood for sickle cell and thalassaemia Commence folic acid Pre-conception Pregnancy Newborn Blood for haemoglobin, group, Rhesus and antibodies as early as possible, or as soon as a woman arrives for care, including labour Blood for syphilis, hepatitis B and HIV as early as possible, or at any stage of the pregnancy, including labour Reoffer screening for infectious diseases if initially declined Hepatitis B vaccination ± immunoglobulin within 24 hours Repeat haemoglobin and antibodies

+1 +2 +3 +4 +5 +6 Birth Key Week Blood for T21, T18 and T13 (combined test) Blood for T21 (quadruple test) Newborn physical examination by 72 hours Newborn blood spot screens (ideally on day 5) for sickle cell disease (SCD), cystic fibrosis (CF), congenital hypothyroidism (CHT) and inherited metabolic diseases (PKU, MCADD, MSUD, IVA, GA1 and HCU). NB: babies who missed the screen can be tested up to 1 year (except CF offered up to 8 weeks) Early pregnancy scan to support T21, T18 and T13 screening Women with type 1 or type 2 diabetes are offered diabetic eye (DE) screening annually. In pregnancy women with type 1 or type 2 diabetes are offered a DE screen when they first present for care Give screening information as soon as possible Give and discuss newborn screening information Follow-up DE screen for women with type 1 or 2 diabetes found to have diabetic retinopathy Further DE screen for women with type 1 or 2 diabetes Detailed ultrasound scan for structural abnormalities, including T18 and T13 Newborn hearing screen Infant physical examination at 6–8 weeks T21, T18, T13 and fetal anomaly ultrasound Sickle cell and thalassaemia Newborn and infant physical examination Newborn blood spot Infectious diseases in pregnancy Diabetic eye Newborn hearing

Health data/informatics • 97

or more often practical, considerations. Epidemiologists therefore seek to minimise bias and confounding by good study analysis and design. They subsequently make causal inferences by balancing the probability that an observed association has been caused by chance, bias and/or confounding against the alternative probability that the relationship is causal. This weighing-up requires an understanding of the frequency and importance of different sources of bias and confounding, as well as the scientific rationale of the putative causal relationship. It was this approach, collectively and over a number of years, that settled the fact that smoking causes lung cancer and, subsequently, heart disease. Health data/informatics As patients pass through health and social care systems, data are recorded concerning their family background, lifestyle and disease states, which is of potential interest to healthcare organisations seeking to deliver services, policy-makers concerned with improving health, scientific researchers trying to understand health, and also pharmaceutical and other commercial organisations aiming to identify markets. There is a long tradition of maintaining health information systems. In most countries, registration of births and deaths is required by law, and in the majority, the cause of death is also recorded (Fig. 5.4). There are many challenges in ensuring such data are useful, especially for comparisons across time and place: • A system of standard terminologies is needed, such as the WHO International Classification of Diseases (ICD-10), which provides a list of diagnostic codes attempting to cover every diagnostic entity. • These terms must be understood to refer to the same, or at least similar, diseases in different places. • Access to diagnostic skill and facilities is required. • Standard protocols for assigning clinical diagnoses to ICD-10 codes are needed • Robust quality control processes are needed to maintain some level of data completeness and accuracy. Many countries employ similar systems for hospitalisations, to allow recovery of health-care utilisation costs or to manage and plan services. Similar data are rarely collected for communitybased health care, nor are detailed data on health-care processes generally included in national data systems. Consequently, there has been considerable interest in using data from information technology systems used to deliver care, such as electronic be systematic differences (biases) in the way people allocated to different groups are treated or studied. Such biases also occur in observational epidemiological study designs, such as cohort, case–control and cross-sectional studies (Box 5.6). These designs are also much more subject to the problem of confounding than are randomised trials. Confounding is where the relationship between an exposure and outcome of interest is confused by the presence of some other causal factor. For example, coffee consumption may be associated with lung cancer because smoking is more common among coffee-drinkers. Here, smoking is said to confound the association between coffee and lung cancer. Despite these limitations, for most causes of diseases, randomised controlled trials are not feasible because of ethical, Fig. 5.3 An example of a clinical trial: streptomycin versus bed rest in tuberculosis. Both prevalences and risks are, in fact, proportions, and are therefore frequently expressed as odds. The reasons for doing so are beyond the scope of this text. Enrolled 107 patients with tuberculosis Effect measures Risk ratio (relative risk, RR) Odds ratio (OR) Absolute risk reduction (ARR) Relative risk reduction (RRR) Number needed to treat to prevent one death (NNT= 1/ARR) Random allocation Streptomycin 55 patients Bed rest 52 patients Follow-up and count deaths Events

Risk 7.3% Odds 0.068 Events

Risk 28.8% Odds 0.224 0.25 0.30 21.6% 74.8% 4.6 5.6 Epidemiological study designs Design Description Example Clinical trial Enrols a sample from a population and compares outcomes after randomly allocating patients to an intervention Medical Research Council (MRC) Streptomycin Trial – demonstrated effectiveness of streptomycin in tuberculosis Cohort Enrols a sample from a population and compares outcomes according to exposures Framingham Study – identified risk factors for cardiovascular disease Case–control Enrols cases with an outcome of interest and controls without that outcome and compares exposures between the groups Doll R, Hill AB. Smoking and carcinoma of the lung. British Medical Journal 1950 – demonstrated that smoking caused lung cancer Cross-sectional Enrols a cross-section (sample) of people from the population of interest; obtains data on exposures and outcomes World Health Organisation Demographic and Health Survey – captures risk factor data in a uniform way across many countries

98 • POPULATION HEALTH AND EPIDEMIOLOGY Further information Books and journal articles GBD 2015 Disease and Injury Incidence and Prevalence Collaborators. Global, regional, and national incidence, prevalence, and years lived with disability for 310 diseases and injuries, 1990–2015: a systematic analysis for the Global Burden of Disease Study 2015. Lancet 2016; 388:1545–1602. GBD 2015 Mortality and Causes of Death Collaborators. Global, regional, and national life expectancy, and cause-specific mortality for 249 causes of death, 1980–2015: a systematic analysis for the Global Burden of Disease Study 2015. Lancet 2016; 388:1459–1544. GBD 2015 Risk Factors Collaborators. Global, regional, and national comparative risk assessment of 79 behavioural, environmental and occupational, and metabolic risks or clusters of risks, 1990–2015: a systematic analysis for the Global Burden of Disease Study 2015. Lancet 2016; 388:1659–1724. Kindig D, Stoddart G. What is population health? Am J Public Health 2003; 93:380–383. Websites fph.org.uk UK Faculty of Public Health: What is public health? gov.uk UK Government: population screening programmes. patient records, drug-dispensing databases, radiological software and clinical laboratory information systems. Data from such systems are, of course, much less structured than those obtained from vital registrations. Moreover, the completeness of such data depends greatly on local patterns of health-care utilisation, as well as how clinicians and others use information technology systems within different settings. As such, deriving useful, unbiased information from such data is a considerable challenge. Much of the discipline of health informatics is concerned with addressing this challenge. One approach has been to develop comprehensive standard classification systems such as SNOMED-CT, ‘a standardised, multilingual vocabulary of terms relating to the care of the individual’, which has been designed for electronic health-care records. An alternative has been to use statistical methods such as natural language processing to derive information automatically from free text (such as culling diagnoses from radiological reports), or to employ ‘machine learning’, in which software algorithms are applied to data in order to derive useful insights. Such approaches are suited to large, messy data where the costs of systematisation would be prohibitive. It is likely that such innovations will, over the coming years, provide useful information to complement that obtained from more traditional health information systems. Fig. 5.4 Completed death certificate. International Classification of Diseases 10 (ICD-10) codes are appended in red. WHO ICD-10, vol. 2; 1990. Available at https://commons.m.wikimedia.org/wiki/File:International_form_of_medical_certificate_of_cause_of_death.png. Cause of death Approximate interval between onset and death I Disease or condition directly leading to death* INTERNATIONAL FORM OF MEDICAL CERTIFICATE OF CAUSE OF DEATH due to (or as a consequence of) due to (or as a consequence of) due to (or as a consequence of) (a) (b) (c) (d) I21.9 E78.0 J47 *This does not mean the mode of dying, e.g. heart failure, respiratory failure. It means the disease, injury, or complication that caused death. Antecedent causes Morbid conditions, if any, giving rise to the above cause, stating the underlying condition last II Other significant conditions contributing to the death, but not related to the disease or condition causing it

Ch02-1 Fundamentals of Medicine

06-6 Principles of infectious disease

6 Principles of infectious disease

Principles of infectious disease JAT Sandoe DH Dockrell Infectious agents 100 Normal microbial flora 102 Host–pathogen interactions 104 Investigation of infection 105 Direct detection of pathogens 105 Culture 106 Indirect detection of pathogens 106 Antimicrobial susceptibility testing 109 Epidemiology of infection 110 Infection prevention and control 111 Health care-associated infection 111 Outbreaks of infection 114 Immunisation 114 Antimicrobial stewardship 115 Treatment of infectious diseases 116 Principles of antimicrobial therapy 116 Antibacterial agents 120 Antimycobacterial agents 125 Antifungal agents 125 Antiviral agents 126 Antiparasitic agents 128

100 • PRINCIPLES OF INFECTIOUS DISEASE tackling infection in resource-poor countries. Microorganisms are continually mutating and evolving; the emergence of new infectious agents and antimicrobial-resistant microorganisms is therefore inevitable. This chapter describes the biological and epidemiological principles of infectious diseases and the general approach to their prevention, diagnosis and treatment. Specific infectious diseases are described in Chapters 11–13 and many of the organ-based chapters. Infectious agents The concept of an infectious agent was established by Robert Koch in the 19th century (Box 6.1). Although fulfilment of ‘Koch’s postulates’ became the standard for the definition of an infectious agent, they do not apply to uncultivable organisms (e.g. Mycobacterium leprae, Tropheryma whipplei ) or members of the normal human flora (e.g. Escherichia coli, Candida spp.). The following groups of infectious agents are now recognised. Viruses Viruses are incapable of independent replication. Instead, they subvert host cellular processes to ensure synthesis of their nucleic acids and proteins. Viruses’ genetic material (the genome) consists of single- or double-stranded DNA or RNA. Retroviruses transcribe their RNA into DNA in the host cell by reverse transcription. An antigenically unique protein coat (capsid) encloses the genome, and together these form the nucleocapsid. In many viruses, the nucleocapsid is packaged within a lipid envelope. Enveloped viruses are less able to survive in the environment and are spread by respiratory, sexual or blood-borne routes, including arthropod-based transmission. Non-enveloped viruses survive better in the environment and are predominantly transmitted by faecal–oral or, less often, respiratory routes. A generic virus life cycle is shown in Figure 6.2. A virus that infects a bacterium is a bacteriophage (phage). Prokaryotes: bacteria (including mycobacteria and actinomycetes) Prokaryotic cells are capable of synthesising their own proteins and nucleic acids, and are able to reproduce autonomously, although they lack a nucleus. The bacterial cell membrane is bounded by a peptidoglycan cell wall, which is thick (20–80 nm) in Gram-positive organisms and thin (5–10 nm) in Gram-negative ones. The Gram-negative cell wall is surrounded by an outer membrane containing lipopolysaccharide. Genetic information is contained within a chromosome but bacteria may also contain rings of extra-chromosomal DNA, known as plasmids, which can be transferred between organisms, without cells having to divide. Bacteria may be embedded in a polysaccharide capsule, ‘Infection’ in its strict sense describes the situation where microorganisms or other infectious agents become established in the host organism’s cells or tissues, replicate, cause harm and induce a host response. If a microorganism survives and replicates on a mucosal surface without causing harm or illness, the host is said to be ‘colonised’ by that organism. If a microorganism survives and lies dormant after invading host cells or tissues, infection is said to be ‘latent’. When the infectious agent, or the host response to it, is sufficient to cause illness or harm, then the process is termed an ‘infectious disease’. Most pathogens (infectious agents that can cause disease) are microorganisms but some are multicellular organisms. The manifestations of disease may aid pathogen dissemination (e.g. diarrhoea). The term ‘infection’ is often used interchangeably with ‘infectious disease’ but not all infections are ‘infectious’, i.e. transmissible from person to person. Infectious diseases transmitted between hosts are called communicable diseases, whereas those caused by organisms that are already colonising the host are described as endogenous. The distinction is blurred in some situations, including health care-associated infections such as meticillinresistant Staphylococcus aureus (MRSA) or Clostridium difficile infection (CDI), in which colonisation precedes infection but the colonising bacteria may have been recently transmitted between patients. The chain of infection (Fig. 6.1) describes six essential elements for communicable disease transmission. Despite dramatic advances in hygiene, immunisation and antimicrobial therapy, infectious agents still cause a massive burden of disease worldwide. Key challenges remain in Fig. 6.1 Chain of infection. The infectious agent is the organism that causes the disease. The reservoir is the place where the population of an infectious agent is maintained. The portal of exit is the point from which the infectious agent leaves the reservoir. Transmission is the process by which the infectious agent is transferred from the reservoir to the human host, either directly or via a vector or fomite. The portal of entry is the body site that is first accessed by the infectious agent. Finally, in order for disease to ensue, the person to whom the infectious agent is transmitted must be a susceptible host. Susceptible host Exit Entry Transmission Infectious agent Reservoir 6.1 Definition of an infectious agent – Koch’s postulates

  1. The same organism must be present in every case of the disease
  2. The organism must be isolated from the diseased host and grown in pure culture
  3. The isolate must cause the disease, when inoculated into a healthy, susceptible animal
  4. The organism must be re-isolated from the inoculated, diseased animal

Infectious agents • 101

Eukaryotes: fungi, protozoa and helminths Eukaryotic cells contain membrane-bound organelles, including nuclei, mitochondria and Golgi apparatus. Pathogenic eukaryotes are unicellular (e.g. fungi, protozoa) or complex multicellular organisms (e.g. nematodes, trematodes and cestodes, p. 288). and motile bacteria are equipped with flagella. Although many prokaryotes are capable of independent existence, some (e.g. Chlamydia trachomatis, Coxiella burnetii ) are obligate intracellular organisms. Bacteria that can grow in artificial culture media are classified and identified using a range of characteristics (Box 6.2); examples are shown in Figures 6.3 and 6.4. Fig. 6.2 A generic virus life cycle. Life cycle components common to most viruses are host cell attachment and penetration, virus uncoating, nucleic acid and protein synthesis, virus assembly and release. Virus release is achieved either by budding, as illustrated, or by lysis of the cell membrane. Life cycles vary between viruses. Host cell 2 Penetration Receptor-mediated endocytosis or, in some enveloped viruses, membrane fusion (shown here)

Uncoating Nucleic acid is liberated from the phagosome (if endocytosed) and/or capsid by complex enzymatic and/or receptor-mediated processes Interaction between host receptor molecule and virus ligand (determines host-specificity of the virus) Adsorption

Lipid envelope Capsid Nucleic acid Virus Assembly 5 Assembly of virus components is mediated by host and/or viral enzymes Release 6 Complete virus particles are released by budding of host cell membrane (shown here) or disintegration of host cell

Synthesis Nucleic acid and protein synthesis is mediated by host and/or viral enzymes. This takes place in nucleus or cytoplasm, depending on the specific virus Gram stain reaction (see Fig. 6.3) • Gram-positive (thick peptidoglycan layer), Gram-negative (thin peptidoglycan) or unstainable Microscopic morphology • Cocci (round cells) or bacilli (elongated cells) • Presence or absence of capsule Cell association • Association in clusters, chains or pairs Colonial characteristics • Colony size, shape or colour • Effect on culture media (e.g. β-haemolysis of blood agar in haemolytic streptococci; see Fig. 6.4) Atmospheric requirements • Strictly aerobic (requires O2), strictly anaerobic (requires absence of O2), facultatively aerobic (grows with or without O2) or microaerophilic (requires reduced O2) Biochemical reactions • Expression of enzymes (oxidase, catalase, coagulase) • Ability to ferment or hydrolyse various biochemical substrates Motility • Motile or non-motile Antibiotic susceptibility • Identifies organisms with invariable susceptibility (e.g. to optochin in Streptococcus pneumoniae or metronidazole in obligate anaerobes) Matrix-assisted laser desorption/ionisation time-of-flight mass spectrometry (MALDI-TOF-MS) • A rapid technique that identifies bacteria and some fungi from their specific molecular composition Sequencing bacterial 16s ribosomal RNA gene • A highly specific test for identification of organisms in pure culture and in samples from normally sterile sites Whole-genome sequencing • Although not yet in routine use, whole-genome sequencing (WGS) offers the potential to provide rapid and simultaneous identification, sensitivity testing and typing of organisms from pure culture and/or directly from clinical samples. As such, WGS is likely to replace many of the technologies described above over the next few years (p. 58) 6.2 How bacteria are identified

102 • PRINCIPLES OF INFECTIOUS DISEASE Fig. 6.3 Flow chart for bacterial identification, including Gram film appearances on light microscopy (×100). (MALDI-TOF-MS = matrix-assisted laser desorption/ionisation time-of-flight mass spectroscopy) Gram-positive bacilli Colony morphology, growth characteristics (e.g. growth in anaerobic atmosphere), Gram stain appearance, MALDI-TOF-MS identification Colony morphology, growth characteristics, oxidase reaction, sugar fermentation/MALDI-TOF-MS identification Colony morphology, growth characteristics, lactose fermentation, oxidase reaction, MALDI-TOF-MS identification Colony morphology (e.g. haemolysis), Gram stain appearance, agglutination reactions, coagulase test, catalase Examples Actinomycetes Arcanobacterium haemolyticum Bacillus spp. Corynebacterium diphtheriae Lactobacillus spp. Listeria monocytogenes Nocardia spp. Clostridium spp. or Examples Neisseria meningitidis Neisseria gonorrhoeae Moraxella catarrhalis Examples Escherichia coli Klebsiella pneumoniae Proteus spp. Enterobacter spp. Serratia spp. Salmonella spp. Shigella spp. Yersinia spp. Vibrio spp. Pseudomonas aeruginosa Gram-positive cocci–clusters Examples Staphylococcus aureus Coagulase-negative staphylococci Gram-negative cocci Gram stain Gram-negative bacilli Gram-positive cocci Gram-positive cocci–chains Examples Oral streptococci Streptococcus pneumoniae (often pairs) Beta-haemolytic streptococci Enterococci (short chains) Fig. 6.4 Beta-haemolytic streptococci (A) and alpha-haemolytic streptococci (B) spread on each half of a blood agar plate (backlit). This image is half life size. ×0.5. Beta-haemolysis renders the agar transparent around the colonies (A) and alpha-haemolysis imparts a green tinge to the agar (B). B A Fungi exist as either moulds (filamentous fungi) or yeasts. Dimorphic fungi exist in either form, depending on environmental conditions (see Fig. 11.59, p. 300). The fungal plasma membrane differs from the human cell membrane in that it contains the sterol, ergosterol. Fungi have a cell wall made up of polysaccharides, chitin and mannoproteins. In most fungi, the main structural component of the cell wall is β-1,3-D-glucan, a glucose polymer. These differences from mammalian cells are important because they offer useful therapeutic targets. Protozoa and helminths are often referred to as parasites. Many parasites have complex multi-stage life cycles, which involve animal and/or plant hosts in addition to humans. Prions Although prions are transmissible and have some of the characteristics of infectious agents, they are not microorganisms and are not diagnosed in microbiology laboratories. Prions are covered on page 250. Normal microbial flora The human body is colonised by large numbers of microorganisms (collectively termed the human microbiota). These colonising

Normal microbial flora • 103

Fig. 6.5 Human non-sterile sites and normal flora in health. Pharynx Haemophilus spp. Moraxella catarrhalis Neisseria spp. (including N. meningitidis) Staph. aureus Strep. pneumoniae Strep. pyogenes (group A) Oral streptococci (α-haemolytic) Oral cavity Oral streptococci (α-haemolytic) Anaerobic Gram-positive bacilli (including Actinomyces spp.) Anaerobic Gram-negative bacilli Prevotella spp. Fusobacterium spp. Candida spp. Small bowel Distally, progressively increasing numbers of large bowel bacteria Candida spp. Large bowel Enterobacteriaceae Escherichia coli Klebsiella spp. Enterobacter spp. Proteus spp. Enterococci E. faecalis E. faecium Streptococcus anginosus group Strep. anginosus Strep. intermedius Strep. constellatus Anaerobic Gram-positive bacilli Clostridium spp. Anaerobic Gram-negative bacilli Bacteroides spp. Prevotella spp. Candida spp. Scalp As for skin Nares Staph. aureus Coagulase-negative staphylococci Skin Coagulase-negative staphylococci Staph. aureus Corynebacterium spp. Propionibacterium spp. Malassezia spp. Hands Resident: as for skin Transient: skin flora (including meticillin-resistant and other Staph. aureus), bowel flora (including Clostridium difficile, Candida spp. and Enterobacteriaceae) Vagina Lactobacillus spp. Staph. aureus Candida spp. Enterobacteriaceae Strep. agalactiae (group B) Perineum As for skin As for large bowel bacteria, also referred to as the ‘normal flora’, are able to survive and replicate on skin and mucosal surfaces. The gastrointestinal tract and the mouth are the two most heavily colonised sites in the body and their microbiota are distinct, in both composition and function. Knowledge of non-sterile body sites and their normal flora is required to inform microbiological sampling strategies and interpret culture results (Fig. 6.5). The microbiome is the total burden of microorganisms, their genes and their environmental interactions, and is now recognised to have a profound influence over human health and disease. Maintenance of the normal flora is beneficial to health. For example, lower gastrointestinal tract bacteria synthesise and excrete vitamins (e.g. vitamins K and B12); colonisation with normal flora confers ‘colonisation resistance’ to infection with pathogenic organisms by altering the local environment (e.g. lowering pH), producing antibacterial agents (e.g. bacteriocins (small antimicrobial peptides/proteins), fatty acids and metabolic waste products), and inducing host antibodies that cross-react with pathogenic organisms. Conversely, normally sterile body sites must be kept sterile. The mucociliary escalator transports environmental material deposited in the respiratory tract to the nasopharynx. The urethral sphincter prevents flow from the non-sterile urethra to the sterile bladder. Physical barriers, including the skin, lining of the gastrointestinal tract and other mucous membranes, maintain sterility of the submucosal tissues, blood stream and peritoneal and pleural cavities, for example. The normal flora contribute to endogenous disease mainly by translocation to a sterile site but excessive growth at the ‘normal’ site (overgrowth) can also cause disease. Overgrowth is exemplified by dental caries, vaginal thrush and ‘blind loop’ syndrome (p. 808). Translocation results from spread along a surface or penetration though a colonised surface, e.g. urinary tract infection caused by perineal/enteric flora, and surgical site infections, particularly of prosthetic materials, caused by skin flora such as staphylococci. Normal flora also contribute to disease by cross-infection, in which organisms that are colonising one individual cause disease when transferred to another, more susceptible, individual. The importance of limiting perturbations of the microbiota by antimicrobial therapy is increasingly recognised. Probiotics are microbes or mixtures of microbes that are given to a patient to prevent or treat infection and are intended to restore a beneficial profile of microbiota. Although probiotics have been used in a number of settings, whether they have demonstrable clinical benefits remains a subject of debate.

104 • PRINCIPLES OF INFECTIOUS DISEASE Histoplasma capsulatum), are able to survive in intracellular environments, including after phagocytosis by macrophages. Pathogenic bacteria express different genes, depending on environmental stress (pH, iron starvation, O2 starvation etc.) and anatomical location. Genetic diversity enhances the pathogenic capacity of bacteria. Some virulence factor genes are found on plasmids or in phages and are exchanged between different strains or species. The ability to acquire genes from the gene pool of all strains of the species (the ‘bacterial supragenome’) increases diversity and the potential for pathogenicity. Viruses exploit their rapid reproduction and potential to exchange nucleic acid with host cells to enhance diversity. Once a strain acquires a particularly effective combination of virulence genes, it may become an epidemic strain, accounting for a large subset of infections in a particular region. This phenomenon accounts for influenza pandemics (see Box 6.10). The host response Innate and adaptive immune and inflammatory responses, which humans use to control the normal flora and respond to pathogens, are reviewed in Chapter 4. Pathogenesis of infectious disease The harmful manifestations of infection are determined by a combination of the virulence of the organism and the host response to infection. Despite the obvious benefits of an intact host response, an excessive response is undesirable. Cytokines and antimicrobial factors contribute to tissue injury at the site of infection, and an excessive inflammatory response may lead to hypotension and organ dysfunction (p. 196). The contribution of the immune response to disease manifestations is exemplified by the immune reconstitution inflammatory syndrome (IRIS). This is seen, for example, in human immunodeficiency virus (HIV) infection, post-transplantation neutropenia or tuberculosis (which causes suppression of T-cell function): there is a paradoxical worsening of the clinical condition as the immune dysfunction is corrected, caused by an exuberant but dysregulated inflammatory response. The febrile response Thermoregulation is altered in infectious disease, which may cause both hyperthermia (fever) and hypothermia. Fever is mediated mainly by ‘pyrogenic cytokines’ (e.g. interleukins IL-1 and IL-6, and tumour necrosis factor alpha (TNF-α)), which are released in response to various immunological stimuli including activation of pattern recognition receptors (PRRs) by microbial pyrogens (e.g. lipopolysaccharide) and factors released by injured cells. Their ultimate effect is to induce the synthesis of prostaglandin E2, which binds to specific receptors in the preoptic nucleus of the hypothalamus (thermoregulatory centre), causing the core temperature to rise. Rigors are a clinical symptom (or sign if they are witnessed) characterised by feeling very cold (‘chills’) and uncontrollable shivering, usually followed by fever and sweating. Rigors occur when the thermoregulatory centre attempts to correct a core temperature to a higher level by stimulating skeletal muscle activity and shaking. There are data to support the hypothesis that raised body temperature interferes with the replication and/or virulence of pathogens. The mechanisms and possible protective role of infection-driven hypothermia, however, are poorly understood, and require further study. Host–pathogen interactions ‘Pathogenicity’ is the capability of an organism to cause disease and ‘virulence’ is the extent to which a pathogen is able to cause disease. Pathogens produce proteins and other factors, termed virulence factors, which contribute to disease. • Primary pathogens cause disease in a proportion of individuals to whom they are exposed, regardless of the host’s immunological status. • Opportunistic pathogens cause disease only in individuals whose host defences are compromised, e.g. by an intravascular catheter, or when the immune system is compromised, by genetic susceptibility or immunosuppressive therapy. Characteristics of successful pathogens Successful pathogens have a number of attributes. They compete with host cells and colonising flora by various methods, including sequestration of nutrients and production of bacteriocins. Motility enables pathogens to reach their site of infection, often sterile sites that colonising bacteria do not reach, such as the distal airway. Many microorganisms, including viruses, use ‘adhesins’ to attach to host cells initially. Some pathogens can invade through tissues. Many bacterial and fungal infections form ‘biofilms’. After initial adhesion to a host surface, bacteria multiply in biofilms to form complex three-dimensional structures surrounded by a matrix of host and bacterial products that afford protection to the colony and limit the effectiveness of antimicrobials. Biofilms forming on man-made medical devices such as vascular catheters or grafts can be particularly difficult to treat. Pathogens may produce toxins, microbial molecules that cause adverse effects on host cells, either at the site of infection, or remotely following carriage through the blood stream. Endotoxin is the lipid component of Gram-negative bacterial outer membrane lipopolysaccharide. It is released when bacterial cells are damaged and has generalised inflammatory effects. Exotoxins are proteins released by living bacteria, which often have specific effects on target organs (Box 6.3). Intracellular pathogens, including viruses, bacteria (e.g. Salmonella spp., Listeria monocytogenes and Mycobacterium tuberculosis), parasites (e.g. Leishmania spp.) and fungi (e.g. 6.3 Exotoxin-mediated bacterial diseases Disease Organism Antibiotic-associated diarrhoea/ pseudomembranous colitis Clostridium difficile (p. 230) Botulism Clostridium botulinum (p. 1126) Cholera Vibrio cholerae (p. 264) Diphtheria Corynebacterium diphtheriae (p. 265) Haemolytic uraemic syndrome Enterohaemorrhagic Escherichia coli (E. coli O157 and other strains) (p. 263) Necrotising pneumonia Staphylococcus aureus (p. 250) Tetanus Clostridium tetani (p. 1125) Toxic shock syndrome Staphylococcus aureus (p. 252) Streptococcus pyogenes (p. 253)

Investigation of infection • 105

organism and its background. Examples include Gram staining of bacteria and Ziehl–Neelsen or auramine staining of acid- and alcohol-fast bacilli (AAFB) in tuberculosis (the latter requires an ultraviolet light source). In histopathological examination of tissue samples, multiple stains are used to demonstrate not only the presence of microorganisms but also features of disease pathology. • Dark field microscopy (in which light is scattered to make organisms appear bright on a dark background) is used, for example, to examine genital chancre fluid in suspected syphilis. • Electron microscopy may be used to examine stool and vesicle fluid to detect enteric and herpesviruses, respectively, but its use has largely been supplanted by nucleic acid detection (see below). • Flow cytometry can be used to analyse liquid samples (e.g. urine) for the presence of particles based on properties such as size, impedance and light scatter. This technique can detect bacteria but may misidentify other particles as bacteria too. Investigation of infection The aims of investigating a patient with suspected infection are to confirm the presence of infection, identify the specific pathogen(s) and identify its susceptibility to specific antimicrobial agents in order to optimise therapy. The presence of infection may be suggested by identifying proteins that are produced in response to pathogens as part of the innate immune and acute phase responses (p. 70). Pathogens may be detected directly (e.g. by culturing a normally sterile body site) or their presence may be inferred by identifying the host response to the organism, (‘indirect detection’, Box 6.4). Careful sampling increases the likelihood of diagnosis (Box 6.5). Culture results must be interpreted in the context of the normal flora at the sampled site (see Fig. 6.5). The extent to which a microbiological test result supports or excludes a particular diagnosis depends on its statistical performance (e.g. sensitivity, specificity, positive and negative predictive value, p. 4). Sensitivity and specificity vary according to the time between infection and testing, and positive and negative predictive values depend on the prevalence of the condition in the test population. The complexity of test interpretation is illustrated in Figure 6.8 below, which shows the ‘windows of opportunity’ afforded by various testing methods. Given this complexity, effective communication between the clinician and the microbiologist is vital to ensure accurate test interpretation. Direct detection of pathogens Some direct detection methods provide rapid results and enable detection of organisms that cannot be grown easily on artificial culture media, such as Chlamydia spp.; they can also provide information on antimicrobial sensitivity, e.g. Mycobacterium tuberculosis. Detection of whole organisms Whole organisms are detected by examination of biological fluids or tissue using a microscope. • Bright field microscopy (in which the test sample is interposed between the light source and the objective lens) uses stains to enhance visual contrast between the 6.5 How to provide samples for microbiological sampling Communicate with the laboratory • Discuss samples that require processing urgently or that may contain hazardous or unusual pathogens with laboratory staff before collection • Communication is key to optimising microbiological diagnosis. If there is doubt about any aspect of sampling, it is far better to discuss it with laboratory staff beforehand than to risk diagnostic delay by inappropriate sampling or sample handling Take samples based on a clinical diagnosis • Sampling in the absence of clinical evidence of infection is rarely appropriate (e.g. collecting urine, or sputum for culture) Use the correct container • Certain tests (e.g. nucleic acid and antigen detection tests) require proprietary sample collection equipment Follow sample collection procedures • Failure to follow sample collection instructions precisely can result in false-positive (e.g. contamination of blood culture samples) or false-negative (e.g. collection of insufficient blood for culture) results Label sample and request form correctly • Label sample containers and request forms according to local policies, with demographic identifiers, specimen type and time/date collected • Include clinical details on request forms • Identify samples carrying a high risk of infection (e.g. blood liable to contain a blood-borne virus) with a hazard label Use appropriate packaging • Close sample containers tightly and package securely (usually in sealed plastic bags) • Attach request forms to samples but not in the same compartment (to avoid contamination, should leakage occur) Manage storage and transport • Transport samples to the microbiology laboratory quickly • If pre-transport storage is required, conditions (e.g. refrigeration, incubation, storage at room temperature) vary with sample type • Notify the receiving laboratory prior to arrival of unusual or urgent samples, to ensure timely processing 6.4 Tests used to diagnose infection Non-specific markers of inflammation/infection • e.g. White cell count in blood sample (WCC), plasma C-reactive protein (CRP), procalcitonin, serum lactate, cell counts in urine or cerebrospinal fluid (CSF), CSF protein and glucose Direct detection of organisms or organism components • Microscopy • Detection of organism components (e.g. antigen, toxin) • Nucleic acid amplification (e.g. polymerase chain reaction) Culture of organisms • ± Antimicrobial susceptibility testing Tests of the host’s specific immune response • Antibody detection • Interferon-gamma release assays (IGRA)

106 • PRINCIPLES OF INFECTIOUS DISEASE even in rapid-culture systems. Certain organisms, such as Mycobacterium leprae and Tropheryma whipplei, cannot be cultivated on artificial media, and others (e.g. Chlamydia spp. and viruses) grow only in culture systems, which are slow and labour-intensive. Blood culture The terms ‘bacteraemia’ and ‘fungaemia’ describe the presence of bacteria and fungi in the blood. ‘Blood-stream infection’ (p. 225) is the association of bacteraemia/fungaemia with clinical evidence of infection. The presence of bacteraemia/fungaemia can be determined by inoculating a liquid culture medium with freshly drawn blood, which is then incubated in a system that monitors it constantly for growth of microorganisms (e.g. by detecting products of microbial respiration using fluorescence; Fig. 6.6). If growth is detected, organisms are identified and sensitivity testing is performed. Traditionally, identification has been achieved by Gram stain appearance and biochemical reactions. However, matrix-assisted laser desorption/ionisation time-of-flight mass spectroscopy (MALDI-TOF-MS; see Box 6.2) is being used increasingly to identify organisms. MALDI-TOF-MS produces a profile of proteins of different sizes from the target microorganism and uses databases of such profiles to identify the organism (Fig. 6.7). It is rapid and accurate. Taking multiple blood samples for culture at different times allows differentiation of transient (one or two positive samples) and persistent (majority are positive) bacteraemia. This can be clinically important in the identification of the source of infection (p. 530). Indirect detection of pathogens Tests may be used to detect the host’s immune (antibody) response to a specific microorganism, and can enable the diagnosis of infection with organisms that are difficult to detect by other methods or are no longer present in the host. The term ‘serology’ describes tests carried out on serum and includes both antigen (direct) and antibody (indirect) detection. Antibody detection Organism-specific antibody detection is applied mainly to blood (Fig. 6.8). Results are typically expressed as titres: that is, the reciprocal of the highest dilution of the serum at which antibody is detectable (for example, detection at serum dilution of 1 : 64 gives a titre of 64). ‘Seroconversion’ is defined as either a change from negative to positive detection or a fourfold rise in titre between acute and convalescent serum samples. An acute sample is usually taken during the first week of disease and the convalescent sample 2–4 weeks later. Earlier diagnosis can be achieved by detection of immunoglobulin M (IgM) antibodies, which are produced early in infection (p. 68). A limitation of these tests is that antibody production requires a fully functional host immune system, so there may be false-negative results in immunocompromised patients. Also, other than in chronic infections and with IgM detection, antibody tests usually provide a retrospective diagnosis. Antibody detection methods are described below (antigen detection methods are also described here as they share similar methodology). Enzyme-linked immunosorbent assay The principles of the enzyme-linked immunosorbent assay (ELISA, EIA) are illustrated in Figure 6.9. These assays rely on linking Detection of components of organisms Components of microorganisms detected for diagnostic purposes include nucleic acids, cell wall molecules, toxins and other antigens. Commonly used examples include Legionella pneumophila serogroup 1 antigen in urine and cryptococcal polysaccharide antigen in cerebrospinal fluid (CSF). Most antigen detection methods are based on in vitro binding of specific antigen/antibody and are described below. Other methods may be used, such as tissue culture cytotoxicity assay for C. difficile toxin. In toxin-mediated disease, detection of toxin may be of greater relevance than identification of the organism itself (e.g. stool C. difficile toxin). Nucleic acid amplification tests In a nucleic acid amplification test (NAAT), specific sequences of microbial DNA and RNA are identified using a nucleic acid primer that is amplified exponentially by enzymes to generate multiple copies of a target nucleotide sequence. The most commonly used amplification method is the polymerase chain reaction (PCR; see Fig. 3.11, p. 53). Reverse transcription (RT) PCR is used to detect RNA from RNA viruses (e.g. hepatitis C virus and HIV-1). The use of fluorescent labels in the reaction enables ‘real-time’ detection of amplified DNA; quantification is based on the principle that the time taken to reach the detection threshold is proportional to the initial number of copies of the target nucleic acid sequence. In multiplex PCR, multiple primer pairs are used to enable detection of several different organisms at once. Determination of nucleotide sequences in a target gene(s) can be used to assign microorganisms to specific strains, which may be relevant to treatment and/or prognosis (e.g. in hepatitis C infection, p. 877). Genes that are relevant to pathogenicity (such as toxin genes) or antimicrobial resistance can also be detected; for example, the mecA gene is used to screen for MRSA. NAATs are the most sensitive direct detection methods and are also relatively rapid. They are used widely in virology, where the possibility of false-positive results from colonising or contaminating organisms is remote, and are applied to blood, respiratory samples, stool and urine. In bacteriology, PCR is used to examine CSF, blood, tissue and genital samples, and multiplex PCR is being developed for use in faeces. PCR is particularly helpful for microorganisms that cannot be readily cultured, e.g. Tropheryma whipplei, and is being used increasingly in mycology and parasitology. Culture Microorganisms may be both detected and further characterised by culture from clinical samples (e.g. tissue, swabs and body fluids). • Ex vivo culture (tissue or cell culture) was widely used in the isolation of viruses but has been largely supplanted by NAAT. • In vitro culture (in artificial culture media) of bacteria and fungi is used to confirm the presence of pathogens, allow identification, test antimicrobial susceptibility and subtype the organism for epidemiological purposes. Culture has its limitations: results are not immediate, even for organisms that are easy to grow, and negative cultures rarely exclude infection. Organisms such as Mycobacterium tuberculosis are slow-growing, typically taking at least 2 weeks,

Investigation of infection • 107

Immunofluorescence assays Indirect immunofluorescence assays (IFAs) detect antibodies by incubating a serum sample with immobilised antigen (e.g. cells known to be infected with virus on a glass slide); any virus-specific antibody present in the serum binds to antigen and is then detected using a fluorescent-labelled anti-human immunoglobulin (‘secondary’ antibody). Fluorescence is visualised using a microscope. This method can also detect organisms in clinical samples (usually tissue or centrifuged cells) using a specific antibody in place of immobilised antigen to achieve capture. Complement fixation test In a complement fixation test (CFT), patient serum is heat-treated to inactivate complement and mixed with the test antigen. Any specific antibody in the serum will complex with the antigen. Complement is then added to the reaction. If antigen–antibody an antibody with an enzyme that generates a colour change on exposure to a chromogenic substrate. Various configurations allow detection of antigens or specific subclasses of immunoglobulin (e.g. IgG, IgM, IgA). ELISA may also be adapted to detect PCR products, using immobilised oligonucleotide hybridisation probes and various detection systems. Immunoblot (Western blot) Microbial proteins are separated according to molecular weight by polyacrylamide gel electrophoresis (PAGE) and transferred (blotted) on to a nitrocellulose membrane, which is incubated with patient serum. Binding of specific antibody is detected with an enzyme–anti-immunoglobulin conjugate similar to that used in ELISA, and specificity is confirmed by its location on the membrane. Immunoblotting is a highly specific test, which may be used to confirm the results of less specific tests such as ELISA (e.g. in Lyme disease, p. 255). Fig. 6.6 An overview of the processing of blood cultures. In laboratories equipped with MALDI-TOF-MS (p. 106), rapid definitive organism identification may be achieved at stage 6 and/or stage 8. Department of Microbiology 1 Patient sampling Contamination minimised by aseptic technique. Maximise sensitivity by sampling correct volume 2 Sample handling Follow local instructions for safety, labelling, and numbers of samples and bottles required 3 Specimen transport Transport samples to laboratory as quickly as possible. Follow manufacturer’s instructions for the blood culture system used if temporary storage is required 4 Incubation Incubate at 35–37°C for 5–7 days. Microbial growth is usually detected by constant automatic monitoring of CO2. If no growth, specimen is negative and discarded 5 Growth detection Time to positivity (TTP) is usually 12–24 hrs in significant bacteraemia, but may be shorter in overwhelming sepsis or longer with fastidious organisms (e.g. Brucella spp.) 6 Preliminary results A Gram film of the blood culture medium is examined and results are communicated immediately to the clinician to guide antibiotic therapy 7 Incubation A small amount of the medium is incubated on a range of culture media. Preliminary susceptibility testing may be carried out 8 Culture results* Preliminary susceptibility results are communicated to the clinician 9 Definitive results Further overnight incubation is often required for definitive identification of organisms (by biochemical testing) and additional susceptibility testing; identification by MALDI-TOF MS (Fig. 6.7) is more rapid Overnight incubation required Urgent communication required 10 Reporting A final summary is released when all testing is complete. For clinical care, communication of interim results (Gram film, preliminary identification and susceptibility) is usually more important than the final report. Effective clinical–laboratory communication is vital

108 • PRINCIPLES OF INFECTIOUS DISEASE For example, in the Weil–Felix test, if a patient’s serum contains antibodies to rickettsial species they cause agglutination when Proteus spp. surface (O) antigens are added because the antibodies cross-react with the Proteus antigens. The test lacks sensitivity and specificity but is still used to diagnose rickettsial infection in resource-limited settings. The Widal test reaction uses a suspension of Salmonella typhi and S. paratyphi ‘A’ and ‘B’, treated to retain only ‘O’ and ‘H’ antigens. These antigens are kept to detect corresponding antibodies in serum from a patient suspected of having typhoid fever. The test is not specific but is still used in some parts of the world. • In indirect (passive) agglutination, specific antigen is attached to the surface of carrier particles, which agglutinate when incubated with patient samples that contain specific antibodies. • In reverse passive agglutination (an antigen detection test), the carrier particle is coated with antibody rather than antigen. Other tests Immunodiffusion involves antibodies and antigen migrating through gels, with or without the assistance of electrophoresis, and forming insoluble complexes where they meet. The complexes are seen on staining as ‘precipitin bands’. Immunodiffusion is used in the diagnosis of dimorphic fungi (p. 300) and some forms of aspergillosis (p. 596). Immunochromatography is used to detect antigen. The system consists of a porous test strip (e.g. a nitrocellulose membrane), at one end of which there is target-specific antibody, complexed with coloured microparticles. Further specific antibody is immobilised in a transverse narrow line some distance along the strip. Test material (e.g. blood or urine) is added to the antibody–particle complexes, which then migrate along the strip by capillary action. If these are complexed with antigen, they will be immobilised by the specific antibody and visualised as a transverse line across the strip. If the test is negative, the antibody–particle complexes will bind to a line of immobilised anti-immunoglobulin antibody placed further along the strip, which acts as a negative control. Immunochromatographic tests are rapid and relatively cheap to perform, and are appropriate for point-of-care testing, e.g. in HIV 1 and malaria (p. 276). complexes are present, the complement will be ‘fixed’ (consumed). Sheep erythrocytes, coated with an anti-erythrocyte antibody, are added. The degree of erythrocyte lysis reflects the remaining complement and is inversely proportional to the quantity of the specific antigen–antibody complex present. Agglutination tests When antigens are present on the surface of particles (e.g. cells, latex particles or microorganisms) and cross-linked with antibodies, visible clumping (or ‘agglutination’) occurs. • In direct agglutination, patient serum is added to a suspension of organisms that express the test antigen. Fig. 6.7 The workings of matrix-assisted laser desorption/ionisation time-of-flight mass spectrometry (MALDI-TOF MS). Adapted from Sobin K, Hameer D, Ruparel T. Digital genotyping using molecular affinity and mass spectrometry. Nature Rev Genet 2003; 4:1001–1008. Lighter m/z Mass spectrum Detector Flight tube Laser Sample plate Voltage grid Intensity Heavier Separation region (electric field-free) Fig. 6.8 Detection of antigen, nucleic acid and antibody in infectious disease. The acute sample is usually taken during the first week of illness, and the convalescent sample 2–4 weeks later. Detection limits and duration of detectability vary between tests and diseases, although in most diseases immunoglobulin M (IgM) is detectable within the first 1–2 weeks. Acute sample Nucleic acid (NA) detection Antigen (Ag) detection IgM NA Ag IgG Limit of detection Antibody detection: IgM Antibody detection: IgG (seroconversion) Antibody detection: IgG (fourfold rise in titre) Convalescent sample Windows of diagnostic opportunity Serum levels

Investigation of infection • 109

Antibody-independent specific immunological tests The interferon-gamma release assay (IGRA) is being used increasingly to diagnose latent tuberculosis infection (LTBI). The principle behind IGRA is discussed on page 594. IGRA cannot distinguish between latent and active tuberculosis infection and is therefore appropriate for use only in countries where the background incidence of tuberculosis is low. Antimicrobial susceptibility testing If growth of microorganisms in culture is inhibited by the addition of an antimicrobial agent, the organism is considered to be susceptible to that antimicrobial. Bacteriostatic agents cause reversible inhibition of growth and bactericidal agents cause cell death; the terms fungistatic/fungicidal are equivalent for antifungal agents, and virustatic/virucidal for antiviral agents. The lowest concentration of antimicrobial agent at which growth is inhibited is the minimum inhibitory concentration (MIC), and the lowest concentration that causes cell death is the minimum bactericidal concentration (MBC). If the MIC is less than or equal to a predetermined breakpoint threshold, the organism is considered susceptible, and if the MIC is greater than the breakpoint, it is resistant. Breakpoints are determined for each antimicrobial agent from a combination of pharmacokinetic (p. 17) and clinical data. The relationship between in vitro antimicrobial susceptibility and clinical response is complex, as response also depends on immune status, pharmacokinetic variability (p. 17), comorbidities that may influence pharmacokinetics or pharmacodynamics, and antibiotic dosing, as well as MIC/MBC. Thus, although treating a patient according to the results of susceptibility testing increases the likelihood of recovery, it does not guarantee therapeutic success. Susceptibility testing is often carried out by disc diffusion (Fig. 6.10). Antibiotic-impregnated filter paper discs are placed on agar plates containing bacteria; antibiotic diffuses into the agar, resulting in a concentration gradient centred on the disc. Bacteria are unable to grow where the antibiotic concentration exceeds the MIC, which may therefore be inferred from the size of the zone of inhibition. The MIC is commonly measured in diagnostic laboratories using ‘diffusion strips’. Fig. 6.9 Antibody (Ab) and antigen (Ag) detection by enzyme-linked immunosorbent assay (ELISA). This can be configured in various ways. A Patient Ab binds to immobilised specific Ag and is detected by addition of anti-immunoglobulin–enzyme conjugate and chromogenic substrate. B Patient Ab binds to immobilised Ig subclass-specific Ab and is detected by addition of specific Ag, followed by antibody–enzyme conjugate and chromogenic substrate. C Patient Ab and antibody–enzyme conjugate bind to immobilised specific Ag. Magnitude of colour change reaction is inversely proportional to concentration of patient Ab. D Patient Ag binds to immobilised Ab and is detected by addition of antibody–enzyme conjugate and chromogenic substrate. In A, the conjugate Ab is specific for human immunoglobulin. In B–D, it is specific for Ag from the disease-causing organism. Antibody capture ELISA Patient Ab Ig subclass-specific Ab Ab specific to Ag from the disease-causing organism Specific Ag Chromogenic substrate Antibody–enzyme conjugate Competitive antibody detection ELISA Double antibody sandwich ELISA (for antigen detection) Antibody detection ELISA A B C D Fig. 6.10 Antimicrobial susceptibility testing by disc diffusion (panels 1-4) and minimum inhibitory concentration (MIC, panel 5).

  1. The test organism is spread over the surface of an agar plate.
  2. Antimicrobial-impregnated discs (A–F) are placed on the surface and the plate is incubated (e.g. overnight). 3–4. After incubation, zones of growth inhibition may be seen. The organism is considered susceptible if the diameter of the zone of inhibition exceeds a pre-determined threshold.
  3. In a ‘diffusion strip’ test, the strip is impregnated with antimicrobial at a concentration gradient that decreases steadily from top to bottom. The system is designed so that the MIC value is the point at which the ellipse cuts a scale on the strip (arrow). 4, Kindly supplied by Charlotte Symes. Zone of inhibition Zone of inhibition

A B C D E F A B C D E F

110 • PRINCIPLES OF INFECTIOUS DISEASE known and thought to have been controlled or eradicated, it is considered to be re-emerging. Many emerging diseases are caused by organisms that infect animals and have undergone adaptations that enable them to infect humans. This is exemplified by HIV-1, which is believed to have originated in higher primates in Africa. The geographical pattern of some recent emerging and re-emerging infections is shown in Figure 6.11. Reservoirs of infection The US Centers for Disease Control (CDC) define a reservoir of infection as any person, other living organism, environment or combination of these in which the infectious agent lives and replicates and on which the infectious agent is dependent for its survival. The infectious agent is transmitted from this reservoir to a susceptible host. Human reservoirs Both colonised individuals and those with infection can act as reservoirs, e.g. with Staph. aureus (including MRSA), Strep. pyogenes and C. difficile. For infected humans to act as reservoirs, the infections caused must be long-lasting in at least a proportion of those affected, to enable onward transmission (e.g. tuberculosis, sexually transmitted infections). Humans are the only reservoir for some infections (e.g. measles). Animal reservoirs The World Health Organization (WHO) defines a zoonosis as ‘a disease or infection that is naturally transmissible from vertebrate animals to humans’. Infected animals may be asymptomatic. Zoonotic agents may be transmitted via any of the routes described below. Primary infection with zoonoses may be transmitted onward between humans, causing secondary disease (e.g. Q fever, brucellosis, Ebola). Environmental reservoirs Many infective pathogens are acquired from an environmental source. However, some of these are maintained in human or animal reservoirs, with the environment acting only as a conduit for infection. Epidemiology of infection The communicability of infectious disease means that, once a clinician has diagnosed an infectious disease, potential exposure of other patients must also be considered. The patient may require separation from other patients (‘isolation’), or an outbreak of disease may need to be investigated in the community (Ch. 5). The approach will be specific to the microorganism involved (Chs 11–13) but the principles are outlined below. Geographical and temporal patterns of infection Endemic disease Endemic disease has a constant presence within a given geographical area or population. The infectious agent may have a reservoir, vector or intermediate host that is geographically restricted, or may itself have restrictive environmental requirements (e.g. temperature range, humidity). The population affected may be geographically isolated or the disease may be limited to unvaccinated populations. Factors that alter geographical restriction include: • expansion of an animal reservoir (e.g. Lyme disease from reforestation) • vector escape (e.g. airport malaria) • extension of host range (e.g. schistosomiasis from dam construction) • human migration (e.g. carbapenemase-producing Klebsiella pneumoniae) • public health service breakdown (e.g. diphtheria in unvaccinated areas) • climate change (e.g. dengue virus and Rift Valley fever). Emerging and re-emerging disease An emerging infectious disease is one that has newly appeared in a population, or has been known for some time but is increasing in incidence or geographical range. If the disease was previously Fig. 6.11 Geographical locations of some infectious disease outbreaks, with examples of emerging and re-emerging diseases. (CPE = carbapenemase-producing Enterobacteriaceae; MDR-TB = multidrug-resistant tuberculosis; MERS-Co-V = Middle East respiratory syndrome coronavirus; XDR-TB = extensively drug-resistant tuberculosis) CPE Ebola virus disease Cholera Cholera Cholera Cryptococcus gattii Cryptococcus gattii Zika virus Zika virus Cyclospora Chikungunya virus Chikungunya virus XDR-TB MERS-Co-V Anthrax MDR-TB

Infection prevention and control • 111

and humans in MRSA. Fomites are inanimate objects such as door handles, water taps and ultrasound probes, which are particularly associated with health care-associated infection (HCAI). The likelihood of infection following transmission of a pathogen depends on organism factors (virulence, p. 104) and host susceptibility. The incubation period is the time between exposure and development of symptoms, and the period of infectivity is the period after exposure during which the patient is infectious to others. Knowledge of incubation periods and of periods of infectivity is important in controlling the spread of disease, although for many diseases these estimates are imprecise (Boxes 6.6 and 6.7). Deliberate release Deliberate release of pathogens with the intention of causing disease is known as biological warfare or bioterrorism, depending on the scale and context. Deliberate release incidents have included a 750-person outbreak of Salmonella typhimurium caused by contamination of salads in 1984 (Oregon, USA) and 22 cases of anthrax (five fatal) from the mailing of finely powdered (weaponised) anthrax spores in 2001 (New Jersey, USA). Diseases with high potential for deliberate release include anthrax, plague, tularaemia, smallpox and botulism (through toxin release). Infection prevention and control Infection prevention and control (IPC) describes the measures applied to populations with the aim of breaking the chain of infection (see Fig. 6.1, p. 100). Health care-associated infection The risk of developing infection following admission to a health-care facility (health care-associated infection, HCAI) in Transmission of infection Communicable diseases may be transmitted by one or more of the following routes: • Respiratory route: inhalation. • Faecal–oral route: ingestion of material originating from faeces. • Sexually transmitted infections: direct contact between mucous membranes. • Blood-borne infections: direct inoculation of blood or body fluids. • Direct contact: very few organisms are capable of causing infection by direct contact with intact skin. Most infection by this route requires contact with damaged skin (e.g. surgical wound). • Via a vector or fomite: the vector/fomite bridges the gap between the infected host or reservoir and the uninfected host. Vectors are animate, and include mosquitoes in malaria, dengue and Zika virus infection, fleas in plague 6.7 Periods of infectivity in common childhood infectious diseases Disease Infectious period Chickenpox1 From 4 days before until 5 days after appearance of the rash (transmission before 48 hrs prior to the onset of rash is rare)4 Measles2 From 4 days before onset to 4 days after onset of the rash Mumps3 From 2–3 days before to 5 days after disease onset5 Rubella3 From 10 days before until 15 days after the onset of the rash, but most infectious during prodromal illness4 Scarlet fever1 Unknown6 Whooping cough1 Unknown6,7 1From Richardson M, Elliman D, Maguire H, et al. Pediatr Infect Dis J 2001; 20:380–388. 2Centers for Disease Control, USA; cdc.gov/measles/hcp/. 3Bennett JE, Dolin R, Blaser MJ. Mandell, Douglas and Bennett’s Principles and practice of infectious diseases, 8th edn. Philadelphia: Elsevier; 2015. 4–6Exclude from contact with non-immune and immunocompromised people for 5 days from 4onset of rash, 5onset of parotitis, or 6start of antibiotic treatment. 7Exclude for 3 weeks if untreated. Durations are approximate and vary between information sources, and these recommendations may differ from local or national guidance. 6.6 Incubation periods of important infections1 Infection Incubation period Short incubation periods Anthrax, cutaneous3 9 hrs to 2 weeks Anthrax, inhalational3 2 days2 Bacillary dysentery5 1–6 days Cholera3 2 hrs to 5 days Dengue haemorrhagic fever6 3–14 days Diphtheria6 1–10 days Gonorrhoea4 2–10 days Influenza5 1–3 days Meningococcaemia3 2–10 days Norovirus1 1–3 days SARS coronavirus3 2–7 days2 Scarlet fever5 2–4 days Intermediate incubation periods Amoebiasis6 1–4 weeks Brucellosis4 5–30 days Chickenpox5 11–20 days Lassa fever3 3–21 days Malaria3 10–15 days Measles5 6–19 days Mumps5 15–24 days Poliomyelitis6 3–35 days Psittacosis4 1–4 weeks Rubella5 15–20 days Typhoid5 5–31 days Whooping cough5 5–21 days Long incubation periods Hepatitis A5 3–7 weeks Hepatitis B4 6 weeks to 6 months Leishmaniasis, cutaneous6 Weeks to months Leishmaniasis, visceral6 Months to years Leprosy (Hansen’s disease)3 5–20 years Rabies4 2–8 weeks2 Trypanosoma brucei gambiense infection6 Months to years Tuberculosis5 1–12 months 1Incubation periods are approximate and may differ from local or national guidance. 2Longer incubation periods have been reported. 3WHO. 4Health Protection Agency (now Health Protection England). 5Richardson M, Elliman D, Maguire H, et al. Pediatr Infect Dis J 2001; 20:380–388. 6Centers for Disease Control, USA. (SARS = severe acute respiratory syndrome)

112 • PRINCIPLES OF INFECTIOUS DISEASE Fig. 6.12 Commonly encountered health care-associated infections (HCAIs) and the factors that predispose to them. Temporary central venous catheter infection Staphylococcus aureus (incl. MRSA) Coagulase-negative staphylococci Coliforms Candida Prosthetic joint infection Coagulase-negative staphylococci Staphylococcus aureus Streptococci Coliforms Propionibacterium acnes Surgical site infection Staphylococcus aureus Beta-haemolytic streptococci Coliforms Anaerobes Cuffed/tunnelled central venous catheter infection Coagulase-negative staphylococci Staphylococcus aureus (incl. MRSA) Coliforms Candida Pseudomonas spp. Enterococcus spp. External ventricular drain and ventriculoperitoneal shunt infection Coagulase-negative staphylococci Staphylococcus aureus Diphtheroids Pseudomonas aeruginosa Peritoneal dialysis-related peritonitis Staphylococcus aureus Coagulase-negative staphylococci Coliforms Pseudomonas spp. Breast implant infection Staphylococcus aureus Coagulase-negative staphylococci the developed world is about 10%. Many nosocomial bacterial infections are caused by organisms that are resistant to numerous antibiotics (multi-resistant bacteria), including MRSA, extendedspectrum β-lactamases (ESBLs) and carbapenemase-producing Enterobacteriaceae (CPE), and glycopeptide-resistant enterococci (GRE). Other infections of particular concern in hospitals include C. difficile (p. 264) and norovirus (p. 249). Some examples are shown in Figure 6.12. IPC measures are described in Box 6.8. The most important is maintenance of good hand hygiene (Fig. 6.13). Hand (CPE = carbapenemase-producing Enterobacteriaceae; GRE = glycopeptide-resistant enterococci; MRSA = meticillin-resistant Staphylococcus aureus) Institutions • Handling, storage and disposal of clinical waste • Containment and safe removal of spilled blood and body fluids • Cleanliness of environment and medical equipment • Specialised ventilation (e.g. laminar flow, air filtration, controlled pressure gradients) • Sterilisation and disinfection of instruments and equipment • Food hygiene • Laundry management Health-care staff • Education • Hand hygiene, including hand-washing (see Fig. 6.13) • Sharps management and disposal • Use of personal protective equipment (masks, sterile and non-sterile gloves, gowns and aprons) • Screening health workers for disease (e.g. tuberculosis, hepatitis B virus, MRSA) • Immunisation and post-exposure prophylaxis Clinical practice • Antibiotic stewardship (p. 115) • Aseptic technique • Perioperative antimicrobial prophylaxis • Screening patients for colonisation or infection (e.g. MRSA, GRE, CPE) Response to infections • Surveillance to detect alert organism (see text) outbreaks and antimicrobial resistance • Antibiotic chemoprophylaxis in infectious disease contacts, if indicated (see Box 6.18) • Isolation (see Box 6.9) • Reservoir control • Vector control 6.8 Measures used in infection prevention and control (IPC)

Infection prevention and control • 113

Fig. 6.13 Hand-washing. Good hand hygiene, whether with soap/water or alcohol handrub, includes areas that are often missed, such as fingertips, web spaces, palmar creases and the backs of hands. Adapted from the ‘How to Handwash’ URL: who.int/gpsc/5may/How_To_Handwash_Poster.pdf © World Health Organization 2009. All rights reserved. Wash hands only when visibly soiled! Otherwise use handrub! Duration of the entire procedure: 40–60 sec.

Wet hands with water using elbow-operated or nontouch taps (if available) Apply enough soap to cover all hand surfaces Rub hands palm to palm

Right palm over left dorsum with interlaced fingers and vice versa Palm to palm with fingers interlaced Backs of fingers to opposing palms with fingers interlaced

Rotational rubbing of left thumb clasped in right palm and vice versa Rotational rubbing, backwards and forwards with clasped fingers of right hand in left palm and vice versa Rinse hands with water

Dry thoroughly with a single-use towel If hand-operated taps have been used, use towel to turn off tap ...and your hands are clean decontamination (e.g. using alcohol gel or washing) is mandatory before and after every patient contact. Decontamination with alcohol gel is usually adequate but hand-washing (with hot water, liquid soap and complete drying) is required after any procedure that involves more than casual physical contact, or if hands are visibly soiled. In situations where the prevalence of C. difficile is high (e.g. a local outbreak), alcohol gel decontamination between patient contacts is inadequate as it does not kill C. difficile spores, and hands must be washed. Some infections necessitate additional measures to prevent cross-infection (Box 6.9). To minimise risk of infection, invasive procedures must be performed using strict aseptic technique. Airborne transmission Contact transmission Droplet transmission Precautions Negative pressure room with air exhausted externally or filtered N95 masks or personal respiratiors for staff; avoid using non-immune staff Private room preferred (otherwise, inter-patient spacing ≥ 1 m) Gloves and gown for staff in contact with patient or contaminated areas Private room preferred (otherwise, inter-patient spacing ≥ 1 m) Surgical masks for staff in close contact with patient Infections managed with these precautions Measles Tuberculosis, pulmonary or laryngeal, confirmed or suspected Enteroviral infections in young children (diapered or incontinent) Norovirus2 C. difficile infection Multidrug-resistant organisms (e.g. MRSA, ESBL, GRE, VRSA, penicillin-resistant Strep. pneumoniae)3 Parainfluenza in infants and young children Rotavirus RSV in infants, children and immunocompromised Viral conjunctivitis, acute Diphtheria, pharyngeal Haemophilus influenzae type B infection Herpes simplex virus, disseminated or severe Influenza Meningococcal infection Mumps Mycoplasma pneumoniae Parvovirus (erythrovirus) B19 (erythema infectiosum, fifth disease) Pertussis Plague, pneumonic/bubonic Rubella Strep. pyogenes (group A), pharyngeal Infections managed with multiple precautions Smallpox, monkeypox, VZV (chickenpox or disseminated disease)4 Adenovirus pneumonia SARS, viral haemorrhagic fever2 6.9 Types of isolation precaution1 1Recommendations based on 2007 CDC guideline for isolation precautions. May differ from local or national recommendations. 2Not a CDC recommendation. 3Subject to local risk assessment. 4Or in any immunocompromised patient until possibility of disseminated infection excluded. (ESBL = extended-spectrum β-lactamase; GRE = glycopeptide-resistant enterococci; MRSA = meticillin-resistant Staph. aureus; RSV = respiratory syncytial virus; SARS = severe acute respiratory syndrome; VRSA = vancomycin-resistant Staph. aureus; VZV = varicella zoster virus)

114 • PRINCIPLES OF INFECTIOUS DISEASE 6.10 Terminology in outbreaks of infection Term Definition Classification of related cases of infectious disease* Cluster An aggregation of cases of a disease that are closely grouped in time and place, and may or may not exceed the expected number Epidemic The occurrence of more cases of disease than expected in a given area or among a specific group of people over a particular period of time Outbreak Synonymous with epidemic. Alternatively, a localised, as opposed to generalised, epidemic Pandemic An epidemic occurring over a very wide area (several countries or continents) and usually affecting a large proportion of the population Classification of affected patients (cases) Index case The first case identified in an outbreak Primary cases Cases acquired from a specific source of infection Secondary cases Cases acquired from primary cases Types of outbreak Common source outbreak Exposure to a common source of infection (e.g. water-cooling tower, medical staff member shedding MRSA). New primary cases will arise until the source is no longer present Point source outbreak Exposure to a single source of infection at a specific point in time (e.g. contaminated food at a party). Primary cases will develop disease synchronously Person-toperson spread Outbreak with both primary and secondary cases. May complicate point source or common source outbreak Adapted from cdc.gov. (MRSA = meticillin-resistant Staphylococcus aureus) 6.11 Reasons for including an infectious disease on a regional/national list of reportable diseases Reason for inclusion Examples Endemic/local disease with the potential to spread and/or cause outbreaks Influenza, Salmonella, tuberculosis Imported disease with the propensity to spread and/or cause outbreaks Typhoid, cholera (depending on local epidemiology) Evidence of a possible breakdown in health protection/public health functions Legionella, Cryptosporidium Evidence of a possible breakdown in food safety practices Botulism, verotoxigenic E. coli Evidence of a possible failure of a vaccination programme Measles, poliomyelitis, pertussis Disease with the potential to be a novel or increasing threat to human health SARS, MERS-CoV, multi-resistant bacteria Evidence of expansion of the range of a reservoir/vector Lyme disease, rabies, West Nile encephalitis Evidence of possible deliberate release Anthrax, tularaemia, plague, smallpox, botulism *Given the different geographical ranges of individual diseases and wide national variations in public health services, vaccination programmes and availability of resources, reporting regulations vary between regions, states and countries. Many diseases are reportable for more than one reason. (MERS-CoV = Middle East respiratory syndrome coronavirus; SARS = severe acute respiratory syndrome) Outbreaks of infection Descriptive terms are defined in Box 6.10. Confirmation of an infectious disease outbreak usually requires evidence from ‘typing’ that the causal organisms have identical phenotypic and/or genotypic characteristics. If this is found not to be the case, the term pseudo-outbreak is used. When an outbreak of infection is suspected, a case definition is agreed. The number of cases that meet the case definition is then assessed by case-finding, using methods ranging from administration of questionnaires to national reporting systems. Case-finding usually includes microbiological testing, at least in the early stages of an outbreak. Temporal changes in cases are noted in order to plot an outbreak curve, and demographic details are collected to identify possible sources of infection. A case–control study, in which recent activities (potential exposures) of affected ‘cases’ are compared to those of unaffected ‘controls’, may be undertaken to establish the outbreak source, and measures are taken to manage the outbreak and control its spread. Good communication between relevant personnel during and after the outbreak is important to inform practice in future outbreaks. Surveillance ensures that disease outbreaks are either prevented or identified early. In hospitals, staff are made aware of the isolation of alert organisms, which have the propensity to cause outbreaks, and alert conditions, which are likely to be caused by such organisms. Analogous systems are used nationally; many countries publish lists of organisms and diseases, which, if detected (or suspected), must be reported to public health authorities (reportable or notifiable diseases). Reasons for a disease to be classified as reportable are shown in Box 6.11. Immunisation Immunisation may be passive or active. Passive immunisation is achieved by administering antibodies targeting a specific pathogen. Antibodies are obtained from blood, so confer some of the risks associated with blood products (p. 933). The protection afforded by passive immunisation is immediate but of short duration (a few weeks or months); it is used to prevent or attenuate infection before or after exposure (Box 6.12). Vaccination Active immunisation is achieved by vaccination with whole organisms or organism components (Box 6.13). Types of vaccine Whole-cell vaccines consist of live or inactivated (killed) microorganisms. Component vaccines contain only extracted or synthesised components of microorganisms (e.g. polysaccharides or proteins). Live vaccines contain organisms with attenuated (reduced) virulence, which cause only mild symptoms but induce T-lymphocyte and humoral responses (p. 68) and are therefore more immunogenic than inactivated whole-cell vaccines. The use of live vaccines in immunocompromised individuals is not generally recommended, but they may be used by specialists following a risk/benefit assessment. Component vaccines consisting only of polysaccharides, such as the pneumococcal polysaccharide vaccine (PPV), are poor activators of T lymphocytes and produce a short-lived antibody response without long-lasting memory. Conjugation of polysaccharide to a protein, as in the Haemophilus influenzae type B (Hib) vaccine and the protein conjugate pneumococcal

Antimicrobial stewardship • 115

vaccinated to curtail further spread. Vaccination is aimed mainly at preventing infectious disease. However, vaccination against human papillomavirus (HPV) was introduced to prevent cervical and other cancers that complicate HPV infection. Vaccination guidelines for individuals are shown in Box 6.14. Vaccination becomes successful once the number of susceptible hosts in a population falls below the level required to sustain continued transmission of the target organism (herd immunity). Naturally acquired smallpox was declared to have been eradicated worldwide in 1980 through mass vaccination. In 1988, the WHO resolved to eradicate poliomyelitis by vaccination; the number of cases worldwide has since fallen from approximately 350 000 per annum to 74 in 2015. Recommended vaccination schedules vary between countries. In addition to standard vaccination schedules, catch-up schedules are specified for individuals who join vaccination programmes later than the recommended age. Antimicrobial stewardship Antimicrobial stewardship (AMS) refers to the systems and processes applied to a population to optimise the use of antimicrobial agents. The populations referred to here may be a nation, region, hospital, or a unit within a health-care organisation (e.g. ward or clinic). AMS aims to improve patient outcomes and reduce antimicrobial resistance (AMR). IPC and AMS complement each other (Fig. 6.14). Elements of AMS include treatment guidelines, antimicrobial formularies and ward rounds by infection specialists. vaccine (PCV), activates T lymphocytes, which results in a sustained response and immunological memory. Toxoids are bacterial toxins that have been modified to reduce toxicity but maintain antigenicity. Vaccine response can be improved by co-administration with mildly pro-inflammatory adjuvants, such as aluminium hydroxide. Use of vaccines Vaccination may be applied to entire populations or to subpopulations at specific risk through travel, occupation or other activities. In ring vaccination, the population immediately surrounding a case or outbreak of infectious disease is Active immunisation is preferred if contact is with a patient who is within 1 week of onset of jaundice. 6.12 Indications for post-exposure prophylaxis with immunoglobulins Human normal immunoglobulin (pooled immunoglobulin) • Hepatitis A (unvaccinated contacts) • Measles (exposed child with heart or lung disease) Human specific immunoglobulin • Hepatitis B (sexual partners, inoculation injuries, infants born to infected mothers) • Tetanus (high-risk wounds or incomplete or unknown immunisation status) • Rabies • Chickenpox (immunosuppressed children and adults, pregnant women) 6.13 Vaccines in current clinical use Live attenuated vaccines • Measles, mumps, rubella (MMR) • Oral poliomyelitis (OPV, not used in UK) • Rotavirus • Tuberculosis (bacille Calmette–Guérin, BCG) • Typhoid (oral typhoid vaccine) • Varicella zoster virus Inactivated (killed) whole-cell vaccines • Cholera • Hepatitis A • Influenza • Poliomyelitis (inactivated polio virus, IPV) • Rabies Component vaccines • Anthrax (adsorbed extracted antigens) • Diphtheria (adsorbed toxoid) • Hepatitis B (adsorbed recombinant hepatitis B surface antigen, HBsAg) • Haemophilus influenzae type B (conjugated capsular polysaccharide) • Human papillomavirus (recombinant capsid proteins) • Meningococcal, quadrivalent A, C, Y, W135 (conjugated capsular polysaccharide) • Meningococcal, serogroup C (conjugated capsular polysaccharide) • Pertussis (adsorbed extracted antigens) • Pneumococcal conjugate (PCV; conjugated capsular polysaccharide, 13 serotypes) • Pneumococcal polysaccharide (PPV; purified capsular polysaccharide, 23 serotypes) • Tetanus (adsorbed toxoid) • Typhoid (purified Vi capsular polysaccharide) 6.14 Guidelines for vaccination against infectious disease • The principal contraindication to inactivated vaccines is an anaphylactic reaction to a previous dose or a vaccine component • Live vaccines should not be given during an acute infection, to pregnant women or to the immunosuppressed, unless the immunosuppression is mild and the benefits outweigh the risks • If two live vaccines are required, they should be given either simultaneously in opposite arms or 4 weeks apart • Live vaccines should not be given for 3 months after an injection of human normal immunoglobulin (HNI) • HNI should not be given for 2 weeks after a live vaccine • Hay fever, asthma, eczema, sickle-cell disease, topical glucocorticoid therapy, antibiotic therapy, prematurity and chronic heart and lung diseases, including tuberculosis, are not contraindications to vaccination Fig. 6.14 The relationship between infection prevention and control (IPC) and antimicrobial stewardship (AMS). Antimicrobial stewardship Infection prevention and control Effective antimicrobial stewardship reduces health care-associated infections Effective infection control reduces the need for antimicrobials

116 • PRINCIPLES OF INFECTIOUS DISEASE • when no single agent’s spectrum covers all potential pathogens (e.g. polymicrobial infection) • when there is a need to reduce development of antimicrobial resistance in the target pathogen, as the organism would need to develop resistance to multiple agents simultaneously (e.g. antituberculous chemotherapy, p. 592; antiretroviral therapy (ART), p. 324). Antimicrobial resistance Microorganisms have evolved in the presence of naturally occurring antibiotics and have therefore developed resistance mechanisms (categorised in Fig. 6.16) to all classes of antimicrobial agent (antibiotics and their derivatives). Intrinsic resistance is an innate property of a microorganism, whereas acquired resistance arises by spontaneous mutation or horizontal transfer of genetic material from another organism (e.g. via a plasmid, p. 100). Plasmids often encode resistance to multiple antibiotics. The mecA gene encodes a penicillin-binding protein, which has a low affinity for penicillins and therefore confers resistance to β-lactam antibiotics in staphylococci. Extended-spectrum β-lactamases (ESBLs) are frequently encoded on plasmids, which are transferred relatively easily between bacteria, including Enterobacteriaceae. Plasmid-encoded carbapenemases have been detected in strains of Klebsiella pneumoniae (e.g. New Delhi metallo-β-lactamase 1, NDM-1). Strains of MRSA have been described that also have reduced susceptibility to glycopeptides through the development of a relatively impermeable cell wall. Treatment of infectious diseases Key components of treating infection are: • optimising antimicrobial therapy while minimising selection for antimicrobial resistance and the impact on commensal flora • addressing predisposing factors, e.g. glycaemic control in diabetes mellitus; viral load control in HIV-1-associated opportunistic infection • considering adjuvant therapy, e.g. removal of an infected medical device or necrotic tissue • managing complications, e.g. severe sepsis (systemic inflammatory response syndrome, or SIRS, p. 196) and acute kidney injury (p. 411). For communicable disease, treatment must also take into account contacts of the infected patient, and may include IPC interventions such as isolation, antimicrobial prophylaxis, vaccination and contact tracing. Principles of antimicrobial therapy In some situations (e.g. pneumonia) it is important to start appropriate antimicrobial therapy promptly, whereas in others prior confirmation of the diagnosis and pathogen is preferred. The principles underlying the choice of antimicrobial agent(s) are discussed below. The WHO ‘World Antibiotic Awareness Week’ campaign is a yearly event aimed at highlighting the importance of prudent antimicrobial prescribing (see ‘Further information’). Antimicrobial action and spectrum Antimicrobial agents may kill or inhibit microorganisms by targeting essential and non-essential cellular processes, respectively. The range, or spectrum, of microorganisms that is killed or inhibited by a particular antimicrobial agent needs consideration when selecting therapy. Mechanisms of action of the major classes of antibacterial agent are listed in Box 6.15 and appropriate agents for some common infecting organisms are shown in Box 6.16. In severe infections and/ or immunocompromised patients, it is customary to use bactericidal agents in preference to bacteriostatic agents. Empiric versus targeted therapy Empiric antimicrobial therapy is selected to treat a suspected infection (e.g. meningitis) before the microbiological cause is known. Targeted or ‘directed’ therapy can be prescribed when the pathogen(s) is known. Empirical antimicrobial regimens need to have activity against the range of pathogens that could be causing the infection in question; because broad-spectrum agents affect many more bacteria than needed, they select for antimicrobial resistance. ‘Start Smart – Then Focus’ (Fig. 6.15) describes the principle of converting from empiric therapy to narrow-spectrum targeted therapy. Optimum empiric therapy depends on the site of infection, patient characteristics and local antimicrobial resistance patterns. National or local guidelines are often used to inform antimicrobial prescribing decisions. Combination therapy It is sometimes appropriate to combine antimicrobial agents: • when there is a need to increase clinical effectiveness (e.g. biofilm infections) 6.15 Target and mechanism of action of common antibacterial agents Aminoglycosides, chloramphenicol, macrolides, lincosamides, oxazolidinones • Inhibition of bacterial protein synthesis by binding to subunits of bacterial ribosomes Tetracyclines • Inhibition of protein synthesis by preventing transfer RNA binding to ribosomes Beta-lactams • Inhibition of cell wall peptidoglycan synthesis by competitive inhibition of transpeptidases (‘penicillin-binding proteins’) Cyclic lipopeptide (daptomycin) • Insertion of lipophilic tail into plasma membrane causing depolarisation and cell death Glycopeptides • Inhibition of cell wall peptidoglycan synthesis by forming complexes with D-alanine residues on peptidoglycan precursors Nitroimidazoles • The reduced form of the drug causes strand breaks in DNA Quinolones • Inhibition of DNA replication by binding to DNA topoisomerases (DNA gyrase and topoisomerase IV), preventing supercoiling and uncoiling of DNA Rifamycins • Inhibition of DNA synthesis by inhibiting DNA-dependent RNA polymerase Sulphonamides and trimethoprim • Inhibition of folate synthesis by dihydropteroate synthase (sulphonamides) and dihydrofolate reductase (trimethoprim) inhibition

Treatment of infectious diseases • 117

6.16 Antimicrobial options for common infecting bacteria Organism Antimicrobial options* Gram-positive organisms Enterococcus faecalis Ampicillin, vancomycin/teicoplanin Enterococcus faecium Vancomycin/teicoplanin, linezolid Glycopeptide-resistant enterococci Linezolid, tigecycline, daptomycin MRSA Clindamycin, vancomycin, rifampicin (never used as monotherapy), linezolid, daptomycin, tetracyclines, tigecycline, co-trimoxazole Staphylococcus aureus Flucloxacillin, clindamycin Streptococcus pyogenes Penicillin, clindamycin, vancomycin Streptococcus pneumoniae Penicillin, cephalosporins, levofloxacin, vancomycin Gram-negative organisms Escherichia coli, ‘coliforms’ (enteric Gram-negative bacilli) Amoxicillin, trimethoprim, cefuroxime, ciprofloxacin, co-amoxiclav Enterobacter spp., Citrobacter spp. Ciprofloxacin, meropenem, ertapenem, aminoglycosides ESBL-producing Enterobacteriaceae Ciprofloxacin, meropenem, ertapenem (if sensitive), temocillin, aminoglycosides Carbapenemase-producing Enterobacteriaceae Ciprofloxacin, aminoglycosides, tigecycline, colistin Haemophilus influenzae Amoxicillin, co-amoxiclav, macrolides, cefuroxime, cefotaxime, ciprofloxacin Legionella pneumophila Azithromycin, levofloxacin, doxycycline Neisseria gonorrhoeae Ceftriaxone/cefixime, spectinomycin Neisseria meningitidis Penicillin, cefotaxime/ceftriaxone, chloramphenicol Pseudomonas aeruginosa Ciprofloxacin, piperacillin–tazobactam, aztreonam, meropenem, aminoglycosides, ceftazidime/cefepime Salmonella typhi Ceftriaxone, azithromycin (uncomplicated typhoid), chloramphenicol (resistance common) Strict anaerobes Bacteroides spp. Metronidazole, clindamycin, co-amoxiclav, piperacillin–tazobactam, meropenem Clostridium difficile Metronidazole, vancomycin (oral), fidaxomicin Clostridium spp. Penicillin, metronidazole, clindamycin Fusobacterium spp. Penicillin, metronidazole, clindamycin Other organisms Chlamydia trachomatis Azithromycin, doxycycline Treponema pallidum Penicillin, doxycycline *Antibiotic selection depends on multiple factors, including local susceptibility patterns, which vary enormously between geographical areas. There are many appropriate alternatives to those listed. (ESBL = extended-spectrum β-lactamase; MRSA = meticillin-resistant Staphylococcus aureus) Fig. 6.15 Stages in the selection and refinement of antimicrobial therapy: ‘Start Smart – Then Focus’. 1 Empiric therapy Based on: • Predicted susceptibility of likely pathogens • Local antimicrobial policies 2 Targeted therapy Based on: • Predicted susceptibility of infecting organism(s) • Local antimicrobial policies 3 Susceptibility-guided therapy Based on: • Susceptibility testing results Antimicrobial susceptibility results Clinical diagnosis Information available: • Organ system involved • Endogenous or exogenous infection • Likely pathogens • Infecting organism(s) • Likely antimicrobial susceptibility Level of knowledge of infecting organism(s) Antimicrobial spectrum of agent(s) used • Antimicrobial susceptibility of infecting organism(s) Laboratory investigations: microbiological diagnosis

118 • PRINCIPLES OF INFECTIOUS DISEASE be stopped when there is no longer any clinical evidence of infection. Pharmacokinetics and pharmacodynamics Pharmacokinetics of antimicrobial agents determine whether adequate concentrations are obtained at the sites of infection. Septic patients often have poor gastrointestinal absorption, so the preferred initial route of therapy is intravenous. Knowledge of anticipated antimicrobial drug concentrations at sites of infection is critical. For example, achieving a ‘therapeutic’ blood level of gentamicin is of little practical use in treating meningitis, as CSF penetration of the drug is poor. Knowledge of routes of antimicrobial elimination is also critical; for instance, urinary tract infection is ideally treated with a drug that is excreted unchanged in the urine. Pharmacodynamics describes the relationship between antimicrobial concentration and microbial killing. For many agents, antimicrobial effect can be categorised as ‘concentrationdependent’ or ‘time-dependent’. The concentration of antimicrobial achieved after a single dose is illustrated in Figure 6.17. The maximum concentration achieved is Cmax and the measure of overall exposure is the area under the curve (AUC). The efficacy of antimicrobial agents whose killing is concentration-dependent (e.g. aminoglycosides) increases with the amount by which Cmax exceeds the minimum inhibitory concentration (Cmax : MIC ratio). For this reason, it has become customary to administer aminoglycosides (e.g. gentamicin) infrequently at high doses (e.g. 7 mg/kg) rather than frequently at low doses. This has the added advantage of minimising toxicity by reducing the likelihood Factors promoting antimicrobial resistance include the inappropriate use of antibiotics (e.g. to treat viral infections), inadequate dosage or unnecessarily prolonged treatment, and use of antimicrobials as growth promoters in agriculture. However, any antimicrobial use exerts a selection pressure that favours the development of resistance. Combination antimicrobial therapy may reduce the emergence of resistance in the target pathogen but not in the normal flora that it also affects. Despite use of combination therapy for M. tuberculosis, multidrug-resistant tuberculosis (MDR-TB, resistant to isoniazid and rifampicin) and extremely drug-resistant tuberculosis (XDR-TB, resistant to isoniazid and rifampicin, any fluoroquinolone and at least one injectable antimicrobial antituberculous agent) have been reported worldwide and are increasing in incidence. The term ‘post-antibiotic era’ has been coined to describe a future in which the acquisition of resistance by bacteria will have been so extensive that antibiotic therapy is rendered useless. A more realistic scenario, which is currently being experienced, is a gradual but inexorable progression of resistance, necessitating the use of ever more toxic and expensive antimicrobials. Duration of therapy Treatment duration reflects the severity of infection and accessibility of the infected site to antimicrobial agents. For most infections, there is limited evidence available to support a specific duration of treatment (Box 6.17). Depending on the indication, initial intravenous therapy can often be switched to oral as soon as the patient is apyrexial and improving. In the absence of specific guidance, antimicrobial therapy should Fig. 6.16 Examples of mechanisms of antimicrobial resistance. (CAT = chloramphenicol acetyltransferase; ESBLs = extended-spectrum β-lactamases; MRSA = meticillin-resistant Staph. aureus; NDM-1 = New Delhi metallo-β-lactamase 1). Impermeability/reduced permeability Carbapenem resistance in Pseudomonas spp. Aminoglycoside resistance in anaerobes (uptake requires O2-dependent transport mechanism) Antimicrobial target Antimicrobial agent Active efflux of antimicrobial agent Tetracycline resistance in Gram-positive and Gram-negative bacteria Fluconazole resistance in Candida spp. Target modification β-lactam resistance in MRSA – altered penicillin-binding protein Glycopeptide resistance in enterococci – altered peptidoglycan amino acid sequence Rifampicin resistance in M. tuberculosis – RNA polymerase mutation Ciprofloxacin resistance in Enterobacteriaceae – DNA gyrase mutation Linezolid resistance in staphylococci and enterococci – 23S rRNA methylation Enzymatic degradation of agent β-lactam resistance in many organisms (penicillinase in Staph. aureus; ESBLs, ampC and NDM-1 in Enterobacteriaceae) Chloramphenicol resistance in staphylococci (CAT)

Treatment of infectious diseases • 119

6.17 Duration of antimicrobial therapy for some common infections* Infection Duration of therapy Viral infections Herpes simplex encephalitis 2–3 weeks Bacterial infections Gonorrhoea Single dose Infective endocarditis (streptococcal, native valve) 4 weeks ± gentamicin for first 2 weeks Infective endocarditis (prosthetic valve) 6 weeks Osteomyelitis 6 weeks Pneumonia (community-acquired, severe) 7–10 days (no organism identified), 14–21 days (Staph. aureus or Legionella spp.) Septic arthritis 2–4 weeks Urinary tract infection (male) 2 weeks Urinary tract infection, upper tract, uncomplicated (female) 7 days Urinary tract infection, lower (female) 3 days Mycobacterial infections Tuberculosis (meningeal) 12 months Tuberculosis (pulmonary) 6 months Fungal infections Invasive pulmonary aspergillosis Until clinical/radiological resolution and reversal of predisposition Candidaemia (acute disseminated) 2 weeks after last positive blood culture and resolution of signs and symptoms All recommendations are indicative. Actual duration takes into account predisposing factors, specific organisms and antimicrobial susceptibility, adjuvant therapies, current guidelines and clinical response. Fig. 6.17 Antimicrobial pharmacodynamics. The curve represents drug concentrations after a single dose of an antimicrobial agent. Factors that determine microbial killing are Cmax : MIC ratio (concentration-dependent killing), time above MIC (time-dependent killing) and AUC : MIC ratio. Time after dose Time above MIC Peak concentration (Cmax) Minimum inhibitory concentration (MIC) Area under the curve (AUC) Concentration of drug accumulation. Conversely, the β-lactam antibiotics and vancomycin exhibit time-dependent killing, and their efficacy depends on Cmax exceeding the MIC for a certain time (which is different for each class of agent). This is reflected in the dosing interval of benzylpenicillin, which is usually given every 4 hours in severe infection (e.g. meningococcal meningitis), and may be administered by continuous infusion. For other antimicrobial agents, the pharmacodynamic relationships are more complex and often less well understood. With some agents, bacterial inhibition persists after antimicrobial exposure (post-antibiotic and post-antibiotic sub-MIC effects). Therapeutic drug monitoring Therapeutic drug monitoring is used to confirm that levels of antimicrobial agents with a low therapeutic index (e.g. aminoglycosides) are not excessive, and that levels of agents with marked pharmacokinetic variability (e.g. vancomycin) are adequate. Specific recommendations for monitoring depend on individual clinical circumstances; for instance, different pre- and post-dose levels of gentamicin are recommended, depending on whether it is being used in traditional divided doses, once daily or for synergy in endocarditis (p. 530). Antimicrobial prophylaxis Antimicrobial prophylaxis is the use of antimicrobial agents to prevent infection. Primary prophylaxis is used to reduce the risk of infection following certain medical procedures (e.g. colonic resection or prosthetic hip insertion), following exposure to a specific pathogen (e.g. Bordetella pertussis) or in specific situations such as post-splenectomy (Box 6.18). It should be 6.18 Recommendations for antimicrobial prophylaxis in adults Infection risk Recommended antimicrobial Bacterial Diphtheria (prevention of secondary cases) Erythromycin Gas gangrene (after high amputation or major trauma) Penicillin or metronidazole Lower gastrointestinal tract surgery Cefuroxime + metronidazole, gentamicin + metronidazole, or co-amoxiclav (single dose only) Meningococcal disease (prevention of secondary cases) Rifampicin or ciprofloxacin Rheumatic fever (prevention of recurrence) Phenoxymethylpenicillin or sulfadiazine Tuberculosis (prevention of secondary cases) Isoniazid ± rifampicin Whooping cough (prevention of secondary cases) Erythromycin Viral HIV, occupational exposure (sharps injury) Combination tenofovir/ emtricitabine and raltegravir. Modified if index case’s virus known to be resistant Influenza A (prevention of secondary cases in adults with chronic respiratory, cardiovascular or renal disease, immunosuppression or diabetes mellitus) Oseltamivir Fungal Aspergillosis (in high-risk haematology patients) Posaconazole (voriconazole or itraconazole alternatives if intolerant) Pneumocystis pneumonia (prevention in HIV and other immunosuppressed states) Co-trimoxazole, pentamidine or dapsone Protozoal Malaria (prevention of travelassociated disease) Specific antimalarials depend on travel itinerary (p. 278) *These are based on current UK practice. Recommendations may vary locally or nationally. Antimicrobial prophylaxis for infective endocarditis during dental procedures is not currently recommended in the UK.

120 • PRINCIPLES OF INFECTIOUS DISEASE Beta-lactam antibiotics These antibiotics have a β-lactam ring structure and exert a bactericidal action by inhibiting enzymes involved in cell wall synthesis (penicillin-binding proteins, PBPs). They are classified in Box 6.21. Pharmacokinetics • Good drug levels are achieved in lung, kidney, bone, muscle and liver, and in pleural, synovial, pericardial and peritoneal fluids. • CSF levels are low, except when meninges are inflamed. • Activity is not inhibited in abscess (e.g. by low pH and PO2, high protein or neutrophils). • Beta-lactams are subject to an ‘inoculum effect’ – activity is reduced in the presence of a high organism burden (PBP expression is down-regulated by high organism density). • Generally safe in pregnancy (except imipenem/cilastatin). Adverse effects Immediate (IgE-mediated) allergic reactions are rare but lifethreatening. Approximately 90% of patients who report a penicillin allergy do not have a true IgE-mediated allergy. Other reactions, such as rashes, fever and haematological effects (e.g. low white cell count), usually follow more prolonged therapy (more than 2 weeks). A large proportion of patients with infectious mononucleosis develop a rash if given aminopenicillins; this does not imply lasting allergy. The relationship between allergy to penicillin and allergy to cephalosporins depends on the specific cephalosporin used; there is significant cross-reactivity with first-generation cephalosporins but cross-reactivity to second-/ third-generation cephalosporins is less common. Avoidance of cephalosporins, however, is recommended in patients who have IgE-mediated penicillin allergy (p. 84). Cross-reactivity between penicillin and carbapenems is rare (approximately 1% by skin testing) and carbapenems may be administered if there are no suitable alternatives and appropriate resuscitation facilities are available. The monobactam aztreonam (p. 121) is the β-lactam least likely to cross-react in patients with penicillin allergy. Gastrointestinal upset and diarrhoea are common, and a mild reversible hepatitis is recognised with many β-lactams. More severe forms of hepatitis can be observed with flucloxacillin and co-amoxiclav. Leucopenia, thrombocytopenia, coagulation associated with minimal adverse effects. In the case of exposure, it may be combined with passive immunisation (see Box 6.12). Secondary prophylaxis is used in patients who have been treated successfully for an infection but remain predisposed to it. It is used in haemato-oncology patients in the context of fungal infection and in HIV-positive individuals with an opportunistic infection until a defined level of immune reconstitution is achieved. Antibacterial agents For details of antibacterial usage in pregnancy and old age, see Boxes 6.19 and 6.20. 6.20 Problems with antimicrobial therapy in old age • Clostridium difficile infection: all antibiotics predispose to some extent, but second- and third-generation cephalosporins, co-amoxiclav and fluoroquinolones (e.g. ciprofloxacin) especially so. • Hypersensitivity reactions: rise in incidence due to increased previous exposure. • Renal impairment: may be significant in old age, despite ‘normal’ creatinine levels (p. 386). • Nephrotoxicity: more likely, e.g. first-generation cephalosporins, aminoglycosides. • Accumulation of β-lactam antibiotics: may result in myoclonus, seizures or coma. • Reduced gastric acid production: gastric pH is higher, which causes increased penicillin absorption. • Reduced hepatic metabolism: results in a higher risk of isoniazid-related hepatotoxicity. • Quinolones: associated with delirium and may increase the risk of seizures. 6.21 Beta-lactam antibiotics Penicillins • Natural penicillins: benzylpenicillin, phenoxymethylpenicillin • Penicillinase-resistant penicillins: meticillin, flucloxacillin, nafcillin, oxacillin • Aminopenicillins: ampicillin, amoxicillin • Carboxy- and ureido-penicillins: ticarcillin, piperacillin, temocillin Cephalosporins • See Box 6.22 Monobactams • Aztreonam Carbapenems • Imipenem, meropenem, ertapenem, doripenem 1Data extracted from Joint Formulary Committee. British National Formulary (online). London: BMJ Group and Pharmaceutical Press; (medicinescomplete. com) [accessed on 16 March 2013]. • Glycopeptides • Linezolid • Meropenem • Penicillins 2Theoretical risk of teratogenicity, not supported by available clinical evidence. 6.19 Antimicrobial agents in pregnancy1 Contraindicated • Chloramphenicol: neonatal ‘grey baby’ syndrome – collapse, hypotension and cyanosis • Fluconazole: teratogenic in high doses • Quinolones: arthropathy in animal studies • Sulphonamides: neonatal haemolysis and methaemoglobinaemia • Tetracyclines, glycylcyclines: skeletal abnormalities in animals in first trimester; fetal dental discoloration and maternal hepatotoxicity with large parenteral doses in second or third trimesters • Trimethoprim: teratogenic in first trimester Relatively contraindicated • Aminoglycosides: potential damage to fetal auditory and vestibular nerves in second and third trimesters • Metronidazole: avoidance of high dosages is recommended2 Not known to be harmful; use only when necessary • Aciclovir • Cephalosporins • Clarithromycin • Clindamycin • Erythromycin

Treatment of infectious diseases • 121

retain good activity against Strep. pneumoniae and β-haemolytic streptococci. Ceftriaxone is administered once daily and is therefore a suitable agent for outpatient intravenous (parenteral) antimicrobial therapy (OPAT). • Fourth-generation agents, e.g. cefipime, have a broad spectrum of activity, including streptococci and some Gram-negatives, including P. aeruginosa. • Fifth-generation agents, such as ceftobiprole and ceftaroline, have an enhanced spectrum of Gram-positive activity that includes MRSA, and also have activity against Gram-negative bacteria; some, such as ceftobiprole, are active against P. aeruginosa. The spectrum of cephalosporins has also been enhanced by adding β-lactamase inhibitors. Monobactams Aztreonam is the only available monobactam. It is active against Gram-negative bacteria, except ESBL-producing organisms, but inactive against Gram-positive organisms or anaerobes. It is a parenteral-only agent and may be used safely in most penicillin-allergic patients other than those with an allergy to ceftazidime, which shares a common side chain with aztreonam. Carbapenems These intravenous agents have the broadest antibiotic activity of the β-lactam antibiotics, covering most clinically significant bacteria, including anaerobes (e.g. imipenem, meropenem, ertapenem). Macrolide and lincosamide antibiotics Macrolides (e.g. erythromycin, clarithromycin and azithromycin) and lincosamides (e.g. clindamycin) are bacteriostatic agents. Both classes bind to the same component of the ribosome, so they are not administered together. Macrolides are used for Legionella, Mycoplasma, Chlamydia and Bordetella infections. Azithromycin is employed for single-dose/short-course therapy for genitourinary Chlamydia/Mycoplasma spp. infections. Clindamycin is used primarily for skin, soft tissue, bone and joint infections. Pharmacokinetics Macrolides • Variable bioavailability (intravenous and oral preparations available). deficiencies, interstitial nephritis and potentiation of aminoglycosidemediated kidney damage are also recognised (p. 122). Seizures and encephalopathy have been reported, particularly with high doses in the presence of renal insufficiency. Thrombophlebitis occurs in up to 5% of patients receiving parenteral β-lactams. Drug interactions Synergism occurs in combination with aminoglycosides in vitro. Ampicillin decreases the biological effect of oral contraceptives and the whole class is significantly affected by concurrent administration of probenecid, producing a 2–4-fold increase in the peak serum concentration. Penicillins Natural penicillins are primarily effective against Gram-positive organisms (except staphylococci, most of which produce a penicillinase) and anaerobic organisms. Strep. pyogenes has remained sensitive to natural penicillins worldwide. According to the European Antimicrobial Resistance Surveillance Network (EARS-Net), the prevalence of non-susceptibility to penicillin in Strep. pneumoniae in Europe in 2014 varied widely from 0% (Cyprus) to 46.7% (Romania). Penicillinase-resistant penicillins are the mainstay of treatment for infections with Staph. aureus, other than MRSA. However, EARS-Net data from 2014 indicate that MRSA rates in Europe vary widely from 0.9% (Netherlands) to 56% (Romania). Aminopenicillins have the same spectrum of activity as the natural penicillins, with additional Gram-negative cover against Enterobacteriaceae. Amoxicillin has better oral absorption than ampicillin. Unfortunately, resistance to these agents is widespread (57.1% of E. coli Europe-wide in 2014, range 34.7–73%), so they are no longer appropriate for empirical use in Gram-negative infections. In many organisms, resistance is due to β-lactamase production, which can be overcome by the addition of β-lactamase inhibitors (clavulanic acid or sulbactam). Carboxypenicillins (e.g. ticarcillin) and ureidopenicillins (e.g. piperacillin) are particularly active against Gram-negative organisms, especially Pseudomonas spp., which are resistant to the aminopenicillins. Beta-lactamase inhibitors may be added to extend their spectrum of activity (e.g. piperacillin–tazobactam). Temocillin is derived from ticarcillin; it has good activity against Enterobacteriaceae, including those that produce ESBL enzymes, but poor activity against Pseudomonas aeruginosa and Grampositive bacteria. Cephalosporins and cephamycins Cephalosporins are broad-spectrum agents. Unfortunately, their use is associated with CDI (p. 264). With the exception of ceftobiprole, the group has no activity against enterococci. Only the cephamycins have anti-anaerobic activity. All cephalosporins are inactivated by ESBL. Cephalosporins are arranged in ‘generations’ (Box 6.22). • First-generation compounds have excellent activity against Gram-positive organisms and some activity against Gram-negatives. • Second-generation drugs retain Gram-positive activity but have extended Gram-negative activity. Cephamycins (e.g. cefoxitin), included in this group, are active against anaerobic Gram-negative bacilli. • Third-generation agents further improve anti-Gramnegative cover. For some (e.g. ceftazidime), this is extended to include Pseudomonas spp. Cefotaxime and ceftriaxone have excellent Gram-negative activity and 6.22 Cephalosporins First generation • Cefalexin, cefradine (oral) • Cefazolin (IV) Second generation • Cefuroxime (oral/IV) • Cefaclor (oral) • Cefoxitin (IV) Third generation • Cefixime (oral) • Cefotaxime (IV) • Ceftriaxone (IV) • Ceftazidime (IV) Fourth generation • Cefepime (IV) Fifth generation (also referred to as ‘next generation’) • Ceftobiprole (IV) • Ceftaroline (IV)

122 • PRINCIPLES OF INFECTIOUS DISEASE are < 1 mg/L and 5–10 mg/L (7–10 mg/L with less sensitive organisms, e.g. P. aeruginosa), respectively. • For other aminoglycosides, consult local guidance. Adverse effects • Renal toxicity (usually reversible) accentuated by other nephrotoxic agents. • Cochlear toxicity (permanent) more likely in older people and those with a predisposing mitochondrial gene mutation. • Neuromuscular blockade after rapid intravenous infusion (potentiated by calcium channel blockers, myasthenia gravis and hypomagnesaemia). Spectinomycin Chemically similar to the aminoglycosides and given intramuscularly, spectinomycin was developed to treat strains of Neisseria gonorrhoeae resistant to β-lactam antibiotics. Unfortunately, resistance to spectinomycin is very common. Its only indication is the treatment of gonococcal urethritis in pregnancy or in patients allergic to β-lactam antibiotics. Quinolones and fluoroquinolones These are effective and generally well-tolerated bactericidal agents. The quinolones have purely anti-Gram-negative activity, whereas the fluoroquinolones are broad-spectrum agents (Box 6.23). Ciprofloxacin has anti-pseudomonal activity but resistance emerges rapidly. In 2014, European surveillance showed that resistance to fluoroquinolones in E. coli ranged between 7.8% (Iceland) and 46.4% (Cyprus). Quinolones and fluoroquinolones are used for a variety of common infections, including urinary tract infection and pneumonia, and less common problems like MDR-TB. Pharmacokinetics • Well absorbed after oral administration but delayed by food, antacids, ferrous sulphate and multivitamins. • Wide volume of distribution; tissue concentrations twice those in serum. • Good intracellular penetration, concentrating in phagocytes. Fig. 6.18 Dosing of aminoglycosides using the Hartford nomogram. The nomogram is used to determine the dose interval for 7 mg doses of gentamicin or tobramycin, using measurements of drug levels in plasma 6–14 hours after a single dose. Dose every 48 hours Dose every 36 hours Dose every 24 hours Hours since administration Concentration in plasma (μg/mL)

• Frequency of administration: erythromycin is administered 4 times daily, clarithromycin twice daily, azithromycin once daily. • High protein binding. • Excellent intracellular accumulation. Lincosamides (e.g. clindamycin) • Good oral bioavailability. • Food has no effect on absorption. • Good bone/joint penetration; limited CSF penetration. Adverse effects • Gastrointestinal upset, especially in young adults (erythromycin 30%). • Cholestatic jaundice with erythromycin estolate. • Prolongation of QT interval can cause torsades de pointes (p. 476). • Clindamycin predisposes to CDI. Aminoglycosides and spectinomycin Aminoglycosides are effective mainly in Gram-negative infections and are therefore commonly used in regimens for intra-abdominal infection. Some aminoglycosides, e.g. amikacin, are important components of therapy for MDR-TB. Because they act synergistically with β-lactam antibiotics they are used in combinations to treat biofilm infections, including infective endocarditis and orthopaedic implant infections. They cause very little local irritation at injection sites and negligible allergic responses. Oto- and nephrotoxicity must be avoided by monitoring of renal function and drug levels and by use of short treatment regimens. Aminoglycosides are not subject to an inoculum effect (p. 120) and they all exhibit a post-antibiotic effect (p. 119). Pharmacokinetics • Negligible oral absorption. • Hydrophilic, so excellent penetration to extracellular fluid in body cavities and serosal fluids. • Very poor intracellular penetration (except hair cells in cochlea and renal cortical cells). • Negligible CSF and corneal penetration and may require intrathecal administration during neurosurgical infections. • Peak plasma levels 30 minutes after infusion. • Monitoring of therapeutic levels required. Gentamicin dosing • Except in certain forms of endocarditis, pregnancy, severe burns, end-stage renal disease and paediatric patients, gentamicin is administered at 7 mg/kg body weight. The appropriate dose interval depends on drug clearance and is determined by reference to the Hartford nomogram (Fig. 6.18). • In streptococcal and enterococcal endocarditis, gentamicin is used with a cell wall active agent (usually a β-lactam), to provide synergy. Commonly used doses are 1 mg/kg 2–3 times daily for enterococcal endocarditis and 3 mg/kg once daily for most strains of oral streptococci. Target pre- and post-dose levels are < 1 mg/L and 3–5 mg/L, respectively, when gentamicin is dosed 3 times daily. • When not used according to the Hartford regimen or for endocarditis, gentamicin is administered twice or 3 times daily at 3–5 mg/kg/day. Target pre- and post-dose levels

Treatment of infectious diseases • 123

Adverse effects • Histamine release due to rapid vancomycin infusion produces a ‘red man’ reaction (rare with modern preparations). • Nephrotoxicity is rare but may occur with concomitant aminoglycoside use, as may ototoxicity. • Teicoplanin can cause rash, bronchospasm, eosinophilia and anaphylaxis. Lipopeptides Daptomycin is a cyclic lipopeptide with bactericidal activity against Gram-positive organisms (including MRSA and GRE) but not Gram-negatives. It is not absorbed orally, and is used intravenously to treat Gram-positive infections, such as soft tissue infections and Staph. aureus infective endocarditis. Daptomycin is not effective for community-acquired pneumonia. Treatment can be associated with increased levels of creatine kinase and eosinophilic pneumonitis. Polymyxins Colistin is a polymyxin antibiotic that binds and disrupts the outer cell membrane of Gram-negative bacteria, including P. aeruginosa and Acinetobacter baumannii. Its use has increased with the emergence and spread of multi-resistant Gram-negative bacteria, including CPEs. It can be administered by oral, intravenous and nebulised routes. Significant adverse effects include neurotoxicity, including encephalopathy, and nephrotoxicity. Folate antagonists These are bacteriostatic antibacterials (p. 109). A combination of a sulphonamide and either trimethoprim or pyrimethamine is most commonly used, which interferes with two consecutive steps in the metabolic pathway. Available combinations include trimethoprim/sulfamethoxazole (co-trimoxazole) and pyrimethamine with either sulfadoxine (used to treat malaria) or sulfadiazine (used in toxoplasmosis). Co-trimoxazole is the first-line drug for Pneumocystis jirovecii infection, the second-line drug for treatment and prevention of B. pertussis (whooping cough) infection, and is also used for a variety of other infections, including Staph. aureus. Dapsone is used to treat leprosy (Hansen’s disease) and to prevent toxoplasmosis and pneumocystis when patients are intolerant of other medications. Folinic acid should be given to prevent myelosuppression if these drugs are used long-term or unavoidably in early pregnancy. Pharmacokinetics • Well absorbed orally. • Sulphonamides are hydrophilic, distributing well to the extracellular fluid. • Trimethoprim is lipophilic with high tissue concentrations. Adverse effects • Trimethoprim is generally well tolerated, with few adverse effects. • Sulphonamides and dapsone may cause haemolysis in glucose-6-phosphate dehydrogenase deficiency (p. 948). • Sulphonamides and dapsone cause skin and mucocutaneous reactions, including Stevens–Johnson syndrome and ‘dapsone syndrome’ (rash, fever and lymphadenopathy). • Dapsone causes methaemoglobinaemia (p. 135) and peripheral neuropathy. Adverse effects • Gastrointestinal side-effects in 1–5%. • Rare skin reactions (phototoxicity). • Tendinitis and Achilles tendon rupture, especially in older people. • Central nervous system effects (delirium, tremor, dizziness and occasional seizures in 5–12%), especially in older people. • Reduces clearance of xanthines and theophyllines, potentially inducing insomnia and increased seizure potential. • Prolongation of QT interval on ECG, cardiac arrhythmias. • Ciprofloxacin use is associated with the acquisition of MRSA and emergence of C. difficile ribotype 027 (p. 264). Glycopeptides Glycopeptides (vancomycin and teicoplanin) are effective against Gram-positive organisms only, and are used against MRSA and ampicillin-resistant enterococci. Some staphylococci and enterococci demonstrate intermediate sensitivity or resistance. Vancomycin use should be restricted to limit emergence of resistant strains. Teicoplanin is not available in all countries. Neither drug is absorbed after oral administration but vancomycin is used orally to treat CDI. Pharmacokinetics Vancomycin • Administered by slow intravenous infusion, good tissue distribution and short half-life. • Enters the CSF only in the presence of inflammation and may require intrathecal administration during neurosurgical infections. • Therapeutic monitoring of intravenous vancomycin is recommended, to maintain pre-dose levels of > 10 mg/L (15–20 mg/L in serious staphylococcal infections). Teicoplanin • Long half-life allows once-daily dosing. Agent Route of administration Typical antimicrobial spectrum Quinolones Nalidixic acid Oral Enteric Gram-negative bacilli (not Pseudomonas aeruginosa) Fluoroquinolones Ciprofloxacin Norfloxacin Ofloxacin IV/oral Oral IV/oral/topical Enteric Gram-negative bacilli, P. aeruginosa, Haemophilus spp., ‘atypical’ respiratory pathogens* Levofloxacin (L-isomer of ofloxacin) IV/oral Haemophilus spp., Strep. pneumoniae, ‘atypical’ respiratory pathogens* Moxifloxacin Oral Strep. pneumoniae, Staph. aureus, ‘atypical’ respiratory pathogens*, Mycobacteria and anaerobes } 6.23 Quinolones and fluoroquinolones *‘Atypical’ pathogens include Mycoplasma pneumoniae and Legionella spp. Fluoroquinolones have variable activity against M. tuberculosis and other mycobacteria.

124 • PRINCIPLES OF INFECTIOUS DISEASE H. influenzae, Strep. pneumoniae and N. meningitidis. It has a very broad spectrum of activity against aerobic and anaerobic organisms, spirochaetes, Rickettsia, Chlamydia and Mycoplasma spp. It competes with macrolides and lincosamides for ribosomal binding sites, so should not be used in combination with these agents. Significant adverse effects are ‘grey baby’ syndrome in infants (cyanosis and circulatory collapse due to inability to conjugate drug and excrete the active form in urine); reversible dose-dependent bone marrow depression in adults receiving high cumulative doses; and severe aplastic anaemia in 1 in 25 000–40 000 exposures (unrelated to dose, duration of therapy or route of administration). Oxazolidinones Linezolid and tedizolid are examples and their good activity against Gram-positive organisms means they are often used to treat skin and soft tissue infections. They may also be used in infection caused by resistant Gram-positive bacteria, including MRSA and GRE. Administration can be intravenous or oral. Common linezolid adverse effects include mild gastrointestinal upset and tongue discoloration. Myelodysplasia and peripheral and optic neuropathy can occur with prolonged use. Linezolid has monoamine oxidase inhibitor (MAOI) activity, and co-administration with other MAOIs or serotonin re-uptake inhibitors should be avoided, as this may precipitate a ‘serotonin syndrome’ (p. 1199). Other antibacterial agents Fusidic acid This antibiotic, active against Gram-positive bacteria, is available in intravenous, oral or topical formulations. It is lipid-soluble and distributes well to tissues. Its antibacterial activity is, however, unpredictable. Fusidic acid is used in combination, typically with antistaphylococcal penicillins, or for MRSA with clindamycin or rifampicin. It interacts with coumarin derivatives and oral contraceptives. Nitrofurantoin This drug has very rapid renal elimination and is active against aerobic Gram-negative and Gram-positive bacteria, including enterococci. It is used only for treatment of urinary tract infection, being generally safe in pregnancy and childhood. With prolonged treatment, however, it can cause eosinophilic lung infiltrates, fever, pulmonary fibrosis, peripheral neuropathy, hepatitis and haemolytic anaemia so its use must be carefully balanced against risks. Fidaxomicin Fidaxomicin is an inhibitor of RNA synthesis, and was introduced for the treatment of CDI in 2012. In non-severe CDI it is noninferior to oral vancomycin and is associated with a lower recurrence rate. Its effectiveness has not been assessed in severe CDI. Fosfomycin Fosfomycin acts by inhibiting cell wall synthesis. It has activity against Gram-negative but also Gram-positive bacteria and can demonstrate in vitro synergy against MRSA when combined with other antimicrobials. It is used for treatment of urinary tract infections but can be employed in other situations against multi-resistant bacteria. Tetracyclines and glycylcyclines Tetracyclines Of this mainly bacteriostatic class, the newer drugs doxycycline and minocycline show better absorption and distribution than older ones. Many streptococci and Gram-negative bacteria are now resistant, in part due to their use in animals (which is banned in Europe). Tetracyclines are indicated for Mycoplasma spp., Chlamydia spp., Rickettsia spp., Coxiella spp., Bartonella spp., Borrelia spp., Helicobacter pylori, Treponema pallidum and atypical mycobacterial infections. Tetracyclines can also be used for malaria prevention. Pharmacokinetics • Best oral absorption is in the fasting state (doxycycline is 100% absorbed unless gastric pH rises) and absorption is inhibited by cations, e.g. calcium or iron, which should not be administered at the same time. Adverse effects • All tetracyclines except doxycycline are contraindicated in renal failure. • Dizziness with minocycline. • Binding to metallic ions in bones and teeth causes discoloration (avoid in children and pregnancy) and enamel hypoplasia. • Oesophagitis/oesophageal ulcers with doxycycline. • Phototoxic skin reactions. Glycylcyclines (tigecycline) Chemical modification of tetracycline has produced tigecycline, a broad-spectrum, parenteral-only antibiotic with activity against resistant Gram-positive and Gram-negative pathogens, such as MRSA and ESBL (but excluding Pseudomonas spp.). Re-analysis of trial data has shown that there was excess mortality following tigecycline treatment as opposed to comparator antibiotics, so tigecycline should be used only when there has been adequate assessment of risk versus benefit. Nitroimidazoles Nitroimidazoles are highly active against strictly anaerobic bacteria, especially Bacteroides fragilis, C. difficile and other Clostridium spp. They also have significant antiprotozoal activity against amoebae and Giardia lamblia. Pharmacokinetics • Almost completely absorbed after oral administration (60% after rectal administration). • Well distributed, especially to brain and CSF. • Safe in pregnancy. Adverse effects • Metallic taste (dose-dependent). • Severe vomiting if taken with alcohol – ‘Antabuse effect’. • Peripheral neuropathy with prolonged use. Phenicols Chloramphenicol is the only example in clinical use. In developed countries its use tends to be reserved for severe and lifethreatening infections when other antibiotics are either unavailable or impractical, largely because of concerns about toxicity. It is bacteriostatic to most organisms but apparently bactericidal to

Treatment of infectious diseases • 125

neurotoxicity); and paraminosalicylic acid (which causes rashes and gastrointestinal upset). Linezolid may also be used and has good CSF penetration, while meropenem with co-amoxiclav is occasionally chosen. New drugs developed for XDR-TB include delamanid and bedaquiline; their adverse effects include QT prolongation and cardiac arrhythmias. Their co-administration with other agents with a similar side-effect profile (e.g. fluoroquinolones) therefore requires careful risk assessment. Clofazimine Clofazimine is used against M. leprae and resistant strains of M. tuberculosis. Its mode of action may involve induction of oxidative stress and it is weakly bactericidal. Oral absorption is variable and it is excreted in the bile. Side-effects include gastrointestinal upset, dry eyes and skin, and skin pigmentation, especially in those with pigmented skin. Antifungal agents See Box 6.24. Antimycobacterial agents Isoniazid Isoniazid is bactericidal for replicating bacteria and bacteriostatic for non-replicating bacteria. It is activated by mycobacterial catalase-peroxidase (KatG) and inhibits the InhA gene product, a reductase involved in mycolic acid synthesis. Mutations in KatG or InhA result in isoniazid resistance, which was reported in 15% of cases of M. tuberculosis infection globally in 2013. Isoniazid is well absorbed orally and metabolised by acetylation in the liver. The major side-effects are hepatitis, neuropathy (ameliorated by co-administration of pyridoxine) and hypersensitivity reactions. Rifampicin Rifampicin inhibits DNA-dependent RNA polymerase and is bactericidal against replicating bacteria. It is also active in necrotic foci, where mycobacteria have low levels of replication, and is therefore important in sterilisation and sputum conversion. Resistance most often involves the β-subunit of RNA polymerase and most often occurs with isoniazid-resistant MDR-TB. Rifampicin is well absorbed orally. It is metabolised by the liver via the microsomal cytochrome P450 system and is one the most potent inducers of multiple P450 isoenzymes, so is subject to extensive drug–drug interactions. Common side-effects include hepatitis, influenza-like symptoms and hypersensitivity reactions. Orange discoloration of urine and body secretions is expected. Pyrazinamide The mechanism of action of pyrazinamide is incompletely defined but includes inhibition of fatty acid synthase and ribosomal trans-translation. Pyrazinamide is often bacteriostatic but can be bactericidal and is active against semidormant bacteria in a low-pH environment. Primary resistance is rare but MDR-TB strains are frequently pyrazinamide-resistant and intrinsic resistance is a feature of Mycobacterium bovis strains. Pyrazinamide is well absorbed orally and metabolised by the liver. Side-effects include nausea, hepatitis, asymptomatic elevation of uric acid and myalgia. Ethambutol Ethambutol is a bacteriostatic agent. It inhibits arabinosyl transferase, which is involved in the synthesis of arabinogalactan, a component of the mycobacterial cell wall. Resistance is usually seen when resistance to other antimycobacterial agents is also present, e.g. in MDR-TB strains. It is orally absorbed but, in contrast to the first-line agents described above, it achieves poor CSF penetration and is renally excreted. The major side-effect is optic neuritis with loss of red–green colour discrimination and impaired visual acuity. It can also cause hepatitis. Streptomycin Streptomycin is an aminoglycoside whose mechanism of action and side-effects are similar to those of other aminoglycosides. It is administered intramuscularly. Other antituberculous agents Second-line agents used in MDR or XDR strains (p. 116) include aminoglycosides (amikacin, capreomycin or kanamycin) and fluoroquinolones (moxifloxacin or levofloxacin), discussed above. Other established second-line agents administered orally are cycloserine (which causes neurological side-effects); ethionamide or prothionamide (which are not active with InhA-gene-mediated resistance but have reasonable CSF penetration; their side-effect profile includes gastrointestinal disturbance, hepatotoxicity and Agent Usual route(s) of administration Clinically relevant antifungal spectrum Imidazoles Miconazole Econazole Clotrimazole Topical Candida spp., dermatophytes Ketoconazole Topical, oral Malassezia spp., dermatophytes, agents of eumycetoma Triazoles Fluconazole Oral, IV Yeasts (Candida and Cryptococcus spp.) Itraconazole Oral, IV Yeasts, dermatophytes, dimorphic fungi (p. 300), Aspergillus spp. Voriconazole Oral, IV Yeasts and most filamentous fungi (excluding mucoraceous moulds) Posaconazole Oral, IV Yeasts and many filamentous fungi (including most mucoraceous moulds) Isavuconazole Oral, IV Yeasts and many filamentous fungi (variable activity against mucoraceous moulds) Echinocandins Anidulafungin Caspofungin Micafungin IV only Candida spp., Aspergillus spp. (no activity against Cryptococcus spp. or mucoraceous moulds) Polyenes Amphotericin B Nystatin IV Topical Yeasts and most dimorphic and filamentous fungi (including mucoraceous moulds) Others 5-fluorocytosine Oral, IV Yeasts Griseofulvin Oral Dermatophytes Terbinafine Topical, oral Dermatophytes } } 6.24 Antifungal agents

126 • PRINCIPLES OF INFECTIOUS DISEASE is similar. Lipid formulations of AmB are used in invasive fungal disease, as empirical therapy in patients with neutropenic fever (p. 1327), and also in visceral leishmaniasis (p. 282). Other antifungal agents Flucytosine Flucytosine (5-fluorocytosine) has particular activity against yeasts. When it is used as monotherapy, acquired resistance develops rapidly, so it should be given in combination with another antifungal agent. Adverse effects include myelosuppression, gastrointestinal upset and hepatitis. Griseofulvin Griseofulvin has been largely superseded by terbinafine and itraconazole for treatment of dermatophyte infections, except in children, for whom these agents remain largely unlicensed. It is deposited in keratin precursor cells, which become resistant to fungal invasion. Terbinafine Terbinafine distributes with high concentration to sebum and skin, with a half-life of more than 1 week. It is used topically for dermatophyte skin infections and orally for onychomycosis. The major adverse reaction is hepatic toxicity (approximately 1: 50 000 cases). Terbinafine is not recommended for breastfeeding mothers. Antiviral agents Most viral infections in immunocompetent individuals resolve without intervention. Antiviral therapy is available for a limited number of infections only (Box 6.25). Antiretroviral agents These agents, used predominantly against HIV, are discussed on page 324. Anti-herpesvirus agents Aciclovir, valaciclovir, penciclovir and famciclovir These antivirals are acyclic analogues of guanosine, which inhibit viral DNA polymerase after being phosphorylated by virus-derived thymidine kinase (TK). Aciclovir is poorly absorbed after oral dosing; better levels are achieved intravenously or by use of the prodrug valaciclovir. Famciclovir is the prodrug of penciclovir. Resistance is mediated by viral TK or polymerase mutations. Ganciclovir Chemical modification of the aciclovir molecule allows preferential phosphorylation by protein kinases of cytomegalovirus (CMV) and other β-herpesviruses (e.g. human herpesvirus (HHV) 6/7) and hence greater inhibition of the DNA polymerase, but at the expense of increased toxicity. Ganciclovir is administered intravenously or as a prodrug (valganciclovir) orally. Cidofovir Cidofovir inhibits viral DNA polymerases with potent activity against CMV, including most ganciclovir-resistant CMV. It also has activity against aciclovir-resistant herpes simplex virus (HSV) and varicella zoster virus (VZV), HHV6 and occasionally adenovirus, poxvirus, papillomavirus or polyoma virus, and may be used to treat these infections in immunocompromised hosts. Azole antifungals The azoles (imidazoles and triazoles) inhibit synthesis of ergosterol, a constituent of the fungal cell membrane. Side-effects vary but include gastrointestinal upset, hepatitis and rash. Azoles are inhibitors of cytochrome P450 enzymes, so tend to increase exposure to cytochrome P450-metabolised drugs (p. 24). Imidazoles Miconazole, econazole, clotrimazole and ketoconazole are relatively toxic and therefore administered topically. Clotrimazole is used extensively to treat superficial fungal infections. Triazoles are used for systemic treatment because they are less toxic. Triazoles Fluconazole is effective against yeasts (Candida and Cryptococcus spp.) and has a long half-life (approximately 30 hours) and an excellent safety profile. The drug is highly water-soluble and distributes widely to all body sites and tissues, including CSF. Itraconazole is lipophilic and distributes extensively, including to toenails and fingernails. CSF penetration is poor. Because oral absorption is erratic, therapeutic drug monitoring is required. Voriconazole is well absorbed orally but variability in levels requires therapeutic drug monitoring. It is used mainly in aspergillosis (p. 596). Side-effects include photosensitivity, hepatitis and transient retinal toxicity. Posaconazole and isavuconazole are broad-spectrum azoles, with activity against Candida spp., Aspergillus spp. and some mucoraceous moulds. Isavuconazole is non-inferior to voriconazole in the management of invasive aspergillosis and may be considered as an alternative when voriconazole is not tolerated. Echinocandins The echinocandins inhibit β-1,3-glucan synthesis in the fungal cell wall. They have few significant adverse effects. Caspofungin, anidulafungin and micafungin are used to treat systemic candidosis, and caspofungin is also used in aspergillosis. Polyenes Amphotericin B (AmB) deoxycholate causes cell death by binding to ergosterol and damaging the fungal cytoplasmic membrane. Its use in resource-rich countries has been largely supplanted by less toxic agents. Its long half-life enables once-daily administration. CSF penetration is poor. Adverse effects include immediate anaphylaxis, other infusionrelated reactions and nephrotoxicity. Nephrotoxicity may be sufficient to require dialysis and occurs in most patients who are adequately dosed. It may be ameliorated by concomitant infusion of normal saline. Irreversible nephrotoxicity occurs with large cumulative doses of AmB. Nystatin has a similar spectrum of antifungal activity to AmB. Its toxicity limits it to topical use, e.g. in oral and vaginal candidiasis. Lipid formulations of amphotericin B Lipid formulations of AmB have been developed to reduce AmB toxicity and have replaced AmB deoxycholate in many regions. They consist of AmB encapsulated in liposomes (liposomal AmB, L-AmB) or complexed with phospholipids (AmB lipid complex, ABLC). The drug becomes active on dissociating from its lipid component. Adverse effects are similar to, but considerably less frequent than, those with AmB deoxycholate, and efficacy

Treatment of infectious diseases • 127

cases of influenza, e.g. in intensive care units. It is now approved for use in adults in a number of countries. An intravenous formulation of zanamivir is also in development for critically ill patients. Laninamivir is approved as an intranasal formulation in Japan. Amantadine and rimantadine These drugs reduce replication of influenza A by inhibition of viral M2 protein ion channel function, which is required for uncoating (see Fig. 6.2). Resistance develops rapidly and is widespread, and amantadine and rimantadine should be used only if the prevalence of resistance locally is known to be low. They are no longer recommended for treatment or prophylaxis in the UK or USA, having been superseded by zanamivir and oseltamivir. However, they may still be indicated to treat oseltamivir-resistant influenza A in patients unable to take zanamivir (e.g. ventilated patients). Other agents used to treat viruses Antiviral agents used to treat hepatitis B and C virus are discussed on pages 875 and 878, and those used against HIV-1 are described on page 324. Foscarnet This analogue of inorganic pyrophosphate acts as a non-competitive inhibitor of HSV, VZV, HHV6/7 or CMV DNA polymerase. It does not require significant intracellular phosphorylation and so may be effective when HSV or CMV resistance is due to altered drug phosphorylation. It has variable CSF penetration. Anti-influenza agents Zanamivir and oseltamivir These agents inhibit influenza A and B neuraminidase, which is required for release of virus from infected cells (see Fig. 6.2, p. 101). They are used in the treatment and prophylaxis of influenza. Administration within 48 hours of disease onset reduces the duration of symptoms by approximately 1–112 days. In the UK, their use is limited mainly to adults with chronic respiratory or renal disease, significant cardiovascular disease, immunosuppression or diabetes mellitus, during known outbreaks. Peramivir has been developed as a distinct chemical structure, which means that it retains activity against some oseltamivir- and zanamivir-resistant strains. It has poor oral bioavailability and has been developed as an intravenous or intramuscular formulation for treatment of severe Drug Route(s) of administration Indications Significant side-effects Antiretroviral therapy (ART, p. 324) Oral HIV infection (including AIDS) CNS symptoms, anaemia, lipodystrophy Anti-herpesvirus agents Aciclovir Topical/oral/IV Herpes zoster Chickenpox (esp. in immunosuppressed) Herpes simplex infections: encephalitis (IV only), genital tract, oral, ophthalmic Significant side-effects rare Hepatitis, renal impairment and neurotoxicity reported rarely Valaciclovir Oral Herpes zoster, herpes simplex As for aciclovir Famciclovir Oral Herpes zoster, herpes simplex (genital) As for aciclovir Penciclovir Topical Labial herpes simplex Local irritation Ganciclovir IV Treatment and prevention of CMV infection in immunosuppressed Gastrointestinal symptoms, liver dysfunction, neurotoxicity, myelosuppression, renal impairment, fever, rash, phlebitis at infusion sites Potential teratogenicity Valganciclovir Oral Treatment and prevention of CMV infection in immunosuppressed As for ganciclovir but neutropenia is predominant Cidofovir IV/topical HIV-associated CMV infections and occasionally other viruses (see text) Renal impairment, neutropenia Foscarnet IV CMV and aciclovir-resistant HSV and VZV infections in immunosuppressed Gastrointestinal symptoms, renal impairment, electrolyte disturbances, genital ulceration, neurotoxicity Anti-influenza agents Zanamivir Inhalation Influenza A and B Allergic reactions (very rare) Oseltamivir Oral Influenza A and B Gastrointestinal side-effects, rash, hepatitis (very rare) Peramivir IV, IM Amantadine, rimantadine Oral Influenza A (but see text) CNS symptoms, nausea Agents used in other virus infections* Ribavirin Oral/IV/inhalation Lassa fever (IV) RSV infection in infants (inhalation) Haemolytic anaemia, cough, dyspnoea, bronchospasm and ocular irritation (when given by inhalation) } 6.25 Antiviral agents *Antiviral agents used in viral hepatitis are discussed on pages 875 and 878. (AIDS = acquired immunodeficiency syndrome; CMV = cytomegalovirus; CNS = central nervous system; HIV = human immunodeficiency virus; HSV = herpes simplex virus; IM = intramuscular; IV = intravenous; RSV = respiratory syncytial virus; VZV = varicella zoster virus)

128 • PRINCIPLES OF INFECTIOUS DISEASE Lumefantrine Lumefantrine is used in combination with artemether to treat uncomplicated falciparum malaria, including chloroquine-resistant strains. Its mechanism of action is unknown. Significant adverse effects are uncommon. Drugs used in trypanosomiasis Benznidazole Benznidazole is an oral agent used to treat South American trypanosomiasis (Chagas’ disease, p. 279). Significant and common adverse effects include dose-related peripheral neuropathy, purpuric rash and granulocytopenia. Eflornithine Eflornithine inhibits biosynthesis of polyamines by ornithine decarboxylase inhibition, and is used in West African trypanosomiasis (T. brucei gambiense infection) of the central nervous system. It is administered as an intravenous infusion 4 times daily, which may be logistically difficult in the geographical areas affected by this disease. Significant adverse effects are common and include convulsions, gastrointestinal upset and bone marrow depression. Melarsoprol This is an arsenical agent, used to treat central nervous system infections in East and West African trypanosomiasis (T. brucei rhodesiense and gambiense). It is administered intravenously. Melarsoprol treatment is associated with peripheral neuropathy and reactive arsenical encephalopathy (RAE), which carries a significant mortality. Nifurtimox Nifurtimox is administered orally to treat South American trypanosomiasis (Chagas’ disease). Gastrointestinal and neurological adverse effects are common. Pentamidine isetionate Pentamidine is an inhibitor of DNA replication used in West African trypanosomiasis (T. brucei gambiense) and, to a lesser extent, in visceral and cutaneous leishmaniasis. It is also prescribed in Pneumocystis jirovecii pneumonia. It is administered via intravenous or intramuscular routes. It is a relatively toxic drug, commonly causing rash, renal impairment, profound hypotension (especially on rapid infusion), electrolyte disturbances, blood dyscrasias and hypoglycaemia. Suramin Suramin is a naphthaline dye derivative, used to treat East African trypanosomiasis (T. brucei rhodesiense). It is administered intravenously. Adverse effects are common and include rash, gastrointestinal disturbance, blood dyscrasias, peripheral neuropathies and renal impairment. Other antiprotozoal agents Pentavalent antimonials Sodium stibogluconate and meglumine antimoniate inhibit protozoal glycolysis by phosphofructokinase inhibition. They are used parenterally (intravenous or intramuscular) to treat leishmaniasis. Adverse effects include arthralgia, myalgias, raised hepatic transaminases, pancreatitis and electrocardiogram changes. Severe cardiotoxicity leading to death is not uncommon. Ribavirin Ribavirin is a guanosine analogue that inhibits nucleic acid synthesis in a variety of viruses. It is used in particular in the treatment of hepatitis C virus but also against certain viral haemorrhagic fevers, e.g. Lassa fever, although it has not been useful against Ebola virus. Antiparasitic agents Antimalarial agents Artemisinin (qinghaosu) derivatives Artemisinin originates from a herb (sweet wormwood, Artemisia annua), which was used in Chinese medicine to treat fever. Its derivatives, artemether and artesunate, were developed for use in malaria in the 1970s. Their mechanism of action is unknown. They are used in the treatment, but not prophylaxis, of malaria, usually in combination with other antimalarials, and are effective against strains of Plasmodium spp. that are resistant to other antimalarials. Artemether is lipid-soluble and may be administered via the intramuscular and oral routes. Artesunate is water-soluble and is administered intravenously or orally. Serious adverse effects are uncommon. Current advice for malaria in pregnancy is that the artemisinin derivatives should be used to treat uncomplicated falciparum malaria in the second and third trimesters, but should not be prescribed in the first trimester until more information becomes available. Atovaquone Atovaquone inhibits mitochondrial function. It is an oral agent, used for treatment and prophylaxis of malaria, in combination with proguanil (see below), without which it is ineffective. It is also employed in the treatment of mild cases of Pneumocystis jirovecii pneumonia, where there is intolerance to co-trimoxazole. Significant adverse effects are uncommon. Folate synthesis inhibitors (proguanil, pyrimethamine–sulfadoxine) Proguanil inhibits dihydrofolate reductase and is used for malaria prophylaxis. Pyrimethamine–sulfadoxine may be used in the treatment of malaria. Quinoline-containing compounds Chloroquine and quinine are believed to act by intraparasitic inhibition of haem polymerisation, resulting in toxic build-up of intracellular haem. The mechanisms of action of other agents in this group (quinidine, amodiaquine, mefloquine, primaquine, etc.) may differ. They are employed in the treatment and prophylaxis of malaria. Primaquine is used for radical cure of malaria due to Plasmodium vivax and P. ovale (destruction of liver hypnozoites). Chloroquine may also be given for extra-intestinal amoebiasis. Chloroquine can cause a pruritus sufficient to compromise adherence to therapy. If used in long-term, high-dose regimens, it causes an irreversible retinopathy. Overdosage leads to lifethreatening cardiotoxicity. The side-effect profile of mefloquine includes neuropsychiatric effects ranging from mood change, nightmares and agitation to hallucinations and psychosis. Quinine may cause hypoglycaemia and cardiotoxicity, especially when administered parenterally. Primaquine causes haemolysis in people with glucose-6-phosphate dehydrogenase deficiency (p. 948), which should be excluded before therapy. Chloroquine is considered safe in pregnancy but mefloquine should be avoided in the first trimester.

Further information • 129

Ivermectin Ivermectin binds to helminth nerve and muscle cell ion channels, causing increased membrane permeability. It is an oral agent, used in Strongyloides infection, filariasis and onchocerciasis. Significant side-effects are uncommon. Niclosamide Niclosamide inhibits oxidative phosphorylation, causing paralysis of helminths. It is an oral agent, used in Taenia saginata and intestinal T. solium infection. Systemic absorption is minimal and it has few significant side-effects. Piperazine Piperazine inhibits neurotransmitter function, causing helminth muscle paralysis. It is an oral agent, used in ascariasis and threadworm (Enterobius vermicularis) infection. Significant adverse effects are uncommon but include neuropsychological reactions such as vertigo, delirium and convulsions. Praziquantel Praziquantel increases membrane permeability to Ca2+, causing violent contraction of worm muscle. It is the drug of choice for schistosomiasis and is also used in T. saginata, T. solium (cysticercosis) and fluke infections (Clonorchis, Paragonimus) and in echinococcosis. It is administered orally and is well absorbed. Adverse effects are usually mild and transient, and include nausea and abdominal pain. Pyrantel pamoate This agent causes spastic paralysis of helminth muscle through a suxamethonium-like action. It is used orally in ascariasis and threadworm infection. Systemic absorption is poor and adverse effects are uncommon. Thiabendazole Thiabendazole inhibits fumarate reductase, which is required for energy production in helminths. It is used orally in Strongyloides infection and topically to treat cutaneous larva migrans. Significant adverse effects are uncommon. Further information Websites cdc.gov Centers for Disease Control and Prevention, Atlanta, USA. Provides information on all aspects of communicable disease, including prophylaxis against malaria. dh.gov.uk UK Department of Health. The publications section provides current UK recommendations for immunisation. ecdc.europa.eu European Centre for Disease Prevention and Control. Includes data on prevalence of antibiotic resistance in Europe. gov.uk/government/organisations/public-health-england Public Health England. Provides information on infectious diseases relating mainly to England, including community infection control. idsociety.org Infectious Diseases Society of America. Publishes up-to-date, evidence-based guidelines. who.int World Health Organization. Provides up-to-date information on global aspects of infectious disease, including outbreak updates. Also has information on the ‘World Antibiotic Awareness Week’ campaign. Diloxanide furoate This oral agent is used to eliminate luminal cysts following treatment of intestinal amoebiasis, or in asymptomatic cyst excreters. The drug is absorbed slowly (enabling luminal persistence) and has no effect in hepatic amoebiasis. It is a relatively non-toxic drug, the most significant adverse effect being flatulence. Iodoquinol (di-iodohydroxyquinoline) Iodoquinol is a quinoline derivative (p. 128) with activity against Entamoeba histolytica cysts and trophozoites. It is used orally to treat asymptomatic cyst excreters or, in association with another amoebicide (e.g. metronidazole), to treat extra-intestinal amoebiasis. Long-term use of this drug is not recommended, as neurological adverse effects include optic neuritis and peripheral neuropathy. Nitazoxanide Nitazoxanide is an inhibitor of pyruvate–ferredoxin oxidoreductasedependent anaerobic energy metabolism in protozoa. It is a broad-spectrum agent, active against various nematodes, tapeworms, flukes and intestinal protozoa. Nitazoxanide also has activity against some anaerobic bacteria and viruses. It is administered orally in giardiasis and cryptosporidiosis. Adverse effects are usually mild and involve the gastrointestinal tract (e.g. nausea, diarrhoea and abdominal pain). Paromomycin Paromomycin is an aminoglycoside (p. 122) that is used to treat visceral leishmaniasis and intestinal amoebiasis. It is not significantly absorbed when administered orally, and is therefore given orally for intestinal amoebiasis and by intramuscular injection for leishmaniasis. It showed early promise in the treatment of HIV-associated cryptosporidiosis but subsequent trials have demonstrated that this effect is marginal at best. Drugs used against helminths Benzimidazoles (albendazole, mebendazole) These agents act by inhibiting both helminth glucose uptake, causing depletion of glycogen stores, and fumarate reductase. Albendazole is used for hookworm, ascariasis, threadworm, Strongyloides infection, trichinellosis, Taenia solium (cysticercosis) and hydatid disease. Mebendazole is used for hookworm, ascariasis, threadworm and whipworm. The drugs are administered orally. Absorption is relatively poor but is increased by a fatty meal. Significant adverse effects are uncommon. Bithionol Bithionol is used to treat fluke infections with Fasciola hepatica. It is well absorbed orally. Adverse effects are mild (e.g. nausea, vomiting, diarrhoea, rashes) but relatively common (approximately 30%). Diethylcarbamazine Diethylcarbamazine (DEC) is an oral agent used to treat filariasis and loiasis. Treatment of filariasis is often followed by fever, headache, nausea, vomiting, arthralgia and prostration. This is caused by the host response to dying microfilariae, rather than the drug, and may be reduced by pre-treatment with glucocorticoids.

7KLVSDJHLQWHQWLRQDOO\OHIWEODQN

Ch03-2 Emergency and Critical Care _67ef

Ch03-2 Emergency and Critical Care _67ef

01-7 Poisoning

7 Poisoning

Poisoning SHL Thomas Comprehensive evaluation of the poisoned patient 132 General approach to the poisoned patient 134 Triage and resuscitation 134 Clinical assessment and investigations 134 Psychiatric assessment 135 General management 135 Poisoning by specific pharmaceutical agents 137 Analgesics 137 Antidepressants 138 Cardiovascular medications 140 Iron 140 Antipsychotic drugs 141 Antidiabetic agents 141 Pharmaceutical agents less commonly taken in poisoning 141 Drugs of misuse 141 Depressants 141 Stimulants and entactogens 143 Hallucinogens 143 Dissociative drugs 144 Volatile substances 144 Body packers and body stuffers 144 Chemicals and pesticides 144 Carbon monoxide 144 Organophosphorus insecticides and nerve agents 145 Carbamate insecticides 146 Paraquat 147 Methanol and ethylene glycol 147 Corrosive substances 147 Aluminium and zinc phosphide 148 Copper sulphate 148 Chemicals less commonly taken in poisoning 148 Chemical warfare agents 149 Environmental poisoning 149 Food-related poisoning 149 Plant poisoning 150

132 • POISONING Insets (Self-cutting) From Douglas G, Nicol F, Robertson C (eds). Macleod’s Clinical examination, 11th edn. Churchill Livingstone, Elsevier Ltd; 2005. (Chemical burn) www.firewiki.net. (Needle tracks) www.deep6inc.com. (Pinpoint pupil) http://drugrecognition.com/images. (Injected conjunctiva) http:// knol.google.com. Movement and muscles Tone, fasciculations, myoclonus, tremor, paralysis, ataxia Chest Evidence of aspiration, bronchoconstriction Reflexes Tendon reflexes, plantar responses, inducible clonus Eyes Miosis or mydriasis, diplopia or strabismus, lacrimation Skin Temperature, cyanosis, flushing, sweating, blisters, pressure areas, piloerection, evidence of self-harm Level of consciousness Presence of seizures, delirium, agitation or psychosis Psychiatric evaluation Features of psychiatric illness, mental capacity Mouth Dry mouth, excessive salivation Airway, breathing, circulation Respiration rate, oxygen saturation, pulse, BP, dysrhythmias Self-cutting Needle tracks Chemical burn Pinpoint pupil Injected conjunctiva

Abdomen Hepatic or epigastric tenderness, ileus, palpable bladder

Comprehensive evaluation of the poisoned patient Taking a history in poisoning • What toxin(s) have been taken and how much? • What time were they taken and by what route? • Has alcohol or any other substance (or substances, including drugs of misuse) been taken as well? • Obtain details from witnesses (e.g. family, friends, ambulance personnel) of the circumstances of the overdose • Assess immediate suicide risk in those with apparent self-harm (full psychiatric evaluation when patient has recovered physically) • Assess capacity to make decisions about accepting or refusing treatment • Establish past medical history, drug history and allergies, social and family history • Record all information carefully

Comprehensive evaluation of the poisoned patient • 133

Clinical signs of poisoning by pharmaceutical agents and drugs of misuse. Cerebellar signs Some anticonvulsants, alcohol Phenothiazines, haloperidol, metoclopramide Extrapyramidal signs Any CNS depressant drug or agent (N.B. consider methaemoglobinaemia caused by dapsone, amyl nitrite etc.) Cyanosis Tachycardia or tachyarrhythmias: tricyclic antidepressants, theophylline, digoxin, antihistamines Bradycardia or bradyarrhythmias: digoxin, β-blockers, calcium channel blockers, opioids, organophosphates Heart rate Needle tracks Drugs of misuse: opioids etc. Hyperthermia and sweating: ecstasy, serotonin re-uptake inhibitors, salicylates Hypothermia: any CNS depressant drug, opioids, chlorpromazine Small: opioids, clonidine, organophosphorus compounds Large: tricyclic antidepressants, amphetamines, cocaine Reduced: opioids, benzodiazepines Increased: salicylates Paracetamol hepatotoxicity, renal toxicity Right upper quadrant /renal angle tenderness Epigastric tenderness NSAIDs, salicylates Rhabdomyolysis Amphetamines, caffeine Hypotension: tricyclic antidepressants, haloperidol Hypertension: cocaine, α-adrenoceptor agonists Respiratory rate Pupil size Body temperature Blood pressure Decontamination and enhanced elimination. One of the key aspects in the evaluation of a poisoned patient is deciding if decontamination and/or enhanced elimination is required. Blood Haemodialysis Haemoperfusion Kidneys Urinary alkalinisation Gastrointestinal tract Multiple-dose activated charcoal Enhancing elimination Direct eye contact Eye irrigation – remove contact lenses Wash eyes thoroughly for at least 15 mins with normal saline or water Remove particles from palpebral fissures If pain persists, insert fluorescein drops and perform slit-lamp examination for corneal damage Skin contact (hazardous chemicals/ pesticides) Remove clothing Wash with copious amounts of soap and water Gastrointestinal decontamination External decontamination Gastrointestinal tract Single-dose oral activated charcoal Gastric lavage

134 • POISONING General approach to the poisoned patient A general approach is shown on pages 132–133. In many countries, poisons centres are available to provide advice on management of suspected poisoning with specific substances. Information is also available online (p. 150). Triage and resuscitation Patients who are seriously poisoned must be identified early so that appropriate management is not delayed. Triage involves: • immediately assessing vital signs • identifying the poison(s) involved and obtaining adequate information about them • identifying patients at risk of further attempts at self-harm and removing any remaining hazards. Those with possible external contamination with chemical or environmental toxins should undergo appropriate decontamination (p. 133). Critically ill patients must be resuscitated (p. 174). The Glasgow Coma Scale (GCS) is commonly employed to assess conscious level, although not specifically validated in poisoning. The AVPU (alert/verbal/painful/unresponsive) scale is also a rapid and simple method. An electrocardiogram (ECG) should be performed and cardiac monitoring instituted in all patients with cardiovascular features or where exposure to potentially cardiotoxic substances is suspected. Patients who may need antidotes should be weighed if possible, so that appropriate weight-related doses can be prescribed. Substances unlikely to be toxic in humans should be identified so that inappropriate admission and intervention are avoided (Box 7.3). Clinical assessment and investigations History and examination are described on page 132. Occasionally, patients may be unaware of or confused about what they have taken, or may exaggerate (or, less commonly, underestimate) the size of the overdose, but rarely mislead medical staff deliberately. In regions of the world where self-poisoning is illegal, patients may be reticent about giving a history. Toxic causes of abnormal physical signs are shown on page 133. The patient may have a cluster of clinical features (‘toxidrome’) suggestive of poisoning with a particular drug type, e.g. anticholinergic, serotoninergic (see Box 7.10), stimulant, sedative, opioid (see Box 7.12) or cholinergic (see Box 7.14) feature clusters. Poisoning is a common cause of coma, especially Acute poisoning is common, accounting for about 1% of hospital admissions in the UK. Common or otherwise important substances involved are shown in Box 7.1. In developed countries, the most frequent cause is intentional drug overdose in the context of self-harm, often involving prescribed or ‘over-the-counter’ medicines. Accidental poisoning is also common, especially in children and the elderly (Box 7.2). Toxicity also results from alcohol or recreational substance use, or following occupational or environmental exposure. Poisoning is a major cause of death in young adults, but most deaths occur before patients reach medical attention, and mortality is low (< 1%) in those admitted to hospital. In developing countries, the frequency of self-harm is more difficult to estimate. Because of their widespread availability and use, household and agricultural products, such as pesticides and herbicides, are common sources of poisoning and have a much higher case fatality. In China and South-east Asia, pesticides account for about 300 000 suicides each year. Snake bite and other forms of envenomation are also important causes of morbidity and mortality internationally and are discussed in Chapter 8. 7.3 Substances of very low toxicity • Writing/educational materials, e.g. pencil lead, crayons, chalk • Decorating products, e.g. emulsion paint, wallpaper paste • Cleaning/bathroom products (except dishwasher tablets and liquid laundry detergent capsules, which can be corrosive) • Pharmaceuticals: oral contraceptives, most antibiotics (but not tetracyclines or antituberculous drugs), vitamins B, C and E, prednisolone, emollients and other skin creams, baby lotion • Miscellaneous: plasticine, silica gel, most household plants, plant food, pet food, soil 7.2 Poisoning in old age • Aetiology: may result from accidental poisoning (e.g. due to delirium or dementia) or drug toxicity as a consequence of impaired renal or hepatic function or drug interaction. Toxic prescription medicines are more likely to be available. • Psychiatric illness: self-harm is less common than in younger adults but more frequently associated with depression and other psychiatric illness, as well as chronic illness and pain. There is a higher risk of subsequent suicide. • Severity of poisoning: increased morbidity and mortality result from reduced renal and hepatic function, lower functional reserve, increased sensitivity to sedative agents and frequent comorbidity. 7.1 Important substances involved in poisoning In the UK • Analgesics: paracetamol and non-steroidal anti-inflammatory drugs (NSAIDs) • Antidepressants: tricyclic antidepressants (TCAs), selective serotonin re-uptake inhibitors (SSRIs) and lithium • Cardiovascular agents: β-blockers, calcium channel blockers and cardiac glycosides • Drugs of misuse: depressants (e.g. opiates, benzodiazepines), stimulants and entactogens (e.g. amphetamines, MDMA, mephedrone, cocaine), hallucinogens (e.g. cannabis, synthetic cannabinoid receptor agonists, LSD) • Carbon monoxide • Alcohol In South and South-east Asia • Organophosphorus and carbamate insecticides • Aluminium and zinc phosphide • Oleander • Corrosives • Snake venoms (Ch. 8) (LSD = lysergic acid diethylamide; MDMA = 3,4-methylenedioxymethamphetamine, ecstasy)

General approach to the poisoned patient • 135

health professional with appropriate training (p. 1187). This should occur after they have recovered from poisoning, unless there is an urgent issue, such as uncertainty about their capacity to decline medical treatment. General management Patients presenting with eye/skin contamination should undergo local decontamination measures. These are described on page 133. Gastrointestinal decontamination Patients who have ingested potentially life-threatening quantities of toxins may be considered for gastrointestinal decontamination if poisoning has been recent (p. 133). in younger people, but it is important to exclude other potential causes (p. 194). Urea, electrolytes and creatinine should be measured in all patients with suspected systemic poisoning. Arterial blood gases should be checked in those with significant respiratory or circulatory compromise, or after poisoning with substances likely to affect acid–base status (Box 7.4). Calculation of anion and osmolar gaps may help to inform diagnosis and management (Box 7.5). Potent oxidising agents may cause methaemoglobinaemia, with consequent blue discoloration of skin and blood, and reduced oxygen delivery to the tissues (Fig. 7.1). For some substances, management may be facilitated by measurement of the amount of toxin in the blood. Qualitative urine screens for potential toxins, including near-patient testing kits, have a limited clinical role. Psychiatric assessment Patients presenting with drug overdose in the context of self-harm should undergo psychiatric evaluation prior to discharge by a 7.5 Anion and osmolar gaps in poisoning Anion gap Osmolar gap Calculation [Na+ + K+] − [Cl− + HCO3 −] [Measured osmolality] − [(2 × Na) + Urea + Glucose]1 Reference range 12–16 mmol/L < 10 Common toxic causes of elevation2 Ethanol Ethylene glycol Methanol Salicylates Iron Cyanide Ethanol Ethylene glycol Methanol 1All units should be in mmol/L, except osmolality, which should be in mOsmol/kg. For non-SI units, the corresponding formula is [Measured osmolality (mOsmol/kg)] − [(2 × Na (mEq/L)) + Urea/2.8 (mg/dL) + Glucose/18 (mg/dL)]. 2Box 14.19 (p. 365) gives non-toxic causes. 7.4 Causes of acidosis in the poisoned patient Cause Normal lactate* High lactate Toxic Salicylates Methanol Ethylene glycol Paraldehyde Metformin Iron Cyanide Sodium valproate Carbon monoxide Other Renal failure Ketoacidosis Severe diarrhoea Shock Unless circulatory shock is present, when it will be high in any case. Fig. 7.1 Methaemoglobinaemia. Causes Non-toxic • Congenital methaemoglobinaemias Toxic (Oxidising agents) • Organic nitrites • Nitrates • Benzocaine • Dapsone • Chloroquine • Aniline dyes • Chlorobenzene • Naphthalene • Copper sulphate Consequences • Haemoglobin–oxygen dissociation curve is shifted to the left (see Fig. 23.5) • Oxygen delivery to tissues is reduced • There is apparent ‘cyanosis’ • Breathlessness, fatigue, headache and chest pain occur • Delirium, impaired consciousness and seizures may occur in severe cases Treatment • Methylthioninium chloride (‘methylene blue’) 1–2 mg/kg (intravenous) is given • Reduces methaemoglobin (see below) • Used for symptomatic patients with severe methaemoglobinaemia (e.g. >30%) • Patients with anaemia or other comorbidities may need treatment at lower concentrations Cytochrome b5 reductase NADH NAD NADP NADPH Methaemoglobin reductase Methylthioninium chloride (reduced) Methylthioninium chloride (oxidised) Methaemoglobin (Fe3+) Haemoglobin (Fe2+)

136 • POISONING for most substances and complications are common, especially pulmonary aspiration. It is contraindicated if strong acids, alkalis or petroleum distillates have been ingested. Use may be justified for life-threatening overdoses of those substances that are not absorbed by activated charcoal (see Box 7.6). Whole bowel irrigation This involves the administration of large quantities of osmotically balanced polyethylene glycol and electrolyte solution (1–2 L/ hr for an adult), usually by a nasogastric tube, until the rectal effluent is clear. It is occasionally indicated to enhance the elimination of ingested packets of illicit drugs or slow-release tablets such as iron and lithium that are not absorbed by activated charcoal. Contraindications include inadequate airway protection, haemodynamic instability, gastrointestinal haemorrhage, obstruction or ileus. Whole bowel irrigation may precipitate nausea and vomiting, abdominal pain and electrolyte disturbances. Urinary alkalinisation Urinary excretion of weak acids and bases is affected by urinary pH, which changes the extent to which they are ionised. Highly ionised molecules pass poorly through lipid membranes and therefore little tubular reabsorption occurs and urinary excretion is increased. If the urine is alkalinised (pH > 7.5) by the administration of sodium bicarbonate (e.g. 1.5 L of 1.26% sodium bicarbonate over 2 hrs), weak acids (e.g. salicylates, methotrexate) are highly ionised, resulting in enhanced urinary excretion. Urinary alkalinisation is currently recommended for patients with clinically significant salicylate poisoning when the criteria for haemodialysis are not met (see below). It is also sometimes used for poisoning with methotrexate. Complications include alkalaemia, hypokalaemia and occasionally alkalotic tetany (p. 367). Hypocalcaemia may occur but is rare. Haemodialysis and haemoperfusion These techniques can enhance the elimination of poisons that have a small volume of distribution and a long half-life after overdose; use is appropriate when poisoning is sufficiently severe. The toxin must be small enough to cross the dialysis membrane (haemodialysis) or must bind to activated charcoal (haemoperfusion) (see Box 7.7). Haemodialysis can also correct acid–base and metabolic disturbances associated with poisoning (p. 135). Lipid emulsion therapy Lipid emulsion therapy is increasingly used for poisoning with lipid-soluble agents, such as local anaesthetics, tricyclic antidepressants, calcium channel blockers and lipid-soluble β-adrenoceptor antagonists (β-blockers) such as propranolol. It involves intravenous infusion of 20% lipid emulsion (e.g. Intralipid, suggested initial dose 1.5 mL/kg, followed by a continued infusion of 0.25 mL/kg/min until there is clinical improvement). It is thought that lipid-soluble toxins partition into the intravenous lipid, reducing target tissue concentrations. The elevated myocardial free fatty acid concentrations may also have beneficial effects on myocardial metabolism and performance by counteracting the inhibition of myocardial fatty acid oxidation produced by some cardiotoxins, enabling increased adenosine triphosphate (ATP) synthesis and energy production. Some animal studies have suggested efficacy and case reports of use in human poisoning have also been 7.7 Poisons effectively eliminated by multiple doses of activated charcoal, haemodialysis or haemoperfusion Multiple doses of activated charcoal • Carbamazepine • Dapsone • Phenobarbital • Quinine • Theophylline Haemodialysis • Ethylene glycol • Isopropanol • Methanol • Salicylates • Sodium valproate • Lithium Haemoperfusion • Theophylline • Phenytoin • Carbamazepine • Phenobarbital • Amobarbital 7.6 Substances poorly adsorbed by activated charcoal Medicines • Iron • Lithium Chemicals • Acids* • Alkalis* • Ethanol • Ethylene glycol • Mercury • Methanol • Petroleum distillates* *Gastric lavage contraindicated. Activated charcoal Given orally as a slurry, activated charcoal absorbs toxins in the bowel as a result of its large surface area. It can prevent absorption of an important proportion of the ingested dose of toxin, but efficacy decreases with time and current guidelines do not encourage use more than 1 hour after overdose, unless a sustained-release preparation has been taken or when gastric emptying may be delayed. Use is ineffective for some toxins that do not bind to activated charcoal (Box 7.6). In patients with impaired swallowing or a reduced level of consciousness, activated charcoal, even via a nasogastric tube, carries a risk of aspiration pneumonitis, which can be reduced (but not eliminated) by protecting the airway with a cuffed endotracheal tube. Multiple doses of oral activated charcoal (50 g 6 times daily in an adult) may enhance the elimination of some substances at any time after poisoning (Box 7.7). This interrupts enterohepatic circulation or reduces the concentration of free drug in the gut lumen, to the extent that drug diffuses from the blood back into the bowel to be absorbed on to the charcoal (‘gastrointestinal dialysis’). A laxative is generally given with the charcoal to reduce the risk of constipation or intestinal obstruction by charcoal ‘briquette’ formation in the gut lumen. Evidence suggests that single or multiple doses of activated charcoal do not improve clinical outcomes after poisoning with pesticides or oleander. Gastric aspiration and lavage Gastric aspiration and/or lavage is very infrequently indicated in acute poisoning, as it is no more effective than activated charcoal

Poisoning by specific pharmaceutical agents • 137

7.8 Complications of poisoning and their management Complication Examples of causative agents Management Coma Sedative agents Appropriate airway protection and ventilatory support Oxygen saturation and blood gas monitoring Pressure area and bladder care Identification and treatment of aspiration pneumonia Seizures NSAIDs Anticonvulsants TCAs Theophylline Appropriate airway and ventilatory support IV benzodiazepine (e.g. diazepam 10–20 mg, lorazepam 2–4 mg) Correction of hypoxia, acid–base and metabolic abnormalities Acute dystonias Typical antipsychotics Metoclopramide Procyclidine, benzatropine or diazepam Hypotension Due to vasodilatation Vasodilator antihypertensives Anticholinergic agents TCAs IV fluids Vasopressors (rarely indicated; p. 206) Due to myocardial suppression β-blockers Calcium channel blockers TCAs Optimisation of volume status Inotropic agents (p. 206) Ventricular tachycardia Monomorphic, associated with QRS prolongation Sodium channel blockers Correction of electrolyte and acid–base abnormalities and hypoxia Sodium bicarbonate (e.g. 50 mL 8.4% solution, repeated if necessary) Torsades de pointes, associated with QTc prolongation Anti-arrhythmic drugs (quinidine, amiodarone, sotalol) Antimalarials Organophosphate insecticides Antipsychotic agents Antidepressants Antibiotics (erythromycin) Correction of electrolyte and acid–base abnormalities and hypoxia Magnesium sulphate, 2 g IV over 1–2 mins, repeated if necessary (NSAID = non-steroidal anti-inflammatory drug; TCA = tricyclic antidepressant) encouraging, with recovery of circulatory collapse reported in cases where other treatment modalities have been unsuccessful. No controlled trials of this technique have been performed, however, and efficacy remains uncertain. Supportive care For most poisons, antidotes and methods to accelerate elimination are inappropriate, unavailable or incompletely effective. Outcome is dependent on appropriate nursing and supportive care, and treatment of complications (Box 7.8). Antidotes Antidotes are available for some poisons and work by a variety of mechanisms (Box 7.9). The use of some of these in the management of specific poisons is described below. Poisoning by specific pharmaceutical agents Analgesics Paracetamol Paracetamol (acetaminophen) is the drug most commonly used in overdose in the UK. Toxicity is caused by an intermediate reactive metabolite that binds covalently to cellular proteins, 7.9 Specific antidotes used to treat poisoning Mechanism of action Examples of antidote Poisoning treated Glutathione repleters Acetylcysteine Methionine Paracetamol Receptor antagonists Naloxone Opioids Flumazenil Benzodiazepines Atropine Organophosphorus compounds Carbamates Alcohol dehydrogenase inhibitors Fomepizole Ethanol Ethylene glycol Methanol Chelating agents Desferrioxamine Iron Hydroxocobalamin Dicobalt edetate Cyanide DMSA Sodium calcium edetate Lead Reducing agents Methylthioninium chloride Organic nitrites Cholinesterase reactivators Pralidoxime Organophosphorus compounds Antibody fragments Digoxin Fab fragments Digoxin (DMSA = dimercaptosuccinic acid)

138 • POISONING Salicylates (aspirin) Clinical features Salicylate overdose commonly causes nausea, vomiting, sweating, tinnitus and deafness. Direct stimulation of the respiratory centre produces hyperventilation and respiratory alkalosis. Peripheral vasodilatation with bounding pulses and profuse sweating occurs in moderately severe cases. Serious poisoning is associated with metabolic acidosis, hypoprothrombinaemia, hyperglycaemia, hyperpyrexia, renal failure, pulmonary oedema, shock and cerebral oedema. Agitation, delirium, coma and fits may occur, especially in children. Toxicity is enhanced by acidosis, which increases salicylate transfer across the blood–brain barrier. Management Activated charcoal should be administered if the patient presents within 1 hour. Multiple doses may enhance salicylate elimination but are not routinely recommended. The plasma salicylate concentration should be measured at least 2 (symptomatic patients) or 4 hours (asymptomatic patients) after overdose and repeated in suspected serious poisoning, as concentrations may continue to rise for several hours. Clinical status, however, is more important than the salicylate concentration when assessing severity. Dehydration should be corrected carefully because of the risk of pulmonary oedema. Metabolic acidosis should be treated with intravenous sodium bicarbonate (8.4%), after plasma potassium has been corrected. Urinary alkalinisation is indicated for adults with salicylate concentrations above 500 mg/L. Haemodialysis is very effective for removing salicylate and correcting associated acid–base and fluid balance abnormalities. It should be considered when serum concentrations are above 700 mg/L in adults with severe toxic features, or in renal failure, pulmonary oedema, coma, convulsions or refractory acidosis. Non-steroidal anti-inflammatory drugs Clinical features Overdose of most non-steroidal anti-inflammatory drugs (NSAIDs) usually causes only minor abdominal discomfort, vomiting and/ or diarrhoea, but convulsions can occur occasionally, especially with mefenamic acid. Coma, prolonged seizures, apnoea, liver dysfunction and renal failure may follow substantial overdose but are rare. Features of toxicity are unlikely to develop in patients who are asymptomatic more than 6 hours after overdose. Management Electrolytes, liver function tests and a full blood count should be checked in all but the most trivial cases. Activated charcoal may be given if the patient presents within 1 hour. Symptomatic treatment for nausea and gastrointestinal irritation may be needed. Antidepressants Tricyclic antidepressants Overdose with tricyclic antidepressants (TCAs) carries a high morbidity and mortality because of their sodium channel-blocking, anticholinergic and α-adrenoceptor-blocking effects. Clinical features Anticholinergic effects are common (Box 7.10). Severe complications include convulsions, coma and arrhythmias (ventricular causing cell death. This results in hepatic and occasionally renal failure. In therapeutic doses, the toxic metabolite is detoxified in reactions requiring glutathione, but in overdose, glutathione reserves become exhausted. Management Activated charcoal may be used in patients presenting within 1 hour. Antidotes for paracetamol act by replenishing hepatic glutathione and should be administered to all patients with acute poisoning and paracetamol concentrations above a ‘treatment line’ provided on paracetamol poisoning nomograms (Fig. 7.2). The threshold used for these nomograms varies between countries, however, and local guidance should be followed. Acetylcysteine given intravenously (or orally in some countries) is highly efficacious if administered within 8 hours of the overdose. However, efficacy declines thereafter, so administration should not be delayed in patients presenting after 8 hours to await a paracetamol blood concentration result. The antidote can be stopped if the paracetamol concentration is shown to be below the nomogram treatment line. Liver and renal function, International Normalised Ratio (INR) and a venous bicarbonate should also be measured. Arterial blood gases and lactate should be assessed in patients with reduced bicarbonate or severe liver function abnormalities; metabolic acidosis indicates severe poisoning. Anaphylactoid reactions are the most important adverse effects of acetylcysteine and are related to dose-related histamine release. Common features are itching and urticaria, and in severe cases, bronchospasm and hypotension. Most cases can be managed by temporary discontinuation of acetylcysteine and administration of an antihistamine. An alternative antidote is methionine 2.5 g orally (adult dose) every 4 hours to a total of four doses, but this may be less effective, especially after delayed presentation. Liver transplantation should be considered for paracetamol poisoning with life-threatening liver failure (p. 856). If multiple ingestions of paracetamol have taken place over several hours (‘staggered overdose’) or days (e.g. chronic therapeutic excess), acetylcysteine may be indicated; specific treatment recommendations vary between countries. Fig. 7.2 Paracetamol treatment nomogram (UK). Above the treatment line, benefits of treatment outweigh risk. Below it, risks of treatment outweigh benefits. 0 0

10 12 Time since overdose (hr) Treatment line 14 16 18 20 22 24

Paracetamol concentration (mg/L) Too early to assess

Poisoning by specific pharmaceutical agents • 139

solution) should be administered and repeated to correct pH. The correction of the acidosis and the sodium loading that results may bring about rapid improvement in ECG features and arrhythmias. Hypoxia and electrolyte abnormalities should also be corrected. Anti-arrhythmic drugs should only be given on specialist advice. Prolonged seizures should be treated initially with intravenous benzodiazepines (see Box 7.8). Selective serotonin and noradrenaline re-uptake inhibitors Selective serotonin re-uptake inhibitor (SSRI) antidepressants (e.g. fluoxetine, paroxetine, fluvoxamine, sertraline, citalopram, escitalopram) are increasingly used to treat depression and are less toxic in overdose than TCAs. The related serotonin– noradrenaline re-uptake inhibitors (SNRIs), such as venlafaxine and duloxetine, are also commonly used but are more toxic than SSRIs in overdose. Clinical features and management Overdose of SSRIs may produce nausea and vomiting, tremor, insomnia and sinus tachycardia. Agitation, drowsiness and convulsions occur infrequently and may be delayed for several hours. Serotonin syndrome may occur (see Box 7.10), especially if SSRIs are taken in combination or with other serotonergic agents. Cardiac arrhythmias occur infrequently and most patients require supportive care only. The toxic effects of SNRIs are similar but tachycardia, hypertension or hypotension and ECG changes (QRS and QT prolongation) may be more prominent and hypoglycaemia can also arise. Lithium Severe lithium toxicity is uncommon after intentional acute overdose but is more often encountered in patients taking therapeutic doses, frequently as a result of interactions with drugs such as diuretics or NSAIDs. Severe toxicity is more common after acute overdose in patients already taking chronic therapy (‘acute on chronic’ poisoning). Clinical features Nausea, diarrhoea, polyuria, dizziness and tremor may progress to muscular weakness, drowsiness, delirium, myoclonus, fasciculations, choreoathetosis and renal failure. Coma, seizures, ataxia, cardiac dysrhythmias such as heart block, blood pressure disturbances and renal failure may occur in severe poisoning. Management Activated charcoal is ineffective. Early gastric lavage is of theoretical benefit, but lithium tablets are likely to remain intact in the stomach and may be too large for aspiration via a lavage tube. Whole bowel irrigation is often used after substantial overdose but efficacy is unproven. Lithium concentrations should be measured immediately (symptomatic patients) or after at least 6 hours (asymptomatic patients) following acute overdose. The usual therapeutic range is 0.4–1.0 mmol/L. Adequate hydration should be maintained with intravenous fluids. Seizures should be treated as in Box 7.8. Haemodialysis should be considered for severe toxicity associated with high lithium concentrations (e.g. > 4.0 mmol/L after chronic or ‘acute on chronic’ poisoning, or > 7.5 mmol/L after acute poisoning). Lithium concentrations are reduced substantially during dialysis, but rebound increases occur after discontinuation and multiple sessions are usually required. tachycardia, ventricular fibrillation and, less commonly, heart block). Hypotension results from inappropriate vasodilatation or impaired myocardial contractility. Serious complications appear more common with dosulepin and amitriptyline. Management Activated charcoal should be administered if the patient presents within 1 hour. A 12-lead ECG should be taken and continuous cardiac monitoring maintained for at least 6 hours. Prolongation of the QRS interval (especially if > 0.16 secs) indicates severe sodium channel blockade and a high risk of arrhythmia (Fig. 7.3). QT interval prolongation may also occur. Arterial blood gases should be measured in suspected severe poisoning. In patients with arrhythmias, significant QRS or QT prolongation or acidosis, intravenous sodium bicarbonate (50 mL of 8.4% Fig. 7.3 ECG in severe tricyclic antidepressant poisoning. This rhythm strip shows a broad QRS complex due to impaired conduction. II 7.10 Anticholinergic and serotonergic feature clusters Anticholinergic Serotonin syndrome Common causes Benzodiazepines Antipsychotics TCAs Antihistamines Scopolamine Benzatropine Belladonna Some plants and mushrooms (see Box 7.18) SSRIs MAOIs TCAs Amphetamines Tryptamines Buspirone Bupropion (especially in combination) Clinical features Cardiovascular Tachycardia, hypertension Tachycardia, hyper- or hypotension Central nervous system Delirium, hallucinations, sedation Delirium, hallucinations, sedation, coma Muscle Myoclonus Shivering, tremor, myoclonus, raised creatine kinase Temperature Fever Fever Eyes Diplopia, mydriasis Normal pupil size Abdomen Ileus, palpable bladder Diarrhoea, vomiting Mouth Dry Skin Flushing, hot, dry Flushing, sweating Complications Seizures Seizures Rhabdomyolysis Renal failure Metabolic acidosis Coagulopathies (MAOI = monoamine oxidase inhibitor; SSRI = selective serotonin re-uptake inhibitor; TCA = tricyclic antidepressant)

140 • POISONING Digoxin and oleander Poisoning with digoxin is usually accidental, arising from prescription of an excessive dose, impairment of renal function or drug interactions. In South Asia, deliberate self-poisoning with yellow oleander (Thevetia peruviana), containing cardiac glycosides, is common. Clinical features Cardiac effects include tachyarrhythmias (either atrial or ventricular) and bradycardias, with or without atrioventricular block. Ventricular bigeminy is common and atrial tachycardia with evidence of atrioventricular block is highly suggestive of the diagnosis. Severe poisoning is often associated with hyperkalaemia. Non-cardiac features include delirium, headache, nausea, vomiting, diarrhoea and (rarely) altered colour vision. Digoxin poisoning can be confirmed by elevated plasma concentration (usual therapeutic range 1.3–2.5 mmol/L). After chronic exposure, concentrations

5 mmol/L suggest serious poisoning. Management Activated charcoal is commonly administered to patients presenting soon after acute ingestion, although evidence of benefit is lacking. Urea, electrolytes and creatinine should be measured, a 12-lead ECG performed and cardiac monitoring instituted. Hypoxia, hypokalaemia (sometimes caused by concurrent diuretic use), hypomagnesaemia and acidosis increase the risk of arrhythmias and should be corrected. Significant bradycardias may respond to atropine, although temporary pacing is sometimes needed. Ventricular arrhythmias may respond to intravenous magnesium (see Box 7.8). If available, digoxin-specific antibody fragments should be administered when there are severe refractory ventricular arrhythmias or bradycardias. These are effective for both digoxin and yellow oleander poisoning. Iron Overdose with iron can cause severe and sometimes fatal poisoning, with toxicity of individual iron preparations related to their elemental iron content. Clinical features Early features include gastrointestinal disturbance with the passage of grey or black stools, progressing to hyperglycaemia, leucocytosis, haematemesis, rectal bleeding, drowsiness, convulsions, coma, metabolic acidosis and cardiovascular collapse in severe cases. Early symptoms may improve or resolve within 6–12 hours, but hepatocellular necrosis can develop 12–24 hours after overdose and occasionally progresses to hepatic failure. Gastrointestinal strictures are late complications. Management Activated charcoal is ineffective but gastric lavage may be considered in patients presenting soon after substantial overdose, although efficacy is unknown. Serum iron concentration should be measured at least 4 hours after overdose or earlier if there are features of toxicity. Desferrioxamine chelates iron and should be administered immediately in patients with severe features, without waiting for serum iron concentrations, as well as symptomatic patients with high serum iron concentrations (e.g. > 5 mg/L). Desferrioxamine may cause hypotension, allergic reactions and occasionally pulmonary oedema. Otherwise, treatment is supportive and directed at complications. Cardiovascular medications Although not common, cardiovascular drug overdose is important because features of toxicity are often severe. Beta-blockers Major features of toxicity are bradycardia and hypotension; heart block, pulmonary oedema and cardiogenic shock occur in severe poisoning. Those with additional sodium channel-blocking effects (e.g. propranolol, acebutolol, carvedilol) may cause seizures, delirium and coma, while sotalol, which also blocks potassium channels, may cause QTc prolongation and torsades de pointes (Box 7.8 and p. 476). Management Intravenous fluids may reverse hypotension but care is required to avoid pulmonary oedema. Bradycardia and hypotension may respond to high doses of atropine (up to 3 mg in an adult) or an infusion of isoproterenol. Glucagon (5–10 mg over 10 mins, then 1–5 mg/hr by infusion) counteracts β-blockade by stimulating intracellular cyclic adenosine monophosphate (cAMP) production and is now more commonly used. In severe cases, ‘hyperinsulinaemia euglycaemic therapy’ has been used, as described under calcium channel blockers below. The efficacy of lipid emulsion therapy in severe poisoning with lipid-soluble β-blockers, such as propranolol, carvedilol and oxprenolol, is uncertain. Calcium channel blockers L-type calcium channel blockers are highly toxic in overdose. Dihydropyridines (e.g. nifedipine, amlodipine) cause vasodilatation, whereas diltiazem and verapamil have predominantly cardiac effects, including bradycardia and reduced myocardial contractility. Clinical features Hypotension due to vasodilatation or myocardial depression is common and bradycardias and heart block may also occur, especially with verapamil and diltiazem. Gastrointestinal disturbances, delirium, metabolic acidosis, hyperglycaemia and hyperkalaemia may also be present. Management Hypotension should be corrected with intravenous fluids, taking care to avoid pulmonary oedema. Persistent hypotension may respond to intravenous calcium gluconate (10 mg IV over 5 mins, repeated as required). Isoproterenol and glucagon may also be useful. Successful use of intravenous insulin with glucose (10–20% dextrose with insulin initially at 0.5–2.0 U/kg/ hr, increasing to 5–10 U/kg/hr according to clinical response), so-called ‘hyperinsulinaemia euglycaemic therapy’, has been reported in patients unresponsive to other strategies. The mechanism of action remains to be fully elucidated, but in states of shock myocardial metabolism switches from use of free fatty acids to glucose. Calcium channel blocker poisoning is also associated with hypoinsulinaemia and insulin resistance, impeding glucose uptake by myocytes. High doses of insulin inhibit lipolysis and increase glucose uptake and the efficiency of glucose utilisation. Cardiac pacing may be needed for severe unresponsive bradycardias or heart block. Lipid emulsion therapy has also been used in severe poisoning with apparent benefit, although evidence is largely anecdotal.

Drugs of misuse • 141

Arterial blood gases and plasma lactate should be taken after metformin overdose; acidosis should be corrected with intravenous sodium bicarbonate (250 mL 1.26% solution or 50 mL 8.4% solution, repeated as necessary). In severe cases, haemodialysis or haemodiafiltration is used. Pharmaceutical agents less commonly taken in poisoning An overview of the clinical features and management for drugs less commonly involved in poisoning is provided in Box 7.11. Drugs of misuse Drugs of misuse are common causes of toxicity requiring hospital admission. Management has recently become more complex because of the emergence of ‘novel psychoactive substances’ (NPS). These are often chemically related to traditional drugs of misuse, but with structural modifications made to evade legal control. The constituents of branded NPS products are often unknown and knowledge about the clinical features and management of NPS toxicity is limited. Depressants These produce CNS depression, including drowsiness, ataxia, delirium and coma, sometimes with respiratory depression, airway compromise, aspiration pneumonia and respiratory arrest Antipsychotic drugs Antipsychotic drugs (p. 1198) are often prescribed for patients at high risk of self-harm or suicide and are often taken in overdose. Clinical features Anticholinergic features (see Box 7.10) including drowsiness, tachycardia and hypotension, are common and convulsions may occur. Acute dystonias, including oculogyric crisis, torticollis and trismus, may occur after overdose with typical antipsychotics like haloperidol or chlorpromazine. QT interval prolongation and torsades de pointes can occur with some typical (e.g. haloperidol) and atypical (e.g. quetiapine, amisulpride, ziprasidone) agents. Management Activated charcoal may be of benefit if given early. Cardiac monitoring should be undertaken for at least 6 hours. Management is largely supportive, with treatment directed at complications (see Box 7.8). Antidiabetic agents Overdose is uncommon but toxic effects can be severe. Clinical features Sulphonylureas, meglitinides (e.g. nateglinide, repaglinide) and parenteral insulin cause hypoglycaemia when taken in overdose, although insulin is non-toxic if ingested by mouth. The duration of hypoglycaemia depends on the half-life or release characteristics of the preparation and may be prolonged over several days with long-acting agents such as glibenclamide, insulin zinc suspension or insulin glargine. Features of hypoglycaemia include nausea, agitation, sweating, aggression, delirium, tachycardia, hypothermia, drowsiness, convulsions and coma (p. 738). Permanent neurological damage can occur if hypoglycaemia is prolonged. Hypoglycaemia can be diagnosed using bedside glucose strips but venous blood should also be sent for laboratory confirmation. Metformin is uncommonly associated with hypoglycaemia. Its major toxic effect is lactic acidosis, which can have a high mortality, and is particularly common in older patients and those with renal or hepatic impairment, or when ethanol has been co-ingested. Other features of metformin overdose are nausea, vomiting, diarrhoea, abdominal pain, drowsiness, coma, hypotension and cardiovascular collapse. There is limited experience of overdose involving thiazolidinediones (e.g. pioglitazone) and dipeptidyl peptidase 4 (DPP-4) inhibitors (e.g. sitagliptin) but significant hypoglycaemia is unlikely. Management Activated charcoal should be considered for recent substantial overdose. Venous blood glucose and urea and electrolytes should be measured and measurement repeated regularly. Hypoglycaemia should be corrected using oral or intravenous glucose (50 mL of 50% dextrose); an infusion of 10–20% dextrose may be required to prevent recurrence. Intramuscular glucagon can be used as an alternative, especially if intravenous access is unavailable. Failure to regain consciousness within a few minutes of normalisation of the blood glucose can indicate that a central nervous system (CNS) depressant has also been ingested, the hypoglycaemia has been prolonged, or there is another cause of coma (e.g. cerebral haemorrhage or oedema). 7.11 Clinical features and specific management of drugs less commonly involved in poisoning Substance Clinical features Management Anticonvulsants Carbamazepine, phenytoin Cerebellar signs Convulsions Cardiac arrhythmias Coma Multiple-dose activated charcoal (carbamazepine) Sodium valproate Coma Metabolic acidosis Haemodialysis for severe poisoning Isoniazid Peripheral neuropathy Convulsions Activated charcoal IV pyridoxine Theophylline Cardiac arrhythmias Convulsions Coma Multiple-dose activated charcoal Antimalarial drugs Chloroquine Acidosis and hypokalaemia Visual loss Convulsions, coma ECG changes and arrhythmias Correction of pH (but not potassium) Monitoring and treatment of cardiac rhythm High-dose diazepam with mechanical ventilation Quinine Tremor, tinnitus, deafness, ataxia, convulsions, coma Haemolysis ECG changes and arrhythmias Retinal toxicity Correction of pH (but not potassium) Monitoring and treatment of cardiac rhythm Multiple-dose activated charcoal No effective treatment for visual loss

142 • POISONING experience, often accompanied by heightened sexual arousal. Physical dependence occurs within a few weeks of regular high-dose use. Withdrawal can start within 12 hours, causing intense craving, rhinorrhoea, lacrimation, yawning, perspiration, shivering, piloerection, vomiting, diarrhoea and abdominal cramps. Examination reveals tachycardia, hypertension, mydriasis and facial flushing. Commonly encountered opioids and clinical features of poisoning are shown in Box 7.12. Needle tracks may be visible in intravenous users and there may be drug-related paraphernalia. Methadone may also cause QTc prolongation and torsades de pointes. Features of opioid poisoning can be prolonged for up to 48 hours after use of long-acting agents such as methadone or oxycodone. Use of the specific opioid antagonist naloxone (0.4–2 mg IV in an adult, repeated if necessary) may obviate the need for intubation, although excessive doses may precipitate acute withdrawal in chronic opiate users and breakthrough pain in those receiving opioids for pain management. Repeated doses or an infusion are often required because the half-life of the antidote is short compared to that of most opiates, especially those with prolonged elimination. Patients should be monitored for at least 6 hours after the last naloxone dose. Rare complications of naloxone therapy include fits, ventricular arrhythmias and pulmonary oedema. (Box 7.12). Other complications of coma include pressure blisters or sores and rhabdomyolysis. Effects are potentiated by other CNS depressants, including alcohol. Essential supportive care is detailed in Box 7.8. Antidotes are available for some depressants. Benzodiazepines Benzodiazepines (e.g. diazepam) and related substances (e.g. zopiclone) are of low toxicity when taken alone in overdose but can enhance CNS and respiratory depression when taken with other sedative agents, including alcohol. They are more hazardous in the elderly and those with chronic lung or neuromuscular disease (see Box 7.12). The specific benzodiazepine antagonist flumazenil (0.5 mg IV, repeated if needed) increases conscious level in patients with benzodiazepine overdose, but carries a risk of seizures and is contraindicated in patients co-ingesting pro-convulsants (e.g. TCAs) and those with a history of epilepsy. Opioids Toxicity may result from misuse of illicit drugs such as heroin or from intentional or accidental overdose of medicinal opiates. Intravenous or smoked heroin gives a rapid, intensely pleasurable 7.12 Stimulant, sedative and opioid feature clusters Stimulant Sedative hypnotic Opioid Common causes Amphetamines MDMA (‘ecstasy’) Ephedrine Pseudoephedrine Cocaine Cannabis Phencyclidine Cathinones (e.g. mephedrone) Benzylpiperazine Benzodiazepines Barbiturates Ethanol GHB Heroin Morphine Methadone Fentanyl and derivatives Oxycodone Dihydrocodeine Codeine Pethidine Buprenorphine Dextropropoxyphene Tramadol Clinical features Respiratory Tachypnoea Reduced respiratory rate and ventilation1 Reduced respiratory rate and ventilation Cardiovascular Tachycardia, hypertension Hypotension1 Hypotension, relative bradycardia Central nervous system Restlessness, anxiety, anorexia, insomnia Delirium, hallucinations, slurred speech Delirium, hallucinations, slurred speech Hallucinations Sedation, coma1 Sedation, coma2 Muscle Tremor Ataxia, reduced muscle tone Ataxia, reduced muscle tone Temperature Fever Hypothermia Hypothermia Eyes Mydriasis Diplopia, strabismus, nystagmus Normal pupil size Miosis Abdomen Abdominal pain, diarrhoea – Ileus Mouth Dry – – Skin Piloerection Blisters, pressure sores Needle tracks2 Complications Seizures Myocardial infarction Dysrhythmias Rhabdomyolysis Renal failure Intracerebral haemorrhage or infarction Respiratory failure1 Aspiration Respiratory failure2 Non-cardiogenic pulmonary oedema Aspiration 1Especially barbiturates. 2IV use. (GHB = gamma hydroxybutyrate; MDMA = 3,4-methylene-dioxymethamphetamine)

Drugs of misuse • 143

include mephedrone and methylenedioxypyrovalerone. Tolerance is common, leading regular users to seek ever higher doses. Toxic features usually appear within a few minutes of use and last 4–6 hours, or substantially longer after a large overdose. Sympathomimetic stimulant and serotonergic effects are common (see Boxes 7.10 and 7.12). Some users develop hyponatraemia as a result of excessive water-drinking or inappropriate vasopressin (antidiuretic hormone, ADH) secretion. Muscle rigidity, pain and bruxism (clenching of the jaw), hyperpyrexia, rhabdomyolysis, metabolic acidosis, acute renal failure, disseminated intravascular coagulation, hepatocellular necrosis, acute respiratory distress syndrome (ARDS) and cardiovascular collapse have all been described following MDMA use. Cerebral infarction and haemorrhage have been reported, especially after intravenous amphetamine use. Management is supportive and directed at complications (see Box 7.8). Hallucinogens Cannabis Derived from the dried leaves and flowers of Cannabis sativa, cannabis produces euphoria, perceptual alterations and conjunctival injection, followed by enhanced appetite, relaxation and occasionally hypertension, tachycardia, slurred speech and ataxia. Effects occur 10–30 minutes after smoking or 1–3 hours after ingestion, and last 4–8 hours. High doses may produce anxiety, delirium, hallucinations and psychosis. Psychological dependence is common, but tolerance and withdrawal symptoms are unusual. Long-term use is thought to increase the lifetime risk of psychosis. Serious acute toxicity is uncommon and supportive treatment is all that is required. Synthetic cannabinoid receptor agonists Large numbers of synthetic cannabinoid receptor agonists (SCRAs), synthetic compounds sometimes referred to collectively as ‘spice’, are now used as legal alternatives to cannabis; examples include PB-22, 5F-PB-22, 5F-AKB-48, STS-135, SF-ADB and MDMB-CHMICA. They are usually sprayed on to a herbal smoking mix and packaged as smoking products with appealing brand names. These may contain more than one SCRA and content may change with time. The toxic effects of SCRAs differ from those of cannabis, being generally more marked and including agitation, panic, delirium, hallucinations, tachycardia, ECG changes, hypertonia, dyspnoea and vomiting. Coma, respiratory acidosis, seizures, hypokalaemia and renal dysfunction are also reported. Treatment of intoxication is supportive. Tryptamines These are predominantly 5-hydroxytryptamine (5-HT, serotonin; especially 5-HT2a) agonists with associated stimulant effects. Typical clinical features include hallucinations, agitation, delirium, hypertension, tachycardia, sweating, anxiety and headache. Serotonin syndrome may occur (see Box 7.10), especially if tryptamines are used in combination with other serotonergic agents. Naturally occurring examples are psilocin and psilocybin, found in ‘magic mushrooms’, and dimethyltryptamine (DMT) in traditional ayahuasca brews. Synthetic tryptamines, such as alpha-methyltryptamine (AMT), have been encountered recently. Gamma hydroxybutyrate Gamma hydroxybutyrate (GHB), and the related compounds gamma butyrolactone (GBL) and 1,4 butanediol are sedative liquids with psychedelic and body-building effects. As well as sedative hypnotic features (see Box 7.12), toxicity may cause nausea, diarrhoea, vertigo, tremor, myoclonus, extrapyramidal signs, euphoria, bradycardia, convulsions, metabolic acidosis, hypokalaemia and hyperglycaemia. Coma usually resolves abruptly within a few hours but occasionally persists for several days. Dependence may develop in regular users, who experience severe, prolonged withdrawal effects if use is discontinued suddenly. Management is largely supportive. All patients should be observed for a minimum of 2 hours and until symptoms resolve, with monitoring of blood pressure, heart rate, respiratory rate and oxygenation. Withdrawal symptoms may require treatment with very high doses of benzodiazepine. Stimulants and entactogens These are sympathomimetic and serotonergic amines that have overlapping clinical features, depending on the balance of their stimulant (see Box 7.12) and serotonergic (see Box 7.10) effects. As well as traditional drugs such as cocaine, amphetamines and ecstasy, the group includes many more recently emerging novel psychoactive substances, including cathinones (e.g. mephedrone), piperazines (e.g. benzylpiperazine), piperadines (e.g. ethylphenidate), benzofurans (e.g. 5-aminopropylbenzofuran) and NBOMe compounds (e.g. 25I-NBOMe). Cocaine Cocaine is available as a water-soluble hydrochloride salt powder suitable for nasal inhalation (‘snorting’), or as insoluble free-base (‘crack’ cocaine) ‘rocks’ that, unlike the hydrochloride salt, vaporise at high temperature and can be smoked, giving a more rapid and intense effect. Effects appear rapidly after inhalation and especially after smoking. Sympathomimetic stimulant effects predominate (see Box 7.12). Serious complications usually occur within 3 hours of use and include coronary artery spasm, leading to myocardial ischaemia or infarction, hypotension and ventricular arrhythmias. Cocaine toxicity should be considered in younger adults presenting with ischaemic chest pain. Hyperpyrexia, rhabdomyolysis, acute renal failure and disseminated intravascular coagulation may occur. A 12-lead ECG and ECG monitoring should be undertaken. ST segment elevation may occur in the absence of myocardial infarction and troponin T estimations are the most sensitive and specific markers of myocardial damage. Benzodiazepines and intravenous nitrates are useful for managing patients with chest pain or hypertension. Acidosis should be corrected and physical cooling measures used for hyperthermia. Beta-blockers may be contraindicated because of the risk of unopposed α-adrenoceptor stimulation, but this is debated. Coronary angiography should be considered in patients with myocardial infarction or acute coronary syndromes. Amphetamines and cathinones Amphetamine-related compounds include amphetamine sulphate (‘speed’), methylamphetamine (‘crystal meth’) and 3,4-methylenedioxymethamphetamine (MDMA, ‘ecstasy’). Synthetic cathinones

144 • POISONING ingested. Cocaine, for example, presents a much higher risk than heroin because of its high toxicity and lack of a specific antidote. Patients suspected of body packing or stuffing should be admitted for observation. A careful history taken in private is important, but for obvious reasons patients may withhold details of the drugs involved. The mouth, rectum and vagina should be examined as possible sites for concealed drugs. A urine toxicology screen performed at intervals may provide evidence of leakage, although positive results may reflect earlier drug use. Packages may be visible on plain abdominal films (Fig. 7.4) but ultrasound and computed tomography (CT) are more sensitive. One of these (preferably CT) should be performed in all suspected body packers. Antimotility agents are often used by body packers to prevent premature passage of packages; it can take several days for packages to pass spontaneously, during which the carrier is at risk from package rupture. Whole bowel irrigation is commonly used to accelerate passage and is continued until all packages have passed. Surgery may be required when there is mechanical bowel obstruction or when evolving clinical features suggest package rupture, especially with cocaine. Chemicals and pesticides Carbon monoxide Carbon monoxide (CO) is a colourless, odourless gas produced by faulty appliances burning organic fuels. It is also present in vehicle exhaust fumes and sometimes in smoke from house fires. It binds with haemoglobin and cytochrome oxidase, reducing tissue oxygen delivery and inhibiting cellular respiration. CO is a common cause of death by poisoning and most patients die before reaching hospital. Clinical features Early features include headache, nausea, irritability, weakness and tachypnoea. The cause of these non-specific features may not be obvious if the exposure is occult, such as from a d-Lysergic acid diethylamide d-Lysergic acid diethylamide (LSD) is a synthetic ergoline usually ingested as small squares of impregnated absorbent paper (often printed with a distinctive design) or as ‘microdots’. The drug causes perceptual effects, such as heightened visual awareness of colours or distortion of images. Hallucinations may be pleasurable or terrifying (‘bad trip’). Other features are delirium, agitation, aggression, dilated pupils, hypertension, pyrexia and metabolic acidosis. Psychosis may sometimes last several days. Patients with psychotic reactions or CNS depression should be observed in hospital, preferably in a quiet, dimly lit room to minimise external stimulation. A benzodiazepine that can be used for sedation is required, avoiding antipsychotics if possible, as they may precipitate cardiovascular collapse or convulsions. Dissociative drugs Ketamine, its N-ethyl derivative methoxetamine and phencyclidine (now rarely encountered) produce a sense of dissociation from reality, often associated with visual and auditory distortions. Memory loss, impaired consciousness, agitation, hallucinations, tremors and numbness may also occur. Long-term ketamine (and probably methoxetamine) use can cause severe chronic cystitis with dysuria, frequency, urgency, haematuria and incontinence. Treatment of intoxication is supportive. Volatile substances Inhalation of volatile nitrites (e.g. amyl nitrite, isobutyl nitrite), often sold in bottles or vials as ‘poppers’, is reported to produce a feeling of pleasure and warmth, relax the anal sphincter and prolong orgasm. These potent vasodilators commonly provoke headache, dizziness, hypotension and tachycardia. They also oxidise haemoglobin to produce methaemoglobinaemia, with resulting breathlessness and delirium. Severe cases are treated with methylthioninium chloride (‘methylene blue’, see Fig 7.1). Several volatile solvents found in household products, such as propane, butane, toluene and trichloroethylene, have a mild euphoriant effect if inhaled. Serious toxic effects can occur, including reduced level of consciousness, seizures and cardiac arrhythmias; there is also a risk of asphyxia from some methods of inhalation. Nitrous oxide is an anaesthetic gas, but small canisters of it are sold for the domestic production of whipped cream and the contents of these can be transferred to balloons for inhalation. The gas has euphoriant effects (‘laughing gas’), but hazards include asphyxia from inhalation without oxygen, or vitamin B12 inactivation from chronic use leading to megaloblastic anaemia, psychosis and other neurological sequelae. Body packers and body stuffers Body packers (‘mules’) attempt to smuggle illicit drugs (usually cocaine, heroin or amphetamines) by ingesting multiple small packages wrapped in several layers of clingfilm or in condoms. Body stuffers are those who have ingested unpackaged or poorly wrapped substances, often to avoid arrest. Both groups are at risk of severe toxicity if the packages rupture. This is more likely for body stuffers, who may develop symptoms of poisoning within 8 hours of ingestion. The risk of poisoning depends on the quality of the wrapping, and the amount and type of drug Fig. 7.4 Abdominal X-ray of a body packer showing multiple drug-filled condoms.

Chemicals and pesticides • 145

complex allows reactivation of the enzyme but, subsequently, loss of a chemical group from the OP–enzyme complex prevents further enzyme reactivation. After this process (termed ‘ageing’) has taken place, new enzyme needs to be synthesised before function can be restored. The rate of ‘ageing’ is an important determinant of toxicity and is more rapid with dimethyl (3.7 hrs) than diethyl (31 hrs) compounds (Box 7.13) and especially rapid after exposure to nerve agents (soman in particular), which cause ‘ageing’ within minutes. Clinical features and management OP poisoning causes an acute cholinergic phase, which may occasionally be followed by the intermediate syndrome or organophosphate-induced delayed polyneuropathy (OPIDN). The onset, severity and duration of poisoning depend on the route of exposure and agent involved. faulty domestic appliance. Subsequently, ataxia, nystagmus, drowsiness and hyper-reflexia may develop, progressing to coma, convulsions, hypotension, respiratory depression, cardiovascular collapse and death. Myocardial ischaemia may result in arrhythmias or myocardial infarction. Cerebral oedema is common and rhabdomyolysis may cause myoglobinuria and renal failure. In those who recover from acute toxicity, longer-term neuropsychiatric effects are common, such as personality change, memory loss and concentration impairment. Extrapyramidal effects, urinary or faecal incontinence, and gait disturbance may also occur. Poisoning during pregnancy may cause fetal hypoxia and intrauterine death. Management Patients should be removed from exposure as soon as possible and resuscitated as necessary. A high concentration of oxygen should be administered via a tightly fitting facemask; this reduces the half-life of carboxyhaemoglobin from 4–6 hours to about 40 minutes. Measurement of carboxyhaemoglobin is useful for confirming exposure; levels > 20% suggest significant exposure but do not correlate well with the severity of poisoning, partly because concentrations fall rapidly after removal of the patient from exposure, especially if supplemental oxygen has been given. An ECG should be performed in all patients with acute CO poisoning, especially those with pre-existing heart disease. Arterial blood gas analysis should be checked in those with serious poisoning. Pulse oximetry may provide misleading oxygen saturations because carboxyhaemoglobin and oxyhaemoglobin are both measured. Excessive intravenous fluid administration should be avoided, particularly in the elderly, because of the risk of pulmonary and cerebral oedema. Convulsions should be controlled with diazepam. Hyperbaric oxygen therapy is controversial. At 2.5 atmospheres, this reduces the half-life of carboxyhaemoglobin to about 20 minutes and increases the amount of oxygen dissolved in plasma 10-fold, but systematic reviews have not consistently shown improved clinical outcomes. The logistical difficulties of transporting sick patients to hyperbaric chambers and managing them therein are substantial. Organophosphorus insecticides and nerve agents Organophosphorus (OP) compounds (Box 7.13) are widely used as pesticides, especially in developing countries. Case fatality following deliberate ingestion is high (5–20%). Nerve agents, developed for chemical warfare, are derived from OP insecticides and are much more toxic. They are commonly classified as G (originally synthesised in Germany) or V (‘venomous’) agents. The ‘G’ agents, such as tabun, sarin and soman, are volatile, absorbed by inhalation or via the skin, and dissipate rapidly after use. ‘V’ agents, such as VX, are contact poisons unless aerosolised, and contaminate ground for weeks or months. The toxicology and management of nerve agent and pesticide poisoning are similar. Mechanism of toxicity OP compounds inactivate acetylcholinesterase (AChE), resulting in the accumulation of acetylcholine (ACh) in cholinergic synapses (Fig. 7.5). Initially, spontaneous hydrolysis of the OP–enzyme 7.13 Organophosphorus compounds Nerve agents • G agents: sarin, tabun, soman • V agents: VX,VE Insecticides Dimethyl compounds Diethyl compounds • Dichlorvos • Fenthion • Malathion • Methamidophos • Chlorpyrifos • Diazinon • Parathion-ethyl • Quinalphos Fig. 7.5 Mechanism of toxicity of organophosphorus compounds and treatment with oxime. Acetylcholinesterase enzyme ‘Ageing’: reactivation not possible Organophosphate Enzyme–substrate complex Elimination of ‘leaving group’ Reactivation with oxime Spontaneous reactivation AChE–OH + X–P–OR1 O OR2 AChE–O–X–P–OR1 O OR2 AChE–O–P–OR1 + AChE–O–P–OR O OR2 OXIME N–OH O O• AChE–OH + HO–P–OR1 O OR2 AChE–OH + OXIME O OR2 N–P–OR1 XH

146 • POISONING given rapidly after exposure. Oximes reactivate AChE that has not undergone ‘ageing’ and are therefore less effective with dimethyl compounds and nerve agents, especially soman. Oximes may provoke hypotension, especially if administered rapidly. Intravenous magnesium sulphate has been reported to increase survival in animals and in small human studies of OP poisoning; however, further clinical trial evidence is needed before this can be recommended routinely. Ventilatory support should be instituted before the patient develops respiratory failure. Benzodiazepines may be used to treat agitation, fasciculations and seizures and for sedation during mechanical ventilation. Exposure is confirmed by measurement of plasma or red blood cell cholinesterase activity but antidote use should not be delayed pending results. Plasma cholinesterase is reduced more rapidly but is less specific than red cell cholinesterase. Values correlate poorly with the severity of clinical features but are usually < 10% in severe poisoning, 20–50% in moderate poisoning and > 50% in subclinical poisoning. The acute cholinergic phase usually lasts 48–72 hours, with most patients requiring intensive cardiorespiratory support and monitoring. Cholinergic features may be prolonged over several weeks with some lipid-soluble agents. Intermediate syndrome About 20% of patients with OP poisoning develop weakness that spreads rapidly from the ocular muscles to those of the head and neck, proximal limbs and the muscles of respiration, resulting in ventilatory failure. This ‘intermediate syndrome’ generally develops 1–4 days after exposure, often after resolution of the acute cholinergic syndrome, and may last 2–3 weeks. There is no specific treatment and supportive care is needed, including maintenance of airway and ventilation. Organophosphate-induced delayed polyneuropathy Organophosphate-induced delayed polyneuropathy (OPIDN) is a rare complication that usually occurs 2–3 weeks after acute exposure. It is a mixed sensory/motor polyneuropathy, affecting long myelinated neurons especially, and appears to result from inhibition of enzymes other than AChE. It is a feature of poisoning with some OPs such as triorthocresyl phosphate but is less common with nerve agents. Early clinical features are muscle cramps followed by numbness and paraesthesiae, proceeding to flaccid paralysis of the lower and subsequently the upper limbs, with foot and wrist drop and a high-stepping gait, progressing to paraplegia. Sensory loss may also be present but is variable. Initially, tendon reflexes are reduced or lost but mild spasticity may develop later. There is no specific therapy for OPIDN. Regular physiotherapy may limit deformity caused by muscle-wasting. Recovery is often incomplete and may be limited to the hands and feet, although substantial functional recovery after 1–2 years may occur, especially in younger patients. Carbamate insecticides Carbamate insecticides such as bendiocarb, carbofuran, carbaryl and methomyl inhibit a number of tissue esterases, including AChE. The mechanism, clinical features and management of toxicity are similar to those of OP compounds. However, clinical features are usually less severe and of shorter duration, because the carbamate–AChE complex dissociates quickly, with a half-life of 30–40 minutes, and does not undergo ageing. Also, carbamates penetrate the CNS poorly. Intermediate syndrome Acute cholinergic syndrome This usually starts within a few minutes of exposure and nicotinic or muscarinic features may be present (Box 7.14). Vomiting and profuse diarrhoea are typical following ingestion. Bronchoconstriction, bronchorrhoea and salivation may cause severe respiratory compromise. Excess sweating and miosis are characteristic and the presence of muscular fasciculations strongly suggests the diagnosis, although this feature is often absent, even in serious poisoning. Subsequently, generalised flaccid paralysis may develop and affect respiratory and ocular muscles, resulting in respiratory failure. Ataxia, coma, convulsions, cardiac repolarisation abnormalities and torsades de pointes may occur. Management The airway should be cleared of excessive secretions, breathing and circulation assessed, high-flow oxygen administered and intravenous access obtained. Appropriate external decontamination is needed (p. 133). Gastric lavage or activated charcoal may be considered if the patient presents sufficiently early. Seizures should be treated as described in Box 7.8. The ECG, oxygen saturation, blood gases, temperature, urea and electrolytes, amylase and glucose should be monitored closely. Early use of sufficient doses of atropine is potentially life-saving in patients with severe toxicity. Atropine reverses ACh-induced bronchospasm, bronchorrhoea, bradycardia and hypotension. When the diagnosis is uncertain, a marked increase in heart rate associated with skin flushing after a 1 mg intravenous dose makes OP poisoning unlikely. In OP poisoning, atropine (2 mg IV) should be administered and this dose should be doubled every 5–10 minutes until clinical improvement occurs. Further bolus doses should be given until secretions are controlled, the skin is dry, blood pressure is adequate and heart rate is > 80 bpm. Large doses may be needed, but excessive doses may cause anticholinergic effects (see Box 7.10). In severe poisoning requiring atropine, an oxime such as pralidoxime chloride or obidoxime is generally recommended, if available, although efficacy is debated. This may reverse or prevent muscle weakness, convulsions or coma, especially if 7.14 Cholinergic features in poisoning* Muscarinic Nicotinic Respiratory Bronchorrhoea, bronchoconstriction Reduced ventilation Circulation Bradycardia, hypotension Tachycardia, hypertension Higher mental function Anxiety, delirium, psychosis Muscle – Fasciculation, paralysis Temperature Fever – Eyes Diplopia, miosis, lacrimation Mydriasis Abdomen Vomiting, profuse diarrhoea – Mouth Salivation – Skin Sweating – Complications Coma, seizures, respiratory depression *Both muscarinic and nicotinic features occur in OP poisoning. Nicotinic features occur in nicotine poisoning and black widow spider bites. Cholinergic features are sometimes seen with some mushrooms.

Chemicals and pesticides • 147

and acute tubular necrosis occur because of renal calcium oxalate precipitation. Hypocalcaemia, hypomagnesaemia and hyperkalaemia are common. Methanol poisoning causes headache, delirium and vertigo. Visual impairment and photophobia develop, associated with optic disc and retinal oedema and impaired pupil reflexes. Blindness may be permanent, although some recovery may occur over several months. Pancreatitis and abnormal liver function have also been reported. Management Urea and electrolytes, chloride, bicarbonate, glucose, calcium, magnesium, albumin, plasma osmolarity and arterial blood gases should be measured in all patients with suspected methanol or ethylene glycol toxicity. The osmolar and anion gaps should be calculated (see Box 7.5). Initially, poisoning is associated with an increased osmolar gap, but as toxic metabolites are produced, an increased anion gap develops, associated with metabolic acidosis. The diagnosis can be confirmed by measurement of ethylene glycol or methanol concentrations but assays are not widely available. An antidote, ideally fomepizole but otherwise ethanol, should be administered to all patients with suspected significant exposure while awaiting the results of laboratory investigations. These block alcohol dehydrogenase and delay the formation of toxic metabolites until the parent drug is eliminated in the urine or by dialysis. The antidote should be continued until ethylene glycol or methanol concentrations are undetectable. Metabolic acidosis should be corrected with sodium bicarbonate (e.g. 250 mL of 1.26% solution, repeated as necessary). Convulsions should be treated with an intravenous benzodiazepine. In ethylene glycol poisoning, hypocalcaemia should be corrected only if there are severe ECG features or if seizures occur, as this may increase calcium oxalate crystal formation. In methanol poisoning, folinic acid should be administered to enhance the metabolism of the toxic metabolite, formic acid. Haemodialysis or haemodiafiltration should be used in severe poisoning, especially if renal failure is present or there is visual loss in the context of methanol poisoning. It should be continued until acute toxic features are no longer present and ethylene glycol/methanol concentrations are undetectable. Corrosive substances Products containing strong acids (e.g. hydrochloric or sulphuric acid) or alkalis (e.g. sodium hydroxide, calcium carbonate) may be ingested, accidentally or intentionally, causing gastrointestinal pain, ulceration and necrosis, with risk of perforation. External decontamination (p. 133), if needed, should be performed after initial resuscitation. Gastric lavage should not be attempted and neutralising chemicals should not be administered after large ingestions because of the risk of tissue damage from heat release. Cardiorespiratory monitoring is necessary and full blood count, renal function, coagulation and acid–base status should be assessed. An erect chest X-ray should be performed if perforation is suspected and may show features of mediastinitis or gas under the diaphragm. Strong analgesics should be administered for pain. Severe abdominal or chest pain, abdominal distension, shock or acidosis may indicate perforation and should prompt an urgent CT scan of chest and abdomen and surgical review. In the absence of perforation, drooling, dysphagia, stridor or oropharyngeal burns suggest possible severe oesophageal and OPIDN are not common features of carbamate poisoning. In spite of this, case fatality can be high for some carbamates, depending on their formulation. Atropine may be given intravenously as for OP poisoning (p. 146). Diazepam may be used to relieve anxiety. The use of oximes is unnecessary. Paraquat Paraquat is a herbicide that is widely used across the world, although it has been banned in the European Union and some other countries for several years. It is highly toxic if ingested, with clinical features including oral burns, vomiting and diarrhoea, progressing to pneumonitis, pulmonary fibrosis and multi-organ failure. Exposure can be confirmed by a urinary dithionite test, while the plasma paraquat concentration indicates prognosis. There is no specific antidote but activated charcoal is commonly administered. Immunosuppression with glucocorticoids and cyclophosphamide is sometimes used but evidence for benefit is weak. Irrespective of treatment, death is common and may occur within 24 hours with substantial poisoning or after 1–2 weeks with lower doses. Methanol and ethylene glycol Ethylene glycol (1,2-ethanediol) is found in antifreeze, brake fluids and, in lower concentrations, windscreen washes. Methanol is present in some antifreeze products and commercially available industrial solvents, and in low concentrations in some screen washes and methylated spirits. It may also be an adulterant of illicitly produced alcohol. Both are rapidly absorbed after ingestion. Methanol and ethylene glycol are not of high intrinsic toxicity but are converted via alcohol dehydrogenase to toxic metabolites that are largely responsible for their clinical effects (Fig. 7.6). Clinical features Early features of poisoning with either methanol or ethylene glycol include vomiting, ataxia, drowsiness, dysarthria and nystagmus. As toxic metabolites are formed, metabolic acidosis, tachypnoea, coma and seizures may develop. Toxic effects of ethylene glycol include ophthalmoplegia, cranial nerve palsies, hyporeflexia and myoclonus. Renal pain Fig. 7.6 Metabolism of methanol and ethylene glycol. Ethanol or fomepizole Inhibits Alcohol dehydrogenase Ethylene glycol Glycoaldehyde Glycolic acid Formaldehyde Formic acid TOXIC METABOLITES Glyoxylic acid Oxalic acid Methanol

148 • POISONING vegetable oil to reduce the release of toxic phosphine, but the benefit is uncertain. Copper sulphate This is used as a fungicide. If it is ingested, clinical features of toxicity include nausea, vomiting, abdominal pain, diarrhoea, discoloured (blue/green) secretions, corrosive effects on the gastrointestinal tract, renal or liver failure, methaemoglobinaemia, haemolysis, rhabdomyolysis, convulsions and coma. Treatment is as for other corrosive substances (see above) and should address complications, including use of methylthioninium chloride for methaemoglobinaemia (see Fig. 7.1). Chelation therapy is unlikely to be beneficial after acute exposure. Chemicals less commonly taken in poisoning An overview of the clinical features and management for chemicals less commonly involved in poisoning is provided in Box 7.15. damage and early endoscopy by an experienced operator should be considered. Delayed endoscopy (e.g. after several days) may carry a higher risk of perforation. Aluminium and zinc phosphide These rodenticides and fumigants are a common means of self-poisoning in northern India. The mortality rate for aluminium phosphide ingestion has been estimated at 60%; zinc phosphide ingestion appears less toxic, at about 2%. When ingested, both compounds react with gastric acid to form phosphine, a potent pulmonary and gastrointestinal toxicant. Clinical features include severe gastrointestinal disturbances, chest tightness, cough and breathlessness progressing to ARDS and respiratory failure, tremor, paraesthesiae, convulsions, coma, tachycardia, metabolic acidosis, electrolyte disturbances, hypoglycaemia, myocarditis, liver and renal failure, and leucopenia. Ingestion of a few tablets can be fatal. Treatment is supportive and directed at correcting electrolyte abnormalities and treating complications; there is no specific antidote. Early gastric lavage is sometimes used, often with 7.15 Clinical features and specific management of chemicals less commonly involved in poisoning Substance Clinical features Management Lead e.g. Chronic occupational exposure, leaded paint, water contaminated by lead pipes, use of kohl cosmetics Abdominal pain Microcytic anaemia with basophilic stippling Headache and encephalopathy Motor neuropathy Nephrotoxicity Hypertension Hypocalcaemia Prevention of further exposure Measurement of blood lead concentration, full blood count and blood film, urea and electrolytes, liver function tests and calcium Abdominal X-ray in children to detect pica Bone X-ray for ‘lead lines’ Chelation therapy with DMSA or sodium calcium edetate Petroleum distillates e.g. White spirit, kerosene Vomiting Aspiration pneumonitis Gastric lavage contraindicated Activated charcoal ineffective Oxygen and nebulised bronchodilators Chest X-ray to assess pulmonary effects Organochlorines e.g. DDT, lindane, dieldrin, endosulfan Nausea, vomiting Agitation Fasciculation Paraesthesiae (face, extremities) Convulsions Coma Respiratory depression Cardiac arrhythmias Hyperthermia Rhabdomyolysis Pulmonary oedema Disseminated intravascular coagulation Activated charcoal (with nasogastric aspiration for liquid preparations) within 1 hr of ingestion Cardiac monitoring Pyrethroid insecticides e.g. Cypermethrin, permethrin, imiprothrin Skin contact: dermatitis, skin paraesthesiae Eye contact: lacrimation, photophobia and oedema of the eyelids Inhalation: dyspnoea, nausea, headaches Ingestion: epigastric pain, nausea, vomiting, headache, coma, convulsions, pulmonary oedema Symptomatic and supportive care Washing contaminated skin makes irritation worse Anticoagulant rodenticides e.g. Brodifacoum, bromadialone and warfarin Abnormal bleeding (prolonged) Monitor INR/prothrombin time Vitamin K1 by slow IV injection if there is coagulopathy Fresh frozen plasma or specific clotting factors for bleeding (DMSA = dimercaptosuccinic acid)

7.16 Chemical warfare agents Examples Clinical effects Antidotes* Nerve agents Tabun Sarin Soman VX See page 145 and Box 7.13 Atropine Oximes (p. 145) Blistering agents Nitrogen/sulphur Mustard Lewisite Eyes: watering, blepharospasm, corneal ulceration Skin: erythema, blistering Respiratory: cough, hoarseness, dyspnoea, pneumonitis None Choking agents Chlorine Phosgene Eyes: watering, blepharospasm, corneal ulceration Respiratory: cough, hoarseness, dyspnoea, pneumonitis None Blood agents Cyanide Cardiovascular: dizziness, shock Respiratory: dyspnoea, cyanosis CNS: anxiety, headache, delirium, convulsions, coma, fixed dilated pupils Other: vomiting, lactic acidosis Dicobalt edetate Hydroxocobalamin *Appropriate resuscitation, decontamination and supportive care are essential after exposure to all chemical warfare agents. Use appropriate personal protective equipment. 7.17 Clinical features of chronic arsenic poisoning Gastrointestinal tract • Anorexia, vomiting, weight loss, diarrhoea, increased salivation, metallic taste Neurological • Peripheral neuropathy (sensory and motor) with muscle wasting and fasciculation, ataxia Skin • Hyperpigmentation, palmar and plantar keratosis, alopecia, multiple epitheliomas, Mee’s lines (transverse white lines on fingernails) Eyes • Conjunctivitis, corneal necrosis and ulceration Bone marrow • Aplastic anaemia Other • Low-grade fever, vasospasm and gangrene, jaundice, hepatomegaly, splenomegaly Increased risk of malignancy • Lung, liver, bladder, kidney, larynx and lymphoid system Chemical warfare agents Some toxins have been developed for use as chemical warfare agents. These are summarised in Box 7.16. Environmental poisoning Arsenism Chronic arsenic exposure from drinking water has been reported in many countries, especially India, Bangladesh, Nepal, Thailand, Taiwan, China, Mexico and South America, where a large proportion of the drinking water (ground water) has a high arsenic content, placing large populations at risk. The World Health Organisation (WHO) guideline value for arsenic content in tube well water is 10 μg/L. Health effects associated with chronic exposure to arsenic in drinking water are shown in Box 7.17. In exposed individuals, high concentrations of arsenic are present in bone, hair and nails. Specific treatments are of no benefit in chronic arsenic toxicity and recovery from the peripheral neuropathy may never be complete, so the emphasis should be on prevention. Fluorosis Fluoride poisoning can result from exposure to excessive quantities of fluoride (> 10 ppm) in drinking water, industrial exposure to fluoride dust or consumption of brick teas. Clinical features include yellow staining and pitting of permanent teeth, osteosclerosis, soft tissue calcification, deformities (e.g. kyphosis) and joint ankylosis. Changes in the bones of the thoracic cage may lead to rigidity that causes dyspnoea on exertion. Very high doses of fluoride may cause abdominal pain, nausea, vomiting, seizures and muscle spasm. In calcium-deficient children, the toxic effects of fluoride manifest even at marginally high exposures to fluoride. In endemic areas, such as Jordan, Turkey, Chile, India, Bangladesh, China and Tibet, fluorosis is a major public health problem, especially in communities engaged in physically strenuous agricultural or industrial activities. Dental fluorosis is endemic in East Africa and some West African countries. Food-related poisoning Paralytic shellfish poisoning Paralytic shellfish poisoning is caused by consumption of bivalve molluscs (e.g. mussels, clams, oysters, cockles and scallops) contaminated with saxitoxins, which are concentrated in the shellfish as a result of constant filtration of toxic algae during algal blooms (e.g. ‘red tide’). Symptoms develop within 10–120 minutes of eating the contaminated shellfish and include gastrointestinal disturbances, paraesthesia around the mouth or in the extremities, ataxia, mental state changes and dysphagia. In severe cases, paralysis and respiratory failure can develop. There is no specific antidote and treatment is supportive. Most cases resolve over a few days. Ciguatera poisoning Ciguatera toxin and related toxins are produced by dinoflagellate plankton that adhere to algae and seaweed. These accumulate in the tropical herbivorous fish that feed on these and in their larger predators (e.g. snapper, barracuda), especially in the

150 • POISONING Further information Books and journal articles Bateman DN, Jefferson R, Thomas SHL, et al. (eds). Oxford desk reference: toxicology. Oxford: Oxford University Press; 2014. Benson BE, Hoppu K, Troutman WG, et al. Position paper update: gastric lavage for gastrointestinal decontamination. Clin Toxicol 2013; 51:140–146. Chyka PA, Seger D, Krenzelok EP, et al. Position paper: single-dose activated charcoal. Clin Toxicol 2005; 43:61–87. Thompson JP, Watson ID, Thanacoody HK, et al. Guidelines for laboratory analyses for poisoned patients in the United Kingdom. Ann Clin Biochem 2014; 51:312–325. Websites curriculum.toxicology.wikispaces.net/ Free access to educational material related to poisoning. toxbase.org Toxbase, the clinical toxicology database of the UK National Poisons Information Service. Free for UK health professionals but registration is required. Access for overseas users by special arrangement. Low-cost smartphone app available. toxnet.nlm.nih.gov US National Library of Medicine’s Toxnet: a hazardous substances databank, including Toxline for references to literature on drugs and other chemicals. who.int/gho/phe/chemical_safety/poisons_centres/en/ World directory of poisons centres held by the WHO, including interactive map and contact details. Pacific and Caribbean. Human exposure occurs through eating contaminated fish, even if well cooked. Nausea, vomiting, diarrhoea and abdominal pain develop within a few hours, followed by paraesthesia, ataxia, blurred vision, ataxia and tremor. Convulsions and coma can occur, although death is uncommon. Fatigue and peripheral neuropathy can be long-term effects. There is no specific treatment. In the South Pacific and Caribbean, there are approximately 50 000 cases per year, with a case fatality of 0.1%. Scombrotoxic fish poisoning Under poor storage conditions, histidine in scombroid fish (e.g. tuna, mackerel, bonito, skipjack and the canned dark meat of sardines) may be converted by bacteria to histamine and other chemicals. Within minutes of consumption, flushing, burning, sweating, urticaria, pruritus, headache, colic, nausea and vomiting, diarrhoea, bronchospasm and hypotension may occur. Management is with nebulised salbutamol, intravenous antihistamines and, occasionally, intravenous fluid replacement. Plant poisoning A substantial number of plants and fungi are potentially toxic if consumed, with patterns of poisoning depending on their geographical distribution. Some toxic examples and the clinical features of toxicity are shown in Box 7.18. 7.18 Some poisonous plants and fungi, with their clinical effects Species (common name) Toxins Important features of toxicity Plants Abrus precatorius (jequirity bean) Abrin Gastrointestinal effects, drowsiness, delirium, convulsions, multi-organ failure Ricinus communis (castor oil plant) Ricin Aconitum napellus (aconite, wolf’s bane, monkshood) Aconitum ferox (Indian aconite, bikh) Aconite Gastrointestinal effects, paraesthesiae, convulsions, ventricular tachycardia Atropa belladonna (deadly nightshade) Datura stramonium (Jimson weed, thorn apple) Brugmansia spp. (angel’s trumpet) Atropine, scopolamine, hyocyamine Anticholinergic toxidrome (see Box 7.10) Colchicum autumnale (autumn crocus) Colchicine Gastrointestinal effects, hypotension, cardiogenic shock Conium maculatum (hemlock) Toxic nicotinic alkaloids Hypersalivation, gastrointestinal effects, followed by muscular paralysis Digitalis purpurea (foxglove) Nerium oleander (pink oleander) Thevetia peruviana (yellow oleander) Cardiac glycosides Cardiac glycoside toxicity (p. 140) Laburnum anagyroides (laburnum) Cytosine Gastrointestinal effects; convulsions in severe cases Taxus baccata (yew) Taxane alkaloids Hypotension, bradycardia, respiratory depression, convulsions, coma, arrhythmias Fungi Amanita phalloides (death cap mushroom) Amatoxins Gastrointestinal effects, progressing to liver failure Cortinarius spp. Orellanine Gastrointestinal effects, fever, progressing to renal failure Psilocybe semilanceata (‘magic mushrooms’) Psilocybin, psilocin Hallucinations

Ch03-2 Emergency and Critical Care _67ef

02-8 Envenomation

8 Envenomation

Envenomation J White Comprehensive evaluation of the envenomed patient 152 Geographical distribution of venomous snakes 153 Bedside tests in the envenomed patient 153 Overview of envenomation 154 Venom 154 Venomous animals 154 Clinical effects 155 General approach to the envenomed patient 156 First aid 156 Assessment and management in hospital 158 Treatment 159 Follow-up 160 Envenomation by specific animals 160 Venomous snakes 160 Scorpions 161 Spiders 161 Paralysis ticks 161 Venomous insects 161 Marine venomous and poisonous animals 162

152 • ENVENOMATION Comprehensive evaluation of the envenomed patient Copyright © Julian White. Cranial nerves Drooling Dysarthria Dysphagia Upper airway compromise Mouth, gums Evidence of bleeding Increased salivation Drooling Chest Pulmonary oedema Diminished respiration Bite/sting site Pain Swelling Bruising Discoloration Necrosis Skin In addition to (6): Piloerection Erythema Blistering Infection Level of consciousness Confusion Agitation Seizures Eyes Miosis or mydriasis Increased lacrimation Corneal injury (venom spit injury) Airway, breathing, circulation Blood pressure Pulse Respiration rate Oxygen saturation Dysrhythmias Bilateral mild ptosis Ptosis and lateral ophthalmoplegia Fixed dilated pupils Chemosis – can indicate capillary leak syndrome Local increased sweating

Local bleeding, blistering Local bleeding

Muscles Weakness Tenderness Pain

Lymph nodes Tender or enlarged nodes draining bite/sting area

Abdomen Intra-abdominal, retroperitoneal or renal pathology

Reflexes Decreased or absent reflexes

Bedside tests in the envenomed patient • 153

Geographical distribution of venomous snakes The geographical location of a snakebite determines the likely animal(s) involved and the nature and risks of the envenomation. Copyright © Julian White. South American rattlesnake Crotalus durissus Indian krait Bungarus caeruleus European adder Vipera aspis Green pit viper Trimeresurus gramineus Russell’s viper Daboia russelii Black-necked spitting cobra Naja nigricollis Monacled cobra Naja kaouthia Common Indian cobra Naja naja Puff adder Bitis arietans Saw-scaled viper Echis carinatus Examination of urine. Haematuria may indicate a coagulopathy. Dark urine is suggestive of myoglobinuria, which is a sign of extensive rhabdomyolysis. Copyright © Julian White. Bedside tests in the envenomed patient Twenty-minute whole-blood clotting test (20WBCT). The presence of coagulopathy is a key indicator of major envenoming for some species. While full laboratory coagulation studies may be the ideal, the 20WBCT has emerged as a simple standardised bedside test of coagulopathy, applicable even in areas with limited health facilities. Copyright © Julian White. 1 Obtain a clean glass container (test tube or bottle) that is either new, or has only been washed with water (not detergent/soap) 2 Place 2–3 mL venous blood in the glass container 3 Allow to stand undisturbed for 20 mins 4 Gently invert/tip the glass container checking for presence of a blood clot 4a Clot present = negative test (no coagulopathy present) 4b Clot absent = positive test (coagulopathy present)

4a 4b

154 • ENVENOMATION Venomous animals There are many animal groups that contain venomous species (Box 8.2). The epidemiological estimates reflect the importance of snakes and scorpions as causes of severe or lethal envenomation, but also the fragmentary nature of the data. For snakes, recent studies have proposed widely varying estimates of epidemiological impact, but even the higher estimates may be too low. A recent Overview of envenomation Envenomation occurs when a venomous animal injects sufficient venom by a bite or a sting into a prey item or perceived predator to cause deleterious local and/or systemic effects. This is defined as a venom-induced disease (VID). Venomous animals generally use their venom to acquire and, in some cases, pre-digest prey, with defensive use a secondary function for many species. Accidental encounters between venomous animals and humans are frequent, particularly in the rural tropics, where millions of cases of venomous bites and stings occur annually. Globally, an increasing number of exotic venomous animals are kept privately, so cases of envenoming may present to hospitals where doctors have insufficient knowledge to manage potentially complex presentations. Doctors everywhere should thus be aware of the basic principles of management of envenomation and how to seek expert support. It is important for doctors to know what types of venomous animal are likely to occur in their geographical area (hospital hinterland; p. 153) and the types of envenoming they may cause. Venom Venom is a complex mixture of diverse components (notably toxins), often with several separate toxins that can cause adverse effects in humans, and each is potentially capable of multiple effects (Box 8.1). Venom is produced at considerable metabolic cost, so is used sparingly; thus only some bites/ stings by venomous animals result in significant envenoming, the remainder being ‘dry bites’. The concept of dry bites is important in understanding approaches to first aid and medical management. 8.2 Venomous animals and human envenoming Phyla Principal venomous animal groups Estimated number of human cases/year Estimated number of human deaths/year Chordata Snakes

2.5 million 100 000 Spiny fish ? > 100 000 Close to zero Stingrays ? > 100 000 ? < 10 Arthropoda Scorpions 1 million ? < 5000 Spiders ? > 100 000 ? < 100 Paralysis ticks ? > 1000 ? < 10 Insects ? > 1 million ? > 1000* Mollusca Cone snails ? < 1000 ? < 10 Blue-ringed octopus ? < 100 ? < 10 Coelenterata Jellyfish ? > 1 million ? < 10 *Social insect stings cause death by anaphylaxis rather than primary venom toxicity, except for massive multiple sting attacks. Copyright © Julian White. Copyright © Julian White. All venom components have lethal potential. 8.1 Key venom effects Venom component Clinical effects Type of venomous animal Neurotoxin Paralytic Flaccid paralysis Some snakes Paralysis ticks Cone snails Blue-ringed octopus Excitatory Neuroexcitation: autonomic storm, cardiotoxicity, pulmonary oedema Some scorpions, spiders, jellyfish (irukandji) Myotoxins Systemic or local myolysis Some snakes Cardiotoxins Direct or indirect cardiotoxicity; cardiac collapse, shock Some snakes, scorpions, spiders and jellyfish (box jellyfish) Haemostasis system toxins Variation from rapid coagulopathy and bleeding to thrombosis, deep venous thrombosis and pulmonary emboli Many snakes and a few scorpions (Hemiscorpius) Brazilian caterpillars (Lonomia) Haemorrhagic toxins Local vessel damage, fluid extravasation, blistering, ecchymosis, shock Mainly some snakes Nephrotoxins Renal damage Some snakes, massed bee and wasp stings Necrotoxins Local tissue injury/necrosis, shock Some snakes, a few scorpions (Hemiscorpius), spiders (recluse spiders), jellyfish and stingrays Allergic toxins Induction of acute allergic response (direct and indirect) Almost all venoms but particularly those of social insects (i.e. bees, wasps, ants)

Overview of envenomation • 155

local effects predominate over systemic, and for some, such as certain snakes, both are important (p. 152). Some species commonly cause local necrosis, notably some snakes, brown recluse spiders, an Iranian scorpion (Hemiscorpius lepturus) and some stingrays. General systemic effects By definition, these are non-specific (Box 8.3). Shock is an important complication of major local envenoming by some snake species and, if inadequately treated, can prove lethal, especially in children. Specific systemic effects These are important in both diagnosis and treatment. • Neurotoxic flaccid paralysis can develop very rapidly, progressing from mild weakness to full respiratory paralysis in less than 30 minutes (blue-ringed octopus bite, cone snail sting), or may develop far more slowly, over hours (some snakes) to days (paralysis tick). For neurotoxic snakes, the cranial nerves are usually involved first, with ptosis a common initial sign, often progressing to partial and later complete ophthalmoplegia, fixed dilated pupils, drooling and loss of upper airway protection (p. 152). From this, paralysis may extend to the limbs, with weakness and loss of deep tendon reflexes, the neck (‘broken neck’ sign), then finally respiratory paralysis affecting the diaphragm. • Excitatory neurotoxins cause an ‘autonomic storm’, often with profuse sweating (p. 152), variable cardiac effects and cardiac failure, sometimes with pulmonary oedema (notably, Australian funnel web spider bite, some scorpions such as Indian red scorpion). This type of envenomation can be rapidly fatal (many scorpions, funnel web spiders), or may cause distressing symptoms but constitute a lesser risk of death (widow spiders, banana spiders). • Myotoxicity can be localised in the bitten limb, or systemic, affecting mostly skeletal muscles. It can initially be silent, then present with generalised muscle pain, tenderness, myoglobinuria (p. 153) and huge rises in serum creatine kinase (CK). Secondary renal failure can precipitate potentially lethal hyperkalaemic cardiotoxicity. • Cardiotoxicity is often secondary but symptoms and signs are non-specific in most cases. For some scorpions, envenomation can cause direct cardiac effects, including decreased cardiac output, arrhythmias and pulmonary oedema. • Haemostasis system toxins cause a variety of effects, depending on the type of toxin (Fig. 8.1). Coagulopathy may present as bruising and bleeding from the bite site (p. 152), gums and intravenous sites. Surgical interventions are high-risk in such cases. Other venoms cause thrombosis, usually presenting as deep venous thrombosis (DVT), pulmonary embolus or stroke (particularly Caribbean/Martinique vipers). • Haemorrhagic toxins cause vascular damage, especially in the bitten limb, with extravasation of fluid and sometimes hypotensive shock; this is a problem associated with some snakebites. The role of these toxins in causing latedeveloping capillary leak syndrome (p. 152), again comprehensive study in India indicated there are at least 45 000 snakebite-related deaths in that country annually, far above both government figures and previous estimates. In many areas of the poor rural tropics, health resources are limited and few envenoming cases are either seen or recorded within the official hospital system, compared to the actual community burden of disease. While fatal cases may gain most attention, long-term disability from envenomation affects significantly more people and has a major social and economic cost. Stings by social insects such as bees and wasps may also cause lethal anaphylaxis. Other venomous animals may commonly envenom humans but cause mostly non-lethal effects. A few animals only rarely envenom humans but have a high potential for severe or lethal envenoming. These include box jellyfish, cone snails, blue-ringed octopus, paralysis ticks and Australian funnel web spiders. Within any given group, particularly snakes, there may be a wide range of clinical presentations. Some are described here but for a more detailed discussion of the types of venomous animal, their venoms and their effects on humans, see toxinology.com. Clinical effects With the exception of dry bites, where no significant toxin effects occur, venomous bites/stings can result in three broad classes of effect. Local effects These vary from trivial to severe (Box 8.3). There may be minimal or no local effects with some snakebites (not even pain), yet lethal systemic envenoming may still be present. For other species, Copyright © Julian White. 8.3 Local and systemic effects of envenomation Local effects • Pain • Sweating • Erythema • Major direct tissue trauma (e.g. stingray injuries) • Blistering • Necrosis • Swelling • Bleeding and bruising Non-specific systemic effects • Headache • Nausea • Vomiting and diarrhoea • Abdominal pain • Tachycardia or bradycardia • Hypertension or hypotension • Pulmonary oedema • Dizziness • Collapse • Convulsions • Shock • Cardiac arrest Specific systemic effects • Neurotoxic flaccid paralysis (descending or ascending) • Excitatory neurotoxicity (catecholamine storm-like and similar) • Rhabdomyolysis (systemic or local) • Coagulopathy (procoagulant/fibrinolytic or anticoagulant or thrombotic or antiplatelet) • Cardiotoxicity (decreased/abnormal cardiac function or arrhythmia or arrest) • Acute kidney injury (polyuria or oliguria or anuria or isolated elevated creatinine/urea)

156 • ENVENOMATION General approach to the envenomed patient First aid First aid can be crucial in determining the outcome for envenomed patients, yet throughout much of the world inappropriate and dangerous first aid is often administered. associated with some snakebites (notably Russell’s viper), is uncertain. • Renal damage in envenoming is mostly secondary, although some species, such as Russell’s vipers, can cause primary renal damage. The presentation is similar in both cases, with changes in urine output (polyuria, oliguria or anuria) or rises in creatinine and urea. In cases with intravascular haemolysis, secondary renal damage is likely. The clinical effects of specific animals in different regions of the world are shown in Boxes 8.4–8.6. Fig. 8.1 Sites of action of venoms on the haemostasis system. Copyright © Julian White. Haemorrhagic metalloproteinases and disintegrins Damage blood vessel wall, cause leakage of blood, degrade platelet plug response Direct fibrinolytics Split fibrinogen, often abnormally, resulting in poor clot formation and a bleeding tendency Procoagulants Activate specific coagulation factors to activate clotting cascade and promote formation of fibrin clots. Can also activate fibrinolytic system, resulting in defibrination and reduced ability to form protective clots Other haemostasis system toxins Target various parts of haemostasis, either as activators (e.g. plasminogen activators), or as inhibitors of coagulation (e.g. serpin inactivators, platelet aggregation inhibitors) Clotting factor pathways Factor II Factor IIa Fibrinogen Fibrin

8.4 Selected important venomous animals in Asia Scientific name1 Common name Clinical effects Antivenom/antidote/treatment Indian subcontinent Bungarus spp. (E) Kraits Flaccid paralysis2,3, myolysis4, hyponatraemia5 Indian PV or specific Naja spp. (E) Cobras Flaccid paralysis3, local necrosis/blistering, shock Indian PV or specific Ophiophagus hannah (E) King cobra Flaccid paralysis3, local necrosis, shock Indian PV or specific Echis spp. (Vv) Saw-scaled vipers Procoagulant coagulopathy, local necrosis/blistering, renal failure Indian PV or specific Daboia russelii (Vv) Russell’s viper Procoagulant coagulopathy, local necrosis/blistering, myolysis, renal failure, shock, flaccid paralysis2 Indian PV or specific Hypnale spp. (Vc) Hump-nosed vipers Procoagulant coagulopathy, shock, renal failure Try Indian PV Trimeresurus6 spp. (Vc) Green pit vipers Procoagulant coagulopathy, local necrosis, shock Indian PV or specific Hottentotta spp. (Sc) Indian scorpions Neuroexcitation, cardiotoxicity Indian specific AV Prazosin East Asia Bungarus spp. (E) Kraits Flaccid paralysis2,3 Specific AV from country Naja spp. (E) Cobras (some spitters) Flaccid paralysis3, local necrosis/blistering, shock Specific AV from country Ophiophagus hannah (E) King cobra Flaccid paralysis3, local necrosis, shock King cobra AV Calloselasma rhodostoma (Vc) Malayan pit viper Procoagulant coagulopathy, local necrosis/blistering, renal failure, shock Specific AV from country Daboia siamensis (Vv) Russell’s viper Procoagulant coagulopathy, local necrosis/blistering, renal failure, shock Specific AV from country Gloydius spp. (Vc) Mamushis, pit vipers Procoagulant coagulopathy, local necrosis/blistering, shock, renal failure, flaccid paralysis2 Specific AV from country Trimeresurus6 spp. (Vc) Green pit vipers, habus Procoagulant coagulopathy, local necrosis/blistering, shock Specific AV from country 1Family names: C = ‘Colubridae’ (mostly ‘non-venomous’; family subject to major taxonomic revisions); E = Elapidae (all venomous); Sc = Scorpionoidea; Vc = Viperidae Crotalinae (New World and Asian vipers); Vv = Viperidae viperinae (Old World vipers). 2Pre-synaptic. 3Post-synaptic. 4Only reported so far for B. candidus, B. niger and B. caeruleus. 5Only reported so far for B. multicinctus and B. candidus. 6Genus is subject to major taxonomic change (split into at least eight genera). (AV = antivenom; PV = polyvalent) More information is available from WHO-SEARO Guidelines for the management of snake-bites and from toxinology.com. Copyright © Julian White.

General approach to the envenomed patient • 157

8.5 Selected important venomous animals in the Americas and Australia Scientific name1 Common name Clinical effects Antivenom/antidote/treatment North America Crotalus spp. (Vc) Rattlesnakes Procoagulant coagulopathy, local necrosis/ blistering (flaccid paralysis2 rare), shock CroFab AV or Bioclon Antivipmyn AV Sistrurus spp. (Vc) Massasaugas Procoagulant coagulopathy, local necrosis/ blistering, shock CroFab AV or Bioclon Antivipmyn AV Agkistrodon spp. (Vc) Copperheads and moccasins Procoagulant coagulopathy, local necrosis/ blistering, shock CroFab AV or Bioclon Antivipmyn AV Micrurus spp. (E) Coral snakes Flaccid paralysis3 Bioclon Coralmyn AV Latrodectus mactans Widow spider Neuroexcitation MSD Widow spider AV Centruroides sculpturatus Arizona bark scorpion Neuroexcitation Bioclon Anascorp AV Central and South America Crotalus spp. (Vc) Rattlesnakes Flaccid paralysis2, myolysis, procoagulant coagulopathy, shock, renal failure Specific AV from country Bothrops spp. (Vc) Lancehead vipers Procoagulant coagulopathy, local necrosis/ blistering, shock, renal failure Specific AV from country Bothriechis spp. (Vc) Eyelash pit vipers Shock, pain and swelling Specific AV from country Lachesis spp. (Vc) Bushmasters Procoagulant coagulopathy, shock, renal failure, local necrosis/blistering Specific AV from country Micrurus spp. (E) Coral snakes Flaccid paralysis2,3, myolysis, renal failure Specific AV from country Tityus serrulatus Brazilian scorpion Neuroexcitation, shock Instituto Butantan scorpion AV Loxosceles spp. Recluse spiders Local necrosis Instituto Butantan spider AV Phoneutria nigriventer Banana spider Neuroexcitation, shock Instituto Butantan spider AV Potamotrygon, Dasyatis spp. Freshwater stingrays Necrosis of bite area, shock, severe pain and oedema No available AV; good wound care Australia Pseudonaja spp. (E) Brown snakes Procoagulant coagulopathy, renal failure, flaccid paralysis2 (rare) CSL brown snake AV or PVAV Notechis spp. (E) Tiger snakes Procoagulant coagulopathy, myolysis, flaccid paralysis2,3, renal failure CSL tiger snake AV or PVAV Oxyuranus spp. (E) Taipans Procoagulant coagulopathy, flaccid paralysis2,3, myolysis, renal failure CSL taipan or PVAV Acanthophis spp. (E) Death adders Flaccid paralysis3 CSL death adder or PVAV Pseudechis spp. Black and mulga snakes Anticoagulant coagulopathy, myolysis, renal failure CSL black snake AV or PVAV Enhydrina schistosa Sea snakes (all species globally) Flaccid paralysis and/or myolysis CSL sea snake AV Atrax, Hadronyche spp. Funnel web spiders Neuroexcitation, shock CSL funnel web spider AV Latrodectus hasseltii Red back spider Neuroexcitation, pain and sweating CSL red back spider AV Chironex fleckeri Box jellyfish Neuroexcitation, cardiotoxicity, local necrosis CSL box jellyfish AV Synanceia spp. Stonefish Severe local pain CSL stonefish AV 1For family name, see Box 8.4. 2Pre-synaptic. 3Post-synaptic. (PVAV = polyvalent antivenom) Copyright © Julian White. A significant proportion of venom is transported from the bite/ sting site via the lymphatic system, particularly for venoms with larger molecular weight toxins, such as many snake venoms. It is recommended that for most forms of envenoming, the patient should be kept still, the bitten limb immobilised with a splint and vital systems supported, where required. A patent upper airway should be specifically ensured and respiratory support provided, if required. For some animals, notably snakes in certain regions, the use of a local pressure pad bandage over the bite site (Myanmar) or a pressure immobilisation bandage (Australia, New Guinea) is recommended. Ineffective or dangerous first aid, such as suction devices, ‘cut and suck’, local chemicals, snake stones (stones of some sort placed over the snakebite) and tourniquets, should not be used. Tourniquets, in particular, have the potential to cause catastrophic distal limb injuries in snakebite when applied too narrowly or too tightly, or left on too long. Transporting patients Where possible, transport should be brought to the patient. It is also vital to obtain medical assessment and intervention at the earliest opportunity, however, so any delay in transporting the patient to a medical facility should be avoided. Severely envenomed patients may develop life-threatening problems, such as shock or respiratory failure, during transport, so ideally the transport method used should allow for management of these problems en route. In resource-poor environments, simple solutions for rapid transport have been successfully employed, such as motorbikes or similar with the patient supported between the driver in front and another person behind the patient. However, this method cannot cope with a patient developing airway compromise or respiratory failure, such as from developing neurotoxicity.

158 • ENVENOMATION dilated pupils, absent reflexes, no withdrawal response to painful stimuli, no movement of limbs, fixed forward gaze with gross ptosis; p. 152) when, in fact, the patient is conscious. Assessment for evidence of envenoming As in other areas of medicine, comprehensive assessment of a patient bitten/stung by a venomous animal requires a good history, a careful targeted examination and, where appropriate, ‘laboratory’ testing (though the latter may just consist of simple bedside tests performed by the doctor; p. 153). Animals that are unlikely to cause serious envenomation in humans should be identified so that inappropriate admission and intervention are avoided. Occasionally, patients may be unaware they have been bitten/stung and thus provide a misleading history. In regions of the world where keeping or handling venomous animals is illegal, patients may be reticent in giving a truthful history. Multiple bites or stings are more likely to cause major envenoming. The following key questions should be asked: • When was the patient exposed to the venomous bite/sting? • Was the organism causing it seen and what did it look like (size, colour)? • What were the circumstances (on land, in water etc.)? • Was there more than one bite/sting? • What first aid was used, when and for how long? • What symptoms has the patient had (local and systemic)? • Are there symptoms suggesting systemic envenoming (paralysis, rhabdomyolysis, coagulopathy etc.)? Assessment and management in hospital On arrival at a health station or hospital, there are two immediate priorities: • identifying and treating any life-threatening problems (e.g. circulatory shock, respiratory failure; see Ch. 16) • determining whether envenoming is present and if that requires urgent treatment. Assessment and management of life-threatening problems Patients who are seriously envenomed must be identified early so that appropriate management is not delayed. Critically ill patients must be resuscitated (p. 202) and this takes precedence over administration of any antivenom. Clinicians should look for signs of: • shock/hypotension • airway and/or respiratory compromise (likely to be secondary to flaccid paralysis) • major bleeding, including internal bleeding (especially intracranial) • impending limb compromise from inappropriate first aid (e.g. a tourniquet) – though beware sudden envenoming on removal of a tourniquet. In a patient with severe neurotoxic flaccid paralysis, who is still able to maintain sufficient respiratory function for survival, clinical assessment may suggest irretrievable brain injury (fixed 8.6 Selected important venomous animals in Africa and Europe Scientific name1 Common name Clinical effects Antivenom/antidote/treatment Africa Naja spp. (E) Cobras Non-spitters Flaccid paralysis3 ± local necrosis/blistering South African PV or Sanofi Pasteur FavAfrica AV Spitters Local necrosis/blistering (flaccid paralysis3 uncommon) South African PV or Sanofi Pasteur FavAfrica AV Dendroaspis spp. (E) Mambas Mamba neurotoxic flaccid paralysis and muscle fasciculation, shock, necrosis (uncommon) South African PV or Sanofi Pasteur FavAfrica AV Hemachatus haemachatus (E) Rinkhals Flaccid paralysis3, local necrosis, shock South African PV Atheris spp. (Vv) Bush vipers Procoagulant coagulopathy, shock, pain and swelling No available AV (can try South African AV) Bitis spp. (Vv) Puff adders etc. Procoagulant coagulopathy, shock, cardiotoxicity, local necrosis/blistering South African PV or Sanofi Pasteur FavAfrica AV Causus spp. (Vv) Night adders Pain and swelling No available AV Echis spp. (Vv) Carpet vipers Procoagulant coagulopathy, shock, renal failure, local necrosis/blistering Specific anti-Echis AV for species/geographical region or Sanofi Pasteur FavAfrica AV Cerastes spp. (Vv) Horned desert vipers Procoagulant coagulopathy, local necrosis, shock Specific or polyspecific AV covering Cerastes from country of origin Dispholidus typus (C) Boomslang Procoagulant coagulopathy, shock Boomslang AV Androctonus spp. North African scorpions Neuroexcitation Specific scorpion AV (Algeria, Tunisia, Sanofi Pasteur Scorpifav) Lelurus quinquestriatus Yellow scorpion Neuroexcitation, shock Specific scorpion AV (Algeria, Tunisia, Sanofi Pasteur Scorpifav) Europe Vipera spp. (Vv) Vipers and adders Shock, local necrosis/blistering, procoagulant coagulopathy (flaccid paralysis2 rare) ViperaTab AV or Zagreb AV or SanofiPasteur Viperfav AV 1For family name, see Box 8.4. 2Pre-synaptic. 3Post-synaptic. More information is available from WHO Guidelines for the prevention and clinical management of snakebite in Africa and from toxinology.com. Copyright © Julian White.

General approach to the envenomed patient • 159

• Is there any significant past medical history and medication use? • Is there a past exposure to antivenom/venom and allergies? If patients state that they have been bitten by a particular species, ensure this information is accurate. Private keepers of venomous animals may not have accurate knowledge of what they are keeping, and misidentification of a snake, scorpion or spider can have dire consequences if the wrong antivenom is used. An outline of some principal findings on examination of the envenomed patient is shown on page 152. The patient may have a cluster of clinical features suggestive of a particular type of envenoming (see Box 8.1). Even with dangerously venomous animals, some bites/stings will be dry bites and will not require antivenom. The time to onset of first symptoms and signs of envenomation is variable, depending on both animal and patient factors. It may range from a matter of minutes post-bite/sting to 24 hours later in some cases. Therefore, the initial assessment, if normal, must be repeated multiple times during the first 24 hours. Some types of envenomation will not cause symptoms or signs at all, or they may appear very late, long after the optimum time for treatment has passed. Evidence of envenomation may become apparent only through laboratory testing. Laboratory investigations Specific tests for venom are currently commercially available only for Australian snakebites but are likely to be developed for snakebites in other regions. They are not available for other types of envenomation, where venom concentrations are low. For snakebite, a screen for envenoming includes full blood count, coagulation screen, urea and electrolytes, creatinine, CK and electrocardiogram (ECG). Lung function tests, peripheral oximetry or arterial blood gases may be indicated in cases with potential or established respiratory failure. In areas without access to routine laboratory tests, the 20-minute whole-blood clotting test (20WBCT) is useful (p. 153). Treatment Once a diagnosis of likely envenoming has been made, the next and urgent decision is whether to give antivenom. Antivenom may not be the only crucial treatment, however. For a snakebite by a potentially lethal species such as Russell’s viper, the patient might have local effects with oedema, blistering, necrosis, and resultant fluid shifts causing shock, and at the same time have systemic effects such as intractable vomiting, coagulopathy, paralysis and secondary renal failure. Specific treatment with antivenom will be required to reverse the coagulopathy and may prevent worsening of the paralysis and reduce the vomiting, but will not greatly affect the local tissue damage or the renal failure or shock. The latter will require intravenous fluid therapy, possibly respiratory support, renal dialysis and local wound care, perhaps including antibiotics. Each venomous animal will cause a particular pattern of envenomation, requiring a tailored response. Listing all of these is beyond the scope of this chapter (see ‘Further information’ below). Antivenom Antivenom, sometimes inappropriately labelled as ‘anti- snake venom’ (ASV), is the most important tool in treating envenoming. It is made by hyperimmunising an animal, usually horses, to produce antibodies against venom. Once refined, these bind to venom toxins and render them inactive or allow their rapid clearance. Antivenom is available only for certain venomous animals and cannot reverse all types of envenoming. With a few exceptions, it should be given intravenously, with adrenaline (epinephrine) ready in case of anaphylaxis. It should be used only when clearly indicated, and indications will vary between venomous animals (Box 8.7). It is critical that the correct antivenom is used at the appropriate dose. Doses vary widely between antivenoms. In some situations (such as the Indian subcontinent), pre-treatment with subcutaneous adrenaline may reduce the chance of anaphylaxis to antivenom. Antivenom can sometimes reverse post-synaptic neurotoxic paralysis (α-bungarotoxin-like neurotoxins) but will not usually reverse established pre-synaptic paralysis (β-bungarotoxin-like neurotoxins), so should be given before major paralysis has occurred (Fig. 8.2). Coagulopathy is best reversed by antivenom, but even after all venom is neutralised, there may be a delay of hours before normal coagulation is restored. More antivenom should not be given because coagulopathy has failed to normalise fully in the first 1–3 hours (except in very particular circumstances). Thrombocytopenia may persist for days, despite antivenom. The role of antivenom in reversing established rhabdomyolysis and renal failure is uncertain. Antivenom may help limit local tissue effects or injury in the bitten limb but this is quite variable and time-dependent. Neuroexcitatory envenoming can respond very well to antivenom (Australian funnel web spider bites and Mexican, South American and Indian scorpion stings) but there is controversy about the effectiveness of antivenom for some species (some North African and Middle Eastern scorpions). The role of antivenom in limiting local venom effects, including necrosis, is also controversial; it is most likely to be effective when given early. All patients receiving antivenom are at risk of both early and late adverse reactions, including anaphylaxis (early; not always related to immunoglobulin E (IgE)) and serum sickness (late). Non-antivenom treatments Anticholinesterases are used as an adjunctive treatment for post-synaptic paralysis. Prazosin (an α-adrenoceptor antagonist) is used in the management of hypertension or pulmonary oedema in scorpion sting cardiotoxicity, particularly for Indian red scorpion stings, though antivenom is now the preferred treatment. 8.7 Indications for antivenom General indications • Shock/cardiac collapse • Respiratory compromise • Rapidly increasing swelling of the bitten limb • Active bleeding • Intractable non-specific symptoms, including recurrent vomiting Specific indications • Developing paralytic features (ptosis etc.) • Developing rhabdomyolysis • Developing coagulopathy • Developing renal failure • Developing neuroexcitatory envenoming Copyright © Julian White.

160 • ENVENOMATION Follow-up Cases with significant envenomation and those receiving antivenom should be followed up to ensure any complications have resolved and to identify any delayed envenoming. Envenomation by specific animals Venomous snakes Venomous snakes represent the single most important cause of envenomation globally, affecting millions of humans annually and resulting in large numbers of deaths and patients left with long-term disability. Of the 3000-plus snake species, more than 1000 either are venomous or produce oral toxins. The most important venomous snake families are the Viperidae (vipers; includes typical vipers (subfamily Viperinae) and pitvipers, with heat-sensing pit organs (subfamily Crotalinae)) and the Elapidae (cobras, kraits, mambas, coral snakes, sea snakes, Australian snakes). However, there are also dangerous species among the Atractaspididae (side-fanged burrowing vipers of Africa and the Middle East) and the non-frontfanged colubrids (NFFC snakes; several families, including the ‘back-fanged’ boomslang and vine snakes of Africa and the keelbacks of Asia). A selection of important species is included in Boxes 8.4–8.6. Clinical features and management As with other forms of envenoming, the management of snakebite follows the standard assessment guidelines described previously (p. 152). The nature of the risks posed will depend on the specific snake fauna in a given region (p. 153). For example, in the Indian subcontinent, the major snakebite risks are claimed to come from the ‘big four’: cobras, kraits, Russell’s viper and saw-scaled vipers. This list is misleading, though, as it omits other important snakes, including the hump-nosed vipers, king cobra and green pit vipers, all of which can cause severe or lethal envenoming and may not be covered by current Indian antivenoms. Even for those snakes recognised as causing envenoming, there may be major geographical variation in venom and features of envenoming. For Russell’s viper (Daboia spp.), Sri Lankan specimens can cause rhabdomyolysis and flaccid paralysis, in addition to classic severe coagulopathy, haemorrhage, local bite site injury and acute kidney injury (AKI). Indian populations of the same snake are not associated with either rhabdomyolysis or paralysis, but in parts of Southern India may cause anterior pituitary haemorrhage and/or capillary leak syndrome (hypotensive shock plus vascular leakage resulting in pulmonary oedema). Capillary leak syndrome is also encountered with populations of Burmese Russell’s viper (Myanmar), where AKI is especially common and severe. Antivenom raised against venom from one population of these snakes is often poorly effective against bites from snakes from other regions. Similarly, each of the several species of saw-scaled vipers (Echis spp.) spread from West Africa across the Middle East to the Indian subcontinent, including Sri Lanka, has specific venoms that may not be neutralised by antivenoms raised against other species in the genus; Indian antivenoms are ineffective against African species. It follows that, in managing snakebite envenomation, it is critically important to choose the appropriate antivenom and to understand that Antibiotics are not routinely required for most bites/stings, though a few animals, such as some South American pit vipers and stingrays, regularly cause significant wound infection or abscess. Tetanus is a risk in some types of bite or sting, such as snakebite, but intramuscular toxoid should not be given until any coagulopathy is reversed. Mechanical ventilation (p. 202) is vital for established respiratory paralysis that will not reverse with antivenom and may be required for prolonged periods (up to several months in some cases). Fasciotomy as a treatment for potential compartment syndrome or severe limb swelling is an overused and often disastrous surgical intervention in snakebite and is associated with poor functional outcomes. It should be reserved as a treatment of last resort and be used only in cases where compartment syndrome is confirmed by intracompartment pressure measurement and after first trying limb elevation and antivenom, and ensuring that any coagulopathy has resolved. Fig. 8.2 Principal snake venom neurotoxins acting at the neuromuscular junction (NMJ). The pre-synaptic neurotoxins (β-bungarotoxin-like) bind to the cell membrane of the terminal axon (1), form a synaptosome (2) and enter the cell, where they disrupt acetylcholine (ACh) production (3) and damage intracellular structures, including ion channels (4). On initial entry, they cause release of excess ACh, followed by cessation of all ACh release, causing irreversible paralysis until the cell is repaired (days to weeks later). The post-synaptic neurotoxins (α-bungarotoxin-like) bind adjacent to the ACh receptor on the external surface of the muscle end plate and block ACh binding (5), thereby ceasing neurotransmission. Because this action is external to the cell and does not cause cell damage, it is potentially a reversible paralysis. Copyright © Julian White. Motor neuron Acetylcholine Ca2+ Voltage-gated calcium channel Acetylcholine receptor Sodium channels in clefts amplify potential change Depolarisation of muscle membrane β-bungarotoxin class snake neurotoxins Normally, acetylcholine packets are released following calcium influx and cross the NMJ to bind to the ACh receptor α-bungarotoxin class snake neurotoxins

Envenomation by specific animals • 161

Spiders There are vast numbers and great species diversity of spiders, with two broad taxonomic groupings: the more ‘primitive’ Mygalomorphs (several medically important species, especially Australian funnel web spiders (Atrax, Hadronyche and Illawarra)) and the far more diverse Araneomorphs (main clinically important species in the genera Latrodectus (widow spiders), Loxosceles (brown recluse spiders) and Phoneutria (banana or wandering spiders)). Clinical features and management While spiders and spider bites are common, only those genera noted above commonly cause medically significant effects. In most cases this is a neuroexcitatory envenoming, sometimes similar to severe scorpion envenoming (notable from Australian funnel web spiders), but the recluse spiders cause an often painless bite that develops into local skin necrosis and sometimes a systemic illness similar to that caused by the Iranian scorpion, H. lepturus, and with similar lethal potential. For most of these spiders, antivenom remains the key treatment and is life-saving in some cases. Recent studies suggesting that anti-Latrodectus antivenom is ineffective have not been confirmed by independent studies and are in contrast to decades of positive clinical experience. Paralysis ticks Most ticks are vectors for disease but a few species in Australia, North America and parts of Africa can cause flaccid paralysis. Toxins in the saliva act as potent pre-synaptic neurotoxins that can cause gradual-onset ascending flaccid paralysis. There are no antivenoms for tick paralysis. Treatment is based on removal of all ticks and supportive care, including intubation/ ventilation where required. The paralysis usually resolves by about 48 hours following removal of all ticks. Venomous insects A number of insects are venomous but very few cause significant envenoming in humans. Venomous lepidopterans The Lonomia caterpillars of South America, especially Brazil, have numerous protective venomous spines that, on contact with the skin, can discharge a potent procoagulant venom that can cause a progressive and sometimes fatal consumptive coagulopathy, with terminal haemorrhagic and/or organ failure events. Treatment includes use of a Brazilian specific antivenom and supportive care. Venomous hymenopterans Many bees, wasps, hornets and some ants have modified ovipositors in the abdomen that act as stings, attached to venom glands. The quantity of venom injected in a single sting is insufficient to cause significant envenomation, but as many of these venoms are potently allergenic, it can cause severe and sometimes fatal anaphylaxis in sensitised persons (p. 75). Massed stings by hundreds of these insects in a swarm, however, can cause life-threatening systemic envenoming, often with intravascular haemolysis, DIC, shock and multi-organ failure. ‘Africanised’ bees are a particular risk for such attacks in South this may not include every antivenom claiming to cover a given species. It is unwise to assume that everything is known about envenoming by snakes because new clinical information and syndromes are emerging as more detailed studies are carried out. For instance, krait bites (Bungarus spp.), long associated with ‘painless’ bites, later development of devastating flaccid paralysis and a high mortality rate, are now known to have some venom diversity. At least some species can cause rhabdomyolysis and/or severe hyponatraemia, and while bites may be painless, systemic envenomation can cause severe abdominal pain in at least some patients. Among cobra bites, the previous division into ‘non-spitting’, neurotoxic species and ‘spitting’, less neurotoxic species that cause local necrosis is less clear. Non-spitters are now known to spit in parts of their range (e.g. Naja kaouthia in West Bengal) and may cause local necrosis in addition to paralysis. Previously clear diagnostic indicators for envenomation by particular types of snakes, such as Russell’s vipers and saw-scaled vipers causing coagulopathy, have also become less sure, as it is now known that other snakes, such as hump-nosed vipers (Hypnale spp.) and green pit vipers (Trimeresurus spp.), found in similar regions, can also cause marked coagulopathy and yet are often not covered by available antivenoms. The ability to cause life-threatening coagulopathy, associated with snakes previously considered harmless, such as the keelbacks in Asia (Rhabdophis spp.), can further complicate the diagnostic and management process, as antivenom against these snakes is currently available only in Japan. Scorpions Scorpions are second only to snakes in their venomous impact on humankind. Most medically important scorpions are in the family Buthidae and have complex neuroexcitatory venoms with highly specific ion-channel toxins. Classically, stings by these scorpions (some key genera listed in Boxes 8.4–8.6) cause moderate to severe local pain and rapid-onset systemic envenoming with development of a catecholamine storm-like syndrome as the toxins target the nervous system. There may be tachycardia or bradycardia, hyper- or hypotension, profuse sweating, salivation, cardiac dysfunction and pulmonary oedema. Cardiac collapse can occur, especially in children. Other clinical features may vary, depending on the scorpion species. The Iranian scorpion, Hemiscorpius lepturus (principally southwest Iran), causes a quite different presentation, with an initial minor sting, followed by progressive development of bite site or limb necrosis and a potentially lethal systemic envenoming, characterised by intravascular haemolysis, disseminated intravascular coagulation (DIC), secondary renal failure and shock. Clinical features and management The approach to management varies with species and region. In Latin America, specific antivenoms are routinely used and associated with improved outcomes and dramatic falls in mortality rate. In India, the past reliance on prazosin has been replaced with use of specific antivenom, again with improved outcomes. In contrast, in parts of North Africa, past reliance on antivenom has been replaced with use of cardiac support and arguably poorer outcomes. In Iran, H. lepturus stings are treated with antivenom, though as presentation is often delayed because the sting initially appears to be minor, the role of late antivenom is unclear.

162 • ENVENOMATION abdomen or chest are potentially lethal and wounds should be adequately explored, cleaned and allowed to heal by secondary intention. For bites by the blue-ringed octopus and stings by cone snails, rapid-acting venom can cause early cardiovascular collapse and flaccid paralysis. Supportive care is crucial in ensuring survival from these potentially lethal and seemingly trivial local wounds. Sea urchin and venomous starfish wounds can result in multiple penetrating spines, which cause pain and act as a nidus for secondary infection, but surgical removal of spines can be difficult and unrewarding. Further information Books and journal articles Meier J, White J. Handbook of clinical toxicology of animal venoms and poisons. Boca Raton: CRC Press; 1995. World Health Organisation, Regional Office for Africa. Guidelines for the prevention and clinical management of snakebite in Africa; 2010 (afro.who.int). World Health Organisation, Regional Office for South-East Asia. Guidelines for the management of snake-bites; 2010 (searo .who.int). Websites toxinology.com Clinical toxinology guide from the University of Adelaide. America and now in parts of North America. The giant wasps and hornets of Asia can similarly cause systemic envenoming with multiple attacks. Invasive ants, such as Solenopsis spp., are colonising new regions and can cause both allergic reactions and unpleasant local reactions. Marine venomous and poisonous animals The marine environment is dominated by animal life, and many species utilise toxins, either self-produced or taken up from the environment, to arm themselves for either defence or predation. Many of these animals can cause adverse effects in humans, either as a direct venom effect on bites/stings (venomous spiny fish, sea snakes, stingrays, jellyfish, sea urchins, some starfish, cone snails, selected octopuses etc.), or through poisoning if eaten (fugu, ciguatera, scombroid, several types of shellfish poisoning; p. 149). For venomous marine animals, there is antivenom available only for sea snakes, which can cause rhabdomyolysis and/paralytic neurotoxicity; box jellyfish, which can cause very rapid cardiac collapse; and stonefish, which cause intense sting-site pain. In general, marine venoms respond to heat; thus a hot water immersion or shower (about 45°C) is effective at reducing local pain, particularly for jellyfish, stinging fish and stingray stings. For stingray stings, the venom may cause local tissue damage both through sting trauma and a venom effect; wounds penetrating the

Ch03-2 Emergency and Critical Care _67ef

03-9 Environmental medicine

9 Environmental medicine

Environmental medicine M Byers Radiation exposure 164 Extremes of temperature 165 High altitude 168 Under water 169 Humanitarian crisis 171

164 • ENVIRONMENTAL MEDICINE representing 1 J/kg. To take account of different types of radiation and variations in the sensitivity of various tissues, weighting factors are used to produce a unit of effective dose, measured in sieverts (Sv). This value reflects the absorbed dose weighted for the damaging effects of a particular form of radiation and is most valuable in evaluating the long-term effects of exposure. ‘Background radiation’ refers to our exposure to naturally occurring radioactivity (e.g. radon gas and cosmic radiation). This produces an average annual individual dose of approximately 2.6 mSv per year, although this figure varies according to local geology. Effects of radiation exposure Effects on the individual are classified as either deterministic or stochastic. Deterministic effects Deterministic (threshold) effects occur with increasing severity as the dose of radiation rises above a threshold level. Tissues with actively dividing cells, such as bone marrow and gastrointestinal mucosa, are particularly sensitive to ionising radiation. Lymphocyte depletion is the most sensitive marker of bone marrow injury, and after exposure to a fatal dose, marrow aplasia is a common cause of death. However, gastrointestinal mucosal toxicity may cause earlier death due to profound diarrhoea, vomiting, dehydration and sepsis. The gonads are highly radiosensitive and radiation may result in temporary or permanent sterility. Eye exposure can lead to cataracts and the skin is susceptible to radiation burns. Irradiation of the lung may induce acute inflammatory reactions or pulmonary fibrosis, and irradiation of the central nervous system may cause permanent neurological deficit. Bone necrosis and lymphatic fibrosis are characteristic following regional irradiation, particularly for breast cancer. The thyroid gland is not inherently sensitive but its ability to concentrate iodine makes it susceptible to damage after exposure to relatively low doses of radioactive iodine isotopes, such as those released from Chernobyl. Stochastic effects Stochastic (chance) effects occur with increasing probability as the dose of radiation increases. Carcinogenesis represents a stochastic effect. With acute exposures, leukaemias may arise after an interval of around 2–5 years and solid tumours after an Environmental medicine deals with the interactions between the environment and human health. While previously concerned mainly with controlling infectious diseases, the focus at present is predominantly on the multiple physical, chemical, biological and social factors that pose risks to human health. As the environment continually alters, whether through population growth, economic development or climate change, it plays an important role in disease causation – one that may increase over time. This chapter deals principally with acute effects of environmental hazards on individuals and should be read in conjunction with the chapters on Poisoning (Ch. 7) and Acute Medicine and Critical Illness (Ch. 10). Chapter 5 deals with more general effects of environmental factors on population health. Radiation exposure Radiation includes ionising (Fig. 9.1) and non-ionising radiations (ultraviolet (UV), visible light, laser, infrared and microwave). While global industrialisation and the generation of fluorocarbons have raised concerns about loss of the ozone layer, leading to an increased exposure to UV rays, and disasters such as the Chernobyl and Fukushima nuclear power station explosions have demonstrated the harm of ionising radiation, it is important to remember that it can be harnessed for medical benefit. Ionising radiation is used in X-rays, computed tomography (CT), radionuclide scans and radiotherapy, and non-ionising UV for therapy in skin diseases and laser therapy for diabetic retinopathy. Types of ionising radiation These include charged subatomic alpha and beta particles, uncharged neutrons or high-energy electromagnetic radiations such as X-rays and gamma rays. When they interact with atoms, energy is released and the resulting ionisation can lead to molecular damage. The clinical effects of different forms of radiation depend on their range in air and tissue penetration (Fig. 9.1). Dosage and exposure The dose of radiation is based on the energy absorbed by a unit mass of tissue and is measured in grays (Gy), with 1 Gy Fig. 9.1 Properties of different ionising radiations. Paper Range in air Range in tissue Few centimetres No penetration Few metres Few millimetres Kilometres Passes through Kilometres Passes through Alpha particles e.g. radium, uranium Beta particles e.g. 14carbon, 90strontium X-rays/gamma rays e.g. 131iodine, 99mtechnetium Neutrons Aluminium foil Lead/concrete Protection

Extremes of temperature • 165

In a cold environment, protective mechanisms include cutaneous vasoconstriction and shivering; however, any muscle activity that involves movement may promote heat loss by increasing convective loss from the skin, and respiratory heat loss by stimulating ventilation. In a hot environment, sweating is the main mechanism for increasing heat loss. This usually occurs when the ambient temperature rises above 32.5°C or during exercise. Hypothermia Hypothermia exists when the body’s normal thermal regulatory mechanisms are unable to maintain heat in a cold environment and core temperature falls below 35°C (Fig. 9.2). Moderate hypothermia occurs below 32°C and severe hypothermia below 28°C. Other systems define hypothermia on the basis of symptoms rather than absolute temperature. While infants are susceptible to hypothermia because of their poor thermoregulation and high body surface area to weight ratio, it is the elderly who are at highest risk (Box 9.2). Hypothyroidism is often a contributory factor in old age, while interval of about 10–20 years. Thereafter the incidence rises with time. An individual’s risk of developing cancer depends on the dose received, the time to accumulate the total dose and the interval following exposure. Management of radiation exposure Exposed people should be removed from ongoing exposure (‘get inside, stay inside’), and should take off affected clothing and shower to stop further contamination. If contamination of food and water supplies may have occurred, only bottled water and food in sealed containers should be consumed. The principal problems after large-dose exposures are maintenance of adequate hydration, control of sepsis and management of marrow aplasia. Associated injuries such as thermal burns need specialist management within 48 hours of active resuscitation. Internal exposure to radioisotopes should be treated with chelating agents (such as Prussian blue used to chelate 137caesium after ingestion). White-cell colony stimulation and haematopoietic stem cell transplantation may need to be considered for marrow aplasia. Extremes of temperature Thermoregulation Body heat is generated by basal metabolic activity and muscle movement, and lost by conduction (which is more effective in water than in air), convection, evaporation and radiation (most important at lower temperatures when other mechanisms conserve heat) (Box 9.1). Body temperature is controlled in the hypothalamus, which is directly sensitive to changes in core temperature and indirectly responds to temperature-sensitive neurons in the skin. The normal ‘set-point’ of core temperature is tightly regulated within the range 37 ± 0.5°C, which is necessary to preserve the normal function of many enzymes and other metabolic processes. The temperature set-point is increased in response to infection (p. 218). Fig. 9.2 Clinical features of abnormal core temperature. The hypothalamus normally maintains core temperature at 37°C, but this set-point is altered in, for example, fever (pyrexia, p. 218), and may be lost in hypothalamic disease (p. 679). In these circumstances, the clinical picture at a given core temperature may be different.

<37 <35 <32 <28

°C Definitions Clinical features Heat stroke Heat exhaustion Mild hypothermia Severe hypothermia Hot and not sweating Multiple organ failure, confusion, aggression, shock Hot and sweating Headache, weakness, fatigue, irritability, tachycardia, dehydration Tachycardia, vasoconstriction Cold and not shivering Cold, pale skin Depressed consciousness Muscle stiffness Bradycardia and hypotension Coma Dilated, unreactive pupils Cardiac standstill Cold and shivering ‘Mumble, stumble, tumble’ Lethargy Dehydration Tachypnoea Moderate hypothermia Violent shivering Slurred speech Slow, laboured movements Ataxia, mild confusion Pale with blue lips 9.1 Thermoregulation: responses to hot and cold environments Mechanism Hot environment Cold environment Heat production Basal metabolic rate → ↓ in hypothermia Muscle activity ↓ by lethargy ↑ by shivering ↓ in severe hypothermia Heat loss Conduction* ↑ by vasodilatation ↓ by vasoconstriction ↑↑ in water < 31°C Convection* ↑ by vasodilatation ↓ by lethargy ↓ by vasoconstriction ↑ by wind and movement Evaporation* ↑↑ by sweating ↓ by high humidity ↑ by hyperventilation Radiation ↑ by vasodilatation ↓ by vasoconstriction (but is the major heat loss in dry cold) *These losses are dependent on the relative ambient and skin temperatures.

166 • ENVIRONMENTAL MEDICINE aminotransferase and creatine kinase may be elevated secondary to muscle damage and the serum amylase is often high due to subclinical pancreatitis. If the cause of hypothermia is not obvious, additional investigations for thyroid and pituitary–adrenal dysfunction (p. 633), hypoglycaemia (p. 725) and the possibility of drug intoxication (p. 134) should be performed. Management Following resuscitation, the objectives of management are to rewarm the patient in a controlled manner while treating associated hypoxia (by oxygenation and ventilation if necessary), fluid and electrolyte disturbance, and cardiovascular abnormalities, particularly arrhythmias. Careful handling is essential to avoid precipitating the latter. The method of rewarming is dependent not on the absolute core temperature, but on haemodynamic stability and the presence or absence of an effective cardiac output. Mild hypothermia Outdoors, continued heat loss is prevented by sheltering the patient from the cold, replacing wet clothing, covering the head and insulating him or her from the ground. Once in hospital, even in the presence of profound hypothermia, if there is an effective cardiac output then forced-air rewarming, heat packs placed in axillae and groins and around the abdomen, inhaled warmed air and correction of fluid and electrolyte disturbances are usually sufficient. Rewarming rates of 1–2°C per hour are effective in leading to a gradual and safe return to physiological normality. Underlying conditions should be treated promptly (e.g. hypothyroidism with triiodothyronine 10 μg IV 3 times daily; p. 640). Severe hypothermia In the case of severe hypothermia (< 28°C), patients with cardiopulmonary arrest (non-perfusing rhythm), or those with cardiac instability (systolic blood pressure < 90 mmHg or ventricular arrhythmias), the aim is to restore perfusion, and rapid rewarming at a rate of > 2°C per hour is required. This is best achieved by cardiopulmonary bypass or extracorporeal membrane oxygenation (ECMO). If these are unavailable, then veno–veno haemofiltration, and pleural, peritoneal, thoracic or bladder lavage with warmed fluids are alternatives. Direct heat sources, such as hot water or heat pads, should be used with caution, as these can provoke cardiac arrhythmias or cause burns. Monitoring of cardiac rhythm and arterial blood gases, including H+ (pH), is essential. Significant acidosis may require correction (p. 364). Cold injury Freezing cold injury (frostbite) This represents the direct freezing of body tissues and usually affects the extremities: in particular, the fingers, toes, ears and face. Risk factors include smoking, peripheral vascular disease, dehydration and alcohol consumption. The tissues may become anaesthetised before freezing and, as a result, the injury often goes unrecognised at first. Frostbitten tissue is initially pale and doughy to the touch and insensitive to pain (Fig. 9.4). Once frozen, the tissue is hard. Rewarming should not occur until it can be achieved rapidly in a water bath. Give oxygen and aspirin 300 mg as soon as possible. Frostbitten extremities should be rewarmed in warm water at 37–39°C, with antiseptic added. Adequate analgesia is necessary, as rewarming is very painful. Vasodilators such as alcohol and other drugs (e.g. phenothiazines) commonly impede the thermoregulatory response in younger people. More rarely, hypothermia is secondary to hypothyroidism, glucocorticoid insufficiency, stroke, hepatic failure or hypoglycaemia. Hypothermia also occurs in healthy individuals whose thermoregulatory mechanisms are intact but insufficient to cope with the intensity of the thermal stress. Typical examples include immersion in cold water, when core temperature may fall rapidly (acute hypothermia), exposure to extreme climates such as during hill walking (subacute hypothermia), and slow-onset hypothermia, as develops in an immobilised older individual (subchronic hypothermia). This classification is important, as it determines the method of rewarming. Clinical features Diagnosis is dependent on recognition of the environmental circumstances and measurement of core (rectal) body temperature. Clinical features depend on the degree of hypothermia (Fig. 9.2). In a cold patient, it is very difficult to diagnose death reliably by clinical means. It has been suggested that, in extreme environmental conditions, irreversible hypothermia is probably present if there is asystole (no carotid pulse for 1 min), the chest and abdomen are rigid, the core temperature is < 13°C and serum potassium is > 12 mmol/L. However, in general, resuscitative measures should continue until the core temperature is normal and only then should a diagnosis of brain death be considered (p. 211). Investigations Blood gases, a full blood count, electrolytes, chest X-ray and electrocardiogram (ECG) are all essential investigations. Haemoconcentration and metabolic acidosis are common, and the ECG may show characteristic J waves, which occur at the junction of the QRS complex and the ST segment (Fig. 9.3). Cardiac arrhythmias, including ventricular fibrillation, may occur. Although the arterial oxygen tension may be normal when measured at room temperature, the arterial PO2 in the blood falls by 7% for each 1°C fall in core temperature. Serum aspartate Fig. 9.3 Electrocardiogram showing J waves (arrows) in a hypothermic patient. 9.2 Thermoregulation in old age • Age-associated changes: impairments in vasomotor function, skeletal muscle response and sweating mean that older people react more slowly to changes in temperature. • Increased comorbidity: thermoregulatory problems are more likely in the presence of pathology such as atherosclerosis and hypothyroidism, and medication such as sedatives and hypnotics. • Hypothermia: this may arise as a primary event, but more commonly complicates other acute illness, e.g. pneumonia, stroke or fracture. • Ambient temperature: financial pressures and older equipment may result in inadequate heating during cold weather.

Extremes of temperature • 167

large extent by adequate replacement of salt and water, although excessive water intake alone should be avoided because of the risk of dilutional hyponatraemia (p. 357). A spectrum of illnesses occurs in the heat (see Fig. 9.2). The cause is usually obvious but the differential diagnosis should be considered (Box 9.3). Heat cramps These painful muscle contractions occur following vigorous exercise and profuse sweating in hot weather. There is no elevation of core temperature. The mechanism is considered to be extracellular sodium depletion as a result of persistent sweating, exacerbated by replacement of water but not salt. Symptoms usually respond rapidly to rehydration with oral rehydration salts or intravenous saline. Heat syncope This is similar to a vasovagal faint (p. 181) and is related to peripheral vasodilatation in hot weather. Heat exhaustion Heat exhaustion occurs with prolonged exertion in hot and humid weather, profuse sweating and inadequate salt and water replacement. There is an elevation in core (rectal) temperature to between 37°C and 40°C, leading to the clinical features shown in Figure 9.2. Blood analyses may show evidence of dehydration with mild elevation of the blood urea, sodium and haematocrit. Treatment involves removal of the patient from the heat, and active evaporative cooling using tepid sprays and fanning (‘strip–spray–fan’). Fluid losses are replaced with either oral rehydration mixtures or intravenous isotonic saline. Up to 5 L positive fluid balance may be required in the first 24 hours. Untreated, heat exhaustion may progress to heat stroke. Heat stroke Heat stroke occurs when the core body temperature rises above 40°C and is a life-threatening condition. The symptoms of heat exhaustion progress to include headache, nausea and vomiting. Neurological manifestations include a coarse muscle tremor and confusion, aggression or loss of consciousness. The patient’s skin feels very hot, and sweating is often absent due to failure of thermoregulatory mechanisms. Complications include hypovolaemic shock, lactic acidosis, disseminated intravascular coagulation, rhabdomyolysis, hepatic and renal failure, and pulmonary and cerebral oedema. Duration of hyperthermia is key to the outcome and immediate cooling should begin at the scene, before transfer to hospital. The aim should be to reduce core temperature by > 0.2°C per minute to approximately 39°C, while avoiding overshooting and hypothermia. The patient should be resuscitated with evaporative or convective cooling. Fluid resuscitation with crystalloid intravenous fluids should be instituted but solutions containing potassium pentoxifylline (a phosphodiesterase inhibitor) have been shown to improve tissue survival. Once it has thawed, the injured part must not be re-exposed to the cold, and should be dressed and rested. While wound débridement may be necessary, amputations should be delayed for 60–90 days, as good recovery may occur over an extended period. As yet, the role of hyperbaric oxygen in the treatment of frostbite requires further research. Non-freezing cold injury (trench or immersion foot) This results from prolonged exposure to cold, damp conditions. The limb (usually the foot) appears cold, ischaemic and numb, but there is no freezing of the tissue. On rewarming, the limb appears mottled and thereafter becomes hyperaemic, swollen and painful. Recovery may take many months, during which period there may be chronic pain and sensitivity to cold. The pathology remains uncertain but probably involves endothelial injury. Gradual rewarming is associated with less pain than rapid rewarming. The pain and associated paraesthesia are difficult to control with conventional analgesia and may require amitriptyline (50 mg nocte), best instituted early. The patient is at risk of further damage on subsequent exposure to the cold. Chilblains Chilblains are tender, red or purplish skin lesions that occur in the cold and wet. They are often seen in horse riders, cyclists and swimmers, and are more common in women than men. They are short-lived and, although painful, not usually serious. Heat-related illness When generation of heat exceeds the body’s capacity for heat loss, core temperature rises. Non-exertional heat illness (NEHI) occurs with a high environmental temperature in those with attenuated thermoregulatory control mechanisms: the elderly, the young, those with comorbidity or those taking drugs that affect thermoregulation (particularly phenothiazines, diuretics and alcohol). Exertional heat illness (EHI), on the other hand, typically develops in athletes when heat production exceeds the body’s ability to dissipate it. Acclimatisation mechanisms to environmental heat include stimulation of the sweat mechanism with increased sweat volume, reduced sweat sodium content and secondary hyperaldosteronism to maintain body sodium balance. The risk of heat-related illness falls as acclimatisation occurs. Heat illness can be prevented to a Fig. 9.4 Frostbite in a female Everest sherpa. 9.3 Differential diagnosis in patients with elevated core body temperature • Heat illness (heat exhaustion, heat stroke) • Sepsis, including meningitis • Malaria • Drug overdose • Serotonin syndrome (pp. 139 and 1199) • Malignant hyperpyrexia • Thyroid storm (p. 639)

168 • ENVIRONMENTAL MEDICINE on the shape of the sigmoid oxygen–haemoglobin dissociation curve (see Fig. 23.5, p. 917) and the ventilatory response. Acclimatisation to hypoxaemia at high altitude involves a shift in this dissociation curve (dependent on 2,3-diphosphoglycerate (2,3-DPG)), erythropoiesis, haemoconcentration, and hyperventilation resulting from hypoxic drive, which is then sustained despite hypocapnia by restoration of cerebrospinal fluid pH to normal in prolonged hypoxia. This process takes several days, so travellers need to plan accordingly. Illnesses at high altitude Ascent to altitudes up to 2500 m or travel in a pressurised aircraft cabin is harmless to healthy people. Above 2500 m high-altitude illnesses may occur in previously healthy people, and above 3500 m these become common. Sudden ascent to altitudes above 6000 m, as experienced by aviators, balloonists and astronauts, may result in decompression illness with the same clinical features as seen in divers (see below), or even loss of consciousness. However, most altitude illness occurs in travellers and mountaineers. Acute mountain sickness Acute mountain sickness (AMS) is a syndrome comprised principally of headache, together with fatigue, anorexia, nausea and vomiting, difficulty sleeping or dizziness. Ataxia and peripheral oedema may be present. The aetiology of AMS is not fully understood but it is thought that hypoxaemia increases cerebral blood flow and hence intracranial pressure. Symptoms occur within 6–12 hours of an ascent and vary in severity from trivial to completely incapacitating. The incidence in travellers to 3000 m may be 40–50%, depending on the rate of ascent. Treatment of mild cases consists of rest and simple analgesia; symptoms usually resolve after 1–3 days at a stable altitude, but may recur with further ascent. Occasionally, there is progression to cerebral oedema. Persistent symptoms indicate the need to descend but may respond to acetazolamide, a carbonic anhydrase inhibitor that induces a metabolic acidosis and stimulates ventilation; acetazolamide may also be used as prophylaxis if a rapid ascent is planned. High-altitude cerebral oedema The cardinal symptoms of high-altitude cerebral oedema (HACE) are ataxia and altered consciousness. HACE is rare, life-threatening and usually preceded by AMS. In addition to features of AMS, the patient suffers confusion, disorientation, visual disturbance, lethargy and ultimately loss of consciousness. Papilloedema and retinal haemorrhages are common and focal neurological signs may be found. Treatment is directed at improving oxygenation. Descent is essential and dexamethasone (8 mg immediately and 4 mg 4 times daily) should be given. If descent is impossible, oxygen therapy in a portable pressurised bag may be helpful. High-altitude pulmonary oedema High-altitude pulmonary oedema (HAPE) is a life-threatening condition that usually occurs in the first 4 days after ascent above 2500 m. Unlike HACE, HAPE may occur de novo without the preceding signs of AMS. Presentation is with symptoms of dry cough, exertional dyspnoea and extreme fatigue. Later, the cough becomes wet and sputum may be blood-stained. Tachycardia and tachypnoea occur at rest and crepitations may often be heard in both lung fields. There may be profound hypoxaemia, pulmonary hypertension and radiological evidence should be avoided. Intravenous dextrose may be necessary, as hypoglycaemia can occur. Appropriate monitoring of fluid balance, including central venous pressure, is important, as overaggressive fluid replacement may precipitate pulmonary oedema or further metabolic disturbance. Investigations for complications include routine haematology and biochemistry, coagulation screen, hepatic transaminases (aspartate aminotransferase and alanine aminotransferase), creatine kinase and chest X-ray. Once emergency treatment is established, heat stroke patients are best managed in intensive care. Heat stroke is an emergency with a significant mortality. However, where temperatures can be reduced to < 40°C within 30 minutes of collapse, death rates can approach zero. Patients who have had core temperatures of > 40°C should be monitored carefully for later onset of rhabdomyolysis, renal damage and other complications before discharge from hospital. Clear advice to avoid heat and heavy exercise during recovery is important. High altitude The physiological effects of high altitude are significant. On Everest, the barometric pressure of the atmosphere falls from sea level by approximately 50% at base camp (5400 m) and approximately 70% at the summit (8848 m). The proportions of oxygen, nitrogen and carbon dioxide in air do not change with the fall in pressure but their partial pressure falls in proportion to barometric pressure (Fig. 9.5). Oxygen tension within the pulmonary alveoli is further reduced at altitude because the partial pressure of water vapour is related to body temperature and not barometric pressure, and so is proportionately greater at altitude, accounting for only 6% of barometric pressure at sea level but 19% at 8848 m. Physiological effects of high altitude Reduction in oxygen tension results in a fall in arterial oxygen saturation (Fig. 9.5). This varies widely between individuals, depending Fig. 9.5 Change in inspired oxygen tension and blood oxygen saturation at altitude. The blue curve shows changes in oxygen availability at altitude and the red curve shows the typical resultant changes in arterial oxygen saturation in a healthy person. Oxygen saturation varies between individuals according to the shape of the oxygen–haemoglobin dissociation curve and the ventilatory response to hypoxaemia. (To convert kPa to mmHg, multiply by 7.5.) Summit of Everest (8848 m) Highest permanent habitation (< 5200 m) Arterial oxygen saturation Partial pressure of inspired oxygen

Partial pressure of oxygen (kPa) Pressurised aircraft cabin (< 2400 m)

Arterial oxygen saturation (%)

Altitude above sea level (m)

Under water • 169

arrhythmia, sickle-cell disease and ischaemic heart disease. Most airlines decline to carry pregnant women after the 36th week of gestation. In complicated pregnancies it may be advisable to avoid air travel at an earlier stage. Patients who have had recent abdominal surgery, including laparoscopy, should avoid flying until all intraperitoneal gas is reabsorbed. Divers should not fly for 24 hours after a dive requiring decompression stops. Ear and sinus pain due to changes in gas volume are common but usually mild, although patients with chronic sinusitis and otitis media may need specialist assessment. A healthy mobile tympanic membrane visualised during a Valsalva manœuvre usually suggests a patent Eustachian tube. On long-haul flights, patients with diabetes mellitus may need to adjust their insulin or oral hypoglycaemic dosing according to the timing of in-flight and subsequent meals (p. 750). Advice is available from Diabetes UK and other websites. Patients should be able to provide documentary evidence of the need to carry needles and insulin. Deep venous thrombosis Air travellers have an increased risk of venous thrombosis (p. 975), due to a combination of factors, including loss of venous emptying because of prolonged immobilisation (lack of muscular activity) and reduced barometric pressure on the tissues, together with haemoconcentration as a result of oedema and perhaps a degree of hypoxia-induced diuresis. Venous thrombosis can probably be prevented by avoiding dehydration and excess alcohol, and by exercising muscles during the flight. Without a clear cost–benefit analysis, prophylaxis with aspirin or heparin cannot be recommended routinely, but may be considered in high-risk cases. Under water Drowning and near-drowning Drowning is defined as death due to asphyxiation following immersion in a fluid, while near-drowning is defined as survival for longer than 24 hours after suffocation by immersion. Drowning remains a common cause of accidental death throughout the world and is particularly common in young children (Box 9.4). In about 10% of cases, no water enters the lungs and death follows intense laryngospasm (‘dry’ drowning). Prolonged immersion in cold water, with or without water inhalation, results in a rapid fall in core body temperature and hypothermia (p. 165). Following inhalation of water, there is a rapid onset of ventilation– perfusion imbalance with hypoxaemia, and the development of diffuse alveolar oedema. It is not known whether the alveolar oedema is a result of mechanical stress on the pulmonary capillaries associated with the high pulmonary arterial pressure, or an effect of hypoxia on capillary permeability. Reduced arterial oxygen saturation is not diagnostic but is a marker for disease progression. Treatment is directed at reversal of hypoxia with immediate descent and oxygen administration. Nifedipine (20 mg 4 times daily) should be given to reduce pulmonary arterial pressure, and oxygen therapy in a portable pressurised bag should be used if descent is delayed. Chronic mountain sickness (Monge’s disease) This occurs on prolonged exposure to altitude and has been reported in residents of Colorado, South America and Tibet. Patients present with headache, poor concentration and other signs of polycythaemia. The haemoglobin concentration is high (> 200 g/L) and the haematocrit raised (> 65%). Affected individuals are cyanosed and often have finger clubbing. High-altitude retinal haemorrhage This occurs in over 30% of trekkers at 5000 m. The haemorrhages are usually asymptomatic and resolve spontaneously. Visual defects can occur with haemorrhage involving the macula but there is no specific treatment. Venous thrombosis This has been reported at altitudes of > 6000 m. Risk factors include dehydration, inactivity and the cold. The use of the oral contraceptive pill at high altitude should be considered carefully, as this is an additional risk factor. Refractory cough A cough at high altitude is common and usually benign. It may be due to breathing dry, cold air and to increased mouth breathing, with consequent dry oral mucosa. This may be indistinguishable from the early signs of HAPE. Air travel Commercial aircraft usually cruise at 10 000–12 000 m, with the cabin pressurised to an equivalent of around 2400 m. At this altitude, the partial pressure of oxygen is 16 kPa (120 mmHg), leading to a PaO2 in healthy people of 7.0–8.5 kPa (53–64 mmHg). Oxygen saturation is also reduced but to a lesser degree (see Fig. 9.5). Although well tolerated by healthy people, this degree of hypoxia may be dangerous in patients with respiratory disease. Advice for patients with respiratory disease The British Thoracic Society has published guidance on the management of patients with respiratory disease who want to fly. Specialist pre-flight assessment is advised for all patients who have hypoxaemia (oxygen saturation < 95%) at sea level, and includes spirometry and a hypoxic challenge test with 15% oxygen (performed in hospital). Air travel may have to be avoided or undertaken only with inspired oxygen therapy during the flight. Asthmatic patients should be advised to carry their inhalers in their hand baggage. Following pneumothorax, flying should be avoided while air remains in the pleural cavity, but can be considered after proven resolution or definitive (surgical) treatment. Advice for other patients Other circumstances in which patients are more susceptible to hypoxia require individual assessment. These include cardiac 9.4 Most common causes of drowning by age Infants/young children • Domestic baths • Garden pools Adolescents • Swimming pools • Rivers, sea, etc. Adults • Water sports, boating, fishing • Occupational Older people • Domestic baths

170 • ENVIRONMENTAL MEDICINE Diving-related illness The underwater environment is extremely hostile. Other than drowning, most diving illness is related to changes in barometric pressure and its effect on gas behaviour. Ambient pressure under water increases by 101 kPa (1 atmosphere, 1 ata) for every 10 metres of seawater (msw) or 33 eet of seawater (fsw) depth. As divers descend, the partial pressures of the gases they are breathing increase (Box 9.5), and the blood and tissue concentrations of dissolved gases rise accordingly. Nitrogen is a weak anaesthetic agent, and if the inspiratory pressure of nitrogen is allowed to increase above 320 kPa (3.2 ata; i.e. a depth of approximately 30 msw), it produces ‘narcosis’, resulting in impairment of cognitive function and manual dexterity, not unlike alcohol intoxication. For this reason, compressed air can be used only for shallow diving. Oxygen is also toxic at inspired pressures above approximately 40 kPa (0.4 ata; inducing apprehension, muscle twitching, euphoria, sweating, tinnitus, nausea and vertigo), so 100% oxygen cannot be used as an alternative. For dives deeper than approximately 30 msw, mixtures of oxygen with nitrogen and/ or helium are used. While drowning remains the most common diving-related cause of death, another important group of disorders usually present once the diver returns to the surface: decompression illness (DCI) and barotrauma. Clinical features Decompression illness This includes decompression sickness (DCS) and arterial gas embolism (AGE). While the vast majority of symptoms of DCI present within 6 hours of a dive, they can also be provoked by flying (further decompression), and thus patients may present to medical services at sites far removed from the dive. Exposure of individuals to increased partial pressures of nitrogen results in additional nitrogen being dissolved in body tissues; the amount dissolved depends on the depth/pressure and on the duration of the dive. On ascent, the tissues become supersaturated with nitrogen, and this places the diver at risk of producing a critical quantity of gas (bubbles) in tissues if the ascent is too fast. The gas so formed may cause symptoms locally, peripherally due to bubbles passing through the pulmonary vascular bed (Box 9.6) or by embolisation elsewhere. Arterial embolisation may occur if the gas load in the venous system exceeds the lungs’ abilities to excrete nitrogen, or when bubbles pass through a patent foramen ovale (present asymptomatically of diffuse pulmonary oedema. Fresh water is hypotonic and, although rapidly absorbed across alveolar membranes, impairs surfactant function, which leads to alveolar collapse and rightto-left shunting of unoxygenated blood. Absorption of large amounts of hypotonic fluid can result in haemolysis. Salt water is hypertonic and inhalation provokes alveolar oedema, but the overall clinical effect is similar to that of freshwater drowning. Clinical features Those rescued alive (near-drowning) are often unconscious and not breathing. Hypoxaemia and metabolic acidosis are inevitable features. Acute lung injury usually resolves rapidly over 48– 72 hours, unless infection occurs (Fig. 9.6). Complications include dehydration, hypotension, haemoptysis, rhabdomyolysis, renal failure and cardiac arrhythmias. A small number of patients, mainly the more severely ill, progress to develop the acute respiratory distress syndrome (ARDS; p. 198). Survival is possible after immersion for up to 30 minutes in very cold water, as the rapid development of hypothermia after immersion may be protective, particularly in children. Long-term outcome depends on the severity of the cerebral hypoxic injury and is predicted by the duration of immersion, delay in resuscitation, intensity of acidosis and the presence of cardiac arrest. Management Initial management requires cardiopulmonary resuscitation with administration of oxygen and maintenance of the circulation (p. 456). It is important to clear the airway of foreign bodies and protect the cervical spine. Continuous positive airways pressure (CPAP; p. 202) should be considered for spontaneously breathing patients with oxygen saturations of < 94%. Observation is required for a minimum of 24 hours. Prophylactic antibiotics are only required if exposure was to obviously contaminated water. Fig. 9.6 Near-drowning. Chest X-ray of a 39-year-old farmer, 2 weeks after immersion in a polluted freshwater ditch for 5 min before rescue. Airspace consolidation and cavities in the left lower lobe reflect secondary staphylococcal pneumonia and abscess formation. 9.5 Physics of breathing compressed air while diving in sea water Depth Lung volume Barometric pressure PiO2 PiN2 Surface 100% 101 kPa (1 ata) 21 kPa (0.21 ata) 79 kPa (0.78 ata) 10 m 50% 202 kPa (2 ata) 42 kPa (0.42 ata) 159 kPa (1.58 ata) 20 m 33% 303 kPa (3 ata) 63 kPa (0.63 ata) 239 kPa (2.34 ata) 30 m 25% 404 kPa (4 ata) 84 kPa (0.84 ata) 319 kPa (3.12 ata)

Humanitarian crisis • 171

The majority of patients make a complete recovery with treatment, although a small but significant proportion are left with neurological disability. Humanitarian crisis Humanitarian crises are common. If the medical profession is to help, it must understand that the emergency treatment of a few sick and injured people is not always the priority and that there is a set of basic needs that must be addressed in order to do the most for the most. A humanitarian crisis can take many forms: an environmental disaster, mass emigration due to drought, conflict or famine, a disease outbreak or any number of natural or man-made events. When this event overwhelms the resources of the affected country’s government, then the international community will often step in to help. Although a full examination of the subject is beyond the scope of this book, there are a few basic principles for managing a humanitarian crisis. The response is broken down into four phases:

  1. recognition (first week)
  2. emergency response (first month)
  3. consolidation phase (to crisis resolution or crisis containment)
  4. handover and withdrawal. Recognition Recognition of a disaster may be obvious in a sudden event such as an earthquake or a tidal wave, but less obvious in a disease outbreak or when it stems from internal conflict. The recognition phase is for the host nation rather than the international community, and requests for support will come from the affected country’s government. Emergency response During the emergency phase, responders (whether international, governmental or the charity sector) will undertake an initial assessment of need, set objectives, mobilise resources, coordinate with other agencies and deploy to the crisis in order to deliver an initial response. Consolidation phase The consolidation phase involves matching resources to need, dealing with the crisis, building resilience, supporting infrastructure (human and physical) and instituting systems to manage the ongoing health needs of the population. Handover and withdrawal Once the crisis is under control and the country is able to manage within resources, a phased withdrawal can occur. Health-care priorities When the normal infrastructure of a country or area fails, then populations are at risk, whether they shelter in place or flee, leading to mass migration. For health-care teams, rather than logisticians, rescue teams or security forces, there are welldefined priorities, which must be in place (Box 9.7). This must all occur during the emergency phase and is followed by the in 25–30% of adults; p. 531). Although DCS and AGE can be indistinguishable, their early treatment is the same. Barotrauma During the ascent phase of a dive, the gas in the diver’s lungs expands due to the decreasing pressure. The diver must therefore ascend slowly and breathe regularly; if ascent is rapid or the diver holds his/her breath, the expanding gas may cause lung rupture (pulmonary barotrauma). This can result in pneumomediastinum, pneumothorax or AGE as a result of gas passing directly into the pulmonary venous system. Other air-filled body cavities may be subject to barotrauma, including the ear and sinuses. Management The patient is nursed horizontally and airway, breathing and circulation are assessed. Treatment includes the following: • High-flow oxygen is given by a tight-fitting mask using a rebreathing bag. This assists in the washout of excess inert gas (nitrogen) and may reduce the extent of local tissue hypoxia resulting from focal embolic injury. • Fluid replacement (oral or intravenous) corrects the intravascular fluid loss from endothelial bubble injury and dehydration associated with immersion. Maintenance of an adequate peripheral circulation is important for the excretion of excess dissolved gas. • Recompression is the definitive therapy. Transfer to a recompression facility may be by surface or air, provided that the altitude remains low (< 300 m) and the patient continues to breathe 100% oxygen. Recompression reduces the volume of gas within tissues (Boyle’s law), forces nitrogen back into solution and is followed by slow decompression, allowing the nitrogen load to be excreted. Information required by diving specialists to decide appropriate treatment. See contact details on page 172. 9.6 Assessment of a patient with decompression illness Evolution • Progressive • Static • Relapsing • Spontaneously improving Manifestations • Pain: often large joints, e.g. shoulder (‘the bends’) • Neurological: any deficit is possible • Audiovestibular: vertigo, tinnitus, nystagmus; may mimic inner ear barotrauma • Pulmonary: chest pain, cough, haemoptysis, dyspnoea; may be due to arterial gas embolism (AGE) • Cutaneous: itching, erythematous rash • Lymphatic: tender lymph nodes, oedema • Constitutional: headache, fatigue, general malaise Dive profile • Depth • Type of gas used • Duration of dive

172 • ENVIRONMENTAL MEDICINE Further information Websites altitude.org A website written by doctors with expertise and experience of expedition and altitude medicine and critical care. diversalertnetwork.org Advice on the clinical management of diving illness and emergency assistance services. emergency.cdc.gov/radiation/ The Centers for Disease Control and Prevention provides information and links on all forms of radiation for patients and professionals. msf.org Information and advice about all aspects of responding to humanitarian crises around the world. Telephone numbers Two organisations can offer national and international advice on diving emergencies and recompression facilities: • Within the UK, the National Diving Accident Helpline on +44 (0)7831 151523 (24 hours). • Outside the UK, contact the Divers Alert Network International Emergency Hotline +1-919-684-9111. implementation of a public health surveillance and reporting system and the mobilisation of local human resources, and their training and deployment during the consolidation phase in order to prepare for handover to the local competent authority and withdrawal. 9.7 Priorities in a humanitarian crisis

  1. Assessment of population need
  2. Safe water and sanitation
  3. Food and nutrition
  4. Shelter and warmth
  5. Emergency health care
  6. Immunisation of risk groups
  7. Control of communicable diseases
  8. Ongoing health surveillance and reporting
  9. Training and deployment of indigenous health-care workers
  10. Handover of responsibility to local authorities
Ch03-2 Emergency and Critical Care _67ef

04-10 Acute medicine and critical illness

10 Acute medicine and critical illness

Acute medicine and critical illness VR Tallentire MJ MacMahon Clinical examination in critical care 174 Monitoring 175 Acute medicine 176 The decision to admit to hospital 176 Ambulatory care 176 Presenting problems in acute medicine 176 Chest pain 176 Acute breathlessness 179 Syncope/presyncope 181 Delirium 183 Headache 185 Unilateral leg swelling 186 Identification and assessment of deterioration 188 Early warning scores and the role of the medical emergency team 188 Immediate assessment of the deteriorating patient 188 Selecting the appropriate location for ongoing management 189 Common presentations of deterioration 190 Tachypnoea 190 Hypoxaemia 190 Tachycardia 191 Hypotension 193 Hypertension 193 Decreased conscious level 194 Decreased urine output/deteriorating renal function 195 Disorders causing critical illness 196 Sepsis and the systemic inflammatory response 196 Acute respiratory distress syndrome 198 Acute circulatory failure (cardiogenic shock) 199 Post cardiac arrest 200 Other causes of multi-organ failure 201 Critical care medicine 201 Decisions around intensive care admission 201 Stabilisation and institution of organ support 202 Respiratory support 202 Cardiovascular support 204 Renal support 208 Neurological support 208 Daily clinical management in intensive care 208 Clinical review 208 Sedation and analgesia 209 Delirium in intensive care 209 Weaning from respiratory support 209 Extubation 210 Tracheostomy 210 Nutrition 210 Other essential components of intensive care 210 Complications and outcomes of critical illness 211 Adverse neurological outcomes 211 Other long-term problems 212 The older patient 212 Withdrawal of active treatment and death in intensive care 213 Discharge from intensive care 213 Critical care scoring systems 213

174 • ACUTE MEDICINE AND CRITICAL ILLNESS Clinical examination in critical care Airway Is the airway patent? Is the end-tidal CO2 trace normal? Are there any signs of airway obstruction? A B Circulation Is the physiology normal (heart rate, blood pressure, peripheral temperature, lactate, urine output)? How much support is required (inotrope,vasopressor)? C D E Glucose What is the glucose level? Is insulin being administered? G G D

Haematology What are the haemoglobin/ platelet levels? Are there any signs of bleeding? H

Infection What is the temperature? Review recent infective markers and trend What antibiotics are being given and what is the duration of treatment? I

Enteral/exposure Feeding regime Stool frequency Abdominal tenderness/bowel sounds present? Disability Level of responsiveness Delirium screen Pupillary responses Doses of sedative drugs F Fluids, electrolytes and renal system What is the fluid balance? Urine volume and colour? Is there any oedema? Review the renal biochemistry and electrolyte levels Breathing Is the physiology normal (SpO2, respiratory rate, tidal volume)? What is the level of support? Are there any abnormal signs on chest examination? Review the ventilator settings, arterial blood gases and recent chest X-ray F E C B A

Monitoring • 175

Bedside physiological data commonly monitored in an intensive care unit setting. Monitoring Electrocardiography Heart rate, rhythm and QRS morphology Arterial line trace Size of the area under the curve is proportional to stroke volume Narrow peaks suggest low stroke volume as shown here Oxygen saturation Saturation of haemoglobin measured by plethysmography (SpO2). Gives an indication of adequacy of oxygenation, and the quality of tissue perfusion can also be inferred – a flat trace suggests poor peripheral perfusion Central venous pressure trace A non-specific guide to volume status and right ventricular function. Increased values in fluid overload and right ventricular failure Capnography Numerical value of end-tidal CO2 (ETCO2) is less than arterial PCO2 (PaCO2) by a variable amount. Shape of trace can signify airway displacement/obstruction, bronchospasm or a low cardiac output (as shown below) kPa mmHg Time (secs)

Normal Steep ‘upstroke’ in early expiration Bronchospasm Shallow ‘upstroke’ in early expiration Partial obstruction/displacement of airway device Decreasing cardiac output Decreasing size of ETCO2 waveform No ventilation (from any cause) Basic principles • Uses the different red and infrared absorption profiles of oxyhaemoglobin and deoxyhaemoglobin to estimate arterial oxyhaemoglobin saturation (SaO2) • Only pulsatile absorption is measured • A poor trace correlates with poor perfusion Sources of error • Carboxyhaemoglobin – absorption profile is the same as oxyhaemoglobin: falsely elevated SpO2 • Methaemoglobinaemia – SpO2 will tend towards 85% • Ambient light/poor application of probe/ severe tricuspid regurgitation (pulsatile venous flow): falsely depressed SpO2 • Reduced accuracy below 80% saturation • Hyperbilirubinaemia does not affect SpO2 Plethysmography (SpO2)

176 • ACUTE MEDICINE AND CRITICAL ILLNESS is required. The requirement for admission is determined by many factors, including the severity of illness, the patient’s physiological reserve, the need for urgent investigations, the nature of proposed treatments and the patient’s social circumstances. In many cases, it is clear early in the assessment process that a patient requires admission. In such cases, a move into a medical receiving unit – often termed a medical admissions unit (MAU) or acute medical unit (AMU) – should be facilitated as soon as the initial assessment has been completed and urgent investigations and/or treatments have been instigated. In hospitals where such units do not exist, patients will need to be moved to a downstream ward once treatment has been commenced and they have been deemed sufficiently stable. Following the initial assessment, it may be possible to discharge stable patients home with a plan for early follow-up (such as a rapid-access specialist clinic appointment). Ambulatory care In some hospitals, it is increasingly possible for patient care to be coordinated in an ambulatory setting, negating the need for a patient to remain in hospital overnight. In the context of acute medicine, ambulatory care can be employed for conditions that are perceived by either the patient or the referring practitioner as requiring prompt clinical assessment by a competent decisionmaker with access to appropriate diagnostic resources. The patient may return on several occasions for investigation, observation, consultation or treatment. Some presentations, such as a unilateral swollen leg (p. 186), lend themselves to this type of management (Box 10.1). If indicated, a Doppler ultrasound can be arranged, and patients with confirmed deep vein thromboses can be anticoagulated on an outpatient basis. Successful ambulatory care requires careful patient selection; while many patients may cherish the opportunity to sleep at home, others may find frequent trips to hospital or clinic too difficult due to frailty, poor mobility or transport difficulties. Presenting problems in acute medicine Chest pain Chest pain is a common symptom in patients presenting to hospital. The differential diagnosis is wide (Box 10.2), and a Hospital medicine is becoming ever more specialised and people are living longer while accruing increasing numbers of chronic disease diagnoses. Rather than diminishing the role of the generalist, these factors paradoxically create a need for experts in the undifferentiated presentation. In the UK such physicians are known as ‘general physicians’, while in the US they are referred to as ‘hospitalists’. Acute illness can present in a large variety of ways, depending on the nature of the illness, the underlying health of the individual, and their cultural and religious background. The skills of prompt diagnosis formation and provision of appropriate treatment rely on the integration of information from all the available sources, along with careful consideration of underlying chronic health problems. Patients who deteriorate while in hospital make up a small but important cohort. If they are well managed, in-hospital cardiac arrest rates will be low. This can be achieved through the combined effects of prompt resuscitation and appropriate end-of-life decision-making. Early recognition of deterioration by ward teams and initial management by health-care professionals operating within a functioning rapid response system are the central tenets of any system designed to improve the outcomes of deteriorating ward patients. Intensive care medicine has developed into a prominent specialty, central to the safe functioning of a modern acute hospital. Scientific endeavour has resulted in a much better understanding of the molecular pathophysiology of processes such as sepsis and acute respiratory distress syndrome, which account for much premature death worldwide. Acute medicine Acute medicine is the part of general medicine that is concerned with the immediate and early management of medical patients who require urgent care. As a specialty, it is closely aligned with emergency medicine and intensive care medicine, but is firmly rooted within general medicine. Acute physicians manage the adult medical take and lead the development of acute care pathways that aim to reduce variability, improve care and cut down hospital admissions. The decision to admit to hospital Every patient presenting to hospital should be assessed by a clinician who is able to determine whether or not admission 10.1 Groups of patients who are potentially suitable for ambulatory care Group Example(s) Quality and safety issues Diagnostic exclusion group Chest pain – possible myocardial infarction; breathlessness – possible pulmonary embolism Even when a specific condition has been excluded, there is still a need to explain the patient’s symptoms through the diagnostic process Low-risk stratification group Non-variceal upper gastrointestinal bleed with low Blatchford score (p. 780); communityacquired pneumonia with low CURB-65 score (p. 583) Appropriate treatment plans should be in place Specific procedure group Replacement of percutaneous endoscopic gastrostomy (PEG) tube; drainage of pleural effusion/ascites The key to implementation is how ambulatory care for this group of patients can be delivered when they present out of hours Outpatient group with supporting infrastructure Deep vein thrombosis (DVT); cellulitis These are distinct from the conditions listed above because the infrastructure required to manage them is quite different

Presenting problems in acute medicine • 177

10.2 Differential diagnosis of chest pain Central Cardiac • Myocardial ischaemia (angina) • Myocardial infarction • Myocarditis • Pericarditis • Mitral valve prolapse syndrome Aortic • Aortic dissection • Aortic aneurysm Oesophageal • Oesophagitis • Oesophageal spasm • Mallory–Weiss syndrome • Oesophageal perforation (Boerhaave’s syndrome) Pulmonary embolus Mediastinal • Malignancy Anxiety/emotion1 Peripheral Lungs/pleura • Pulmonary infarct • Pneumonia • Pneumothorax • Malignancy • Tuberculosis • Connective tissue disorders Musculoskeletal2 • Osteoarthritis • Rib fracture/injury • Acute vertebral fracture • Costochondritis (Tietze’s syndrome) • Intercostal muscle injury • Epidemic myalgia (Bornholm disease) Neurological • Prolapsed intervertebral disc • Herpes zoster • Thoracic outlet syndrome 1May also cause peripheral chest pain. 2Can sometimes cause central chest pain. Characteristics Pleurisy, a sharp or ‘catching’ chest pain aggravated by deep breathing or coughing, is indicative of respiratory pathology, particularly pulmonary infection or infarction. However, the pain associated with myocarditis or pericarditis is often also described as ‘sharp’ and may ‘catch’ during inspiration, coughing or lying flat. It typically varies in intensity with movement and the phase of respiration. A malignant tumour invading the chest wall or ribs can cause gnawing, continuous local pain. The pain of myocardial ischaemia is typically dull, constricting, choking or ‘heavy’, and is usually described as squeezing, crushing, burning or aching. Patients often emphasise that it is a discomfort rather than a pain. Angina occurs during (not after) exertion and is promptly relieved (in less than 5 minutes) by rest. It may also be precipitated or exacerbated by emotion but tends to occur more readily during exertion, after a large meal or in a cold wind. In crescendo or unstable angina, similar pain may be precipitated by minimal exertion or at rest. The increase in venous return or preload induced by lying down may also be sufficient to provoke pain in vulnerable patients (decubitus angina). Patients with reversible airways obstruction, such as asthma, may also describe exertional chest tightness that is relieved by rest. This may be difficult to distinguish from myocardial ischaemia. Bronchospasm may be associated with wheeze, atopy and cough (p. 556). Musculoskeletal chest pain is variable in site and intensity but does not usually fall into any of the patterns described above. The pain may vary with posture or movement of the upper body, or be associated with a specific movement (bending, stretching, turning). Many minor soft tissue injuries are related to everyday activities, such as driving, manual work and sport. Onset The pain associated with myocardial infarction (MI) typically takes several minutes or even longer to develop to its maximal intensity; similarly, angina builds up gradually in proportion to the intensity of exertion. Pain that occurs after, rather than during, exertion is usually musculoskeletal or psychological in origin. The pain of aortic dissection (severe and ‘tearing’), massive pulmonary embolism (PE) or pneumothorax is usually very sudden in onset. Other causes of chest pain tend to develop more gradually, over hours or even days. Associated features The pain of MI, massive PE or aortic dissection is often accompanied by autonomic disturbance, including sweating, nausea and vomiting. Some patients describe a feeling of impending death, referred to as ‘angor animi’. Breathlessness, due to pulmonary congestion arising from transient ischaemic left ventricular dysfunction, is often a prominent feature of myocardial ischemia. Breathlessness may also accompany any of the respiratory causes of chest pain and can be associated with cough, wheeze or other respiratory symptoms. Patients with myocarditis or pericarditis may describe a prodromal viral illness. Gastrointestinal disorders, such as gastro-oesophageal reflux or peptic ulceration, may present with chest pain that is hard to distinguish from myocardial ischaemia; it may even be precipitated by exercise and be relieved by nitrates. However, it is usually possible to elicit a history relating chest pain to supine posture or eating, drinking or oesophageal reflux. The pain of gastro-oesophageal reflux often radiates to the interscapular region and dysphagia may be present. Severe chest pain arising after retching or vomiting, or following oesophageal instrumentation, should raise the possibility of oesophageal perforation. detailed history and thorough clinical examination are paramount to ensure that the subsequent investigative pathway is appropriate. Presentation Chest ‘pain’ is clearly a subjective phenomenon and may be described by patients in a variety of different ways. Whether the patient describes ‘pain’, ‘discomfort’ or ‘pressure’ in the chest, there are some key features that must be elicited from the history. Site and radiation Pain secondary to myocardial ischaemia is typically located in the centre of the chest. It may radiate to the neck, jaw, and upper or even lower arms. Occasionally, it may be experienced only at the sites of radiation or in the back. The pain of myocarditis or pericarditis is characteristically felt retrosternally, to the left of the sternum, or in the left or right shoulder. The severe pain of aortic dissection is typically central with radiation through to the back. Central chest pain may also occur with tumours affecting the mediastinum, oesophageal disease (p. 791) or disease of the thoracic aorta (p. 505). Pain situated over the left anterior chest and radiating laterally is unlikely to be due to cardiac ischaemia and may have many causes, including pleural or lung disorders, musculoskeletal problems or anxiety. Rarely, sharp, left-sided chest pain that is suggestive of a musculoskeletal problem may be a feature of mitral valve prolapse (p. 520).

178 • ACUTE MEDICINE AND CRITICAL ILLNESS side. Local tenderness of the chest wall is likely to indicate musculoskeletal pain but can also be found in pulmonary infarction. Subdiaphragmatic inflammatory pathology, such as a liver abscess, cholecystitis or ascending cholangitis, can mimic pneumonia by causing fever, pleuritic chest pain and a small sympathetic pleural effusion, usually on the right. Likewise, acute pancreatitis can present with thoracic symptoms, and an amylase or lipase level should be requested where appropriate. It is imperative that the abdomen is examined routinely in all patients presenting with pleuritic chest pain. Initial investigations Chest X-ray, ECG and biomarkers (e.g. troponin, D-dimer) play a pivotal role in the evaluation of chest pain. However, indiscriminate ordering of such investigations may result in diagnostic confusion and over-investigation. The choice of investigation(s) is intimately linked to the history and examination findings. A chest X-ray and 12-lead ECG should be performed in the vast majority of patients presenting to hospital with chest pain. Pregnancy is not a contraindication to chest X-ray, but particular consideration should be given to whether the additional diagnostic information justifies breast irradiation. The chest X-ray may confirm the suspected diagnosis, particularly in the case of pneumonia. Small pneumothoraces are easily missed, as are rib fractures or small metastatic deposits, and all should be considered individually during chest X-ray review. A widened mediastinum suggests acute aortic dissection but a normal chest X-ray does not exclude the diagnosis. Provided it has been more than 1 hour since the onset of pain, chest X-ray in oesophageal rupture may reveal subcutaneous emphysema, pneumomediastinum or a pleural effusion. Patients with a history compatible with myocardial ischaemia require an urgent 12-lead ECG. Acute chest pain with ECG changes indicating a ST segment elevation myocardial infarction (STEMI) suggests that the patient is likely to benefit from immediate reperfusion therapy. Specific information relating to cocaine or amphetamine use should be sought, particularly in younger Anxiety-induced chest pain may be associated with breathlessness (without hypoxaemia), throat tightness, perioral tingling and other evidence of emotional distress. It is important to remember, however, that chest pain itself can be an extremely frightening experience, and so psychological and organic features often coexist. Anxiety may amplify the effects of organic disease and a confusing clinical picture may result. A detailed and clear history is key to narrowing the differential diagnosis of chest pain. Figure 10.1 shows how certain features of the history, particularly when combined, can tip the balance of evidence towards or away from ischaemic cardiac chest pain. Clinical assessment Cardiorespiratory examination may detect clinical signs that help guide ongoing investigation. Patients with a history compatible with myocardial ischaemia should have a 12-lead electrocardiogram (ECG) performed while clinical examination proceeds. Ongoing chest pain with clinical features of shock or pulmonary oedema, or ECG evidence of ventricular arrhythmia or complete heart block should prompt urgent cardiology review and referral to a higher level of care. Chest pain that is accompanied by clinical evidence of increased intracardiac pressure (especially a raised jugular venous pressure) increases the likelihood of myocardial ischaemia or massive PE. The legs should be examined for clinical evidence of deep vein thrombosis. A large pneumothorax should be evident on clinical examination, with absent breath sounds and a hyper-resonant percussion note on the affected side. Other unilateral chest signs, such as bronchial breathing or crackles, are most likely to indicate a respiratory tract infection, and a chest X-ray should be expedited. Pericarditis may be accompanied by a pericardial friction rub. In aortic dissection, syncope or neurological deficit may occur. Examination may reveal asymmetrical pulses, features of undiagnosed Marfan’s syndrome (p. 508) or a new early diastolic murmur representing aortic regurgitation. Any disease process involving the pleura may restrict rib movement and a pleural rub may be audible on the affected Fig. 10.1 Identifying ischaemic cardiac pain: the ‘balance’ of evidence. Ischaemic cardiac chest pain Non-cardiac chest pain Relieving factors Respiratory, gastrointestinal, locomotor or psychological Rest Quick response to nitrates Precipitation Spontaneous, not related to exertion, provoked by posture, respiration or palpation Precipitated by exertion and/or emotion Character Sharp, stabbing, catching Tight, squeezing, choking Radiation Other or no radiation Jaw/neck/shoulder/arm (occasionally back) Location Peripheral, localised Central, diffuse Associated features Not relieved by rest Slow or no response to nitrates Breathlessness

Presenting problems in acute medicine • 179

differential diagnosis list to chronic exertional breathlessness. The presence of associated cardiovascular (chest pain, palpitations, sweating and nausea) or respiratory symptoms (cough, wheeze, haemoptysis, stridor) can narrow the differential diagnosis yet further. A previous history of left ventricular dysfunction, asthma or exacerbations of chronic obstructive pulmonary disease (COPD) is important. In the severely ill patient, it may be necessary to obtain the history from accompanying witnesses. In children, the possibility of inhalation of a foreign body (Fig. 10.2) or acute epiglottitis should always be considered. There is often more than one underlying diagnosis; a thorough assessment should continue, even after a possible diagnosis has been reached, particularly if the severity of symptoms does not seem to be adequately explained. The causes of acute severe breathlessness are covered here; chronic exertional dyspnoea is discussed further on page 557. Clinical assessment Airway obstruction, anaphylaxis and tension pneumothorax require immediate identification and treatment. If any of these is suspected, treatment should not be delayed while additional investigations are performed, and anaesthetic support is likely to be required. In the absence of an immediately life-threatening cause, the following should be assessed and documented: • level of consciousness • degree of central cyanosis • work of breathing (rate, depth, pattern, use of accessory muscles) • adequacy of oxygenation (SpO2) patients. In the context of a compatible history, an ECG showing ischaemic changes that do not meet STEMI criteria should prompt regular repeat ECGs and treatment for non-ST segment elevation myocardial infarction (NSTEMI)/unstable angina. Measurement of serum troponin concentration on admission is often helpful in cases where there is diagnostic doubt, but a negative result should always prompt a repeat sample 6–12 hours after maximal pain. Acute coronary syndrome may be diagnosed with confidence in patients with a convincing history of ischaemic pain (Fig. 10.1) and either ECG evidence of ischaemia or an elevated serum troponin. If an elevated serum troponin is found in a patient who has an atypical history or is at low risk of ischaemic heart disease, then alternative causes of raised troponin should be considered (Box 10.3). Further management of acute coronary syndromes is discussed on page 498. In the absence of convincing ECG evidence of myocardial ischaemia, other life-threatening causes of chest pain, such as aortic dissection, massive PE and oesophageal rupture, should be considered. Suspicion of aortic dissection (background of hypertension, trauma, pregnancy or previous aortic surgery) should prompt urgent thoracic computed tomography (CT) or transoesophageal echocardiography. An ECG in the context of massive PE most commonly reveals only a sinus tachycardia, but may show new right axis deviation, right bundle branch block or a dominant R wave in V1. The classical finding of S1Q3T3 (a deep S wave in lead I, with a Q wave and T wave inversion in lead III) is rare. If massive PE is suspected and the patient is haemodynamically unstable, a transthoracic echocardiogram, to seek evidence of right heart strain and exclude alternative diagnoses such as tamponade, is extremely useful. If the patient is deemed to be at low risk of PE, a D-dimer test can be informative, as a negative result effectively excludes the diagnosis. The D-dimer test should be performed only if there is clinical suspicion of PE, as false-positive results can lead to unnecessary investigations. If the D-dimer is positive, there is high clinical suspicion, or there is other convincing evidence of PE (such as features of right heart strain on the ECG), prompt imaging should be arranged (p. 619 and Fig. 17.67). Acute breathlessness In acute breathlessness, the history, along with a rapid but careful examination, will usually suggest a diagnosis that can be confirmed by routine investigations including chest X-ray, 12-lead ECG and arterial blood gas (ABG) sampling. Presentation A key feature of the history is the speed of onset of breathlessness. Acute severe breathlessness (over minutes or hours) has a distinct Fig. 10.2 Inhaled foreign body. A Chest X-ray showing a tooth lodged in a main bronchus. B Bronchoscopic appearance of inhaled foreign body (tooth) with a covering mucous film. A B 10.3 Causes of elevated serum troponin other than acute coronary syndrome Cardiorespiratory causes • Pulmonary embolism • Acute pulmonary oedema • Tachyarrhythmias • Myocarditis/myopericarditis • Aortic dissection • Cardiac trauma • Cardiac surgery/ablation Non-cardiorespiratory causes • Prolonged hypotension • Severe sepsis • Severe burns • Stroke • Subarachnoid haemorrhage • End-stage renal failure

180 • ACUTE MEDICINE AND CRITICAL ILLNESS onset of atrial fibrillation in a patient with mitral stenosis. In such cases, the classic mid-diastolic rumbling murmur with pre-systolic accentuation may be heard. Patients sometimes describe chest tightness as ‘breathlessness’. However, myocardial ischaemia may also induce true breathlessness by provoking transient left ventricular dysfunction. When breathlessness is the dominant or sole feature of myocardial ischaemia, it is known as ‘angina equivalent’. A history of chest tightness or close correlation with exercise should be sought. Initial investigations As shown in Box 10.4, amalgamation of a clear history and thorough clinical examination with chest X-ray, ECG and ABG findings will usually indicate the primary cause of breathlessness. If bronchospasm is suspected, measurement of peak expiratory flow will assist in the assessment of severity and should be performed whenever possible. An ABG will often provide additional information to SpO2 measurement alone, particularly if there is clinical evidence (drowsiness, delirium, asterixis) or a strong likelihood of hypercapnia. An acute rise in PaCO2 will increase the HCO3 − by only a small amount, resulting in inadequate buffering and acidaemia. Renal compensation and a large rise in HCO3 − will take at least 12 hours. In acute type II respiratory failure (p. 565), the rate of rise of PaCO2 is a better indicator of severity than the absolute value. An ABG is essential in the context of smoke inhalation to measure carboxyhaemoglobin level, and is central to the identification of metabolic acidosis or the diagnosis of psychogenic hyperventilation (Box 10.4). If ‘angina equivalent’ is suspected, • ability to speak (in single words or sentences) • cardiovascular status (heart rate and rhythm, blood pressure (BP) and peripheral perfusion). Pulmonary oedema is suggested by a raised jugular venous pressure and bi-basal crackles or diffuse wheeze, while asthma or COPD is characterised by wheeze and prolonged expiration. A hyper-resonant hemithorax with absent breath sounds raises the possibility of pneumothorax, while severe breathlessness with normal breath sounds may indicate PE. Leg swelling may suggest cardiac failure or, if asymmetrical, venous thrombosis. The presence of wheeze is not always indicative of bronchospasm. In acute left heart failure, an increase in the left ventricular diastolic pressure causes the pressure in the left atrium, pulmonary veins and pulmonary capillaries to rise. When the hydrostatic pressure of the pulmonary capillaries exceeds the oncotic pressure of plasma (about 25–30 mmHg), fluid moves from the capillaries into the interstitium. This stimulates respiration through a series of autonomic reflexes, producing rapid, shallow respiration, and congestion of the bronchial mucosa may cause wheeze (sometimes known as cardiac asthma). Sitting upright or standing may provide some relief by helping to reduce congestion at the apices of the lungs. The patient may be unable to speak and is typically distressed, agitated, sweaty and pale. Respiration is rapid, with recruitment of accessory muscles, coughing and wheezing. Sputum may be profuse, frothy and blood-streaked or pink. Extensive crepitations and rhonchi are usually audible in the chest and there may also be signs of right heart failure. Any arrhythmia may cause breathlessness, but usually does so only if the heart is structurally abnormal, such as with the 10.4 Clinical features in acute breathlessness Condition History Signs Chest X-ray ABG ECG Pulmonary oedema Chest pain, palpitations, orthopnoea, cardiac history* Central cyanosis, ↑JVP, sweating, cool extremities, basal crackles* Cardiomegaly, oedema/pleural effusions* ↓PaO2 ↓PaCO2 Sinus tachycardia, ischaemia*, arrhythmia Massive pulmonary embolus Risk factors, chest pain, pleurisy, syncope*, dizziness* Central cyanosis, ↑JVP*, absence of signs in the lung*, shock (tachycardia, hypotension) Often normal Prominent hilar vessels, oligaemic lung fields* ↓PaO2 ↓PaCO2 Sinus tachycardia, RBBB, S1Q3T3 pattern ↑T(V1–V4) Acute severe asthma History of asthma, asthma medications, wheeze* Tachycardia, pulsus paradoxus, cyanosis (late), →JVP*, ↓peak flow, wheeze* Hyperinflation only (unless complicated by pneumothorax)* ↓PaO2 ↓PaCO2 (↑PaCO2 in extremis) Sinus tachycardia (bradycardia in extremis) Acute exacerbation of COPD Previous episodes*, smoker. If in type II respiratory failure, may be drowsy Cyanosis, hyperinflation*, signs of CO2 retention (flapping tremor, bounding pulses)* Hyperinflation*, bullae, complicating pneumothorax ↓ or ↓↓PaO2 ↑PaCO2 in type II failure ± ↑H+, ↑HCO3 − in chronic type II failure Normal, or signs of right ventricular strain Pneumonia Prodromal illness*, fever*, rigors*, pleurisy* Fever, delirium, pleural rub*, consolidation*, cyanosis (if severe) Pneumonic consolidation* ↓PaO2 ↓PaCO2 (↑ in extremis) Tachycardia Metabolic acidosis Evidence of diabetes mellitus or renal disease, aspirin or ethylene glycol overdose Fetor (ketones), hyperventilation without heart or lung signs*, dehydration*, air hunger Normal PaO2 normal ↓↓PaCO2, ↑H+ ↓HCO3 − Psychogenic Previous episodes, digital or perioral dysaesthesia No cyanosis, no heart or lung signs, carpopedal spasm Normal PaO2 normal* ↓↓PaCO2, ↓H+* *Valuable discriminatory feature. (ABG = arterial blood gas; COPD = chronic obstructive pulmonary disease; JVP = jugular venous pressure; RBBB = right bundle branch block)

Presenting problems in acute medicine • 181

Presentation The history from the patient and a witness is the key to establishing a diagnosis. The terms used for describing the symptoms associated with syncope vary so much among patients that they should not be taken for granted. Some patients use the term ‘blackout’ to describe a purely visual symptom, rather than loss of consciousness. Some may understand ‘dizziness’ to mean an abnormal perception of movement (vertigo), some will consider this a feeling of faintness, and others will regard it as unsteadiness. The clinician thus needs to elucidate the exact nature of the symptoms that the patient experiences. The potential differential diagnoses of syncope and presyncope, on the basis of the symptoms described, is shown in Figure 10.3. The history should always be supplemented by a direct eyewitness account if available. Careful history with corroboration will usually establish whether there has been full consciousness, altered consciousness, vertigo, transient amnesia or something else. Attention should be paid to potential triggers (e.g. medication, micturition, exertion, prolonged standing), the patient’s appearance (e.g. colour, seizure activity), the duration of the episode, and the speed of recovery (Box 10.6). Cardiac syncope is usually sudden but can be associated with premonitory lightheadedness, palpitation or chest discomfort. The blackout is usually brief and recovery rapid. Exercise-induced syncope can be the presenting feature of a number of serious pathologies (such as hypertrophic obstructive cardiomyopathy or exercise-induced arrhythmia) and always requires further investigation. Neurocardiogenic syncope will often be associated with a situational trigger (such as pain or emotion), and the patient may experience flushing, nausea, malaise and clamminess for several minutes afterwards. Recovery is usually quick and without subsequent delirium, provided the patient has assumed a supine position. There is often some brief stiffening and limb-twitching, which requires differentiation from seizure-like movements. It is rare for syncope to cause injury or to cause amnesia after regaining awareness. Patients with seizures do not exhibit pallor, may have abnormal movements, usually take more than 5 minutes to recover and are often confused. Aspects of the history that can help to differentiate seizure from syncope are shown in Box 10.7. A diagnosis of psychogenic blackout (also known as nonepileptic seizure, pseudoseizure or psychogenic seizure) may be suggested by specific emotional triggers, dramatic movements objective evidence of myocardial ischaemia from stress testing may help to establish the diagnosis. Syncope/presyncope The term ‘syncope’ refers to sudden loss of consciousness due to reduced cerebral perfusion. ‘Presyncope’ refers to lightheadedness, in which the individual thinks he or she may ‘black out’. Dizziness and presyncope are particularly common in old age (Box 10.5). Symptoms are disabling, undermine confidence and independence, and can affect a person’s ability to work or to drive. There are three principal mechanisms that underlie recurrent presyncope or syncope: • cardiac syncope due to mechanical cardiac dysfunction or arrhythmia • neurocardiogenic syncope (also known as vasovagal or reflex syncope), in which an abnormal autonomic reflex causes bradycardia and/or hypotension • postural hypotension, in which physiological peripheral vasoconstriction on standing is impaired, leading to hypotension. There are, however, other causes of loss of consciousness, and differentiating syncope from seizure is a particular challenge. Psychogenic blackouts (also known as non-epileptic seizures or pseudoseizures) also need to be considered in the differential diagnosis. 10.5 Dizziness in old age • Prevalence: common, affecting up to 30% of people aged

65 years. • Symptoms: most frequently described as a combination of unsteadiness and lightheadedness. • Most common causes: postural hypotension and cardiovascular disease. Many patients have more than one underlying cause. • Arrhythmia: can present with lightheadedness either at rest or on activity. • Anxiety: frequently associated with dizziness but rarely the only cause. • Falls: multidisciplinary workup is required if dizziness is associated with falls. 10.6 Typical features of cardiac syncope, neurocardiogenic syncope and seizures Cardiac syncope Neurocardiogenic syncope Seizures Premonitory symptoms Often none Lightheadedness Palpitation Chest pain Breathlessness Nausea Lightheadedness Sweating Delirium Hyperexcitability Olfactory hallucinations ‘Aura’ Unconscious period Extreme ‘death-like’ pallor Pallor Prolonged (> 1 min) unconsciousness Motor seizure activity* Tongue-biting Urinary incontinence Recovery Rapid (< 1 min) Flushing Slow Nausea Lightheadedness Prolonged delirium (> 5 mins) Headache Focal neurological signs *N.B. Cardiac syncope can also cause convulsions by inducing cerebral anoxia.

182 • ACUTE MEDICINE AND CRITICAL ILLNESS 10.7 How to differentiate seizures from syncope Seizure Syncope Aura (e.g. olfactory) + − Cyanosis + − Lateral tongue-biting + −/+ Post-ictal delirium + − Post-ictal amnesia + − Post-ictal headache + − Rapid recovery − + Fig. 10.3 The differential diagnosis of syncope and presyncope. Labyrinthine dysfunction • Infection • ‘Vestibular neuronitis’ • Benign positional vertigo • Ménière’s disease • Ischaemia/infarction • Trauma • Perilymph fistula • Other (e.g. drugs, otosclerosis) Central vestibular dysfunction • ‘Physiological’ (visual– vestibular mismatch) • Demyelination • Migraine • Posterior fossa mass lesion • Vertebro-basilar ischaemia • Other (e.g. disorders of cranio-vertebral junction) • Ataxia • Weakness • Loss of joint position sense • Gait dyspraxia • Joint disease • Visual disturbance • Fear of falling (Chs 24 and 25) Impaired cerebral perfusion Cardiac disease • Arrhythmia • Left ventricular dysfunction • Aortic stenosis • Hypertrophic obstructive cardiomyopathy Other causes • Vasovagal syncope • Postural hypotension • Micturition syncope • Cough syncope • Carotid sinus sensitivity • Hypoglycaemia (Ch. 20) • Anxiety* • Hyperventilation • Post-concussive syndrome • Panic attack • Non-epileptic attack • Epileptic seizure Presyncope (reduced cerebral perfusion) Syncope (loss of cerebral perfusion) Sensation of movement? (vertigo) Loss of balance? Lightheaded? Other description Funny turn or blackout

Presenting problems in acute medicine • 183

cardiomyopathy are important findings, particularly if paired with a history of lightheadedness or syncope on exertion. BP taken when supine and then after 1 and 3 minutes of standing may, when combined with symptoms, provide robust evidence of symptomatic postural hypotension. Clinical suspicion of hypersensitive carotid sinus syndrome (sensitivity of carotid baroreceptors to external pressure such as a tight collar) should prompt monitoring of the ECG and BP during carotid sinus pressure, provided there is no carotid bruit or history of cerebrovascular disease. A positive cardio-inhibitory response is defined as a sinus pause of 3 seconds or more; a positive vasodepressor response is defined as a fall in systolic BP of more than 50 mmHg. Carotid sinus pressure will produce positive findings in about 10% of elderly individuals, but fewer than 25% of these experience spontaneous syncope. Symptoms should not, therefore, be attributed to hypersensitive carotid sinus syndrome unless they are reproduced by carotid sinus pressure. Initial investigations A 12-lead ECG is essential in all patients presenting with syncope or presyncope. Lightheadedness may occur with many arrhythmias, but blackouts (Stokes–Adams attacks, p. 477) are usually due to profound bradycardia or malignant ventricular tachyarrhythmias. The ECG may show evidence of conducting system disease (e.g. sinus bradycardia, atrioventricular block, bundle branch block), which would predispose a patient to bradycardia, but the key to establishing a diagnosis is to obtain an ECG recording while symptoms are present. Since minor rhythm disturbances are common, especially in the elderly, symptoms must occur at the same time as a recorded arrhythmia before a diagnosis can be made. Ambulatory ECG recordings are helpful only if symptoms occur several times per week. Patient-activated ECG recorders are useful for examining the rhythm in patients with recurrent dizziness but are not helpful in assessing sudden blackouts. When these investigations fail to establish a cause in patients with presyncope or syncope, an implantable ECG recorder can be sited subcutaneously over the upper left chest. This device continuously records the cardiac rhythm and will activate automatically if extreme bradycardia or tachycardia occurs. The ECG memory can also be tagged by the patient, using a hand-held activator as a form of ‘symptom diary’. Stored ECGs can be accessed by the implanting centre, using a telemetry device in a clinic, or using a home monitoring system via an online link. Head-up tilt-table testing is a provocation test used to establish the diagnosis of vasovagal syncope. It involves positioning the patient supine on a padded table that is then tilted to an angle of 60–70° for up to 45 minutes, while the ECG and BP responses are monitored. A positive test is characterised by bradycardia (cardio-inhibitory response) and/or hypotension (vasodepressor response), associated with typical symptoms. Delirium Delirium is a syndrome of transient, reversible cognitive dysfunction that is more common in old age. It is associated with high rates of mortality, complications and institutionalisation, and with longer lengths of stay. The recognised risk factors for delirium are shown in Box 10.8. Presentation Delirium manifests as a disturbance of arousal with global impairment of mental function, causing drowsiness with 10.8 Risk factors for delirium Predisposing factors • Old age • Dementia • Frailty • Sensory impairment • Polypharmacy • Renal impairment Precipitating factors • Intercurrent illness • Surgery • Change of environment or ward • Sensory deprivation (e.g. darkness) or overload (e.g. noise) • Medications (e.g. opioids, psychotropics) • Dehydration • Pain • Constipation • Urinary catheterisation • Acute urinary retention • Hypoxia • Fever • Alcohol withdrawal 10.9 How to make a diagnosis of delirium: the 4AT

  1. Alertness This includes patients who may be markedly drowsy (e.g. difficult to rouse and/or obviously sleepy during assessment) or agitated/ hyperactive. Observe the patient. If asleep, attempt to wake with speech or gentle touch on shoulder. Ask the patient to state their name and address to assist rating: • Normal (fully alert, but not agitated, throughout assessment)

• Mild sleepiness for <10 secs after waking, then normal

• Clearly abnormal

  1. AMT4 Age, date of birth, place (name of the hospital or building), current year: • No mistakes

• 1 mistake

• ≥2 mistakes/untestable

  1. Attention Say to the patient: ‘Please tell me the months of the year in backwards order, starting at December.’ To assist initial understanding, one prompt of ‘What is the month before December?’ is permitted: • Achieves ≥7 months correctly

• Starts but scores < 7 months/refuses to start

• Untestable (cannot start because unwell, drowsy, inattentive)

  1. Acute change or fluctuating course Evidence of significant change or fluctuation in: alertness, cognition, other mental function (e.g. paranoia, hallucinations) arising over the last 2 weeks and still evident in last 24 hrs: • No

• Yes

Total 4AT score (maximum possible score 12) ≥4: possible delirium ± cognitive impairment 1–3: possible cognitive impairment 0: delirium or severe cognitive impairment unlikely (but delirium still possible if information in 4 incomplete) (AMT4 = Abbreviated Mental Test 4) disorientation, perceptual errors and muddled thinking. The three broad subtypes of delirium – hypoactive, hyperactive and mixed – can be differentiated on the basis of psychomotor changes. Patients with hyperactive delirium are often agitated and restless, whereas hypoactive delirium can present as lethargy and sedation, and is frequently misdiagnosed as depression or dementia. Fluctuation is typical and delirium is often worse at

184 • ACUTE MEDICINE AND CRITICAL ILLNESS • pyrexia and any signs of infection in the chest, skin, abdomen or urine (on dipstick testing) • oxygen saturation and signs of CO2 retention • signs of alcohol withdrawal or psychoactive drug use, such as tremor or sweating • any focal neurological signs. Certain psychiatric conditions, such as depressive pseudodementia and dissociative disorder, can easily be mistaken for delirium. Mental state examination is necessary to seek evidence of associated mood disorder, hallucinations, delusions or behavioural abnormalities. Examination should also include cognitive testing with a tool such as the Mini-Mental State Examination (MMSE) or the Montreal Cognitive Assessment (MoCA) (p. 1181). Investigations and management Common causes of delirium, along with appropriate investigative pathways, are shown in Figure 10.4. Alongside investigation and treatment of underlying causes, delirium and disorientation should be minimised by a well-lit and quiet environment, with hearing aids and glasses readily available. Good nursing is needed to preserve orientation, prevent pressure sores and falls, and maintain hydration, nutrition and continence. Sedatives may worsen delirium and should be used as a last resort. Resolution of delirium, particularly in the elderly, may be slow and incomplete. Many patients fail to recover to their pre-morbid level of cognition. night, when delirious patients can present significant management difficulties. Emotional disturbance (anxiety, irritability or depression) is common. History-taking from a delirious patient is frequently impossible, and every effort should be made to obtain a collateral history from a close friend or relative. As delirium is particularly common in patients with dementia, the collateral history should ask specifically about onset and course of delirium, along with any functional consequences in comparison to the patient’s norm. Clinical assessment In order to manage delirium effectively, the first step is to make a diagnosis. Tools such as the 4AT (Box 10.9) or the Confusion Assessment Method (CAM) can be used to detect delirium and differentiate it from dementia; such screening tools should be applied to all older patients admitted to hospital. Once a diagnosis of delirium has been established, attempts should be made to identify all of the reversible precipitating factors. Symptoms suggestive of a physical illness, such as an infection or stroke, should be elicited. An accurate drug and alcohol history is required, especially to ascertain whether any drugs have been recently stopped or started (see Fig. 10.4 for commonly implicated drugs). Although not always possible in its entirety, a full physical examination of all delirious patients should be attempted, noting in particular: Fig. 10.4 Common causes and investigation of delirium. All investigations are performed routinely, except those in italics. Tend to present over weeks to months rather than hours to days. The chest X-ray shows right mid- and lower zone consolidation. The CT scan shows a subdural haematoma. (COPD = chronic obstructive pulmonary disease; CRP = C-reactive protein; MI = myocardial infarction; SSRI = selective serotonin re-uptake inhibitor; UTI = urinary tract infection) Infection Metabolic disturbance Toxic insult Acute neurological conditions Pain, hypoxia Pneumonia UTI Skin: cellulitis, abscess Gram-negative sepsis Full blood count, CRP Chest X-ray Urinalysis and culture Others as appropriate: sputum, blood cultures, wound swabs Digoxin level if prescribed Urea and electrolytes Plasma calcium Capillary blood and plasma glucose Liver function tests Thyroid function tests B12 and folate CT brain: only when intracranial lesion is suspected (focal neurological signs, recent fall or head injury) or no other physical cause of delirium is identified Lumbar puncture: only if meningitis or encephalitis is suspected Pulse oximetry (arterial blood gases if low) Chest X-ray ECG Acute renal impairment Hyponatraemia/hypernatraemia Hypercalcaemia Hypoglycaemia Hepatic encephalopathy Thiamin deficiency Hypothyroidism B12 deficiency* Any drug but particularly • Anticholinergics • Digoxin • Opiates • Psychotropics • High-dose glucocorticoids Withdrawal of alcohol, opiate, SSRI or benzodiazepine Acute stroke Subdural haematoma Encephalitis or meningitis Seizure (post-ictal) Space-occupying lesion, e.g. tumour Pulmonary embolism Pneumonia Pulmonary oedema COPD exacerbation Acute MI

Presenting problems in acute medicine • 185

photophobia/phonophobia, may support a diagnosis of migraine but others, such as progressive focal symptoms or constitutional upset like weight loss, may suggest a more sinister cause. The headache of cerebral venous thrombosis may be ‘throbbing’ or ‘band-like’ and associated with nausea, vomiting or hemiparesis. Raised intracranial pressure (ICP) headache tends to be worse in the morning and when lying flat or coughing, and associated with nausea and/or vomiting. A description of neck stiffness along with headache and photophobia should raise the suspicion of meningitis (Box 10.12), although this may present in atypical ways in immunosuppressed, alcoholic or pregnant patients. The behaviour of the patient during headache is often instructive; migraine patients typically retire to bed to sleep in a dark room, whereas cluster headache often induces agitated and restless behaviour. The pain of a subarachnoid haemorrhage frequently causes significant distress. Headache duration is also important to elicit; headaches that have been present for months or years are almost never sinister, whereas new-onset headache, especially in the elderly, is more of a concern. In a patient over 60 years with head pain localised to one or both temples, scalp tenderness or jaw claudication, temporal arteritis (p. 1042) should be considered. Clinical assessment An assessment of conscious level (using the Glasgow Coma Scale (GCS); Fig. 10.5) should be performed early and constantly reassessed. A decreased conscious level suggests raised ICP and urgent CT scanning (with airway protection if necessary) is indicated. A full neurological examination may provide clues as to the pathology involved; for example, brainstem signs in the context of acute-onset occipital headache may indicate vertebrobasilar dissection. Neurological signs may, however, be ‘falsely localising’, as in large subarachnoid haemorrhage or bacterial meningitis. Care should be taken to examine for other evidence of meningitis such as a rash (not always petechial), fever or signs of shock. Unilateral headache with agitation, ipsilateral lacrimation, facial sweating and conjunctival injection is typical of cluster headache. Conjunctival injection may also be seen in acute glaucoma, accompanied by peri- or retro-orbital pain, clouding of the cornea, decreased visual acuity and, often, systemic upset. Temporal headaches in patients over 60 should prompt examination for enlarged or tender temporal arteries and palpation of temporal pulses (often absent in temporal arteritis). Visual acuity should be assessed promptly, as visual loss is an important complication of temporal arteritis. Initial investigations If there is any alteration of conscious level, focal neurological signs, new-onset seizures or a history of head injury, then CT scanning of the head is indicated. The urgency of scanning will depend on the clinical picture and trajectory but in many circumstances 10.10 Primary and secondary headache syndromes Primary headache syndromes • Migraine (with or without aura) • Tension-type headache • Trigeminal autonomic cephalalgia (including cluster headache) • Primary stabbing/coughing/exertional/sex-related headache • Thunderclap headache • New daily persistent headache syndrome Secondary causes of headache • Medication overuse headache (chronic daily headache) • Intracranial bleeding (subdural haematoma, subarachnoid or intracerebral haemorrhage) • Raised intracranial pressure (brain tumour, idiopathic intracranial hypertension) • Infection (meningitis, encephalitis, brain abscess) • Inflammatory disease (temporal arteritis, other vasculitis, arthritis) • Referred pain from other structures (orbit, temporomandibular joint, neck) Headache Headache is common and causes considerable worry amongst both patients and clinicians, but rarely represents sinister disease. The causes may be divided into primary or secondary, with primary headache syndromes being vastly more common (Box 10.10). Presentation The primary purpose of the history and clinical examination in patients presenting with headache is to identify the small minority of patients with serious underlying pathology. Key features of the history include the temporal evolution of a headache; a headache that reached maximal intensity immediately or within 5 minutes of onset requires rapid assessment for possible subarachnoid haemorrhage. Other ‘red flag’ symptoms are shown in Box 10.11. It is important to establish whether the headache comes and goes, with periods of no headache in between (usually migraine), or whether it is present all or almost all of the time. Associated features, such as preceding visual symptoms, nausea/vomiting or 10.11 ‘Red flag’ symptoms in headache Symptom Possible explanation Sudden onset (maximal immediately or within 5 mins) Subarachnoid haemorrhage Cerebral venous sinus thrombosis Pituitary apoplexy Meningitis Focal neurological symptoms (other than for typically migrainous) Intracranial mass lesion: Vascular Neoplastic Infection Constitutional symptoms: Weight loss General malaise Pyrexia Meningism Rash Meningitis Encephalitis Neoplasm (lymphoma or metastases) Inflammation (vasculitis) Raised intracranial pressure (worse on waking/lying down, associated vomiting) Intracranial mass lesion New onset aged > 60 years Temporal arteritis 10.12 Identification of bacterial meningitis In patients presenting with headache, identification of those with bacterial meningitis is a top priority to facilitate rapid antibiotic treatment. In almost all cases there will be one of the following features: • meningism (neck stiffness, photophobia, positive Kernig’s sign) • fever > 38°C • signs of shock (tachycardia, hypotension, elevated serum lactate) • rash (not always petechial)

186 • ACUTE MEDICINE AND CRITICAL ILLNESS after headache onset, to look for evidence of xanthochromia. It is increasingly accepted, however, that a negative CT scan within 6 hours of headache onset has such a high degree of sensitivity for excluding subarachnoid haemorrhage that an LP is not necessary. In such circumstances, a CT angiogram should be considered to exclude other pathology, such as arterial dissection. Many headaches require prompt involvement of specialists. Features of acute glaucoma, for example, require immediate ophthalmological review for measurement of intraocular pressures. Suspected temporal arteritis with an erythrocyte sedimentation rate (ESR) of

50 mm/hr should prompt immediate glucocorticoid therapy and rheumatological referral (see p. 1042 for management). Features of raised ICP in the absence of a mass lesion on neuroimaging may indicate idiopathic intracranial hypertension; CSF opening pressure is likely to be informative. Unilateral leg swelling Most leg swelling is caused by oedema, the accumulation of fluid within the interstitial space. There are three explanatory mechanisms for development of oedema that are described in Box 10.13. Unilateral swelling usually indicates a localised pathology in either the venous or the lymphatic system, while bilateral oedema often represents generalised fluid overload combined with the effects of gravity. However, all causes of unilateral leg swelling may present bilaterally, and generalised fluid overload may present with asymmetrical (and therefore apparently unilateral) oedema. Fluid overload may be the result of cardiac failure, pulmonary hypertension (even in the absence of right ventricular failure), renal failure, hypoalbuminaemia or drugs (calcium channel blockers, glucocorticoids, mineralocorticoids, non-steroidal anti-inflammatory drugs (NSAIDs) and others); see Box 16.14 (p. 463) for other causes. The remainder of this section focuses on the causes of ‘unilateral’ oedema. Presentation Any patient who presents with unilateral leg swelling should be assessed with the possibility of deep vein thrombosis (DVT) in mind. The pain and swelling of a DVT is often fairly gradual in onset, over hours or even days. Sudden-onset pain in the posterior aspect of the leg is more consistent with gastrocnemius muscle tear (which may be traumatic or spontaneous) or a ruptured Baker’s cyst. Leg swelling and pain associated with paraesthesia or paresis, or in the context of lower limb injury or reduced conscious level, should always prompt concern regarding the possibility of compartment syndrome (Box 10.14). Clinical assessment Lower limb DVT characteristically starts in the distal veins, causing an increase in temperature of the limb and dilatation of the superficial veins. Often, however, symptoms and signs are minimal. will be immediately required. Intracranial haemorrhage or a space-occupying lesion with mass effect should prompt urgent neurosurgical referral. If bacterial meningitis is suspected (Box 10.12), cerebrospinal fluid (CSF) analysis is required to make a definite diagnosis. Antibiotics should not be delayed for lumbar puncture (LP), which needs to be preceded by CT scanning only if raised ICP is suspected. In cases of thunderclap headache (peak intensity within 5 minutes and lasting over an hour), a normal CT scan should be followed by an LP performed more than 12 hours Fig. 10.5 Assessment of the Glasgow Coma Scale (GCS) score in an obtunded patient. Avoid using a sternal rub, as it causes bruising. Hello, Mr XXX. Can you open your eyes, please? Score best eyes/ motor/verbal response Trapezius pinch Score response looking at arms for localisation/ flexion/abnormal flexion Pressure on supra-orbital ridge Score response Firm nail-bed pressure Score if withdrawal present or any eye/verbal response No response No response No response 10.13 Mechanisms of oedema There are three explanatory mechanisms for the development of oedema that may occur in isolation or combination: • increased hydrostatic pressure in the venous system due to increased intravascular volume or venous obstruction • decreased oncotic pressure secondary to a decrease in the plasma proteins that retain fluid within the circulation • obstruction to lymphatic drainage (‘lymphoedema’)

Presenting problems in acute medicine • 187

10.14 Identification of compartment syndrome • Compartment syndrome classically occurs following extrinsic compression of a limb due to trauma or reduced conscious level (especially when caused by drugs or alcohol) • It usually presents with a tense, firm and exquisitely painful limb • The pain is characteristically exacerbated by passive muscle stretching or squeezing the compartment • Altered sensation may be evident distally • Absent peripheral pulses are a late sign and their presence does not exclude the diagnosis • Clinical suspicion of compartment syndrome should prompt measurement of creatine kinase and urgent surgical review Cellulitis is usually characterised by erythema and skin warmth localised to a well-demarcated area of the leg and may be associated with an obvious source of entry of infection (e.g. leg ulcer or insect bite). The patient may be febrile and systemically unwell. Superficial thrombophlebitis is more localised; erythema and tenderness occur along the course of a firm, palpable vein. Examination of any patient presenting with leg swelling should include assessment for malignancy (evidence of weight loss, a palpable mass or lymphadenopathy). Malignancy is a risk factor for DVT, but pelvic or lower abdominal masses can also produce leg swelling by compressing the pelvic veins or lymphatics. Early lymphoedema is indistinguishable from other causes of oedema. More chronic lymphoedema is firm and non-pitting, often with thickening of the overlying skin, which may develop a ‘cobblestone’ appearance. Chronic venous insufficiency is a cause of long-standing oedema that, particularly when combined with another cause of leg swelling, may acutely worsen. Characteristic skin changes (haemosiderin deposition, hair loss, varicose eczema, ulceration) and prominent varicosities are common, and sometimes cause diagnostic confusion with cellulitis. See Box 10.14 for the examination findings associated with compartment syndrome. Initial investigations Clinical criteria can be used to rank patients according to their likelihood of DVT, by using scoring systems such as the Wells score (Box 10.15). Figure 10.6 gives an algorithm for investigation of suspected DVT based on initial Wells score. In patients with a low (‘unlikely’) pre-test probability of DVT, D-dimer levels can be measured; if these are normal, further investigation for DVT is unnecessary. In those with a moderate or high (‘likely’) probability of DVT or with elevated D-dimer levels, objective diagnosis of DVT should be obtained using appropriate imaging, usually a Doppler ultrasound scan. The investigative pathway for DVT, therefore, differs according to the pre-test probability (p. 11) of DVT. For low-probability DVT, the negative predictive value of the D-dimer test (the most important parameter in this context) is over 99%; if the test is negative, the clinician can discharge the patient with confidence. In patients with a high probability of DVT, the negative predictive value of a D-dimer test falls to somewhere in the region of 97–98%. While this may initially appear to be a high figure, to discharge 2 or 3 patients in every 100 incorrectly would generally be considered an unacceptable error rate. Hence, with the exception of pregnancy (Box 10.16), a combination of clinical probability and blood test results should be used in the diagnosis of venous thromboembolism. If cellulitis is suspected, serum inflammatory markers, skin swabs and blood cultures should be sent, ideally before antibiotics 10.15 Predicting the pre-test probability of deep vein thrombosis (DVT) using the Wells score* Clinical characteristic Score Previous documented DVT

Active cancer (patient receiving treatment for cancer within previous 6 months or currently receiving palliative treatment)

Paralysis, paresis or recent plaster immobilisation of lower extremities

Recently bedridden for ≥ 3 days, or major surgery within previous 4 weeks

Localised tenderness along distribution of deep venous system

Entire leg swollen

Calf swelling at least 3 cm larger than that on asymptomatic side (measured 10 cm below tibial tuberosity)

Pitting oedema confined to symptomatic leg

Collateral superficial veins (non-varicose)

Alternative diagnosis at least as likely as DVT –2 Clinical probability Total score DVT low probability < 1 DVT moderate probability 1–2 DVT high probability

2 From Wells PS. Evaluation of D-dimer in the diagnosis of suspected deep-vein thrombosis. N Engl J Med 2003; 349:1227; copyright © 2003 Massachusetts Medical Society. *A dichotomised revised Wells score, which classifies patients as ‘unlikely’ or ‘likely’, may also be used. Fig. 10.6 Investigation of suspected deep vein thrombosis. Pre-test probability is calculated in Box 10.15. See also page 11. Pre-test probability (see Box 10.15) Low D-dimer −ve D-dimer +ve +ve +ve −ve −ve Probability low, or moderate with −ve D-dimer Probability high, or moderate with +ve D-dimer Repeat compression ultrasound in 7 days Treat Exclude Compression ultrasound Moderate or high are given. Ruptured Baker’s cyst and calf muscle tear can both be readily diagnosed on ultrasound. If pelvic or lower abdominal malignancy is suspected, a prostate-specific antigen (PSA) level should be measured in males and appropriate imaging with ultrasound (transabdominal or transvaginal) or CT should be undertaken.

188 • ACUTE MEDICINE AND CRITICAL ILLNESS Fig. 10.7 Identifying and responding to physiological deterioration. A An example of an early warning score chart. (NEWS = National Early Warning Score; V/P/U = Verbal/Pain/Unresponsive) NEWS Key

Sp02 Date: Time: ≥25 21–24 12–20 9–11 ≤8 Default Chronic Hypoxia ≥91 ≥39° 38° 37° 36° ≤35°

140

Regular Y/N Alert V/P/U New confusion Unrecordable ≥88 94–95 Medical signature required to use scale for patients with Chronic Hypoxia Sign 92–93 86–87 ≤91 ≤85 Unrecordable % or litres Inspired 02 Temperature NEWS SCORE uses Systolic BP If manual BP mark as M Heart Rate Conscious Level Respiratory Rate A Identification and assessment of deterioration Early warning scores and the role of the medical emergency team There are many systems that have been developed with the aim of rapidly identifying and managing physiological deterioration. These are referred to as ‘rapid response systems’. One popular example of a rapid response system is a medical emergency team (MET). A MET system operates on the basis that when a patient meets certain physiological criteria, the team is alerted. The team is expected to make a rapid assessment and institute immediate management. This may include escalation to critical care or, following liaison with the parent clinical team, ongoing ward-based care. The trigger for a ‘MET’ call may be a single parameter – such as a low BP or tachycardia – or may consist of a composite early warning score. Early warning score systems function by the observer allocating a value between 0 and 3 for abnormalities in respiratory rate, SpO2, temperature, BP, heart rate, neurological response and urine output (Fig. 10.7). The values are summed and the composite score gives an indication of the severity of physiological derangement. Early warning systems can be automated into an electronic format that calculates the score and even alerts the responsible clinician(s) by email or text message. There are advantages and disadvantages to having a separate MET system, compared with allowing the responsible clinical team to manage deterioration, and to having a composite score or a single parameter detection system. These are outlined in Box 10.17. Immediate assessment of the deteriorating patient An approach to assessment of the deteriorating patient can be summarised by the mnemonic ‘C-A-B-C-D-E’. C – Control of obvious problem For example, if the patient has ventricular tachycardia on the monitor or significant blood loss is apparent, immediate action is required. A and B – Airway and breathing If the patient is talking in full sentences, then the airway is clear and breathing is adequate. A rapid history should be obtained while the initial assessment is undertaken. Breathing should be assessed with a focused respiratory examination. Oxygen saturations and ABGs should be checked early (p. 190). 10.16 Swollen legs in pregnancy • Benign swollen legs: common in pregnancy; this is usually benign. • DVT: pregnancy is a significant risk factor, however. • D-dimer: should not be measured in pregnancy; it has not been validated in this group. • Imaging: should be arranged on the basis of clinical suspicion alone, and the threshold for undertaking a definite diagnostic test should be low.

Identification and assessment of deterioration • 189

• Inform registered nurse • Registered nurse assessment using ABCDE • Review frequency of observations • Inform Nurse in Charge • If ongoing concern, escalate to Medical Team • Continue routine NEWS monitoring with every set of observations Minimum 12 hourly/4 hourly in admission areas Frequency of Observations NEWS Score Total 0* Total 1–4* Total 7* or more Total 5–6* or 3 in one parameter *Regardless of NEWS always escalate if concerned about a patient’s condition Clinical Response Minimum 4 hourly Consider Structured Response Tool Consider Fluid Balance Chart Increase frequency to a minimum of 1 hourly Start Structured Response Tool Start Fluid Balance Chart Continuous monitoring of vital signs Start Structured Response Tool Start Fluid Balance Chart • Registered nurse assessment • Inform Nurse in Charge • Escalate to Medical Team as per local escalation • Urgent medical assessment • Management plan to be discussed with Senior Trainee or above • Consider level of monitoring required in relation to clinical care • Registered nurse to assess immediately • Inform Nurse in Charge • Request immediate assessment by Senior Trainee or above • Case to be discussed with supervising Consultant • If appropriate contact Critical Care for review B B Responses to physiological deterioration. A and B, From Royal College of Physicians. National Early Warning Score (NEWS): standardising the assessment of acute-illness severity in the NHS. Report of a working party. London: RCP, 2012. Fig. 10.7, cont’d 10.17 Advantages and disadvantages of different rapid response systems System Advantages Disadvantages Single parameter trigger High sensitivity. Probably picks up subclinical deterioration and allows optimisation Low specificity. Much time will be spent with patients who are not deteriorating Composite early warning scoring system, e.g. NEWS or MEWS score Combines good sensitivity with improved specificity May miss single parameter deterioration that is still significant, e.g. a drop of 2 GCS points may not trigger an alert MET system Brings expertise in deteriorating patients immediately to the bedside Expensive to have well-trained individuals who are free from other clinical duties. May deskill the ward-based teams in acute care. May not have expertise in highly specific areas of medicine Clinical team review Patient is seen by clinicians familiar with the patient and condition Clinical team may be busy with other urgent duties. There may not be expertise in acute care within the ward-based team (GCS = Glasgow Coma Scale; MET = Medical Emergency Team; MEWS = Modified Early Warning Score; NEWS = National Early Warning Score) C – Circulation A focused cardiovascular examination should include heart rate and rhythm, jugular venous pressure, evidence of bleeding, signs of shock and abnormal heart sounds. The carotid pulse should be palpated in the collapsed or unconscious patient, but peripheral pulses also should be checked in conscious patients. The radial, brachial, foot and femoral pulses may disappear as shock progresses, and this indicates the severity of circulatory compromise. D – Disability Conscious level should be assessed using the GCS (see Fig. 10.5 and Box 10.24, pp. 186 and 194). A brief neurological examination looking for focal signs should be performed. Capillary blood glucose should always be measured to exclude hypoglycaemia or severe hyperglycaemia. E – Exposure and evidence ‘Exposure’ indicates the need for targeted clinical examination of the remaining body systems, particularly the abdomen and lower limbs. ‘Evidence’ may be gathered via a collateral history from other health-care professionals or family members, recent investigations, prescriptions or monitoring charts. Selecting the appropriate location for ongoing management Any patient who will gain benefit from a critical care area should be admitted. Such patients generally fall into two groups: those with organ dysfunction severe enough to require organ support and those in whom the disease process is clearly setting them on a downward trajectory and in whom early, aggressive management may alter the outcome. Whether an individual patient should be

190 • ACUTE MEDICINE AND CRITICAL ILLNESS Analysis of an arterial blood sample is especially helpful in narrowing the differential diagnosis and confirming clinical suspicion of severity. The ‘base excess’ provides rapid quantification of the component of disease that is metabolic in origin. A base excess lower than −2 mEq/L (or, put another way, a ‘base deficit’ of more than 2 mEq/L) is likely to represent a metabolic acidosis. A simple rule of thumb is that a lactate of more than 4 mmol/L or a base deficit of more than 10 mEq/L should cause concern and trigger escalation to a higher level of care. In addition to clinical examination, chest radiography and bedside ultrasound can help to distinguish the cause of poor air entry; consolidation and effusion can be readily identified and a significant pneumothorax can be excluded (as shown in Fig. 10.8). Hypoxaemia Pathophysiology Low arterial partial pressure of oxygen (PaO2) is termed hypoxaemia. It is a common presenting feature of deterioration. Hypoxia is defined as an inadequate amount of oxygen in tissues (or the inability of cells to use the available oxygen for cellular respiration). Hypoxia may be due to hypoxaemia, or may be secondary to impaired cardiac output, the presence of inadequate or dysfunctional haemoglobin, or intracellular dysfunction (such as in cyanide poisoning, where oxygen utilisation at the cellular level is impaired). Over 97% of oxygen carried in the blood is bound to haemoglobin. The haemoglobin–oxygen dissociation curve delineates the relationship between the percentage saturation of haemoglobin with oxygen (SO2) and the partial pressure (PO2) of oxygen in the blood. A shift in the curve will influence the uptake and release of oxygen by the haemoglobin molecule. As capillary PCO2 rises, the curve moves to the right, increasing the offloading of oxygen in the tissues (the Bohr effect). This increases capillary PO2 and hence cellular oxygen supply. Shifts of the oxyhaemoglobin dissociation curve can have significant implications in certain disease processes (Fig. 10.9). admitted to the intensive care or high-dependency unit (ICU/ HDU) will depend on local arrangements. A useful tool to assist with the decision regarding location is the ‘level of care’ required (Box 10.18). Many intensive care units are a mix of level 2 and level 3 beds, which streamlines the admission process. Common presentations of deterioration As patients become critically unwell, they usually manifest physiological derangement. The principle underpinning critical care is the simultaneous assessment of illness severity and the stabilisation of life-threatening physiological abnormalities. The goal is to prevent deterioration and effect improvements, as the diagnosis is established and treatment of the underlying disease process is initiated. It can be useful to consider the physiological changes as a starting point to help delineate urgent investigations and supportive treatment, which should proceed alongside the search for a definitive diagnosis. Tachypnoea Pathophysiology A raised respiratory rate (tachypnoea) is the earliest and most sensitive sign of clinical deterioration. Tachypnoea may be primary (i.e. a problem within the respiratory system) or secondary to pathology elsewhere in the body. Cardiopulmonary causes of tachypnoea have been covered on page 179. Secondary tachypnoea is usually due to a metabolic acidosis, most commonly observed in the context of sepsis, haemorrhage, ketoacidosis or visceral ischaemia. More detailed information on metabolic acidosis can be found on page 364. Assessment and management A simple assessment of a patient’s clinical status and basic physiology will usually indicate whether urgent intervention is required. In the examination, attention should be paid to the adequacy of chest expansion, air entry and the presence of added sounds such as wheeze. 10.18 Levels of care and the corresponding admission criteria for intensive care unit (ICU) and high-dependency unit (HDU) Level of care Criteria Appropriate location

Patients requiring/likely to require endotracheal intubation and invasive mechanical ventilatory support Patients requiring support of two or more organ systems (e.g. inotropes and haemofiltration) Patients with chronic impairment of one or more organ systems (e.g. COPD or severe ischaemic heart disease) who require support for acute reversible failure of another organ ICU

Patients requiring detailed observation or monitoring that cannot be provided at ward level: Direct arterial BP monitoring CVP monitoring Fluid balance Neurological observations, regular GCS recording Patients requiring support for a single failing organ system, excluding invasive ventilatory support (IPPV): Non-invasive respiratory support (p. 202) Moderate inotropic or vasopressor support Renal replacement therapy in an otherwise stable patient Step-down from intensive care requiring additional monitoring or single organ support HDU

Patients in whom frequent but intermittent observations and medical review are sufficient General ward setting (BP = blood pressure; COPD = chronic obstructive pulmonary disease; CVP = central venous pressure; GCS = Glasgow Coma Scale; IPPV = intermittent positive pressure ventilation)

Common presentations of deterioration • 191

with acute stroke, those with MI and those who chronically retain CO2. Adverse effects of hyperoxia include: • free radical-induced tissue damage • less efficient buffering of carbon dioxide by oxyhaemoglobin (compared to deoxyhaemoglobin) • less efficient ventilation–perfusion matching in lung units (due to loss of hypoxic vasoconstriction of under-ventilated lung units) • decreased hypoxic respiratory drive in individuals with chronic hypercapnia. When attempting to determine the cause of hypoxaemia, it is useful to consider whether the primary physiological mechanism is a type of shunt, or one of the many causes of ventilation–perfusion mismatch, such as alveolar or central hypoventilation (Fig. 10.10). A classification of common causes of hypoxaemia in hospitalised patients is shown in Box 10.20. In reality, the observed physiological abnormality may represent a combination of inter-related processes, such as severe pulmonary oedema leading to exhaustion, which in turn causes hypoventilation. Evaluation of risk factors, history and examination will help to differentiate the likely aetiology and guide specific management. Further management of respiratory failure is discussed on page 202. Tachycardia Pathophysiology A heart rate of > 110 beats/min in an adult should always be considered abnormal and not attributed to anxiety until other causes have been excluded. Intrinsic cardiac causes (atrial fibrillation (AF), atrial flutter, supraventricular tachycardia and Due to the shape of the curve, a small drop in arterial PO2 (PaO2) below 8 kPa (60 mmHg) will cause a marked fall in SaO2. Relative hypoxaemia refers to the comparison between the observed PaO2 and that which might be expected for a given fraction of inspired oxygen (FiO2). With the patient breathing air, PaO2 of 12–14 kPa (90–105 mmHg) would be expected; with the patient breathing 100% oxygen, a PaO2 of > 60 kPa (450 mmHg) would be normal. Assessment and management Oxygen therapy should be titrated to avoid hyperoxia (too high a PaO2; Box 10.19). Hyperoxia is theoretically harmful via a number of mechanisms. This has a clinically significant effect in patients Fig. 10.8 Using ultrasound to rule out an anterior pneumothorax. A Probe position and orientation. B and C Two-dimensional (2D) ultrasound images. D and E M-mode ultrasound images. Key: (1) Intercostal muscle. (2) Rib. (3) Normal bright pleural line –‘shimmering appearance’ of sliding pleura. (4) Lung. (5) Absent ‘shimmering’ in pneumothorax and lung not visible. (6) Normal – ‘sea shore’ sign excludes pneumothorax at that location. The ‘sea shore’ is represented by the bright granular line with lung (sea) deeper to the bright line. (7) Absent granular pleural line and a repeating linear pattern or ‘barcode’ sign suggest the presence of pneumothorax. Normal (no pneumothorax) Normal (no pneumothorax)

3 4 B D C A E Abnormal (pneumothorax cannot be excluded) Abnormal (pneumothorax cannot be excluded) Fig. 10.9 The haemoglobin–oxygen dissociation curve and the effect of CO2 on oxygen saturations. In pulmonary embolism, compensatory hyperventilation often occurs. PaCO2 decreases, shifting the oxyhaemoglobin saturation curve to the left (green line). Therefore, despite a low PaO2 (8 kPa/60 mmHg), the saturation reading is 93%. = 6.0 kPa = 45 mmHg PO2 (kPa or mmHg) Haemoglobin saturation (SO2) % = 4.1 kPa = 31 mmHg kPa mmHg P75 P50

9 10 11 12 13 14

10.19 Prescribing oxygen in critical illness • Oxygen should be prescribed to achieve a target saturation of 94–98% for most critically unwell patients. • 88–92% is a more appropriate target range for those at risk of hypercapnic respiratory failure.

192 • ACUTE MEDICINE AND CRITICAL ILLNESS Hypovolaemia should not be missed. Concealed bleeding (e.g. into the pleura, gastrointestinal tract or retroperitoneum) may not be apparent initially and assessment of haemoglobin in an acute haemorrhage, when < 30 mL/kg of fluid has been administered, can be misleadingly high. Sepsis and other hyper-metabolic conditions may present with a tachycardia that is accompanied by tachypnoea, peripheral vasodilatation and a raised temperature. Other organ dysfunction should be noted from a brief general examination and salient points from the history. Assessment and management The management of a tachycardic patient should focus on treating the cause. Treating the rate alone with beta-blockade in an unwell or deteriorating patient should be done only under specialist guidance, in controlled conditions, and when a clear evaluation of the risk–benefit ratio has been undertaken. The recognition and management of primary cardiac dysrhythmias are discussed on page 468. The most appropriate method of rate control in AF depends primarily on the degree of haemodynamic compromise. An intravenous loading dose of amiodarone is well tolerated and efficacious in the majority of critically ill patients with AF and a very rapid ventricular rate. There are thromboembolic concerns regarding chemical cardioversion of AF of unknown duration. However, in deteriorating patients, the low incidence of embolic events makes this concern of secondary importance to achieving haemodynamic stability. Digoxin continues to have a role in the treatment of AF in critically unwell but haemodynamically stable patients, when ventricular dysrhythmias) are less common in the general inpatient population than secondary causes of tachycardia. A cardiac monitor or 12-lead ECG early in the examination will help both determine severity (heart rate > 160 beats/min should prompt urgent escalation to a higher level of care) and narrow the differential diagnosis. AF with a rapid ventricular response should usually be regarded as secondary to another insult (mostly commonly, infection) until other diagnoses have been excluded. Fig. 10.10 Theoretical mechanisms of hypoxaemia. A Normal physiology. B Shunt caused by alveolar filling, e.g. in pneumonia or alveolar haemorrhage. The mixture of oxygenated and deoxygenated blood causes arterial desaturation. C Shunt caused by interstitial pathology, e.g. pulmonary oedema or fibrosis. Interstitial thickening causes inadequate transfer of oxygen from the alveolus to the blood, leading to shunting and arterial desaturation. Because minute volume is usually maintained, this causes type I respiratory failure. D Ventilation–perfusion (V/Q ) mismatch caused by alveolar hypoventilation, e.g. in chronic obstructive pulmonary disease (COPD)/asthma. Alveoli are under-ventilated relative to perfusion. Alveolar PO2 falls and PCO2 rises, causing type II respiratory failure. E V/Q mismatch caused by central hypoventilation, e.g. in neuromuscular disease or narcotic use. The alveoli are relatively over-perfused, causing type II respiratory failure. F V/Q mismatch caused by a perfusion defect, e.g. a small pulmonary embolism. Pulmonary blood flow is diverted to other alveoli, causing them to be relatively over-perfused and thus reducing alveolar PO2. Minute volume is increased, so PCO2 is not elevated. Terminal bronchus Alveolus Alveolus filled with blood/secretions or collapsed. Blood will pass this alveolus without becoming oxygenated Pulmonary vein SO2 98% Pulmonary artery SO2 75% Pulmonary vein SO2 98% SO2 75% SO2 75% SO2 98% A B SO2 90% SO2 75% SO2 90% Interstitium thickened by fluid, inflammatory exudate or cells SO2 75% SO2 98% C D SO2 75% SO2 75% SO2 94% SO2 90% ↓[O2] ↑[CO2] ↓[O2] ↑[CO2] ↓[O2] ↓[CO2] SO2 75% SO2 90% E F 10.20 Common causes of hypoxaemia in hospitalised patients Hypoxaemia due to shunt • Lung collapse • Consolidation/alveolar haemorrhage • Interstitial oedema or interstitial infiltration (e.g. fibrosis) • Silent aspiration of gastric contents Hypoxaemia due to ventilation–perfusion mismatch • Pulmonary embolism • Acute exacerbation of asthma • COPD (with high minute volume) Hypoxaemia from hypoventilation • Effects of opiates • Severe COPD (with low minute volume) • Neuromuscular disease/general weakness from other illness (COPD = chronic obstructive pulmonary disease)

Common presentations of deterioration • 193

early identification. If shock is suspected, resuscitation should be commenced (p. 204). Hypotensive patients who do not have any evidence of shock are still at significant risk of organ dysfunction. Hypotension should serve as a ‘red flag’ that there may be serious underlying pathology. Organ failure occurs despite normal or elevated oxygen delivery, so a full assessment of the patient is indicated. A review of the drug chart is essential, as many inpatients will be on antihypertensive medications that are contributing to hypotension. Non-cardiac medications may also have a negative influence on BP; for example, some drugs used for urine outflow tract obstruction, such as tamsulosin, have an α-adrenoceptor-blocking effect. Hypertension Pathophysiology High BP (hypertension) is common and is usually benign in a critical care context. However, it can be the presenting feature of a number of serious disease processes. Furthermore, acute hypertension can result in an acute rise in vascular tone that increases left ventricular end-systolic pressure (afterload). The left ventricle may be unable to eject blood against the increased aortic pressure, and acute pulmonary oedema can result (referred to as ‘flash’ pulmonary oedema.) Assessment and management Before treating an acute rise in BP, it is worth considering a few important diagnoses that may impact on the immediate management: • Intracranial event. Ischaemia of the brainstem (commonly via a pressure effect) will cause acute increases in BP. A neurological examination and CT scan of the head should be considered. • Fluid overload. Once the capacity of the venous blood reservoir becomes saturated, increases in fluid volume will lead to increases in BP. This can occur in younger patients without the onset of peripheral oedema and originate from myocardial dysfunction or impaired renal clearance. • Underlying medical problems. A brief search for a history of renal disease, spinal injury and less common metabolic causes such as phaeochromocytoma can be worthwhile. In women of child-bearing age, pregnancy-induced its inotropic properties can be helpful. Electrical cardioversion is reserved for dysrhythmias with extremely high heart rates, following failure of pharmacological management, and/or for those of ventricular origin. It is rarely successful in dysrhythmias secondary to systemic illness. Hypotension Pathophysiology Low BP (hypotension) should always be defined in relation to a patient’s usual BP. The calculation of mean arterial pressure (MAP) is shown in Box 10.21; it unifies the systolic and diastolic BPs into a single reference value. A MAP of > 65 mmHg will maintain renal perfusion in the majority of patients, although a MAP of up to 80 mmHg may be required in patients with chronic hypertension. Assessment and management The first stage of assessment is to decide if the hypotension is physiological or pathological. The MAP is useful as, despite low systolic pressures, it is rare to see a physiological MAP of < 65 mmHg. Urine output is particularly useful in the determination of the desirable MAP for an individual patient; oliguria suggests that measures to increase the MAP should be sought (p. 204). If the hypotension is pathological, an assessment of severity should look at whether it is causing physiological harm to the patient (i.e. the patient is shocked). Shock Shock means ‘circulatory failure’. It can be defined as a level of oxygen delivery (DO2) that fails to meet the metabolic requirements of the tissues (Box 10.22). Hypotension is a common presentation of shock but the terms are not synonymous. Patients can be hypotensive but not shocked, and oxygen delivery can be critically low in the context of a ‘normal’ BP. Along with the signs of low cardiac output (Box 10.23), objective markers of inadequate tissue oxygen delivery, such as increasing base deficit, elevated blood lactate and reduced urine output, can aid 10.21 Calculation of mean arterial pressure (MAP) MAP Diastolic blood pressure systolic diastolic

− ( )

At normal heart rates, the heart, on average, spends two-thirds of the cycle in diastole. The MAP reflects this by weighting the value towards the diastolic blood pressure *Oxygen is almost exclusively bound to haemoglobin; only tiny amounts are dissolved in blood at atmospheric pressure. 10.22 Oxygen content and delivery • Oxygen content of blood = *Haemoglobin level × oxygen saturation × constant • Cardiac output = Heart rate × stroke volume • Stroke volume is dependent on cardiac filling (preload) and contractility • In shock, the most productive measures to improve oxygen delivery are optimising the haemoglobin level and the cardiac output 10.23 Hypotension in relation to cardiac output: clinical signs and possible causes High cardiac output Low cardiac output Signs Warm hands Pulsatile head movement High-volume/strong pulse Low venous pressure Cold/clammy peripheries Peripheral cyanosis Raised venous pressure Causes Sepsis Allergy Drug overdose (e.g. antihypertensive) Acidosis (e.g. diabetic ketoacidosis) Thyrotoxicosis Beri-beri Bleeding Aortic stenosis and failed compensation Dysrhythmia Obstructive (pulmonary embolism/tamponade/ dynamic hyperinflation as in severe asthma) Chronic heart failure

194 • ACUTE MEDICINE AND CRITICAL ILLNESS aspiration or obstruction), but a motor score of less than 5 would suggest significant risk. Coma is defined as a persisting state of deep unconsciousness. In practice, this means a sustained GCS of 8 or less. There are many causes of coma (Box 10.26), including neurological (structural or non-structural brain disease) and non-neurological (e.g. type II respiratory failure) ones. The mode of onset of coma and any precipitating event is crucial to establishing the cause, and should be obtained from witnesses. Failure to obtain an adequate history for patients in coma is a common cause of diagnostic delay. Once the patient is stable from a cardiorespiratory perspective, examination should include accurate assessment of conscious level and a thorough general medical examination, looking for clues such as needle tracks indicating drug abuse, rashes, fever and focal signs of infection, including neck stiffness or evidence of head injury. Focal neurological signs may suggest a structural explanation (stroke or tumour) or may be falsely localising (for example, 6th nerve palsy can occur as a consequence of raised intracerebral pressure). It is vital to exclude non-neurological causes of coma. Sodium and glucose should be measured urgently as part of the initial assessment, as acute hyponatraemia (p. 358) and hypoglycaemia (p. 738) are easily corrected and can cause irreversible brain injury if missed. hypertension and pre-eclampsia must always be considered. • Primary cardiac problems. Myocardial ischaemia, acute heart failure and aortic dissection can all present with hypertension. • Drug-related problems. Most commonly, these involve a missed antihypertensive medication, but sympathomimetic drugs such as cocaine and amphetamines can be implicated. The management of hypertension is discussed further on page 510. Decreased conscious level Assessment A reduction in conscious level should prompt an urgent assessment of the patient, a search for the likely cause and an evaluation of the risk of airway loss. The GCS was developed to risk-stratify head injury, but it has become the most widely recognised assessment tool for conscious level (see Box 10.24 for breakdown of GCS assessment, Box 10.25 for how to communicate the findings and Fig. 10.5 for how to assess GCS). While disorders that affect language or limb function (e.g. left hemisphere stroke, locked-in syndrome) may reduce its usefulness, evaluation of the GCS usually provides helpful prognostic information, and serial recordings can plot improvement or deterioration. It is not possible to define a total score below which a patient is unlikely to be able to protect the airway (from 10.25 How to communicate conscious level to other health-care professionals • It is best to state the physical response along with the numerical score • For example, ‘a patient who doesn’t open his eyes, withdraws to pain and makes groaning noises, having a GCS of E1, M4, V2, making a total of 7’ is preferable to ‘a male with a GCS of 7’ Record the best score observed. When the patient is intubated, there can be no verbal response. The suffix ‘T’ should replace the verbal component of the score, and the remainder of the score is therefore a maximum of 10. 10.24 Glasgow Coma Scale (GCS) Eye-opening (E) • Spontaneous

• To speech

• To pain

• Nil

Best motor response (M) • Obeys commands

• Localises to painful stimulus

• Flexion to painful stimulus or withdraws hand from pain

• Abnormal flexion (internal rotation of shoulder, flexion of wrist)

• Extensor response (external rotation of shoulder, extension of wrist)

• Nil

Verbal response (V) • Orientated

• Confused conversation

• Inappropriate words

• Incomprehensible sounds

• Nil

Coma score = E + M + V Always present GCS as breakdown, not a sum score (unless 3 or 15) • Minimum sum

• Maximum sum

10.26 Causes of coma Metabolic disturbance • Drug overdose • Diabetes mellitus: Hypoglycaemia Ketoacidosis Hyperosmolar coma • Hyponatraemia • Uraemia • Hepatic failure (hyperammonaemia) • Inborn errors of metabolism causing hyperammonaemia • Hyperammonaemia on refeeding following profound anorexia • Respiratory failure • Hypothermia • Hypothyroidism Trauma • Cerebral contusion • Extradural haematoma • Subdural haematoma • Diffuse axonal injury Vascular disease • Subarachnoid haemorrhage • Brainstem infarction/ haemorrhage • Intracerebral haemorrhage • Cerebral venous sinus thrombosis Infections • Meningitis • Encephalitis • Cerebral abscess • Systemic sepsis Others • Epilepsy • Brain tumour • Functional (‘pseudo-coma’)

Common presentations of deterioration • 195

Further investigations should be guided by the clinical presentation and examination findings; a sudden onset suggests a vascular cause. An early CT scan of the brain may demonstrate any gross pathology but if a brainstem stroke is suspected (Fig. 10.11), a CT angiogram of the circle of Willis will provide more useful information, as a non-contrast CT is frequently negative in this context. If there are features suggestive of cerebral venous thrombosis, such as thrombophilia or sinus infection, a CT venogram should be performed. Meningitis or encephalitis may be suggested by the history, signs of infection or subtle radiological findings. If these diagnoses are considered, it is best to commence treatment with broad-spectrum antibiotics and antivirals while awaiting more definitive diagnostic information. Other drug, metabolic and hepatic causes of reduced conscious level are dealt with in the relevant chapters. An ammonia level (sent on ice) can narrow the differential diagnosis to a metabolic or hepatic cause if there is diagnostic doubt; levels > 100 μmol/L (140 μg/dL) are significantly abnormal. Psychiatric conditions such as catatonic depression or neurological conditions such as the autoimmune encephalitides can cause a reduced level of consciousness, but they are diagnoses of exclusion and will require specialist input. Management Moving an unconscious patient into the recovery position is best for airway protection while preparations are made for escalation to a higher level of care. The decision regarding intubation for airway protection is always difficult. Length of stay in intensive care is significantly reduced if there is no secondary organ Fig. 10.11 Hyperacute changes in conscious state are commonly of vascular origin. CT of the brain is unlikely to identify many vascular causes but a CT angiogram of the circle of Willis is a high-yield investigation in this context. A Non-contrast CT of the head showing hyperdense thrombus in the basilar artery (arrow). This is a specific, but not sensitive, sign. B CT angiogram of the circle of Willis demonstrating thrombosis in the basilar artery (arrow). This has better sensitivity for acute vascular occlusion. B A dysfunction. Therefore, early intubation and the prevention of lung injury constitute the safer option if there is any doubt about a patient’s ability to protect the airway from obstruction or aspiration. Decreased urine output/deteriorating renal function Assessment A urine output of 0.5 mL/kg/hr is a commonly quoted, though admittedly arbitrary target. Although some patients can produce urine volumes below this level with no change in their renal biochemistry, such low volumes should alert the clinician to the possibility of suboptimal renal perfusion. Oliguria in association with hypotension or an increase in serum creatinine level (even if small) should prompt examination for the underlying cause. Pre-renal causes predominate in the general inpatient population, so optimising the MAP by administration of intravenous fluids (and possibly vasopressors) is the first priority. In the majority of inpatients there is no role for high volumes (i.e.

30 mL/kg) of intravenous fluid if the MAP is normal. Exceptions to this rule include patients with clinical dehydration or high fluid losses such as in burns, diabetes emergencies (pp. 735 and

  1. and diabetes insipidus (p. 687), where fluid management should be guided by local protocols. Diagnosis and management Further assessment and management of oliguria are explained on page 391. Two other important causes of renal failure in the inpatient population are abdominal compartment syndrome and rhabdomyolysis. Abdominal compartment syndrome Abdominal compartment syndrome occurs when raised pressure within the abdomen reduces perfusion to the abdominal organs. It is most commonly seen in surgical patients, but can occur in medical conditions with extreme fluid retention such as liver cirrhosis. When it is suspected, intra-abdominal pressure can be monitored via a pressure transducer connected to a urinary catheter (following instillation of 25 mL of 0.9% saline into the bladder). Values over 20 mmHg suggest abdominal compartment syndrome is present. Urgent measures should be taken to reduce the pressure, such as decompression of the stomach, bladder and peritoneum if ascites is present. If conservative measures fail, a laparostomy should be considered. Rhabdomyolysis Rhabdomyolysis occurs when there is an injury to a large volume of skeletal muscle, usually because a single limb or muscle compartment has been ischaemic for a prolonged period. It can also occur following trauma and crush injury or after over-exertion of muscles. Over-exertion can occur after intense physical exercise or as part of a medical condition that causes widespread muscular activity, such as malignant hyperpyrexia or neuroleptic malignant syndrome. A creatine kinase (CK) level of > 1000 U/L is highly suggestive, although it can rise to tens of thousands in severe cases. Management should focus on identification and correction of the underlying cause and support for multi-organ dysfunction. Forced alkaline diuresis (using intravenous bicarbonate infusion and furosemide) can be used to maintain a good flow of less acidic fluid within the renal tubules and reduce myoglobin precipitation.

196 • ACUTE MEDICINE AND CRITICAL ILLNESS non-infective processes, such as pancreatitis, burns, trauma, major surgery and drug reactions, can cause alarmins to be released and initiate the process of systemic inflammation. Propagation of the inflammatory response Once activated, immune cells such as macrophages release the inflammatory cytokines interleukin-2 (IL-2), IL-6 and tumour necrosis factor alpha, which, in turn, activate neutrophils. Activated neutrophils express adhesion factors and release various other inflammatory and toxic substances; the net effects are vasodilatation (via activation of inducible nitric oxide synthase enzymes) and damage to the endothelium. Neutrophils migrate into the interstitial space; fluid and plasma proteins will also leak through the damaged endothelium, leading to oedema and intravascular fluid depletion. Activation of the coagulation system Damaged endothelium triggers the coagulation cascade (via tissue factor, factor VII, and reduced activity of proteins C and S) and thrombus forms within the microvasculature. A vicious circle of endothelial injury, intravascular coagulation and microvascular occlusion develops, causing more tissue damage and further release of inflammatory mediators. In severe sepsis, intravascular coagulation can become widespread. This is referred to as disseminated intravascular coagulation (DIC) and usually heralds the onset of multi-organ failure. Specific aspects of the diagnosis and management of DIC are discussed on page 978. Organ damage from sepsis Any and all organs may be injured by severe sepsis. The pathological mechanisms are shown in Figure 10.12. Lactate physiology Lactate is an excellent biomarker for the severity of sepsis. Hyperlactataemia (serum lactate > 2.4 mmol/L or 22 mg/dL) is used as a marker of severity. Figure 10.13 explains the physiology of hyperlactataemia; it is caused by all types of shock and therefore is not specific to sepsis. A lactate level of

8 mmol/L (>73 mg/dL) is associated with an extremely high mortality and should trigger immediate escalation. Measures to optimise oxygen delivery should be sought, and the adequacy of resuscitation measured by lactate clearance. The anti-inflammatory cascade As the inflammatory state develops, a compensatory antiinflammatory system is activated involving the release of antiinflammatory cytokines such as IL-4 and IL-10 from immune cells. While such mechanisms are necessary to keep the inflammatory response in check, they may lead to a period of immunosuppression after the initial septic episode. Patients recovering from severe sepsis are prone to developing secondary infections due to a combination of this immunosuppression and the presence of indwelling devices. Management The most important action is to consider sepsis as the cause of a patient’s deterioration. Aligned to this is the requirement to consider other diagnoses that could be causing the presentation, such as haemorrhage, PE, anaphylaxis or a low cardiac output state. Resuscitation in sepsis General resuscitative measures are discussed on page 204. Early resuscitation can be aided by following the requirements of the From the Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). 10.27 Definitions of sepsis and septic shock Sepsis Patients with suspected infection who have 2 or more of: • Hypotension – systolic blood pressure < 100 mmHg • Altered mental status – Glasgow Coma Scale score ≤ 14 • Tachypnoea – respiratory rate ≥ 22 breaths/min Sepsis can also be diagnosed by suspected infection and an increase of ≥ 2 points on the Sequential Organ Failure Assessment (SOFA) score (p. 214) Septic shock A subset of sepsis with underlying circulatory or cellular/metabolic abnormalities associated with a substantially increased mortality: • Sepsis and both of (after fluid resuscitation):

  1. Persistent hypotension requiring vasopressors to maintain a MAP

65 mmHg

  1. Serum lactate > 2 mmol/L (18 mg/dL) Disorders causing critical illness Sepsis and the systemic inflammatory response Sepsis is one of the most common causes of multi-organ failure. Sepsis requires the presence of infection with a resultant systemic inflammatory state; organ dysfunction occurs from a combination of the two processes. The definition of sepsis has undergone various iterations and there is still a lack of consensus as to the exact wording that best reflects this complex, multisystem process (Box 10.27). Aetiology and pathogenesis To understand how an infection can lead to progressive multiorgan failure, it is essential to have a grasp of the pathophysiology. Initiation of the inflammatory response The process begins with infection in one part of the body that triggers a localised inflammatory response. Appropriate source control and a competent immune system will, in most cases, contain the infection at this stage. However, if certain factors are present, the infection may become systemic. The causative factors are not fully elucidated but probably include: • a genetic predisposition to sepsis • a large microbiological load • high virulence of the organism • delay in source control (either surgical or antimicrobial) • resistance of the organism to treatment • patient factors (immune status, nutrition, frailty). Mediators are released from damaged cells (called ‘alarmins’) and these, coupled with direct stimulation of immune cells by the molecular patterns of the microorganism, trigger the inflammatory response. An example of such direct stimulation is that of lipopolysaccharide, which is found on the surface of Gram-negative bacteria. It strongly stimulates an immune response and is commonly used in research settings to initiate a septic cascade. Viral and fungal infections can cause a syndrome that is clinically indistinguishable from bacterial sepsis. Likewise, numerous

Disorders causing critical illness • 197

crystalloid. Early intubation is recommended in severe cases to facilitate further management and reduce oxygen demand. Appropriate antibiotics should be administered as early as possible (Box 10.29). The antibiotic choice will depend on local patterns of resistance, patient risk factors and the likely source of infection. Information on likely organisms and appropriate antibiotics can be found on pages 117 and 226. Microbiological samples (such as blood cultures, urine or CSF) should be taken, but this should not delay antibiotic administration, if obtaining samples is difficult. Early source control Source control requires an accurate diagnosis; urgent investigations should be performed as soon as physiological stability has been established. A CT scan of the chest and abdomen with contrast is a high-yield test in this context. Specific points in the history should be reviewed, such as risk factors for human immunodeficiency virus (HIV), contacts with tuberculosis and underlying immune status. Immunocompromised patients will be susceptible to a far broader spectrum of infectious microorganisms (p. 223). ‘Sepsis Six’ (Box 10.28). Red cell transfusion should be used to target a haemoglobin concentration of 70–90 g/L (7–9 g/dL). Albumin 4% can be used as colloid solution and has the theoretical benefit of remaining in the intravascular space for longer than Fig. 10.12 Pathophysiology of organ damage in sepsis. Macrovascular. Severe hypovolaemia, vasodilatation or septic cardiomyopathy can reduce oxygen delivery, causing tissue hypoxia. Paradoxically, most patients with sepsis have an increased cardiac output and oxygen delivery. Microvascular. Tissue injury can occur from hypoxia secondary to microvascular injury and thrombosis. Damaged epithelium permits neutrophils, proteins and fluid to leak out. Shunting. Organs fail in sepsis despite supranormal blood flow. It is likely that arteriovenous shunt pathways exist within vascular beds; these shunts open up in septic shock. Cellular. Cells are damaged by a number of mechanisms in sepsis: (1) direct injury by microorganisms; (2) injury from toxins produced by immune cells, e.g. oxygen free radicals; (3) mitochondrial injury causing cytopathic hypoxia – cells are unable to metabolise oxygen; (4) apoptosis – if the cell injury is sufficient, capsase enzymes are activated within the nucleus and programmed cell death occurs; (5) hypoxia from micro- and macrovascular pathology. Arterioles M A C R O V A S C U L A R Capillaries Mitochondria Neutrophil Bacteria Nucleus Neutrophil Arteriovenous shunt Venules Microemboli M I C R O V A S C U L A R C E L L U L A R Fig. 10.13 Physiology of hyperlactataemia. Inadequate oxygen delivery Tissue hypoxia e.g. Ischaemic gut Shock (from any cause) Drugs e.g. Adrenaline (epinephrine) Salbutamol Excess muscle activity e.g. Extreme exercise Seizure Anaerobic metabolism Excess production Inadequate clearance β2-adrenoceptor stimulation High lactate Excess tissue production Hepatic failure Congenital enzyme deficiencies (rare) Other causes: Metformin Thiamin deficiency Haematological malignancy Drugs, e.g. antiretrovirals International recommendations for the immediate management of suspected sepsis from the Surviving Sepsis Campaign (all to be delivered within 1 hr of the initial diagnosis of sepsis). 10.28 The ‘Sepsis Six’

  1. Deliver high-flow oxygen
  2. Take blood cultures
  3. Administer intravenous antibiotics
  4. Measure serum lactate and send full blood count
  5. Start intravenous fluid replacement
  6. Commence accurate measurement of urine output 10.29 Early administration of antibiotics in suspected sepsis • Broad-spectrum antibiotics should be administered as soon as possible after sepsis is suspected • Every hour of delayed treatment is associated with a 5–10% increase in mortality

198 • ACUTE MEDICINE AND CRITICAL ILLNESS Acute respiratory distress syndrome Aetiology and pathogenesis Acute respiratory distress syndrome (ARDS) is a diffuse neutrophilic alveolitis caused by a range of conditions and characterised by bilateral radiographic infiltrates and hypoxaemia (Box 10.32). Activated neutrophils are sequestered into the lungs and capillary permeability is increased, with damage to cells within the alveoli. The pathophysiology is part of the inflammatory spectrum described in ‘Sepsis’ above, and the triggers are similar: infective and non-infective inflammatory processes. These processes result in exudation and accumulation of protein-rich cellular fluid within alveoli and the formation of characteristic ‘hyaline membranes’. Local release of cytokines and chemokines by activated macrophages and neutrophils results in progressive recruitment of inflammatory cells. Secondary effects include loss of surfactant and impaired surfactant production. The net effect is alveolar collapse and reduced lung compliance, most marked in dependent regions of the lung (mainly dorsal in supine patients). The affected airspaces become fluid-filled and can no longer contribute to ventilation, resulting in hypoxaemia (due to increased pulmonary shunt) and hypercapnia (due to inadequate ventilation in some areas of the lung): that is, ventilation–perfusion mismatch. Diagnosis and management ARDS can be difficult to distinguish from fluid overload or cardiac failure. Classic chest X-ray and CT appearances are shown in Figures 10.14 and 10.15, respectively. Occasionally, conditions may present in a similar way to ARDS but respond to alternative treatments; an example of this might be a glucocorticoidresponsive interstitial pneumonia (p. 605). Management of ARDS is supportive, including use of lung-protective mechanical ventilation, inducing a negative fluid balance and treating the underlying cause. Establishing the severity of ARDS (Box 10.33) is useful, as severe disease will require more proactive management such as prone positioning or extracorporeal membrane oxygenation (ECMO; p. 204). Noradrenaline (norepinephrine) for refractory hypotension Central venous access should be established early in the resuscitation process and a noradrenaline infusion commenced. If there is severe hypotension, it is not necessary to wait until 30 mL/kg of fluid has been administered before commencing noradrenaline; early vasopressor use may improve the outcome from acute kidney injury. Measurement of central and mixed venous oxygen saturations may provide additional prognostic information (Box 10.30). Other therapies for refractory hypotension Refractory hypotension is due to either inadequate cardiac output or inadequate systemic vascular resistance (vasoplegia). When vasoplegia is suspected, it may be necessary to add vasopressin (antidiuretic hormone, ADH). This is a potent vasoconstrictor that may be used to augment noradrenaline (norepinephrine) in achieving an acceptable MAP. Intravenous glucocorticoids are also commonly used in refractory hypotension. There is little evidence that they improve the overall outcome, but they do lead to a more rapid reversal of the shocked state. There is a small increased risk of secondary infection following glucocorticoid use. Septic cardiomyopathy The myocardium can be affected by the septic process, presenting as either acute left or right ventricular dysfunction. A bedside echocardiogram is particularly useful to confirm the diagnosis, as ECG changes are usually non-specific. Dobutamine or adrenaline (epinephrine) can be used to augment cardiac output, and intravenous calcium should be replaced if ionised calcium is low. Other interventions such as intravenous bicarbonate in profound metabolic acidosis, high-volume haemofiltration/haemodialysis and extracorporeal support are sometimes used, but currently lack evidence of benefit. Review of the underlying pathology While sepsis is the most common cause of acute systemic inflammation, up to 20% of patients initially treated for sepsis will have a non-infectious cause: that is, a sepsis mimic (Box 10.31). These conditions should be considered where the clinical picture is not typical, no source of sepsis can be found, or the inflammatory response seems excessive in the context of local infection. Early reconsideration of the diagnosis of sepsis is crucial, as many of the ‘sepsis mimics’ offer a finite time window for specific intervention, after which irreversible organ damage will have occurred. 10.31 Sepsis mimics • Pancreatitis • Drug reactions • Widespread vasculitis – catastrophic antiphospholipid syndrome, Goodpasture’s syndrome • Autoimmune diseases – inflammatory bowel disease, rheumatoid arthritis, systemic lupus erythematosus • Malignancy – carcinoid syndrome • Haematological conditions – haemophagocytic syndrome, diffuse lymphoma, thrombotic thrombocytopenic purpura 10.32 Berlin definition of ARDS • Onset within 1 week of a known clinical insult, or new or worsening respiratory symptoms • Bilateral opacities on chest X-ray, not fully explained by effusions, lobar/lung collapse or nodules • Respiratory failure not fully explained by cardiac failure or fluid overload. Objective assessment (e.g. by echocardiography) must exclude hydrostatic oedema if no risk factor is present • Impaired oxygenation (see Box 10.33) 10.30 Central and mixed venous oxygen saturations • Saturation of venous blood sampled from the right atrium or superior vena cava (central) or pulmonary artery (mixed venous) • Both values reflect the balance of supply and demand of oxygen to the tissues • Mixed venous oxygen saturation is a measure of whole-body supply and demand of oxygen; central venous oxygen saturation measures the supply and demand of oxygen from the upper body. Normal mixed venous oxygen saturation is 70%. Lower values than this suggest inadequate oxygen delivery • Central venous oxygen saturation is more variable, depending on whether the patient is awake or anaesthetised, but a value of 70% is considered normal • Where cytopathic hypoxia occurs, oxygen extraction is impaired and the central and mixed venous oxygen saturations may be > 80%. This is often a poor prognostic sign

Disorders causing critical illness • 199

infarction and rupture of the septum) and acute mitral regurgitation (due to infarction or rupture of the papillary muscles). Severe myocardial systolic dysfunction causes a fall in cardiac output, BP and coronary perfusion pressure. Diastolic dysfunction causes a rise in left ventricular end-diastolic pressure, pulmonary congestion and oedema, leading to hypoxaemia that worsens myocardial ischaemia. This is further exacerbated by peripheral vasoconstriction. These factors combine to create the ‘downward spiral’ of cardiogenic shock (Fig. 10.17). Hypotension, oliguria, delirium and cold, clammy peripheries are the manifestations of a low cardiac output, whereas breathlessness, hypoxaemia, cyanosis and inspiratory crackles at the lung bases are typical features of pulmonary oedema. If necessary, a Swan–Ganz catheter can be used to measure the pulmonary artery pressures and cardiac output (p. 206). These findings can be used to categorise patients with acute MI into four haemodynamic subsets (Box 10.34) and titrate therapy accordingly. In cardiogenic shock associated with acute MI, immediate percutaneous coronary intervention should be performed (p. 491). The viable myocardium surrounding a fresh infarct may contract poorly for a few days and then recover. This phenomenon is known as myocardial stunning and means that acute heart failure Fig. 10.14 Chest X-ray in acute respiratory distress syndrome (ARDS). Note bilateral lung infiltrates, pneumomediastinum, pneumothoraces with bilateral chest drains, surgical emphysema, and fractures of the ribs, right clavicle and left scapula. Fig. 10.15 CT scan of the thorax in a patient with severe ARDS. Note the pathology is mainly in the dorsal (dependent) parts of the lung. 10.33 Determining the severity of ARDS Severity of hypoxaemia is calculated using a Pa/FiO2 ratio. This is a number calculated by using the PaO2 from an arterial blood gas measurement divided by the fraction of inspired oxygen (FiO2, expressed as a fraction). For example, a patient with a PaO2 of 10 kPa (75 mmHg) on 50% oxygen, i.e. FiO2 of 0.5, would have a Pa/FiO2 ratio of 20 kPa (150 mmHg). This would be defined as moderately severe ARDS, if the other Berlin criteria were met (see Box 10.32). All measurements should be taken on a minimum of 5 cmH2O of PEEP or CPAP. • Mild: 40–26.6 kPa (300–200 mmHg) • Moderate: 26.6–13.3 kPa (200–100 mmHg) • Severe: ≤ 13.3 kPa (≤ 100 mmHg) (CPAP = continuous positive airway pressure; PEEP = positive end-expiratory pressure) 10.34 Acute myocardial infarction: haemodynamic subsets Cardiac output Pulmonary oedema No Yes Normal Good prognosis and requires no treatment for heart failure Due to moderate left ventricular dysfunction. Treat with vasodilators and diuretics Low Due to right ventricular dysfunction or concomitant hypovolaemia. Give fluid challenge and consider pulmonary artery catheter to guide therapy Extensive myocardial infarction and poor prognosis. Consider intra-aortic balloon pump, vasodilators, diuretics and inotropes Acute circulatory failure (cardiogenic shock) Definition and aetiology Cardiogenic shock is defined as hypoperfusion due to inadequate cardiac output or, more technically, a cardiac index of < 2.2 L/min/ m2 (see Box 10.42). While cardiogenic shock is the final common pathway of many disease processes (e.g. sepsis, anaphylaxis, haemorrhage), the important primary causes of acute heart failure or cardiogenic shock (Fig. 10.16) are described here. Myocardial infarction In the majority of cases, cardiogenic shock following acute MI is due to left ventricular dysfunction. However, it may also be due to infarction of the right ventricle, or a variety of mechanical complications, including tamponade (due to infarction and rupture of the free wall), an acquired ventricular septal defect (due to

200 • ACUTE MEDICINE AND CRITICAL ILLNESS should be treated intensively because overall cardiac function may subsequently improve. Acute massive pulmonary embolism Massive PE may complicate leg or pelvic vein thrombosis and usually presents with sudden collapse. The clinical features and treatment are discussed on page 619. Bedside echocardiography may demonstrate a small, under-filled, vigorous left ventricle with a dilated right ventricle; it is sometimes possible to see thrombus in the right ventricular outflow tract or main pulmonary artery. In practice, it can be difficult to distinguish massive PE from a right ventricular infarct on transthoracic echocardiogram. CT pulmonary angiography usually provides a definitive diagnosis. Acute valvular pathology, aortic dissection and cardiac tamponade These conditions should be considered in an undifferentiated presentation of shock. The diagnosis and management of these conditions is discussed on pages 514, 506 and 544. Post cardiac arrest The initial management of cardiac arrest is discussed on page 456. Following the return of spontaneous circulation (ROSC), the majority of cardiac arrest survivors will need a period of time in intensive care to achieve physiological stability, identify Fig. 10.16 Some common causes of cardiogenic shock. Aorta Cardiac tamponade PA RA RV LV LA Aorta Endocarditis of mitral valve PA RA RV LV LA Aorta Right ventricular infarct PA RA RV LV LA Aorta Pulmonary embolism PA RA RV LV LA Aorta Dysrhythmia caused by: Left ventricular damage Myocardial infarction Myocarditis PA RA RV LV LA Ventricular tachycardia Aorta PA RA RV LV LA Left ventricular infarct Fig. 10.17 The downward spiral of cardiogenic shock. Ventricular dysfunction Systolic Diastolic ↓ Cardiac output ↓ Blood pressure ↓ Coronary perfusion Further ischaemia ↑ Left ventricular diastolic pressure ↑ Pulmonary congestion Hypoxaemia

Critical care medicine • 201

the most specific test to predict irrecoverable brain injury. This test is performed by administering an electrical impulse over a peripheral nerve and recording the electrical impulses measured by the scalp electrodes overlying the part of the brain expected to receive the impulse. Where this is not available, prognostication based on all other available information, along with the perceived wishes relating to the level of disability the individual would be prepared to accept, should allow a decision regarding ongoing treatment to be made. Where there is doubt, more time should be given to allow assessment of neurological recovery. Other causes of multi-organ failure As previously discussed, sepsis is the most common cause of multi-organ failure. However, multi-organ failure secondary to single organ dysfunction, such as cardiac failure, liver failure, renal failure or respiratory failure, is also common. The multisystem insult in these disease processes goes beyond the direct biochemical damage and tissue hypoxia caused by the primary organ dysfunction. It probably reflects cellular signalling pathways and the release of other systemic toxins by the failing organ, referred to as organ ‘crosstalk’. Multi-organ failure can also be caused by a physiological insult that damages a wide variety of cells in different organs, including toxins from extrinsic sources such as envenomation and intrinsic sources such as myoglobin in rhabdomyolysis (p. 195). Multi-organ failure can also be caused by profound physical injury to cells from processes such as nuclear radiation, heat exposure or blast trauma. Critical care medicine Decisions around intensive care admission Being a patient in intensive care is seldom a pleasant experience. The interventions are usually painful and the loss of liberties that are normally taken for granted can be devastating. While much of the unpleasant sensory and emotional experience can be modified with high-quality care and analgesia, there is a strong case that it can only be morally ‘right’ to admit a patient to intensive care if the end justifies the means. There must be a realistic hope that the patient will regain a quality of life that would be worth the pain and suffering that he or she will experience in intensive care. Few patients are able to comprehend fully what it means to be critically ill, so the physician should guide the process of determining who should be admitted to intensive care. Selecting the appropriate level of intervention for an individual patient can be very difficult. The decision-making process should involve an assessment of the likelihood of reversibility of the disease, the magnitude of the interventions required, the underlying level of frailty, and the personal beliefs and wishes of the patient (commonly expressed through their next of kin). As technology and science have improved, conditions that were previously regarded as terminal can now be supported and life can be considerably prolonged (Box 10.37). There have been several prominent examples of individuals who have received intensive care, but where an onlooker might have considered treatment to be futile owing to frailty, comorbidity or profound neurological injury. Such cases will, in part, shape the views and expectations of society, and it is unlikely that making decisions in this area will become any easier. Some suggested techniques to aid decision-making are listed in Box 10.38. 10.36 Prognostication after cardiac arrest: predictors of poor neurological recovery Coexisting problems • Multi-organ failure • Significant comorbidities Clinical • Persisting and generalised myoclonus • Absence of pupillary or corneal reflexes • Poor motor response (absent or extensor response) Biochemical • A neuron-specific enolase > 33 μg/L Imaging • CT showing loss of grey–white differentiation • Focal cause or consequence of cardiac arrest, e.g. subarachnoid haemorrhage Electrophysiology • EEG patterns may suggest brain injury, e.g. burst suppression • Somato-sensory evoked potentials – bilateral absence of the N20 spike (recorded from scalp electrodes from cutaneous electrical impulse over the median nerve) 10.35 Physiological targets following a return of spontaneous circulation (ROSC) • Temperature management. Facilitate maintenance of temperature at 36°C and avoidance of pyrexia by the use of a cooling blanket. This should be continued for 72 hrs. Muscle relaxants may be required to prevent shivering • Blood pressure management. Aim for a MAP of at least 70 mmHg and a systolic blood pressure of > 120 mmHg • Glucose control. Control the glucose to 6–10 mmol/L (108– 180 mg/dL) • Normal CO2 (4.5–6 kPa, 33–45 mmHg) and oxygen saturation (94–98%). Avoid both hypoxaemia and hyperoxia and manage the underlying cause of the arrest, and optimise neurological recovery. Acute management A MAP of > 70 mmHg should be maintained to optimise cerebral perfusion. Shock is common following ROSC and is caused by a combination of the underlying condition leading to the arrest, myocardial stunning and a post-arrest vasodilated state. Support with inotropes, vasopressors and occasionally mechanical support from an intra-aortic balloon pump or venous–arterial ECMO (p. 207) may be required. Specific cardiac interventions and their indications are described in Chapter 16. Other physiological targets are listed in Box 10.35. Prognosis Predicting which patients will not recover from the brain injury sustained at the time of cardiac arrest is very difficult. Certain features suggest that the outcome will be poor: for example, the absence of pupillary and corneal reflexes, absence of a motor response and persistent myoclonic jerking. Tools to assist prognostication following cardiac arrest are shown in Box 10.36. The clinician should, where feasible, delay prognostication until a period of 72 hours of targeted temperature management has been completed. The bilateral absence of the ‘N20’ spike on the somato-sensory evoked potential is

202 • ACUTE MEDICINE AND CRITICAL ILLNESS Respiratory support Non-invasive respiratory support Non-invasive respiratory support provides a bridge between simple oxygen delivery devices and invasive ventilation. It can be used in patients who are in respiratory distress but do not have an indication for invasive ventilation, or in those who are not suitable for intubation and ventilation for chronic health reasons. Patients must be cooperative, able to protect their airway, and have the strength to breathe spontaneously and cough effectively. Clinicians should avoid using non-invasive respiratory support to prolong the dying process in irreversible conditions such as end-stage lung disease. Likewise, a failure to respond to treatment or further deterioration should trigger a decision regarding intubation, as delayed invasive ventilation in this context is associated with worse outcome. High-flow nasal cannulae High-flow nasal cannulae (HFNCs) are devices that provide very high gas flows of fully humidified oxygen and air. They offer distinct advantages over non-invasive ventilation (NIV) in selected patients, mainly those with type I respiratory failure (particularly pneumonia) who have not reached an indication for invasive ventilation. They allow patient comfort and increased expectoration while providing some degree of positive end-expiratory pressure (PEEP) and a high oxygen concentration that can be titrated to the SO2. Continuous positive pressure ventilation Continuous positive pressure ventilation therapy involves the application of a continuous positive airway pressure (CPAP) throughout the patient’s breathing cycle, typically 5–10 cmH2O. It helps to recruit collapsed alveoli and can enhance clearance of alveolar fluid. It is particularly effective at treating pulmonary atelectasis (which may be post-operative) and pulmonary oedema. It uses a simpler device than NIV but otherwise offers no direct benefit over it. Non-invasive ventilation or bi-level ventilation NIV provides ventilatory support via a tight-fitting nasal or facial mask. It can be delivered by using a simple bi-level ventilation (BiPAP) turbine ventilator, or an intensive care ventilator. These machines can deliver pressure at a higher level (approximately 15–25 cmH2O) for inspiration and a lower pressure (usually 4–10 cmH2O) to allow expiration. Ventilation can be spontaneous (triggered by a patient’s breaths) or timed (occurring at a set frequency). Systems that synchronise with a patient’s efforts are better tolerated and tend to be more effective in respiratory failure. Timed breaths are used for patients with central apnoea. NIV is the first-line therapy in patients with type II respiratory failure secondary to an acute exacerbation of COPD because it reduces the work of breathing and offloads the diaphragm, allowing it to recover strength. It is also useful in pulmonary oedema, obesity hypoventilation syndromes and some neuromuscular disorders. It should be initiated early, especially when severe respiratory acidosis secondary to hypercapnia is present. NIV can also be used to support selected patients with hypercapnia secondary to pneumonia, or during weaning from invasive ventilation, but its effectiveness in these contexts is less certain; early intubation or re-intubation is probably more beneficial. Stabilisation and institution of organ support In order to stabilise a critically unwell patient, the primary problem should be corrected as quickly as possible: for example, source control in sepsis and control of the bleeding point in haemorrhage. Immediate resuscitation and prioritisation of the safety of the patient are clearly important, but there is only a limited role for ‘optimising’ the patient if such measures may significantly delay a definitive treatment, such as laparotomy for a perforated viscus. In some cases, the definitive treatment is not readily apparent or treatments take time to have their full effect. In these cases, adequate organ support to stabilise the patient while the treatment is given becomes the main goal of care. 10.38 Techniques to improve admission decision-making • Always act in the best interests of the patient: external influences are commonly present but these should be of only secondary importance • Maximise patient capacity: wherever possible, the patient should be involved in discussions of escalation and resuscitation status • Communicate openly and honestly with the next of kin: when communicating potential outcomes, it is best to use natural frequencies rather than percentages. For example, ‘If we had 100 patients with the same illness as your mother, only 10 would survive’ is easier for most people to understand than ‘there is a 90% chance of death’ • Reach mutual agreement with the next of kin: it is rare for there to be discord between clinicians and family, and in most cases the most appropriate course of action is clear • Seek additional opinions: other clinicians involved in the care of the patient will provide useful input. The premise should be to err on the side of escalation where the most appropriate course of action is unclear. Where there is an unresolvable difference in opinion, a mediation process or court ruling may be required to make the final decision. Thankfully, this is a very infrequent occurrence • Plan ahead: advance planning in chronic, progressive disease can make the decision easier. Some health facilities use an escalation form, which specifies the interventions that should be offered or are acceptable to the patient. This can be useful as the binary decision of for/not for resuscitation fails to account for the array of interventions that can be performed before cardiac arrest occurs 10.37 Critical illness in the context of congenital conditions • Longer survival: there are many congenital conditions that would, in the past, have been fatal in childhood, but now patients survive into adulthood. Decision-making can be difficult when the adolescent has impaired decision-making capacity. • Parental views: in such circumstances, the views of the parent or legal guardian become paramount. • Goals of care: often a detailed explanation of what is, and is not, achievable in intensive care allows the direction of care to be switched to palliative when life expectancy is poor and quality of life is severely impaired. • Decision-making: such conversations may require input from experts in the patient’s congenital condition(s), and advanced decision-making regarding ICU admission should be encouraged whenever patients and families feel able to discuss such issues.

Stabilisation and institution of organ support • 203

breathe spontaneously once it is safe to do so. The determination of what constitutes critical will depend on the status of each patient. For example, a patient with raised ICP will have a strong indication for normocapnia (because hypercapnia increases ICP). Unfortunately, achieving the minute volumes required to maintain normocapnia can, in itself, be harmful to the lungs (p. 204). Ventilator modes Following intubation, most patients have a period of paralysis from the muscle relaxation. Mandatory ventilation is, therefore, required for a variable period, depending on the severity of the lung injury, the underlying disease process and the general condition of the patient. Mandatory ventilation means that the ventilator will deliver set parameters (either a set tidal volume or a set inspiratory pressure), regardless of patient effort. A physician can choose to support additional patient effort in between mandatory breaths with pressure support. This requires sufficient patient effort to ‘trigger’ the ventilator to deliver a synchronised breath, in time with the patient’s own ventilation. Other parameters that should be considered when using mechanical ventilation are shown in Figure 10.18. As a patient’s illness resolves, or if the lung injury necessitating intubation is not severe, periods of spontaneous breathing with pressure support are commenced. While spontaneous breathing is preferable to mandatory ventilation modes, the shearing forces of patient effort can exacerbate lung injury in patients with severely damaged lungs. It is, therefore, important that a patient is permitted to breathe in a planned and controlled way. Intubation and intermittent positive pressure ventilation Taking control of the respiratory system in a critically ill patient is one of the most significant and risky periods in a patient’s journey. Critical incidents are common because the patient is often deteriorating rapidly and is exhausted. The potential for cardiovascular collapse is further exacerbated by the negatively inotropic and vasodilating drugs used to induce anaesthesia, and the period of apnoea invoked to facilitate intubation (Box 10.39). The main aims of intermittent positive pressure ventilation (IPPV) are to avoid critical hypoxaemia and hypercapnia while minimising damage to the alveoli and encouraging the patient to 10.39 Optimising safety during intubation • Intervene early in the disease process (once it has become clear that the disease trajectory is downward) • Use a stable anaesthetic technique: low doses of sedative agents and rapidly acting paralytic agents • Remember that intubation should be performed by the most experienced operator available • Use techniques to optimise oxygenation and ventilation in the period around intubation, e.g. keeping non-invasive ventilation in situ for pre-oxygenation, leaving high-flow nasal cannulae on for the intubation process, and using a video-laryngoscope in an anticipated difficult intubation Fig. 10.18 Settings to be considered when commencing mechanical ventilation. Respiratory rate and minute volume Depend on the minute volume required to achieve the desired PCO2, and whether the patient is breathing spontaneously. Rates are commonly 20–30 breaths/min Ventilator mode Mandatory, spontaneous, or mandatory with the ability to take spontaneous breaths (as shown here) FiO2 Fraction of inspired oxygen. This is usually titrated to oxygen saturations targeting 92–95% Tidal volume Usual target is 6 mL/kg of predicted body weight (PBW) Positive end-expiratory pressure (PEEP) The pressure within the respiratory system during expiration, commonly 5–15 cmH2O. Higher levels of PEEP often improve oxygenation but put strain on the right heart (as it makes it harder to pump blood through the pulmonary circulation) Plateau pressure Airway pressure during an inspiratory hold. Keeping plateau pressure as low as possible above PEEP is the most protective strategy for the lungs Pressure–time graph Volume–time graph Flow–time graph

204 • ACUTE MEDICINE AND CRITICAL ILLNESS in the prone position for 12–24 hours and then rotated back to the supine position for a similar period. This cycle continues until there is evidence of resolving lung injury. Extracorporeal respiratory support Sometimes, despite optimal invasive ventilation, it is not possible to maintain adequate oxygenation or prevent a profound respiratory acidosis. When a patient has a reversible cause of respiratory failure (or is a potential lung transplant recipient) and facilities are available, extracorporeal respiratory support should be considered. Venous–venous extracorporeal membrane oxygenation In venous–venous extracorporeal membrane oxygenation (V V ECMO), large-bore central venous cannulae are inserted into the superior vena cava (SVC) and/or the inferior vena cava (IVC) via the femoral or jugular veins, and advanced under ultrasound or fluoroscopic guidance (Fig. 10.19). Venous blood is then pumped through a membrane oxygenator. This device has thousands of tiny silicone tubes with air/oxygen gas on the other side of the tubes (the membrane). This facilitates the passage of oxygen into the blood and diffusion of carbon dioxide across the membrane, where it is removed by a constant flow of gas (sweep gas). The oxygenated blood is then returned to the right atrium, from where it flows through the lungs as it would in the physiological state. This means that even if the lungs are contributing no oxygenation or carbon dioxide removal, a patient can remain well oxygenated and normocapnic. Extracorporeal carbon dioxide removal In some patients it is possible to maintain oxygenation but there is refractory hypercapnia. There are devices available that can remove carbon dioxide using a much lower blood flow rate than V V ECMO. Consequently, smaller venous cannulae, similar to those used in renal dialysis, can be sufficient to have a ‘CO2 dialysis’ effect. This can be useful in patients in whom normocapnia is essential (such as those with a raised ICP), or those with refractory hypercapnia and adequate oxygenation. In addition, extracorporeal carbon dioxide removal can be used to reduce the required minute volume, which is a beneficial strategy for protecting the lungs against VILI or facilitating early extubation. Cardiovascular support Initial resuscitation A brief assessment can usually yield enough information to determine whether a patient is at significant risk of an imminent cardiac arrest. If the patient is obtunded and there is no palpable radial or brachial pulse, then treatment should proceed as described on page 457. In anaphylactic shock, or undifferentiated shock in a peri-arrest situation, a single dose of intramuscular adrenaline (epinephrine) 0.5 mg (0.5 mL of 1 : 1000) can be life-saving. If expertise is available, a small dose of intravenous adrenaline can delay cardiac arrest long enough to identify the cause of shock and institute other supportive measures; a suggested dose would be 50 μg (0.5 mL of 1 : 10 000). If haemorrhage is considered a possibility, a ‘major haemorrhage’ alert should be activated, facilitating rapid access to large volumes of blood and blood products. A classification of shock is shown in Box 10.40. Ventilator-induced lung injury Every positive-pressure breath causes cyclical inflation of alveoli followed by deflation. The resultant damage to alveoli occurs via several possible mechanisms: • distending forces from the tidal volume, termed ‘volutrauma’ • the pressure used to inflate the lung, referred to as ‘barotrauma’ • alveoli collapsing at the end of expiration, called ‘atelectotrauma’ • the release of inflammatory cytokines in response to cyclical distension, called ‘biotrauma’. The threshold of injurious ventilation is unique to each patient. Moderate ventilator pressures and volumes used to ventilate healthy lungs may not cause ventilator-induced lung injury (VILI), but the same settings may cause significant VILI if delivered to a patient with lungs that are already damaged from another disease process. Strategies that may reduce the incidence and severity of VILI include: • Permissive hypercapnia. In the majority of patients who are ventilated for respiratory failure, it is preferable to tolerate moderate degrees of hypercapnia rather than strive for normal blood gases at the expense of VILI. For example, in a patient with isolated respiratory failure, a physician may choose to tolerate a PaCO2 of up to 10 kPa (75 mmHg), provided the H+ is < 63 nmol/L (pH > 7.2). • ‘Open lung’ ventilation. Maintaining a positive pressure within the airways at the end of expiration prevents atelectotrauma. Use of low tidal volumes, higher levels of PEEP (Fig. 10.18) and recruitment manœuvres (occasional short periods of sustained high airway pressures to open up alveoli that have collapsed) can reduce the incidence of VILI. • Paralysis. When respiratory failure is severe, patient effort may worsen VILI. An infusion of muscle relaxant can be used to moderate dyssynchrony with the ventilator. Advanced respiratory support Airway pressure release ventilation Airway pressure release ventilation (APRV) is a mode of ventilation that lengthens the inspiratory time to the extreme, with a very short period of time for expiration. It relies on spontaneous movement of the diaphragm from patient effort to facilitate the mixing of gas within the respiratory system during the long period in full inspiration, followed by a very short period of low pressure to allow passive expiration. It has not, however, been demonstrated to be superior to conventional modes of ventilation, but may have a role in moderate to severe ARDS. Prone positioning In ARDS, the posterior parts of the lung lose airspaces due to atelectasis and inflammatory exudate. By placing patients on their front, the pattern of fluid distribution within the lung changes, and ventilation–perfusion matching is improved. This is used to enhance oxygenation in moderate to severe ARDS, and may have some disease-modifying effects as the dependent areas of the lung are changed periodically. Although there are risks associated with nursing a patient in the prone position, it is becoming a widespread therapy. Patients are usually placed

Stabilisation and institution of organ support • 205

Fig. 10.19 Principles of extracorporeal membrane oxygenation (ECMO). A Basic ECMO circuit: venous–arterial (VA) and venous–venous (V V). B Example of a V V ECMO circuit. C Example of a VA ECMO circuit. Gas out Membrane oxygenator Controller console RPM

Pressures Saturations Flow Oxygenated blood returned to vein (V–V) or artery (V–A) Venous blood from patient (usually inferior vena cava) Centrifugal pump Venous ‘return’ cannula Superior vena cava Right atrium now full of oxygenated blood Tricuspid valve Right ventricle Inguinal ligament Femoral artery Access ECMO cannula Femoral vein Skin puncture site in proximal thigh From ECMO circuit To ECMO circuit Venous ‘return’ cannula Venous ‘access’ cannula Gas in A B Pulmonary vein (left) Pulmonary vein (right) Right atrium Proximal aorta Mitral valve Aortic valve Left ventricle Blood from ECMO circuit Blood from ‘normal’ circulation (native circulation) Where the two circulations meet depends on the native cardiac output; if very low, they will meet very proximally/at the aortic valve Oxygenated blood at high pressure will flow proximally up the aorta to perfuse organs Blood will also flow distally to perfuse the legs Arterial ‘return’ cannula Arterial ‘return’ cannula To ECMO circuit From ECMO circuit Venous ‘access’ cannula C

206 • ACUTE MEDICINE AND CRITICAL ILLNESS agent: for example, in cardiogenic shock or shock associated with bradycardia. If there is evidence of low cardiac output, adrenaline (epinephrine) or dobutamine should be commenced. Both agents are equally effective, but dobutamine causes more vasodilatation and additional noradrenaline may be required to maintain an adequate MAP. Vasopressin is added if hypotension persists despite high doses of noradrenaline and cardiac output is thought to be adequate. In extreme situations it is acceptable to start infusions of inotropes through a well-sited, large-bore peripheral cannula, although central venous access and an arterial line (for monitoring) should be inserted as soon as possible. The actions of commonly used vasoactive drugs are summarised in Box 10.41. Advanced haemodynamic monitoring There are many different devices available to estimate cardiac output. Such devices employ a variety of mechanisms, including the Doppler effect of moving blood, changes in electrical impedance of the thorax, or the dilution of either an indicator substance or heat (thermodilution). The information is processed within the equipment, and often integrated with additional data, such as the arterial pressure waveform, to give an estimate of cardiac output and stroke volume. When the aetiology of shock is straightforward and the patient is responding as predicted to treatment, the value of devices that estimate cardiac output is limited. Portable echocardiography has the advantage of giving qualitative information – for example, demonstrating aortic stenosis or a regional wall motion abnormality – as well as quantitative information on stroke volume, but it requires technical expertise. Pulmonary artery (PA) catheters, sometimes referred to as Swan–Ganz catheters (Fig. 10.20), are invasive but provide useful information on pulmonary pressures, cardiac output, mixed venous oxygen saturations (see Box 10.30) and, by extrapolation, whether the cause of the shock is vasodilatation or pump failure. They can be helpful in complex cases, such as shock after cardiac surgery, or in patients with suspected pulmonary hypertension (Box 10.42). However, PA catheters are associated with some rare but serious complications, including lung infarction, PA rupture and thrombosis of the catheter itself. Such complications occur infrequently in centres that use PA catheters regularly; it should be stressed that a lack of familiarity within the wider clinical team is a relative contraindication to their use. Mechanical cardiovascular support When shock is so severe that it is not possible to maintain sufficient organ perfusion with fluids and inotropic support, it is Venous access for the administration of drugs and fluids is vital but often difficult in critically unwell patients. Wide-bore cannulae are required for rapid fluid administration. In extremis, the external jugular vein can be cannulated; it is often prominent in low cardiac output states and readily visible on the lateral aspect of the neck. Occluding the vein distally with finger pressure makes it easier to cannulate, but care must be taken to remain high in the neck to avoid causing a pneumothorax. Intra-osseous or central venous access can be established if there are no visible peripheral veins. Ultrasound can provide assistance for rapid and safe venous cannulation. Rapid infusion devices are widely available and should be used for the delivery of warmed, air-free fluid and blood products. Fluid and vasopressor use Resuscitation of the shocked patient should include a 10 mL/ kg fluid challenge. Using colloid or crystalloid is acceptable; starch solutions are associated with additional renal dysfunction and should be avoided. The fluid challenge can be repeated if shock persists, to a maximum total of 30 mL/ kg of fluid. However, commencing vasopressor therapy early in resuscitation is better than delaying until a large volume of fluid has been given. Amongst other beneficial effects, vasopressors induce venoconstriction, reducing the capacitance of the circulation and effectively mobilising more fluid into the circulation. If a patient remains shocked after 30 mL/kg of fluid has been administered, a re-evaluation of the likely cause is required, looking particularly for concealed haemorrhage or an obstructive pathology. A bedside echocardiogram is especially useful at this stage to evaluate cardiac output and exclude tamponade. Noradrenaline (norepinephrine) should be commenced as the first-line vasoactive agent in most cases, unless there is a strong indication to use a pure inotropic or chronotropic 10.40 Categories of shock Category Description Hypovolaemic Can be haemorrhagic or non-haemorrhagic in conditions such as hyperglycaemic hyperosmolar state (p. 738) and burns Cardiogenic See page 199 Obstructive Obstruction to blood flow around the circulation, e.g. major pulmonary embolism, cardiac tamponade, tension pneumothorax Septic See page 196 Anaphylactic Inappropriate vasodilatation triggered by an allergen (e.g. bee sting), often associated with endothelial disruption and capillary leak (p. 75) Neurogenic Caused by major brain or spinal injury, which disrupts brainstem and neurogenic vasomotor control. High cervical cord trauma may result in disruption of the sympathetic outflow tracts, leading to inappropriate bradycardia and hypotension. Guillain–Barré syndrome (p. 1140) can involve the autonomic nervous system, resulting in periods of severe hypo- or hypertension Others e.g. Drug-related such as calcium channel blocker overdose; Addisonian crisis 10.41 Actions of commonly used vasoactive agents Drug Action Vasoconstrictor Inotrope Chronotrope Adrenaline (epinephrine) ++ +++ ++ Noradrenaline (norepinephrine) ++++ + + Dobutamine – ++++ +++ Vasopressin +++++ No action – (reflex bradycardia)

Stabilisation and institution of organ support • 207

in cardiogenic shock. There are risks associated with thrombosis formation on the balloon, mesenteric ischaemia and femoral artery pseudo-aneurysm following removal of the device. Venous–arterial extracorporeal membrane oxygenation Venous–arterial extracorporeal membrane oxygenation (VA ECMO) can be life-saving in profound cardiogenic shock and has even been used effectively in refractory cardiac arrest. The circuit and principles are very similar to those described in ‘V V ECMO’ above (see p. 204 and Fig. 10.19) with one important difference: oxygenated blood is returned to the arterial system (rather than into the right atrium). This means that the pump needs to generate sufficient pressure to allow blood to flow sometimes necessary to use an internal device to augment or replace the inadequate native cardiac output. Intra-aortic balloon pump An intra-aortic balloon counter-pulsation device is a long tube that is usually inserted into the femoral artery and fed proximally into the thoracic aorta. The basic principle is that a helium-filled balloon is able to inflate and deflate rapidly in time with the cardiac cycle. It is inflated in diastole, thus augmenting forward flow of blood to the abdominal organs and improving diastolic pressure proximal to the balloon, thereby optimising coronary perfusion. While the principle is appealing, and an intra-aortic balloon pump (IABP) is often effective in achieving predetermined physiological goals, this does not translate into improved survival Fig. 10.20 A pulmonary artery (Swan–Ganz) catheter. A There is a small balloon at the tip of the catheter and pressure can be measured through the central lumen. The catheter is inserted via an internal jugular, subclavian or femoral vein and advanced through the right heart until the tip lies in the pulmonary artery. When the balloon is deflated, the pulmonary artery pressure can be recorded. B Advancing the catheter with the balloon inflated will ‘wedge’ the catheter in the pulmonary artery. Blood cannot then flow past the balloon, so the tip of the catheter will now record the pressure transmitted from the pulmonary veins and left atrium (known as the pulmonary artery capillary wedge pressure), which provides an indirect measure of the left atrial pressure. (LA = left atrium; LV = left ventricle; RA = right atrium; RV = right ventricle)

mmHg Right ventricular pressure Wedge (left atrial) pressure Balloon inflated Balloon Right atrial pressure Pulmonary artery pressure A B Aorta RA RV LV LA Pulmonary artery 10.42 Interpreting haemodynamic data Variable Units Reference range Interpretation Cardiac output (CO) litres/minute (L/min) 4–8 L/min Low cardiac output suggests pump failure Cardiac index (CI) Cardiac output referenced to the size of the patient litres/minute/metre2 (L/min/m2) 2.5–4 L/min/m2 More useful than raw cardiac output alone, especially in smaller patients Central venous pressure (CVP) mmHg 0–6 mmHg Reflects right atrial pressure – a non-specific measurement of right ventricular (RV) function and volume status Low levels suggest good RV function or hypovolaemia Pulmonary artery systolic pressure (PA systolic) mmHg 15–30 mmHg Difficult to interpret in isolation Low levels suggest vasodilatation, hypovolaemia or right heart failure High levels are seen in many pathologies, e.g. left heart failure, primary pulmonary arterial hypertension (PAH), fluid overload Pulmonary artery diastolic pressure (PA diastolic) mmHg 5–15 mmHg As with PA systolic pressure, difficult to interpret in isolation Pulmonary artery capillary wedge pressure (PACWP) mmHg 2–10 mmHg (should be within a few mmHg of PA diastolic) Reasonable indication of left atrial pressure – raised in left heart failure and fluid overload Measurement is associated with injury to PA so should only be taken occasionally Transpulmonary gradient (PA diastolic – PACWP) mmHg 1–5 mmHg A high gradient suggests the pathology is in the pulmonary arteries, e.g. primary PAH

208 • ACUTE MEDICINE AND CRITICAL ILLNESS • Manage status epilepticus using antiepileptic agents such as levetiracetam, phenytoin and benzodiazepines. In refractory cases an infusion of sodium thiopental or ketamine may be required. The aim of management in acute brain injury is to optimise cerebral oxygen delivery by maintaining normal arterial oxygen content and a cerebral perfusion pressure (CPP) of > 60 mmHg. Secondary insults to the brain, such as hypoxaemia, hyper-/ hypoglycaemia and prolonged seizures, must be avoided. ICP rises in acute brain injury as a result of haematoma, contusions, oedema or ischaemic swelling. Raised ICP causes damage to the brain in two ways: direct damage to the brainstem and motor tracts as a result of downward pressure and herniation through the tentorium cerebelli and foramen magnum, and indirect damage by reducing CPP. Cerebral blood flow is dependent on an adequate CPP. The CPP is determined by the formula: CPP MAP ICP

− ICP can be measured by pressure transducers that are inserted directly into the brain tissue. The normal upper limit for ICP is 15 mmHg and an upper acceptable limit of 20 mmHg is usually adopted in intensive care. Sustained pressures of > 30 mmHg are associated with a poor prognosis. Various strategies are used to control ICP: maintaining normocapnia, preventing any impedance to venous drainage from the head, giving osmotic agents such as mannitol and hypertonic saline, and using hypothermia and decompressive craniectomy. No single technique has been shown to improve outcome in severe intracranial hypertension. CPP should be maintained above 60 mmHg by ensuring adequate fluid replacement and, if necessary, by treating hypotension with a vasopressor such as noradrenaline (norepinephrine). Complex neurological monitoring must be combined with frequent clinical assessment of GCS, pupillary response to light, and focal neurological signs. Daily clinical management in intensive care Clinical review In intensive care, detailed clinical examination should be performed daily to identify changes to a patient’s condition and review the latest diagnostic information. Further focused clinical reviews are usually incorporated into twice-daily ward rounds. Each ward round offers an ideal opportunity to monitor and document compliance with relevant care bundles. A care bundle is a group of interventions that, when implemented concurrently, have provided evidence of clinical benefit. The mnemonic ‘FAST HUG’ provides a useful checklist of interventions that reduce intensive care complications: feeding, analgesia, sedation, thromboprophylaxis, head of bed elevation (to reduce the incidence of passive aspiration), ulcer prophylaxis and glucose control. Other key aspects of the daily review are outlined on page 174. The overarching aim of the review is to identify the issues that are impeding recovery from critical illness, and make alterations to address them. In addition, specific and realistic goals for each relevant organ system should be defined, facilitating the autonomous titration of therapy by the bedside critical care nurse. An example of daily goals may be: ‘Titrate the noradrenaline (norepinephrine) to achieve a MAP of 65 mmHg, aim for a negative fluid balance, titrate FiO2 to achieve oxygen saturations through the systemic circulation. The sites of venous and arterial access can be either central (via a thoracotomy or sternotomy) or peripheral via cannulae in the IVC/SVC and the femoral/ subclavian artery. If the return cannula is peripherally sited (e.g. in the femoral artery), blood will flow back up the aorta from distal to proximal and perfuse the organs. The outcome depends on the avoidance of complications (primarily, bleeding at the cannula site, intracranial haematoma, air embolism, infection and thrombosis) and improvement of the underlying condition. Most causes of profound cardiogenic shock are unlikely to resolve, and the potential availability of a longer-term solution, such as cardiac transplantation or insertion of a ventricular assist device, is a prerequisite for commencing VA ECMO in most centres. Renal support Renal replacement therapy (RRT) is explained in detail on page 420. The key points relating to RRT in an intensive care context are: • Haemodynamic instability is common. Continuous therapies are widely believed to cause less haemodynamic instability than intermittent dialysis. However, many units use intermittent dialysis without significant problems. • Haemodialysis and haemofiltration are equally good. Although there are theoretical benefits to removing inflammatory cytokines with haemofiltration, this does not translate into improved survival. • Anticoagulation is usually achieved using citrate or heparin. Citrate has a better profile for anticoagulating the extracorporeal circuit without inducing an increased bleeding risk, but may accumulate in patients with profound multi-organ failure and should be avoided in very unstable individuals. • Most patients who survive intensive care will regain adequate renal function to live without long-term renal support. • A thorough investigation for reversible causes of renal dysfunction should always be undertaken in conjunction with instigation of renal support (see Fig. 15.18, p. 411). • Shock appears to reverse more rapidly when renal support is instituted. Commencing renal support soon after a patient develops renal ‘injury’ (when serum creatinine is more than two times higher than baseline) is probably beneficial in the context of septic shock. Neurological support A diverse range of neurological conditions require management in intensive care. These include the various causes of coma, spinal cord injury, peripheral neuromuscular disease and prolonged seizures. The goals of care in such cases are to: • Protect the airway, if necessary by endotracheal intubation. • Provide respiratory support to correct hypoxaemia and hypercapnia. • Treat circulatory problems, e.g. neurogenic pulmonary oedema in subarachnoid haemorrhage, autonomic disturbances in Guillain–Barré syndrome, and spinal shock following high spinal cord injuries. • Manage acute brain injury with control of ICP.

Daily clinical management in intensive care • 209

noise reduction, cessation of drugs known to precipitate delirium, and treatment of potential underlying causes such as thiamin replacement in patients at risk of Wernicke’s encephalopathy. Patients with agitated delirium that is refractory to verbal de-escalation should initially be managed with small doses of intramuscular antipsychotics, changed to the enteral route once control is established. Atypical antipsychotics such as olanzapine and quetiapine are more efficacious than traditional drugs such as haloperidol. Pharmacological interventions are not useful as prophylaxis or in hypoactive delirium. Additional information on diagnosis and management of delirium can be found on page 184. Weaning from respiratory support As the condition that necessitated ventilation resolves, respiratory support is gradually reduced: the process of ‘weaning’ from ventilation. Some approaches to weaning are described below. of 92–95% and titrate sedation to a RASS score of 0 to −1’ (Box 10.44). Sedation and analgesia Most patients require sedation and analgesia to ensure comfort, relieve anxiety and tolerate mechanical ventilation. Some conditions, such as critically high ICP or critical hypoxaemia, require deep sedation to reduce tissue oxygen requirements and protect the brain from the peaks in ICP associated with coughing or gagging. For the majority of patients, however, optimal sedation is an awake and lucid patient who is comfortable and able to tolerate an endotracheal tube (termed ‘tube tolerance’). Over-sedation is associated with longer ICU stays, a higher prevalence of delirium, prolonged requirement for mechanical ventilation, and an increased incidence of ICU-acquired infection. Box 10.43 compares the various agents used for sedation in intensive care. The key principles are that the patient should primarily receive analgesia, rather than anaesthesia, and caution should be used with drugs that accumulate in hepatic and renal dysfunction. Often a combination of drugs is used to achieve the optimal balance of sedation and analgesia. Sedation is monitored via clinical sedation scales that record responses to voice and physical stimulation. The Richmond Agitation–Sedation Scale (RASS) is the best-recognised tool (see Box 10.44 for details). Regular use of a scoring system to adjust sedation is associated with a shorter ICU stay. Many ICUs also have a daily ‘sedation break’, when all sedation is stopped in appropriate cases for a short period. This is commonly combined with a trial of spontaneous breathing aiming to shorten the duration of mechanical ventilation. Delirium in intensive care Delirium is discussed on page 183. It is extremely common in critically ill patients and often becomes apparent as sedation is reduced. Hypoactive delirium is far more common than hyperactive delirium, but is easily missed unless routine screening is undertaken. A widely used bedside assessment is the CAM-ICU score. The patient is requested to squeeze the examiner’s hand in response to instruction and questions, aiming to ascertain whether disordered thought or sensory inattention is present. Delirium of any type is associated with poorer outcome. Management is focused on non-pharmacological interventions such as early mobilisation, reinstatement of day–night routine, 10.44 Richmond Agitation–Sedation Scale (RASS) Score Term Description +4 Combative Overtly combative, violent or immediate danger to staff +3 Very agitated Pulls on/removes tubes or catheters, or aggressive to staff +2 Agitated Frequent non-purposeful movement or patient–ventilator dyssynchrony +1 Restless Anxious or apprehensive but no aggressive or vigorous movements

Alert and calm −1 Drowsy Not fully alert but sustained awakening (> 10 secs) with eye opening/contact to voice −2 Light sedation Brief awakening (<10 secs) with eye contact to voice −3 Moderate sedation Movement but no eye contact to voice −4 Deep sedation Movement to physical stimulation but no response to voice −5 Unrousable No response to voice or physical stimulation 10.43 Properties of sedative and analgesic agents used in ICU Drug Mode of action Advantages Disadvantages Propofol Intravenous anaesthetic Rapid onset and offset Large cumulative doses can cause multi-organ failure, especially in children – the ‘propofol infusion syndrome’ Alfentanil Potent opiate analgesic Rapid onset and offset High doses may be required Agitation may persist Morphine Opioid Analgesia Active metabolites and accumulation cause slow offset Midazolam Benzodiazepine sedative Can be used in children Active metabolites and accumulation cause slow offset Remifentanil Very potent opiate Analgesia and tube tolerance Respiratory depression – extreme caution in non-intubated patients Dexmedetomidine α2-adrenergic agonist Excellent tube tolerance Less delirium Can be used in awake patients Cost and availability

210 • ACUTE MEDICINE AND CRITICAL ILLNESS patients are important to identify, as emergency management in the event of a tracheostomy problem (blockage or displacement) must be through the tracheostomy site; access will not be possible via the upper airway. Nutrition It is crucial that critically ill patients receive adequate calories, protein and essential vitamins and minerals. Calculation of exact requirements is complex and requires the expertise of a dietitian. It is, however, useful to make a rough estimation of requirements (p. 705). Under-feeding leads to muscle wasting and delayed recovery, while over-feeding can lead to biliary stasis, jaundice and steatosis. Enteral feeding is preferred where possible because it avoids the infective complications of total parenteral nutrition (TPN) and helps to maintain gut integrity. However, TPN is recommended for patients who are likely to have a sustained period without effective enteral feeding, or who are already malnourished. Caution must be taken to avoid the consequences of refeeding syndrome (p. 706). Other essential components of intensive care Survival after critical illness depends, to a large extent, on the prevention of medical complications during recovery from the primary insult. Thromboprophylaxis DVT, venous catheter-related thrombosis and PE are common in critically ill patients. Low-molecular-weight heparin (LMWH) should be administered to all patients, unless there is a contraindication. Often patients at highest risk of thrombosis, such as those with hepatic dysfunction or those who have suffered major trauma, have a relative contraindication to heparin. Such cases mandate daily evaluation of the risk–benefit ratio, and LMWH should be administered as soon as it is deemed safe to do so. Mechanical thromboprophylaxis, such as intermittent calf compression devices, are useful adjuvants in high-risk patients. Glucose control Hyperglycaemia is harmful in critical illness and may occur in people with pre-existing diabetes or undiagnosed diabetes, following administration of high-dose glucocorticoids, or as Spontaneous breathing trials A spontaneous breathing trial involves the removal of all respiratory support followed by close observation of how long the patient is able to breathe unassisted. The technique is particularly effective when linked to a reduction in sedation. PEEP and pressure support are reduced to low levels, or patients are disconnected from the ventilator and breathe oxygen or humidified air through the endotracheal tube. Signs of failure include rapid shallow breathing, hypoxaemia, rising PaCO2, sweating and agitation. Patients who pass a spontaneous breathing trial are assessed for suitability of extubation (endotracheal tube removal). Progressive reduction in pressure support ventilation Progressive reduction in pressure support ventilation (PSV) is applied to each breath over a period of hours or days, according to patient response. Some ICU ventilators have software that allows the facility to wean the support provided automatically. A useful tool to guide the weaning process is the rapid shallow breathing index (RSBI). This composite score of a patient’s spontaneous respiratory rate and tidal volume (respiratory rate divided by tidal volume in litres) gives a numerical indication of how difficult the patient is finding breathing at that particular level of support. A RSBI value of > 100 suggests that a patient is working at a level that would be unsustainable for longer periods. Extubation It is not possible to predict whether a patient is ready to be extubated accurately; the timing relies heavily on clinical judgement. There are, however, some simple rules that can aid decision-making. Patients must have stable ABGs with resolution of hypoxaemia and hypercapnia despite minimal ventilator pressure support and a low FiO2. Conscious level must be adequate to protect the airway, comply with physiotherapy, and cough. Furthermore, an assessment must be made as to whether the patient can sustain the required minute volume without ventilator support. This depends on the condition of patients’ lungs, their strength and other factors affecting the PaCO2, such as temperature and metabolic rate. The need for re-intubation following extubation is associated with poorer outcome, but patients who are not given the opportunity to breathe without a ventilator will also be at increased risk of ventilator-associated complications such as pneumonia and myopathy. Tracheostomy A tracheostomy is a percutaneous tube passed into the trachea (usually between the first and second, or second and third tracheal rings) to facilitate longer-term ventilation. The advantages and disadvantages of tracheostomy insertion are listed in Box 10.45. When ventilation weaning has been unsuccessful, a tracheostomy provides a bridge between intubation and extubation; the patient can have increasing periods free of ventilator support but easily have support reinstated. A tracheostomy can be inserted percutaneously, using a bronchoscope in the trachea for guidance, or surgically under direct vision. Occasionally, a patient will have a tracheostomy in situ following a laryngectomy. Such 10.45 Advantages and disadvantages of tracheostomy Advantages • Patient comfort • Improved oral hygiene • Access for tracheal toilet • Ability to speak with cuff deflated and a speaking valve attached • Reduced equipment ‘dead space’ (the volume of tubing) • Earlier weaning and ICU discharge • Reduced sedation requirement • Reduced vocal cord damage Disadvantages • Immediate complications: hypoxaemia, haemorrhage • Tracheostomy site infection • Tracheal damage; late stenosis

Complications and outcomes of critical illness • 211

function (and thus consciousness), but a lesion in the ventral pons (usually caused by infarction) results in complete paralysis. The term ‘vegetative state’ implies some retention of brainstem function and minimal cortical function, with loss of awareness of the environment. In contrast, ‘minimally conscious state’ implies that there is some degree of awareness and intact brainstem function. Confident distinction between these states is important and requires careful assessment, often over a period of time. Brain death is, by definition, irreversible but other states may offer hope for improvement. ICU-acquired weakness Weakness is common among survivors of critical illness. It is usually symmetrical, proximal and most marked in the lower limbs. Critical illness polyneuropathy and myopathy can occur simultaneously and, within the constraints of an altered sensorium, it can be impossible to distinguish the two conditions clinically. Risk factors for both processes include the severity of multi-organ failure, poor glycaemic control and the use of muscle relaxants and glucocorticoids. Critical illness polyneuropathy This is due to peripheral nerve axonal loss and characteristically presents as proximal muscle weakness with preserved sensation. a consequence of ‘stress hyperglycaemia’. Hyperglycaemia is commonly managed by infusion of intravenous insulin titrated against a ‘sliding scale’. Intensive management of hyperglycaemia with insulin can result in hypoglycaemia, which may also be harmful in critical illness. Therefore, a compromise is to titrate insulin to a blood glucose level of 6–10 mmol/L (108–180 mg/dL). Blood transfusion Many critically ill patients become anaemic due to reduced red cell production and red cell loss through bleeding and blood sampling. However, red cell transfusion carries inherent risks of immunosuppression, fluid overload, organ dysfunction from microemboli, and transfusion reactions. In stable patients, a haemoglobin level of 70 g/L (7 g/dL) is a safe compromise between optimisation of oxygen delivery and the risks of transfusion. This transfusion threshold should be adjusted upwards for situations where oxygen delivery is critical, such as in patients with active myocardial ischaemia. Peptic ulcer prophylaxis Stress ulceration during critical illness is a serious complication. Proton pump inhibitors or histamine-2 receptor antagonists are effective at reducing the incidence of ulceration. There is, however, a suggestion that the use of these agents, particularly in conjunction with antibiotics, may increase the incidence of nosocomial infection, especially with Clostridium difficile (p. 264). It is therefore common practice to stop ulcer prophylaxis once consistent absorption of enteral feed is established. Complications and outcomes of critical illness The majority of patients will survive their episode of critical illness. While some will return to full, active lives, there are many who have ongoing physical, emotional and psychological problems. Adverse neurological outcomes Brain injury Head injury, hypoxic–ischaemic injury and infective, inflammatory and vascular pathologies can all irreversibly injure the brain. If treatment is unsuccessful, patients will either die or be left with a degree of disability. In the latter situation, the provision of ongoing organ support will depend on the severity of the injury, the prognosis, and the wishes of the patient (usually expressed via relatives). Brain death is a state in which cortical and brainstem function is irreversibly lost. Diagnostic criteria for brain death vary between countries (Box 10.46); if satisfied, these criteria allow physicians to withdraw active treatment and discuss the potential for organ donation. Diagnosing brain death is complex and should be done only by physicians with appropriate expertise, as clinical differentiation from reduced consciousness can be challenging (Box 10.47). Where there is doubt – for example, in patients with coexisting spinal injury or localised brainstem pathology – additional investigations should be performed. The ‘locked-in’ syndrome, in which the patient is paralysed except for eye movements, requires preserved hemispheric 10.46 UK criteria for the diagnosis of brain death Preconditions for considering a diagnosis of brain death • The patient is deeply comatose:

a. There must be no suspicion that coma is due to depressant drugs, such as narcotics, hypnotics, tranquillisers

b. Hypothermia has been excluded – rectal temperature must exceed 35°C

c. There is no profound abnormality of serum electrolytes, acid–base balance or blood glucose concentrations, and any metabolic or endocrine cause of coma has been excluded • The patient is maintained on a ventilator because spontaneous respiration has been inadequate or has ceased. Drugs, including neuromuscular blocking agents, must have been excluded as a cause of the respiratory failure • The diagnosis of the disorder leading to brain death has been firmly established. There must be no doubt that the patient is suffering from irremediable structural brain damage Tests for confirming brain death • All brainstem reflexes are absent:

a. The pupils are fixed and unreactive to light

b. The corneal reflexes are absent

c. The vestibulo-ocular reflexes are absent – there is no eye movement following the injection of 20 mL of ice-cold water into each external auditory meatus in turn

d. There are no motor responses to adequate stimulation within the cranial nerve distribution

e. There is no gag reflex and no reflex response to a suction catheter in the trachea • No respiratory movement occurs when the patient is disconnected from the ventilator for long enough to allow the carbon dioxide tension to rise above the threshold for stimulating respiration (PaCO2 must reach 6.7 kPa/50 mmHg) The diagnosis of brain death should be made by two doctors of a specified status and experience. The tests are usually repeated after a short interval to allow blood gases to normalise before brain death is finally confirmed

212 • ACUTE MEDICINE AND CRITICAL ILLNESS Other long-term problems The experience of critical illness and the necessary invasive management can leave patients with profound psychological sequelae akin to the post-traumatic stress syndrome seen in many survivors of conflict. Specialist help is required in managing these issues. Sometimes recovering patients benefit from returning to the ICU to see the environment in a different way and gain a better understanding of the processes and procedures that haunt them. Long-term physical consequences are also common. Many diseases are not completely cured but follow a relapsing–remitting course; patients who have been critically ill with sepsis are far more likely than others in the general population to suffer from it again. Organ damage often persists and iatrogenic complications are common (e.g. damage to the vocal cords or tracheal stenosis from mucosal pressure caused by the cuff of the endotracheal tube). Intensive care follow-up clinics provide an excellent forum for addressing such issues, and for coordinating care involving a variety of medical specialties. The older patient Critically ill older patients present additional challenges following intensive care discharge (Box 10.48). As the ability to make a full recovery depends on frailty rather than chronological age, it can be helpful to use a validated frailty scoring system (p. 1306) to inform admission decision-making. Rehabilitation medicine has much to offer survivors of critical illness, and an early referral is beneficial when it is clear that a patient is likely to survive with significant morbidity. 10.47 Classification of brain death and reduced conscious states Diagnosis Features Investigation Prognosis Brain death See Box 10.46 Often not required if cranial imaging shows compatible cause and patient meets clinical criteria In diagnostic doubt: four-vessel angiogram (fluoroscopic or CT) of cerebral vessels or isotope scan of brain to demonstrate absence of cerebral blood flow Time of confirmed brain death is recorded as time of death Potential to donate organs – donation after brain death (DBD) donor Vegetative state (VS) ‘Persistent VS’ > 1 month ‘Permanent VS’ > 1 year No reaction to verbal stimuli Some reaction to noxious stimuli Sleep–wake cycles (periods of eye opening) Maintained respiratory drive Intact brainstem reflexes Occasional automatic movements (yawning, swallowing) Cranial imaging for primary cause Maintained cortical blood flow Poor. May be better with traumatic aetiology Minimally conscious state Some reaction to verbal stimuli Some reaction to noxious stimuli Spontaneous movements Intact brainstem reflexes EEG demonstrates reactivity Variable. Recovery of function more likely than in VS Locked-in syndrome Cortex is intact but bilateral motor tracts are damaged Can be partial or complete, i.e. some response to verbal stimuli (e.g. vertical eye movements to communicate) Variable brainstem reflexes No limb movement to noxious stimuli Imaging for primary cause – commonly MRI or CT will show brainstem or pontine infarction Variable and depends on cause – progress can continue over months to years It may also manifest as failure to wean from the ventilator secondary to respiratory muscle weakness. Electrophysiological studies of the affected nerves can be helpful, especially to rule out other potential causes such as Guillain–Barré syndrome. Conduction studies typically show reduced amplitude of transmitted voltage action potential with preserved velocity (compare with findings in Guillain–Barré syndrome; pp. 1076 and 1140). There are no specific treatments aside from resolution of the underlying cause and rehabilitation. Weakness may persist long into the convalescence stage of illness. In some cases, the clinical picture may be more in keeping with individual nerve involvement. This may be due to local pressure effects or part of a generalised picture. Great care must be taken to avoid pressure on high-risk areas such as the neck of the fibula where the common peroneal nerve navigates a superficial course. Nerve palsies such as foot drop can be permanent. Critical illness myopathy Although loss of muscle bulk is related to immobility and the catabolic state of critical illness, it is likely that microvascular and intracellular pathophysiological processes are also involved in critical illness myopathy. These processes result in loss of actin myofibrils and muscle weakness. Typically, the CK is normal or only mildly elevated. Like critical illness polyneuropathy, critical illness myopathy is usually a clinical diagnosis. Nerve conduction studies and electromyography may be suggestive of critical illness myopathy, and helpful in ruling out other pathology, but a muscle biopsy is required to confirm the diagnosis (p. 1076). It characteristically shows selective loss of the thick myofibrils and muscle necrosis. Management is conservative and the prognosis is good in ICU survivors.

Complications and outcomes of critical illness • 213

patient continues to be ventilated. The practice of organ donation varies throughout the world but the principles remain the same. Organ donation specialists are contacted and they begin the process of establishing the suitability of any organs for transplantation and matching potential recipients. Many patients will have expressed their wishes through an organ donor registration scheme but agreement of family and next of kin is a moral (and sometimes legal) prerequisite. Once the organ retrieval theatre team have been assembled and all preliminary tests have been completed, the deceased patient is transferred to the operating theatre and the organs are sequentially removed. Donation after cardiac death If a patient does not meet brain death criteria but withdrawal of treatment has been agreed, donation of organs with residual function may be appropriate. This is termed ‘donation after cardiac death’ (DCD). If the patient dies within a short period following the commencement of ‘warm ischaemic time’ (the time to asystole following the onset of physiological derangement after the withdrawal of active treatment), then DCD can proceed. The deceased patient is transferred to an operating theatre and the agreed organs (often lungs, liver, kidney and pancreas) are retrieved. As heart valves and corneas can be retrieved later (within a longer time frame), tissue retrieval may occur in the mortuary. Postmortem examination or autopsy There are several indications to request a postmortem examination. A coroner (or legal equivalent) may initiate the process if a death is unexpected or violent, or has occurred under suspicious circumstances. The treating physician(s) may request one if they are unable to establish a cause of death or there is agreement that it may yield information of interest to the family or clinical team. The postmortem diagnosis is frequently at odds with the antemortem diagnosis and it is a very useful learning exercise to review the results with all those involved in the patient’s care. Discharge from intensive care Discharge is appropriate when the original indication for admission has resolved and the patient has sufficient physiological reserve to continue to recover without the facilities of intensive care. Many ICUs and HDUs function as combined units, allowing ‘step-down’ of patients to HDU care without changing the clinical team involved. Discharge from ICU is stressful for patients and families, and clear communication with the clinical team accepting responsibility is vital. Nursing ratios change from 1 : 1 (one nurse per patient) or 1 : 2 to much lower staffing levels. Discharges from ICU or HDU to standard wards should take place within normal working hours to ensure adequate medical and nursing support and detailed handover. Discharge outside normal working hours is associated with higher ICU re-admission rates and increased mortality. The receiving team should be provided with a written summary, including the information listed in Box 10.49. The ICU team should remain available for advice; many ICU teams provide an outreach service to supply advice and facilitate continuity of care. Critical care scoring systems Admission and discharge criteria vary between ICUs, so it is important to define the characteristics of the patients admitted in Withdrawal of active treatment and death in intensive care Futility The idea of futility is not new: Hippocrates stated that physicians should ‘refuse to treat those who are overmastered by their disease, realising that in such cases medicine is powerless’. In intensive care, where the concept of futility is often used as a criterion to limit or withdraw life-sustaining treatment, it is helpful to have a working definition on which families and physicians can agree. It is, therefore, reasonable to define futility in such circumstances as the point at which recovery to a quality of life that the patient would find acceptable has passed. The primary insult may be neurological (irreversible brain injury not meeting criteria for brain death), or multi-organ failure that is refractory to treatment. Death Whilst most patients prefer to die at home, many spend their final days in hospital. Chapter 34 details the medical, legal and ethical priorities that should guide patient management once the decision to withdraw active treatment has been made (p. 1354). The decision to shift the focus of care to palliation should not change its intensity; it is the over-arching objective that changes. Only interventions that will improve the quality of a patient’s remaining life should be offered. In the ICU, it is often appropriate to continue infusions of sedatives and analgesics, as reducing or stopping them may cause unnecessary pain and agitation. Measures that were instituted to prolong life should be withdrawn (usually including cessation of inotropes and extubation) to allow the patient to die peacefully with their family and friends present. Organ donation Donation after brain death The diagnosis of brain death is discussed on page 211. Once brain death has been confirmed, consideration should be given to organ donation, termed ‘donation after brain death’ (DBD). Time of death is recorded as the time when the first series of brain death tests are undertaken, although the deceased 10.48 The critically ill older patient • ICU demography: increasing numbers of critically ill older patients are admitted to the ICU; more than 50% of patients in many general ICUs are over 65 years old. • Outcome: affected to some extent by age, as reflected in APACHE II (see Box 10.50), but age should not be used as the sole criterion for withholding or withdrawing ICU support. • Cardiopulmonary resuscitation (CPR): successful hospital discharge following in-hospital CPR is rare in patients over 70 years old in the presence of significant chronic disease. • Functional independence: tends to be lost during an ICU stay and prolonged rehabilitation may subsequently be necessary. • Specific problems: Skin fragility and ulceration Poor muscle strength: difficulty weaning from ventilator and mobilising Delirium: compounded by sedatives and analgesics High prevalence of underlying nutritional deficiency.

214 • ACUTE MEDICINE AND CRITICAL ILLNESS into the management of patients with that diagnosis, in order to identify aspects of care that could be improved. Further information Websites criticalcarereviews.com Reviews and appraisal of ICU topics. emcrit.org Online podcasts and general information on emergency medicine and critical care. esicm.org European Society of Intensive Care Medicine: guidelines, recommendations, consensus conference reports. lifeinthefastlane.com Information on a range of intensive care and emergency medicine topics. survivingsepsis.org Surviving Sepsis website. order to assess the effects of the care provided on the outcomes achieved. Two systems are widely used to measure severity of illness (see Box 10.50 for further details): • APACHE II: Acute Physiology Assessment and Chronic Health Evaluation • SOFA score: Sequential Organ Failure Assessment tool. When combined with the admission diagnosis, scoring systems have been shown to correlate well with the risk of death in hospital. Such outcome predictions are useful at a population level but lack the specificity to be of use in decision-making for individual patients. This is in contrast to well-validated, disease-specific tools, such as the CURB-65 tool for pneumonia, which can be helpful in guiding individual management (see Fig. 17.32, p. 583). Predicted mortality figures by diagnosis have been calculated from large databases generated from a range of ICUs. These allow a particular unit to evaluate its performance compared to the reference ICUs by calculating standardised mortality ratios (SMRs) for each diagnostic group. A value of unity indicates the same performance as the reference ICUs, while a value below 1 indicates a better than predicted outcome. If a unit has a high SMR in a certain diagnostic category, it should prompt investigation 10.50 Comparison of APACHE II and SOFA scores APACHE II score • An assessment of admission characteristics (e.g. age and pre-existing organ dysfunction) and the maximum/minimum values of 12 routine physiological measurements during the first 24 hours of admission (e.g. temperature, blood pressure, GCS) that reflect the physiological impact of the illness • Composite score out of 71 • Higher scores are given to patients with more serious underlying diagnoses, medical history or physiological instability; higher mortality correlates with higher scores SOFA score • A score of 1–4 is allocated to six organ systems (respiratory, cardiovascular, liver, renal, coagulation and neurological) to represent the degree of organ dysfunction, e.g. platelet count

150 × 109/L scores 1 point, < 25 × 109/L scores 4 points • Composite score out of 24 • Higher scores are associated with increased mortality 10.49 How to write an ICU discharge summary: information to be included • Summary of diagnosis and progress in intensive care • Current medications and changes to regular medications with justifications • Antibiotic regime and suggested review dates • Results of positive microbiological tests • Positions of invasive devices and insertion dates • Escalation plan in the event of deterioration • Pending investigations and specialty consultations • If the physiology remains abnormal due to chronic disease, rapid response triggers should be adjusted accordingly

Ch04-3 Clinical Medicine

Ch04-3 Clinical Medicine

01-11 Infectious disease

11 Infectious disease

Infectious disease DH Dockrell S Sundar BJ Angus Clinical examination of patients with infectious disease 216 Presenting problems in infectious diseases 218 Fever 218 Positive blood culture 225 Sepsis 226 Acute diarrhoea and vomiting 227 Infections acquired in the tropics 230 Infections in adolescence 234 Infections in pregnancy 234 Viral infections 236 Systemic viral infections with exanthem 236 Systemic viral infections without exanthem 240 Viral infections of the skin 247 Gastrointestinal viral infections 249 Respiratory viral infections 249 Viral infections with neurological involvement 249 Viral infections with rheumatological involvement 250 Prion diseases 250 Bacterial infections 250 Bacterial infections of the skin, soft tissues and bones 250 Systemic bacterial infections 254 Gastrointestinal bacterial infections 262 Respiratory bacterial infections 265 Bacterial infections with neurological involvement 267 Mycobacterial infections 267 Rickettsial and related intracellular bacterial infections 270 Chlamydial infections 272 Protozoal infections 273 Systemic protozoal infections 273 Leishmaniasis 281 Gastrointestinal protozoal infections 286 Infections caused by helminths 288 Intestinal human nematodes 288 Tissue-dwelling human nematodes 290 Zoonotic nematodes 293 Trematodes (flukes) 294 Cestodes (tapeworms) 297 Ectoparasites 299 Fungal infections 300 Superficial mycoses 300 Subcutaneous mycoses 300 Systemic mycoses 301

216 • INFECTIOUS DISEASE Clinical examination of patients with infectious disease Insets (splinter haemorrhages) Courtesy of Dr Nick Beeching, Royal Liverpool University Hospital; (Roth’s spots) Courtesy of Prof. Ian Rennie, Royal Hallamshire Hospital, Sheffield.

Figs A–C opposite Courtesy of Dr Ravi Gowda, Royal Hallamshire Hospital, Sheffield. Heart and lungs Tachycardia, hypotension Murmurs or prosthetic heart sounds Pericardial rub Signs of consolidation Pleural or pericardial effusion Skin Generalised erythema Rash (see opposite) IV injection track marks Surgical scars Prosthetic devices, e.g. central venous catheters Tattoos Oropharynx Dental caries Tonsillar enlargement or exudate Candidiasis Hands and nails Finger clubbing Splinter haemorrhages Janeway lesions Signs of chronic liver disease Vasculitis lesions Head and neck Lymphadenopathy Parotidomegaly Abnormal tympanic membranes Chest X-ray consolidation in pneumonia Roth’s spots in endocarditis Testicular swelling in adult mumps Musculoskeletal Joint swelling, erythema or tenderness Localised tender spine suggestive of epidural abscesses or discitis Draining sinus of chronic osteomyelitis Eyes Conjunctival petechiae Painful red eye in uveitis Loss of red reflex in endophthalmitis Roth’s spots in infective endocarditis Haemorrhages and exudates of cytomegalovirus retinitis Choroidal lesions of tuberculosis Streptococcal tonsillitis Splinter haemorrhages in endocarditis Abdomen Hepatosplenomegaly Ascites Renal angle tenderness Localised tenderness or guarding with decreased bowel sounds, e.g. in left iliac fossa with diverticulitis Mass lesions Surgical drains Neurological Neck stiffness Photophobia Delirium Focal neurological signs Genitalia and rectum Ulceration or discharge Testicular swelling or nodules Inguinal lymphadenopathy Prostatic tenderness Rectal fluctuance Observation • Temperature • Sweating • Weight loss • Respiratory distress • Altered consciousness • Pallor • Jaundice

Clinical examination of patients with infectious disease • 217

1 Skin lesions in infectious diseases Streptococcal toxic shock syndrome. A Meningococcal sepsis. B Shingles. C Erythema nodosum. D • Diffuse erythema, e.g. A • Migrating erythema, e.g. enlarging rash of erythema migrans in Lyme disease (see Fig. 11.21, p. 256) • Purpuric or petechial rashes, e.g. B • Macular or papular rashes, e.g. primary infection with HIV (see Box 12.8, p. 312) • Vesicular or blistering rash, e.g. C • Erythema multiforme (see Fig. 29.53 and Box 29.32, pp. 1264 and 1265) • Nodules or plaques, e.g. Kaposi’s sarcoma (p. 315) • Erythema nodosum ( D and Box 29.33, p. 1265) Always consider non-infectious aetiologies in the differential diagnosis. (HBV/HCV = hepatitis B/C virus; HIV-1 = human immunodeficiency virus-1; TB = tuberculosis) Presenting complaint • Diverse manifestations of infectious disease make accurate assessment of features and duration critical; e.g. fever and cough lasting 2 days imply an acute respiratory tract infection but suggest TB if they last 2 months Review of systems • Must be comprehensive Past medical history • Define the ‘host’ and likelihood of infection(s) • Include surgical and dental procedures involving prosthetic materials • Document previous infections Medication history • Include non-prescription drugs, use of antimicrobials and immunosuppressants • Identify medicines that interact with antimicrobials or that may cause fever Allergy history • Esp. to antimicrobials, noting allergic manifestation (e.g. rash versus anaphylaxis) Family and contact history • Note infections and their duration • Sensitively explore exposure to key infections, e.g. TB and HIV Travel history • Include countries visited and where previously resident (relevant to exposure and likely vaccination history, e.g. likelihood of BCG vaccination in childhood) Occupation • e.g. Anthrax in leather tannery workers Recreational pursuits • e.g. Leptospirosis in canoeists and windsurfers Animal exposures • Include pets, e.g. dogs/hydatid disease Dietary history • Consider under-cooked meats, shellfish, unpasteurised dairy products or well water • Establish who else was exposed, e.g. to food-borne pathogens History of intravenous drug injection or receipt of blood products • Risks for blood-borne viruses, e.g. HIV-1, HBV and HCV Sexual history • Explore in a confidential manner (Ch. 13); remember that the most common mode of HIV-1 transmission is heterosexual (Ch. 12) Vaccination history and use of prophylactic medicines • Consider occupation- or age-related vaccines • In a traveller or infection-predisposed patient, establish adherence to prophylaxis History-taking in suspected infectious disease Documentation of fever • ‘Feeling hot’ or sweaty does not necessarily signify fever – diagnosed only when a body temperature of over 38.0°C is recorded • Axillary and aural measurement is less accurate than oral or rectal • Outpatients may be trained to keep a temperature chart Rigors • Shivering (followed by excessive sweating) occurs with a rapid rise in body temperature from any cause Night sweats • Associated with particular infections (e.g. TB, infective endocarditis); sweating from any cause is worse at night Excessive sweating • Alcohol, anxiety, thyrotoxicosis, diabetes mellitus, acromegaly, lymphoma and excessive environmental heat all cause sweating without temperature elevation Recurrent fever • There are various causes, e.g. Borrelia recurrentis, bacterial abscess Accompanying features • Severe headache and photophobia, although characteristic of meningitis, may accompany other infections. • Delirium during fever is more common in young children or the elderly • Myalgia may occur with viral infections, such as influenza, and with sepsis including meningococcal sepsis • Shock may accompany severe infections and sepsis (p. 196) Fever

218 • INFECTIOUS DISEASE • other specimens, as indicated by history and examination, e.g. wound swab; sputum culture; stool culture, microscopy for ova and parasites, and Clostridium difficile toxin assay • specific tests and their priority, indicated by geographical location: malaria films on 3 consecutive days or a malaria rapid diagnostic test (antigen detection, p. 276), a test for non-structural protein 1 (NS1) in dengue (antigen detection) and blood cultures for Salmonella Typhi, as well as abdominal ultrasound, would be standard initial tests in many regions in Africa, Asia, Oceania, and Central and South America. Subsequent investigations in patients with HIV-related (p. 313), immune-deficient (p. 223), nosocomial or travel-related (p. 230) pyrexia and in individuals with associated symptoms or signs of involvement of the respiratory, gastrointestinal or neurological systems are described elsewhere. Management Fever and its associated systemic symptoms can be treated with paracetamol, and by tepid sponging to cool the skin. Replacement of salt and water is important in patients with drenching sweats. Further management is focused on the underlying cause. Fever with localising symptoms or signs In most patients, the site of infection is apparent after clinical evaluation (p. 216), and the likelihood of infection is reinforced by investigation results (e.g. neutrophilia with raised ESR and CRP in bacterial infections). Not all apparently localising symptoms are reliable, however; headache, breathlessness and diarrhoea can occur in sepsis or malaria without localised infection in the central nervous system (CNS), respiratory tract or gastrointestinal tract, and abdominal pain may be a feature of basal pneumonia. Careful interpretation of the clinical features is vital (e.g. severe headache associated with photophobia, rash and neck stiffness suggests meningitis, whereas moderate headache with cough and rhinorrhoea is consistent with a viral upper respiratory tract infection). Common infections that present with fever are shown in Figure 11.1. Further investigation and management are specific to the cause, but may include empirical antimicrobial therapy (p. 116) pending confirmation of the microbiological diagnosis. Pyrexia of unknown origin Pyrexia of unknown origin (PUO) was classically defined as a temperature above 38.0°C on multiple occasions for more than 3 weeks, without diagnosis, despite initial investigation in hospital for 1 week. The definition has been relaxed to allow for investigation over 3 days of inpatient care, three outpatient visits or 1 week of intensive ambulatory investigation. Subsets of PUO are described as HIV-1 related, immune-deficient or nosocomial. Up to one-third of cases of PUO remain undiagnosed. Clinical assessment Major causes of PUO are outlined in Box 11.2. Rare causes, such as periodic fever syndromes (p. 81), should be considered in those with a family history. Children and younger adults are more likely to have infectious causes – in particular, viral infections. Older adults are more likely to have certain infectious and non-infectious causes (see Box 11.1). Detailed history and examination should be repeated at regular intervals to detect emerging features (e.g. rashes, signs of infective endocarditis 11.1 Fever in old age • Temperature measurement: fever may be missed because oral temperatures are unreliable. Rectal measurement may be needed but core temperature is increasingly measured using eardrum reflectance. • Delirium: common with fever, especially in those with underlying cerebrovascular disease or dementia. • Prominent causes of pyrexia of unknown origin: include tuberculosis and intra-abdominal abscesses, complicated urinary tract infection and infective endocarditis. Non-infective causes include polymyalgia rheumatica/temporal arteritis and tumours. A smaller fraction of cases remain undiagnosed than in young people. • Pitfalls in the elderly: conditions such as stroke or thromboembolic disease can cause fever but every effort must be made to exclude concomitant infection. • Common infectious diseases in the very frail (e.g. nursing home residents): pneumonia, urinary tract infection, soft tissue infection and gastroenteritis. The principles of infection and its investigation and therapy are described in Chapter 6. This chapter and the following ones on human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) and sexually transmitted infection (STI) describe the approach to patients with potential infectious disease, the individual infections and the resulting syndromes. Presenting problems in infectious diseases Infectious diseases present with myriad clinical manifestations. Many of these are described in other chapters or below. Fever ‘Fever’ implies an elevated core body temperature of more than 38.0°C (p. 138). Fever is a response to cytokines and acute phase proteins (pp. 65 and 70), and occurs in infections and in non-infectious conditions. Clinical assessment The differential diagnosis is very broad so clinical features are used to guide the most appropriate investigations. The systematic approach described on page 216 should be followed. Box 11.1 describes the assessment of elderly patients. Investigations If the clinical features do not suggest a specific infection, then initial investigations should include: • a full blood count (FBC) with differential, including eosinophil count • urea and electrolytes, liver function tests (LFTs), blood glucose and muscle enzymes • inflammatory markers, erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) • a test for antibodies to HIV-1 (p. 310) • autoantibodies, including antinuclear antibodies (ANA) • chest X-ray and electrocardiogram (ECG) • urinalysis and urine culture • blood culture (p. 106) • throat swab for culture or polymerase chain reaction (PCR)

Presenting problems in infectious diseases • 219

• induced sputum or other specimens for mycobacterial stains and culture • serological tests, including an HIV test, and ferritin estimation • imaging of the abdomen by ultrasonography or computed tomography (CT) • echocardiography. Lesions identified on imaging should usually be biopsied in order to seek evidence of relevant pathogens by culture, histopathology or nucleic acid detection. Particularly in patients who have received prior antimicrobials, 16S rRNA analysis (Box 6.2, p. 101) may aid diagnosis if a microorganism is not cultured. The chance of a successful diagnosis is greatest if procedures for obtaining (p. 527) or features of vasculitis). In men, the prostate should be considered as a potential source of infection. Clinicians should be alert to the possibility of factitious fever, in which high temperature recordings are engineered by the patient (Box 11.3). Investigations If initial investigation of fever is negative, further microbiological and non-microbiological investigations should be considered (Boxes 11.4 and 11.5). As with initial investigation of fever described above, the selection and prioritisation of tests will be influenced by the geographical location of potential exposure to pathogens (Box 11.4). These will usually include: Fig. 11.1 Common infectious syndromes presenting with fever and localised features. Major causes are grouped by approximate anatomical location and include central nervous system infection; respiratory tract infections; abdominal, pelvic or urinary tract infections; and skin and soft tissue infections (SSTIs) or osteomyelitis. For each site of infection, particular syndromes and their common causes are described elsewhere in the book. The causative organisms vary, depending on host factors, which include whether the patient has lived in or visited a tropical country or particular geographical location, has acquired the infection in a health-care environment or is immunocompromised. Insets (cellulitis of the leg) Courtesy of Dr Ravi Gowda, Royal Hallamshire Hospital, Sheffield; (pulmonary tuberculosis) Courtesy of Dr Ann Chapman, Royal Hallamshire Hospital, Sheffield; (empyema, pyogenic liver abscess, diverticular abscess, tuberculous osteomyelitis) Courtesy of Dr Robert Peck, Royal Hallamshire Hospital, Sheffield. Meningitis Endophthalmitis Encephalitis Brain abscess Neurosurgical infection MRI with enhancement of the temporal lobe in herpes simplex encephalitis Chest X-ray from a patient with pulmonary tuberculosis CT thorax in empyema Cellulitis of the leg Tuberculous osteomyelitis of the lower tibia CT abdomen showing a pyogenic liver abscess CT abdomen showing a diverticular abscess Liver abscess Pancreatic abscess Hepatitis Biliary infection Pyelonephritis Diverticulitis Peritonitis Tubulo-ovarian abscess Appendiceal abscess Cellulitis Impetigo Erysipelas Subcutaneous fat Deeper fascial planes Necrotising fasciitis Muscle Epidermis Dermis Pyomyositis Bone Osteomyelitis Colitis Sinusitis Pharyngitis Tuberculosis Pneumonia Empyema Lung abscess

220 • INFECTIOUS DISEASE and transporting the correct samples in the appropriate media are carefully planned between the clinical team, the radiologist or surgeon performing the procedure, and the local microbiologist and histopathologist. Positron emission tomography (PET) scans may aid diagnosis of vasculitis or help selection of biopsy sites. Liver biopsy may be justified – for example, to identify idiopathic granulomatous hepatitis – if there are biochemical or radiological abnormalities. Bone marrow biopsies have a diagnostic yield of up to 15%, most often revealing haematological malignancy, myelodysplasia or tuberculosis, and also identifying brucellosis, typhoid fever or visceral leishmaniasis. Bone marrow should be sent for culture, as well as microscopy. Laparoscopy is occasionally undertaken with biopsy of abnormal tissues. Splenic aspiration in specialist centres is the diagnostic test of choice for 11.3 Clues to the diagnosis of factitious fever • A patient who looks well • Bizarre temperature chart with absence of diurnal variation and/or temperature-related changes in pulse rate • Temperature > 41°C • Absence of sweating during defervescence • Normal erythrocyte sedimentation rate and C-reactive protein despite high fever • Evidence of self-injection or self-harm • Normal temperature during supervised (observed) measurement • Infection with multiple commensal organisms (e.g. enteric or mouth flora) Infections (~30%) Specific locations • Abscesses: hepatobiliary, diverticular, urinary tract (including prostate), pulmonary, CNS • Infections of oral cavity (including dental), head and neck (including sinuses) • Bone and joint infections • Infective endocarditis* Specific organisms • TB (particularly extrapulmonary)* • HIV-1 infection • Other viral infections: cytomegalovirus (CMV), Epstein–Barr virus (EBV) • Fungal infections (e.g. Aspergillus spp., Candida spp. or dimorphic fungi) • Infections with fastidious organisms (e.g. Bartonella spp., Tropheryma whipplei ) Specific patient groups • Recently spent time in a region with geographically restricted infection: Malaria*, dengue, rickettsial infections, Brucella spp., amoebic liver abscess, enteric fevers (Africa, Asia, Oceania, Central and South America), Leishmania spp. (southern Europe, India, Africa and Latin America), Burkholderia pseudomallei (South-east Asia), Middle East respiratory syndrome coronavirus (MERS-CoV; Arabian Peninsula) • Residence in or travel to a region with endemic infection: TB* (Africa, Asia, Central and South America), extensively drug-resistant TB (XDR-TB; South Africa), Brucella spp. (Africa, Asia, Central and South America), HIV-1 (Africa, Asia), Trypanosoma cruzi (Central and South America) • Nosocomial infections: Pneumonia*, infections related to prosthetic materials and surgical procedures, urinary tract infections, central venous catheter infections • HIV-positive individuals: Acute retroviral syndrome AIDS-defining infections (disseminated Mycobacterium avium complex (DMAC), Pneumocystis jirovecii pneumonia, CMV and others) Malignancy (~20%) Haematological malignancy • Lymphoma*, leukaemia and myeloma Solid tumours • Renal, liver, colon, stomach, pancreas Connective tissue disorders (~15%) Older adults • Temporal arteritis/polymyalgia rheumatica* Younger adults • Still’s disease (juvenile rheumatoid arthritis)* • Systemic lupus erythematosus (SLE) • Vasculitic disorders, including polyarteritis nodosa, rheumatoid disease with vasculitis and granulomatosis with polyangiitis (formerly known as Wegener’s granulomatosis) • Polymyositis • Behçet’s disease • Rheumatic fever (in regions where still endemic, e.g. Asia, Oceania and parts of Africa) Miscellaneous (~20%) Cardiovascular • Atrial myxoma, aortitis, aortic dissection Respiratory • Sarcoidosis, pulmonary embolism and other thromboembolic disease, extrinsic allergic alveolitis Gastrointestinal • Inflammatory bowel disease, granulomatous hepatitis, alcoholic liver disease, pancreatitis Endocrine/metabolic • Thyrotoxicosis, thyroiditis, hypothalamic lesions, phaeochromocytoma, adrenal insufficiency, hypertriglyceridaemia Haematological • Haemolytic anaemia, paroxysmal nocturnal haemoglobinuria, thrombotic thrombocytopenic purpura, myeloproliferative disorders, Castleman’s disease, graft-versus-host disease (after allogeneic haematopoietic stem cell transplantation) Inherited • Familial Mediterranean fever and periodic fever syndromes Drug reactions* • e.g. Antibiotic fever, drug hypersensitivity reactions etc. Factitious fever Idiopathic (~15%) *Most common causes within each group. 11.2 Aetiology of pyrexia of unknown origin (PUO)

Presenting problems in infectious diseases • 221

11.5 Additional investigations in PUO • Serological tests for connective tissue disorders: Autoantibody screen Complement levels Immunoglobulins Cryoglobulins • Ferritin • Echocardiography • Ultrasound of abdomen • CT/MRI of thorax, abdomen and/or brain • Imaging of the skeletal system: Plain X-rays CT/MRI spine Isotope bone scan • Labelled white cell scan • Positron emission tomography (PET)/single-photon emission computed tomography (SPECT) • Biopsy: Bronchoscopy and lavage ± transbronchial biopsy Lymph node aspirate or biopsy Biopsy of radiological lesion Biopsy of liver Bone marrow aspirate and biopsy Lumbar puncture Laparoscopy and biopsy Temporal artery biopsy Location-independent investigations Microscopy • Blood for atypical lymphocytes (EBV, CMV, HIV-1, hepatitis viruses or Toxoplasma gondii ) • Respiratory samples for mycobacteria and fungi • Stool for ova, cysts and parasites • Biopsy for light microscopy (bacteria, mycobacteria, fungi) and/or electron microscopy (viruses, protozoa (e.g. microsporidia) and other fastidious organisms (e.g. Tropheryma whipplei )) • Urine for white or red blood cells and mycobacteria (early morning urine × 3) Culture • Aspirates and biopsies (e.g. joint, deep abscess, debrided tissues) • Blood, including prolonged culture and special media conditions • Sputum for mycobacteria • CSF • Gastric aspirate for mycobacteria • Stool • Swabs • Urine ± prostatic massage in older men Antigen detection • Blood, e.g. HIV p24 antigen, cryptococcal antigen, Aspergillus galactomannan ELISA and for Aspergillus and other causes of invasive, fungal infection (1,3)-β-D-glucan • CSF for cryptococcal antigen • Bronchoalveolar lavage fluid for Aspergillus galactomannan • Nasopharyngeal aspirate/throat swab for respiratory viruses, e.g. IAV or RSV • Urine, e.g. for Legionella antigen Nucleic acid detection • Blood for Bartonella spp. and viruses • CSF for viruses and key bacteria (meningococcus, pneumococcus, Listeria monocytogenes) • Nasopharyngeal aspirate/throat swab for respiratory viruses • Sputum for Mycobacterium tuberculosis (MTB) and rifampicin (RIF) resistance with geneXpert MTB/RIF cartridge-based nucleic acid amplification test • Bronchoalveolar lavage fluid, e.g. for respiratory viruses • Tissue specimens, e.g. for T. whipplei • Urine, e.g. for Chlamydia trachomatis, Neisseria gonorrhoeae • Stool, e.g. for norovirus, rotavirus Immunological tests • Serology (antibody detection) for viruses, including HIV-1, and some bacteria • Interferon-gamma release assay for diagnosis of exposure to tuberculosis (but note this will not distinguish latent from active disease and can only be used to trigger further investigations of active disease) Geographically restricted tests2 Microscopy • Blood for trypanosomiasis, malaria and Borrelia spp. • Stool for geographically restricted ova, cysts and parasites • Biopsy for light microscopy (dimorphic fungi, Leishmania spp. and other parasites) • Urine for red blood cells and schistosome ova Antigen detection • Blood, e.g. dengue virus NS1 antigen, Histoplasma antigen (restricted availability) and malaria antigen (e.g. HRP-2 for Plasmodium falciparum or parasite-specific LDH for P. falciparum and P. vivax) Nucleic acid detection • Blood for causes of viral haemorrhagic fever • CSF for geographically restricted viruses, e.g. Japanese encephalitis virus • Nasopharyngeal aspirate/throat swab or bronchoalveolar lavage fluid for geographically restricted respiratory viruses, e.g. MERS-CoV Immunological tests • Serology (antibody detection) for viruses, dimorphic fungi and protozoa (CMV = cytomegalovirus; CSF = cerebrospinal fluid; EBV = Epstein–Barr virus; ELISA = enzyme-linked immunosorbent assay; HIV-1 = human immunodeficiency virus-1; HRP-2 = histidine-rich protein 2; IAV = influenza A virus; LDH = lactate dehydrogenase; MERS-CoV = Middle East respiratory syndrome coronavirus; NS1 = non-structural 1; RSV = respiratory syncytial virus) 1This list does not apply to every patient with a pyrexia of unknown origin. Appropriate tests should be selected in a stepwise manner, according to specific predisposing factors, epidemiological exposures and local availability, and should be discussed with a microbiologist. 2Addition of these tests should be guided by the location of presentation or travel history. 11.4 Microbiological investigation of pyrexia of unknown origin1

222 • INFECTIOUS DISEASE large veins of the groin and neck necessitated by progressive thrombosis of superficial peripheral veins. The most common causes of fever are soft tissue or respiratory infections. Clinical assessment The history should address the following risk factors: • Site of injection. Femoral vein injection is associated with vascular complications such as deep venous thrombosis (50% of which are septic) and accidental arterial injection with false aneurysm formation or a compartment syndrome due to swelling within the fascial sheath. Local complications include ilio-psoas abscess, and septic arthritis of the hip joint or sacroiliac joint. Injection of the jugular vein can be associated with cerebrovascular complications. Subcutaneous and intramuscular injection has been related to infection by clostridial species, the spores of which contaminate heroin. Clostridium novyi suspected visceral leishmaniasis. Temporal artery biopsy should be considered in patients over the age of 50 years, even in the absence of physical signs or a raised ESR. ‘Blind’ biopsy of other structures in the absence of localising signs or laboratory or radiology results is unhelpful. Prognosis No cause is found in approximately 10% of PUO cases, but as long as there is no significant weight loss or signs of another disease, the long-term mortality is low. Fever in the injection drug-user Intravenous injection of recreational drugs is widespread in many parts of the world (p. 1184). Infective organisms are introduced by non-sterile (often shared) injection equipment (Fig. 11.2). The risks increase with prolonged drug use and injection into Fig. 11.2 Fever in the injection drug-user: key features of clinical examination. Full examination (p. 216) is required but features most common amongst injection drug-users are shown here. (DVT = deep venous thrombosis; JVP = jugular venous pulse) Hands and nails Splinter haemorrhages Signs of chronic liver disease Oropharynx Dental infections Oropharyngeal candidiasis or other signs of HIV-1 infection Skin and soft tissues (any site) Cellulitis Purulent drainage Abscesses Ulcers Bullae or extreme pain suggestive of necrotising fasciitis Optic fundi Roth’s spots Candidal cotton wool spots Nervous system Signs of drug intoxication Encephalopathy Signs of meningitis Focal neurological features or seizures in septic embolism/ mycotic aneurysm/abscess Cranial nerve palsies of botulism Trismus, muscle rigidity or spasms in tetanus Localised pain over vertebrae with epidural abscess Cardiovascular system Systolic ‘V’ waves in JVP of tricuspid regurgitation (p. XXX) Regurgitant murmurs in endocarditis Respiratory system Consolidation in pneumonia Upper lobe signs in tuberculosis Pleural rub with septic pulmonary emboli Abdomen Jaundice ± tender liver edge with hepatitis Pain in left upper quadrant with splenic abscess Bone and joints Osteomyelitis Septic arthritis Injection sites Abscesses Fistula Haematoma Pseudoaneurysm Femoral stretch test Passive extension of the hip joint causes pain and reflex muscle spasm in ilio-psoas abscess Legs Signs of DVT Vasculitis or ischaemic signs of septic emboli, endocarditis or vasospasm Compartment syndrome Hip flexor spasm in an injection drug-user with ilio-psoas abscess Skin abscesses in an injection drug-user Sharing injecting equipment may transmit blood-borne viruses Observation

Presenting problems in infectious diseases • 223

glycopeptide (e.g. vancomycin) or lipopeptide (e.g.daptomycin). Once microbiological results are available, therapy can be narrowed to focus on the microorganism identified. In injection drug-users, meticillin-sensitive Staph. aureus is customarily treated with high-dose intravenous flucloxacillin, with shorter durations for uncomplicated right-sided endocarditis. Right-sided endocarditis caused by MRSA is usually treated with 4 weeks of vancomycin plus gentamicin for the first week. Specialist advice should be sought. For localised infections of the skin and soft tissues, oral therapy with agents active against staphylococci, streptococci and anaerobes is appropriate (e.g. flucloxacillin plus co-amoxiclav or clindamycin). Non-adherence to prescribed antimicrobial regimens leads to a high rate of complications. Fever in the immunocompromised host Immunocompromised hosts include those with congenital immunodeficiency (p. 77), HIV infection (Ch. 12) and iatrogenic causes a local lesion with significant toxin production, leading to shock and multi-organ failure. Tetanus, wound botulism, anthrax and gas gangrene also occur. • Technical details of injection. Sharing of needles and other injecting paraphernalia (including spoons and filters) increases the risk of blood-borne virus infection (e.g. HIV-1, hepatitis B or C virus). Some users lubricate their needles by licking them prior to injection, thus introducing mouth organisms (e.g. anaerobic streptococci, Fusobacterium spp. and Prevotella spp.). Contamination of commercially available lemon juice, used to dissolve heroin before injection, has been associated with blood-stream infection with Candida spp. • Substances injected. Injection of cocaine is associated with a variety of vascular complications. Certain formulations of heroin have been linked with particular infections, e.g. wound botulism with black tar heroin. Drugs are often mixed with other substances, e.g. talc. • Blood-borne virus status. Results of previous HIV-1 and hepatitis virus tests or vaccinations for hepatitis viruses should be recorded. • Surreptitious use of antimicrobials. Addicts may use antimicrobials to self-treat infections, masking initial blood culture results. Key findings on clinical examination are shown in Figure 11.2. It can be difficult to distinguish the effects of infection from the effects of drugs or drug withdrawal (excitement, tachycardia, sweating, marked myalgia, delirium). Stupor and delirium may result from drug administration but may also indicate meningitis or encephalitis. Non-infected venous thromboembolism is also common in this group. Investigations The initial investigations are as for any fever (see above), including a chest X-ray and blood cultures. Since blood sampling may be difficult, contamination is often a problem. Echocardiography to detect infective endocarditis should be performed in all injection drug-users with bacteraemia due to Staphylococcus aureus or other organisms associated with endocarditis (Fig. 11.3A); thromboembolic phenomena; or a new or previously undocumented murmur. Endovascular infection should also be suspected if lung abscesses or pneumatoceles are detected radiologically. Infected thrombus at injection sites, such as the groin, is common, and may lead to abscess formation. Additional imaging should be focused on sites of injection or of localising symptoms and signs (Fig. 11.3B). Any pathological fluid collections should be sampled. Urinary toxicology tests may suggest a non-infectious cause of the presenting complaint. While being investigated, all injection drug-users should be offered testing for infection with hepatitis B and C virus and HIV-1. Injection drug-users may have more than one infection. Skin and soft tissue infections are most often due to Staph. aureus or streptococci, and sometimes to Clostridium spp. or anaerobes. Pulmonary infections are most often due to the common pathogens causing community-acquired pneumonia, tuberculosis or septic emboli (Fig. 11.3C). Endocarditis with septic emboli commonly involves Staph. aureus and viridans streptococci, but Pseudomonas aeruginosa and Candida spp. are also encountered. Management Empirical therapy of fever in the injection drug-user includes an antistaphylococcal penicillin (e.g. flucloxacillin) or, if meticillinresistant Staph. aureus (MRSA) is prevalent in the community, a Fig. 11.3 Causes of fever in injection drug-users. A Endocarditis: large vegetation on the tricuspid valve (arrow). B Septic arthritis of the left sternoclavicular joint (arrow A) (note the erosion of the bony surfaces at the sternoclavicular joint) with overlying soft tissue collection (arrow B). C Tricuspid valve endocarditis caused by Staphylococcus aureus. Thoracic CT scan shows multiple embolic lesions with cavitation (arrows). The patient presented with haemoptysis. C, Courtesy of Dr Julia Greig, Royal Hallamshire Hospital, Sheffield. A B A B C

224 • INFECTIOUS DISEASE Neutropenic fever Neutropenic fever is defined as a neutrophil count of less than 0.5 × 109/L (p. 925) and a single axillary temperature above 38.5°C or three recordings above 38.0°C over a 12-hour period, although the infection risk increases progressively as the neutrophil count drops below 1.0 × 109/L. Patients with neutropenia are particularly prone to bacterial and fungal infection. Gram-positive organisms are the most common pathogens, particularly in association with in-dwelling catheters. Empirical broad-spectrum antimicrobial therapy is commenced as soon as neutropenic fever occurs and cultures have been obtained. The most common regimens for neutropenic sepsis are broad-spectrum penicillins, such as piperacillin–tazobactam IV. The routine addition of aminoglycosides to these agents is not supported by trial data. If fever has not resolved after 3–5 days, empirical antifungal therapy (e.g. caspofungin) is added (p. 125). An alternative antifungal strategy is to use azole prophylaxis in high-risk patients and markers of early fungal infection, such as galactomannan and/or fungal PCR, to guide initiation of antifungal treatment (a ‘pre-emptive approach’). Post-transplantation fever Fever in transplant recipients may be due to infection, episodes of graft rejection in solid organ transplant recipients, or graftversus-host disease following HSCT (p. 936). Infections in solid organ transplant recipients are grouped according to the time of onset (Box 11.6). Those in the first month are mostly related to the underlying condition or surgical complications. Those occurring 1–6 months after transplantation are characteristic of impaired T-cell function. Risk factors for CMV infection have been identified; patients commonly receive either prophylaxis or intensive monitoring involving regular testing for CMV DNA by PCR and early initiation of anti-CMV therapy using intravenous ganciclovir or oral valganciclovir if tests become positive. Following HSCT, infections in the first 4 weeks are more common in patients receiving a myeloablative-conditioning immunosuppression induced by chemotherapy (p. 1330), transplantation (p. 88) or immunosuppressant medicines, including high-dose glucocorticoids. Metabolic abnormalities, such as under-nutrition or hyperglycaemia, may also contribute. Multiple elements of the immune system are potentially compromised. A patient may have impaired neutrophil function from chemotherapy, impaired T-cell and/or B-cell responses due to underlying malignancy, T-cell and phagocytosis defects due to glucocorticoids, mucositis from chemotherapy and an impaired skin barrier due to insertion of a central venous catheter. Fever may result from infectious or non-infectious causes, including drugs, vasculitis, neoplasm, lymphoproliferative disease, graft-versus-host disease (in recipients of haematopoietic stem cell transplants (HSCT); p. 936), organising pneumonitis or Sweet’s syndrome (reddish nodules or plaques with fever and leucocytosis, in association with haematological malignancy). Clinical assessment The following should be addressed in the history: • Identification of the immunosuppressant factors and nature of the immune defect. • Any past infections and their treatment. Infections may recur and antimicrobial resistance may have been acquired in response to prior therapy. • Exposure to infections, including opportunistic infections that would not cause disease in an immunocompetent host. • Prophylactic medicines and vaccinations administered. Examination should include inspection of the normal physical barriers provided by skin and mucosal surfaces and, in particular, central venous catheters, the mouth, sinuses, ears and perianal area (digital rectal examination should be avoided). Disseminated infections can manifest as cutaneous lesions. The areas around fingernails and toenails should also be inspected closely. Investigations Initial screening tests are as described above (p. 218). Immunocompromised hosts often have decreased inflammatory responses leading to attenuation of physical signs, such as neck stiffness with meningitis, radiological features and laboratory findings, such as leucocytosis. Chest CT scan should be considered in addition to chest X-ray when respiratory symptoms occur. Abdominal imaging may also be warranted, particularly if there is right lower quadrant pain, which may indicate typhlitis (inflammation of the caecum) in neutropenic patients. Blood cultures from a central venous catheter, urine cultures, and stool cultures if diarrhoea is present are also recommended. Nasopharyngeal aspirates are sometimes diagnostic, as immunocompromised hosts may shed respiratory viruses for prolonged periods. Skin lesions should be biopsied if nodules are present, and investigation should include fungal stains. Useful molecular techniques include PCR for cytomegalovirus (CMV) and Aspergillus spp. DNA, and antigen assays (e.g. cryptococcal antigen (CrAg) for Cryptococcus neoformans, galactomannan for Aspergillus spp. in blood, and (1,3)-β-D-glucan for Aspergillus spp. and other causes of invasive fungal infection (though this will not identify mucoraceous moulds) or Legionella pneumophila type 1 in urine). Antibody detection is rarely useful in immunocompromised patients. Patients with respiratory signs or symptoms should be considered for bronchoalveolar lavage to detect Pneumocystis jirovecii, other fungi, bacteria and viruses. 11.6 Infections in transplant recipients Time post transplantation Infections Solid organ transplant recipients 0–1 month Bacterial or fungal infections related to the underlying condition or surgical complications 1–6 months CMV, other opportunistic infections (e.g. Pneumocystis jirovecii pneumonia)

6 months Bacterial pneumonia, other bacterial community-acquired infections, shingles, cryptococcal infection, PTLD Myeloablative haematopoietic stem cell transplant recipients Pre-engraftment (typically 0–4 weeks) Bacterial and fungal infections, respiratory viruses or HSV reactivation Post-engraftment: Early (< 100 days) CMV, Pneumocystis jirovecii pneumonia, moulds or other opportunistic infections Late (> 100 days) Community-acquired bacterial infections, shingles, CMV, PTLD (CMV = cytomegalovirus; HSV = herpes simplex virus; PTLD = post-transplant lymphoproliferative disorder)

Presenting problems in infectious diseases • 225

bacteraemia or blood culture contamination but, in view of their association with infective endocarditis, significant infection must always be excluded. Bacillus spp. (‘aerobic spore bearers’) and Clostridium spp. often represent incidental transient bacteraemia or contamination, but certain species (e.g. C. septicum) are more likely to be genuine pathogens. Further investigations are influenced by the causative organism and setting. Initial screening tests are similar to those for fever (p. 218) and should include chest X-ray, urine culture and, in many cases, ultrasound or other imaging of the abdomen. Imaging should also include any areas of bone or joint pain and any prosthetic material, e.g. a prosthetic joint or an aortic graft. Echocardiography should be considered for those patients with BSI who have valvular heart disease or clinical features of endocarditis (p. 527), those whose cultures reveal an organism that is a common cause of endocarditis (e.g. Staph. aureus, viridans streptococci or enterococci), those in whom multiple blood cultures are positive for the same organism, and those with a rapid positive result on culture. The sensitivities of transthoracic echocardiography (TTE) and transoesophageal echocardiography (TOE) for the detection of vegetations are 50–90% and over 95%, respectively. Therefore, if TTE is negative, TOE should be performed. Certain rare causes of BSI have specific associations that warrant further investigation. Endocarditis caused by Streptococcus gallolyticus subsp. gallolyticus (formerly Strep. bovis biotype I) and BSI with C. septicum are both associated with colonic carcinoma and their isolation is an indication for colonoscopy. Management BSI requires antimicrobial therapy and attention to the source of infection, including surgical drainage if appropriate. Two weeks of therapy may be sufficient for Staph. aureus BSI from central and peripheral venous catheter infections when the source is identified and removed, for uncomplicated skin and soft tissue infections, and for uncomplicated right-sided infective endocarditis. Other Staph. aureus BSIs are usually treated for 4–6 weeks. Central venous catheter infections Infections of central venous catheters typically involve the catheter lumen and are associated with fever, positive blood cultures and, in some cases, signs of purulence or exudate at the site of insertion. Infection is more common in temporary catheters inserted into the groin or jugular vein than in those in the subclavian vein. Tunnelled catheters, e.g. Hickman catheters, may also develop tunnel site infections. Staphylococci account for 70–90% of catheter infections, with coagulase-negative staphylococci more common than Staph. aureus. Other causes include enterococci and Gram-negative bacilli. Unusual Gram-negative organisms, such as Citrobacter freundii and Pseudomonas fluorescens, raise the possibility of non-sterile infusion equipment or infusate. Candida spp. are a common cause of line infections, particularly in association with total parenteral nutrition. Non-tuberculous mycobacteria may cause tunnel infections. Investigations and management In bacteraemic patients with fever and no other obvious source of infection, a catheter infection is likely. Local evidence of erythema, purulence or thrombophlebitis supports the diagnosis. However, microbiological confirmation is essential (p. 106). Catheter-related infection is suggested by higher colony counts regimen (Box 11.6). Later infections are more common if an allogeneic procedure is performed. Post-transplant lymphoproliferative disorder (PTLD) is an Epstein–Barr virus (EBV)-associated lymphoma that can complicate transplantation, particularly when primary EBV infection occurs after transplantation. Positive blood culture Blood-stream infection (BSI) is a frequent presentation of infection. This can be community-acquired or hospital-acquired (‘nosocomial’). The most common causes are shown in Box 11.7. In immunocompromised hosts, a wider range of microorganisms may be isolated, e.g. fungi in neutropenic hosts. Primary BSI describes the situation in which there is no known extravascular source of infection (e.g. pneumonia or urinary tract infection), and is more common in Staph. aureus BSI. In community-acquired Staph. aureus bacteraemia, 20–30% of cases are associated with infectious endocarditis and up to 10% are due to osteomyelitis. Peripheral and central venous catheters are an important source of nosocomial BSI. BSI has an associated mortality of 15–40%, depending on the setting, host and microbial factors. Clinical assessment The history should determine the setting in which BSI has occurred. Host factors predisposing to infection include skin disease, diabetes mellitus, injection drug use, the presence of a central venous, urinary or haemodialysis catheter, and surgical procedures, especially those involving the implantation of prosthetic materials (in particular, endovascular prostheses). Physical examination should focus on signs of endocarditis (p. 527), evidence of bone or joint infection (tenderness or restriction of movement), and abdominal or flank tenderness. Central venous catheters should be examined for erythema or purulence at the exit site. Particularly in cases with Candida spp. infection or suspected infectious endocarditis, fundoscopy after pupil dilatation should be performed. Investigations Positive blood cultures may be caused by contaminants. When isolated from only one bottle, or from all bottles from one venesection, coagulase-negative staphylococci often represent contamination. Repeated isolation of this organism, however, should raise suspicion of infective endocarditis or, in a patient with any form of prosthetic material, prosthesis infection. Viridans streptococci occasionally cause transient non-significant 11.7 Common causes of blood-stream infection Community-acquired • Escherichia coli • Staphylococcus aureus, including MRSA • Streptococcus pneumoniae • Other streptococci Nosocomial • Staph. aureus, including MRSA • Coagulase-negative staphylococci • Enterococci, including VRE • Gram-negative bacteria • Candida spp. (MRSA = meticillin-resistant Staphylococcus aureus; VRE = vancomycin-resistant enterococci)

226 • INFECTIOUS DISEASE Sepsis Sepsis is discussed on page 196 and there are many causes (Box 11.8). The results of blood cultures and pre-existing host factors guide initial investigations. Patients who are immunocompromised may have a broader range of causal pathogens that may be harder to culture, including mycobacteria and fungi. In many regions, malaria and dengue must also be excluded. Severe skin and soft tissue infections Skin and soft tissue infections (SSTIs) are an important cause of sepsis. Cases can be classified as in Box 11.9, according to the clinical features and microbiological findings. In some cases, severe systemic features may be out of keeping with mild local features. Necrotising fasciitis In necrotising fasciitis, cutaneous erythema and oedema progress to bullae or areas of necrosis. Unlike in cellulitis, pain may be disproportionately intense in relation to the visible cutaneous features or may spread beyond the zone of erythema. The infection spreads quickly along the fascial plane. Type 1 necrotising fasciitis is a mixed infection with Gram-negative bacteria and anaerobes, often seen post-operatively in diabetic or immunocompromised hosts. Subcutaneous gas may be present. Type 2 necrotising fasciitis is caused by group A or other streptococci. Approximately 60% of cases are associated with streptococcal toxic shock syndrome (p. 253). Type 3 infection or shorter time to positivity in blood cultures obtained through the catheter than in peripheral blood cultures. If the line is removed, a semi-quantitative culture of the tip may confirm the presence of 15 or more colony-forming units, but this is retrospective and does not detect luminal infection. For coagulase-negative staphylococcal line infections, the options are to remove the line and provide 5–7 days’ therapy or, particularly in the case of tunnelled catheters, to treat empirically with a glycopeptide antibiotic, e.g. vancomycin, with or without the use of antibiotic-containing lock therapy to the catheter for approximately 14 days. For Staph. aureus infection, the chance of curing an infection with the catheter in situ is low and the risks from infection are high. Therefore, unless the risks of catheter removal outweigh the benefits, treatment involves catheter removal, followed by 14 days of antimicrobial therapy; the same applies to infections with Pseudomonas aeruginosa, Candida spp., atypical mycobacteria or Bacillus spp. Infections complicated by endocarditis, thrombophlebitis, metastatic infection or tunnel infection also require catheter removal. Infection prevention is a key component of the management of vascular catheters. Measures include strict attention to hand hygiene, optimal siting, full aseptic technique on insertion and subsequent interventions, skin antisepsis with chlorhexidine and isopropyl alcohol, daily assessment of catheter sites (e.g. with visual infusion phlebitis (VIP) score; see Box 11.37, p. 251), and daily consideration of the continuing requirement for catheterisation. The use of catheters impregnated with antimicrobials, such as chlorhexidine or silver, is advocated in some settings. 11.8 Causes of sepsis Infection Setting Bacterial Staphylococcus aureus, coagulase-negative staphylococci Bacteraemia may be associated with endocarditis, intravascular cannula infection, or skin or bone foci Streptococcus pneumoniae Invasive pneumococcal disease, usually with pneumonia or meningitis; asplenia Other streptococci Invasive streptococcal disease, especially necrotising fasciitis Viridans streptococci in neutropenic host with severe mucositis Staphylococcal or streptococcal toxic shock syndrome Toxin-mediated, blood cultures negative; clues include erythrodermic rash and epidemiological setting Enterococci Most often with abdominal focus Neisseria meningitidis Sepsis in children or young adults with petechial rash and/or meningitis Escherichia coli, other Gram-negative bacteria Urinary or biliary tract infection, or other abdominal infections Pseudomonas aeruginosa, multidrug-resistant Gram-negative bacteraemia Nosocomial infection Salmonella Typhi or Paratyphi In countries with a high incidence of enteric fever Yersinia pestis In plague Burkholderia pseudomallei Endemic in areas of Thailand; more likely to involve patients with diabetes mellitus or immunocompromised Capnocytophaga canimorsus Associated with dog bites and asplenic individuals Clostridium difficile Severe colitis, particularly in the elderly Polymicrobial infection with Gram-negatives and anaerobes Bowel perforation, bowel ischaemia Mycobacterium tuberculosis, M. avium complex (MAC) HIV-positive or immunocompromised with miliary tuberculosis or disseminated MAC Fungal Candida spp. Line infection or post-operative complication, nosocomial or immunocompromised host Histoplasma capsulatum, other dimorphic fungi Immunocompromised host Parasitic Falciparum malaria Malaria with high-level parasitaemia and multi-organ failure or as a complication of bacterial superinfection Babesia microti Asplenic individual Strongyloides stercoralis hyperinfection syndrome Gram-negative infection complicating Strongyloides infection in immunocompromised host

Presenting problems in infectious diseases • 227

infection. Infection may be limited to tissue that is already damaged (anaerobic cellulitis) or may involve healthy muscle (gas gangrene). In anaerobic cellulitis, usually due to C. perfringens or other clostridia infecting devitalised tissue following a wound, gas forms locally and extends along tissue planes but bacteraemia does not occur. Prompt surgical débridement of devitalised tissue and therapy with penicillin or clindamycin is usually effective. Gas gangrene (clostridial myonecrosis) is defined as acute invasion of healthy living muscle undamaged by previous trauma, and is most commonly caused by C. perfringens. In at least 70% of cases, it follows deep penetrating injury sufficient to create an anaerobic (ischaemic) environment and allow clostridial introduction and proliferation. Severe pain at the site of the injury progresses rapidly over 18–24 hours. Skin colour changes from pallor to bronze/purple discoloration and the skin is tense, swollen, oedematous and exquisitely tender. Gas in tissues may be obvious, with crepitus on clinical examination, or visible on X-ray, CT or ultrasound. Signs of systemic toxicity develop rapidly, with high leucocytosis, multi-organ dysfunction, raised creatine kinase and evidence of disseminated intravascular coagulation and haemolysis. Antibiotic therapy with high-dose intravenous penicillin and clindamycin is recommended, coupled with aggressive surgical débridement of the affected tissues. Alternative agents include cephalosporins and metronidazole. Hyperbaric oxygen has a putative but controversial role. Other SSTIs ‘Synergistic gangrene’ is a polymicrobial infection with anaerobes and other bacteria (Staph. aureus or Gram-negatives). When this affects the genital/perineal area, it is known as ‘Fournier’s gangrene’. Severe gangrenous cellulitis in immunocompromised hosts may involve Gram-negative bacteria or fungi. Entamoeba histolytica can cause soft tissue necrosis following abdominal surgery in areas of the world where infection is common. Contact with sea water or shellfish consumption in tropical to subtropical regions worldwide, such as the Gulf of Mexico, can lead to infection with Vibrio vulnificus. This infection causes soft tissue necrosis and bullae, and may lead to necrotising fasciitis. Patients with chronic liver disease are particularly susceptible to this infection and can develop sepsis. Acute diarrhoea and vomiting Acute diarrhoea (p. 783), sometimes with vomiting, is the predominant symptom in infective gastroenteritis (Box 11.10). Acute diarrhoea may also be a symptom of other infectious and non-infectious diseases (Box 11.11). Stress, whether psychological or physical, can also produce loose stools. The World Health Organisation (WHO) estimates that there are more than 1.7 billion cases of acute diarrhoea annually globally, with 760 000 deaths in children under 5. In developed countries, diarrhoea remains an important problem, with the elderly being most vulnerable (Box 11.12). The majority of episodes are due to infections spread by the faecal–oral route and transmitted either on fomites, on contaminated hands, or in food or water. Measures such as the provision of clean drinking water, appropriate disposal of human and animal sewage, and the application of simple principles of food hygiene can all limit gastroenteritis. The clinical features of food-borne gastroenteritis vary. Some organisms (Bacillus cereus, Staph. aureus and Vibrio cholerae) elute exotoxins that cause vomiting and/or so-called ‘secretory’ diarrhoea (watery diarrhoea without blood or faecal leucocytes, involves organisms such as Aeromonas hydrophila and Vibrio vulnificus, which is found in tropical to subtropical regions and is associated with marine exposure. Type 4 is caused by fungi such as mucoraceous moulds and may also vary geographically in incidence with recent reports of increased cases in India and other regions. Necrotising fasciitis is a medical emergency, requiring immediate surgical débridement with inspection of the involved muscle groups, in addition to antimicrobial therapy (Fig. 11.4). Empirical treatment is with broad-spectrum agents (e.g. piperacillin– tazobactam plus clindamycin; meropenem with clindamycin). Ceftazidime or ciprofloxacin with doxycycline may be used where marine exposure is a factor, and antifungals for suspected fungal necrotising fasciitis, but it is important to combine these with effective coverage against streptococcal infection. MRSAassociated necrotising fasciitis has emerged in some regions and in these places appropriate therapy for MRSA, such as a glycopeptide or linezolid, should be added to the empirical regimen until microbiological results allow narrowing of the antimicrobial spectrum. Hyperbaric oxygen therapy may be considered for polymicrobial infection. Group A streptococcal infection is treated with benzylpenicillin plus clindamycin, and often immunoglobulin, though to date clinical trials have not provided clear evidence of the benefit of immunoglobulin. Gas gangrene Although Clostridium spp. may colonise or contaminate wounds, no action is required unless there is evidence of spreading Fig. 11.4 Excision following necrotising fasciitis in an injection drug-user. 11.9 Severe necrotising soft tissue infections • Necrotising fasciitis (primarily confined to subcutaneous fascia and fat) • Clostridial anaerobic cellulitis (confined to skin and subcutaneous tissue) • Non-clostridial anaerobic cellulitis • Progressive bacterial synergistic gangrene (Staphylococcus aureus

228 • INFECTIOUS DISEASE reflecting small bowel dysfunction). In general, the time from ingestion to the onset of symptoms is short and, other than dehydration, little systemic upset occurs. Other organisms, such as Shigella spp., Campylobacter spp. and enterohaemorrhagic Escherichia coli (EHEC), may directly invade the mucosa of the small bowel or produce cytotoxins that cause mucosal ulceration, typically affecting the terminal small bowel and colon. The incubation period is longer and more systemic upset occurs, with prolonged bloody diarrhoea. Salmonella spp. are capable of invading enterocytes and of causing both a secretory response and invasive disease with systemic features. This is seen with Salmonella Typhi and Salmonella Paratyphi (enteric fever), but may occasionally be seen with other non-typhoidal Salmonella spp., particularly in the immunocompromised host and the elderly. Clinical assessment The history should address foods ingested (Box 11.13), duration and frequency of diarrhoea, presence of blood or steatorrhoea, abdominal pain and tenesmus, and whether other people have been affected. Fever and bloody diarrhoea suggest an invasive, colitic, dysenteric process. An incubation period of less than 18 hours suggests toxin-mediated food poisoning, and longer than 5 days suggests diarrhoea caused by protozoa or helminths. Person-to-person spread suggests certain infections, such as shigellosis or cholera. Examination includes assessment of the degree of dehydration. Assessment for early signs of hypotension, such as thirst, headache, altered skin turgor, dry mucous membranes and postural hypotension, is important, particularly in tropical regions where dehydration progresses rapidly. Signs of more marked dehydration include supine hypotension and tachycardia, decreased urinary output, delirium and sunken eyes. The blood pressure, pulse rate, urine output and ongoing stool losses should be monitored closely. 11.13 Foods associated with infectious illness, including gastroenteritis Raw seafood • Norovirus • Vibrio spp. • Hepatitis A Raw eggs • Salmonella serovars Undercooked meat or poultry • Salmonella serovars • Campylobacter spp. • EHEC • Hepatitis E (pork products) • Clostridium perfringens Unpasteurised milk or juice • Salmonella serovars. • Campylobacter spp. • EHEC • Yersinia enterocolitica Unpasteurised soft cheeses • Salmonella serovars • Campylobacter spp. • ETEC • Yersinia enterocolitica • Listeria monocytogenes Home-made canned goods • Clostridium botulinum Raw hot dogs, pâté • Listeria monocytogenes (EHEC = enterohaemorrhagic Escherichia coli; ETEC = enterotoxigenic E. coli ) 11.12 Infectious diarrhoea in old age • Incidence: not increased but the impact is greater. • Mortality: most deaths due to gastroenteritis in the developed world are in adults aged over 70. Most are presumed to be caused by dehydration leading to organ failure. • Clostridium difficile infection (CDI): more common, especially in hospital and nursing home settings, usually following antibiotic exposure. 11.11 Differential diagnosis of acute diarrhoea and vomiting Infectious causes • Gastroenteritis • Clostridium difficile infection (p. 264) • Acute diverticulitis (p. 833) • Sepsis (p. 196) • Pelvic inflammatory disease (p. 336) • Meningococcaemia (p. 1119) • Pneumonia (especially ‘atypical disease’, p. 582) • Malaria (p. 273) Non-infectious causes Gastrointestinal • Inflammatory bowel disease (p. 813) • Bowel malignancy (p. 827) • Overflow from constipation (p. 834) • Enteral tube feeding Metabolic • Diabetic ketoacidosis (p. 735) • Thyrotoxicosis (p. 635) • Uraemia (p. 414) • Neuro-endocrine tumours releasing (e.g.) VIP or 5-HT Drugs and toxins • NSAIDs • Cytotoxic agents • Antibiotics • Proton pump inhibitors • Dinoflagellates (p. 149) • Plant toxins (p. 150) • Heavy metals • Ciguatera fish poisoning (p. 149) • Scombrotoxic fish poisoning (p. 150) (5-HT = 5-hydroxytryptamine, serotonin; NSAIDs = non-steroidal antiinflammatory drugs; VIP = vasoactive intestinal peptide) 11.10 Causes of infectious gastroenteritis Toxin in food: < 6 hrs incubation • Bacillus cereus (p. 262) • Staphylococcus aureus (p. 262) • Clostridium spp. enterotoxin (p. 262) Bacterial: 12–72 hrs incubation • Enterotoxigenic Escherichia coli (ETEC, p. 263) • Shiga toxin-producing E. coli (EHEC, p. 263)* • Enteroinvasive E. coli (EIEC, p. 263)* • Vibrio cholerae (p. 264) • Salmonella (p. 262) • Shigella * (p. 265) • Campylobacter * (p. 262) • Clostridium difficile * (p. 264) Viral: short incubation • Rotavirus (p. 249) • Norovirus (p. 249) Protozoal: long incubation • Giardiasis (p. 287) • Cryptosporidiosis (pp. 287 and 317) • Microsporidiosis (p. 317) • Amoebic dysentery (p. 286)* • Cystoisosporiasis (p. 233) *Associated with bloody diarrhoea.

Presenting problems in infectious diseases • 229

infection, particularly if the clinical features suggest a syndrome other than gastroenteritis. Management All patients with acute, potentially infective diarrhoea should be appropriately isolated to minimise person-to-person spread of infection. If the history suggests a food-borne source, public health measures must be implemented to identify the source and to establish whether other linked cases exist (p. 114). Fluid replacement Replacement of fluid losses in diarrhoeal illness is crucial and may be life-saving. Although normal daily fluid intake in an adult is only 1–2 L, there is considerable additional fluid movement in and out of the gut in secretions (see Fig. 21.7, p. 769). Altered gut resorption with diarrhoea can result in substantial fluid loss; for example, 10–20 L of fluid may be lost in 24 hours in cholera. The fluid lost in diarrhoea is isotonic, so both water and electrolytes need to be replaced. Absorption of electrolytes from the gut is an active process requiring energy. Infected mucosa is capable of very rapid fluid and electrolyte transport if carbohydrate is available as an energy source. Oral rehydration solutions (ORS) therefore contain sugars, as well as water and electrolytes (Box 11.14). ORS can be just as effective as intravenous replacement fluid, even in the management of cholera. In mild to moderate gastroenteritis, adults should be encouraged to drink fluids and, if possible, continue normal dietary food intake. If this is impossible – due to vomiting, for example – intravenous fluid administration will be required. In very sick patients or those with cardiac or renal disease, monitoring of urine output and central venous pressure may be necessary. The volume of fluid replacement required should be estimated based on the following considerations: • Replacement of established deficit. After 48 hours of moderate diarrhoea (6–10 stools per 24 hrs), the average adult will be 2–4 L depleted from diarrhoea alone. Associated vomiting will compound this. Adults with this symptomatology should therefore be given rapid replacement of 1–1.5 L, either orally (ORS) or by intravenous infusion (normal saline), within the first 2–4 hours of presentation. Longer symptomatology or more persistent/severe diarrhoea rapidly produces fluid losses comparable to diabetic ketoacidosis and is a metabolic emergency requiring active intervention. The severity of diarrhoea may be assessed by reference to the Bristol stool form scale (Bristol stool chart), which allows an objective assessment of stool consistency by providing a verbal and visual reference scale (Fig. 11.5). The Bristol stool form scale was developed in the 1990s to monitor patients with irritable bowel syndrome, but its main use (at least in UK hospitals) is to monitor hospital inpatients with loose stool to assist in decisions on stool sampling and infection prevention precautions, especially in relation to C. difficile. Investigations These include stool inspection for blood and microscopy for leucocytes, and also an examination for ova, cysts and parasites if the history indicates residence or travel to areas where these infections are prevalent. Stool culture should be performed and C. difficile toxin sought. FBC and serum electrolytes indicate the degree of inflammation and dehydration. Where cholera is prevalent, examination of a wet film with dark-field microscopy for darting motility may provide a diagnosis. In a malarious area, a blood film for malaria parasites should be obtained. Blood and urine cultures and a chest X-ray may identify alternative sites of Fig. 11.5 Bristol stool chart. The stool is given a ‘score’ of 1–7 by reference to the verbal and visual description. This is recorded on a chart (usually known as a ‘Bristol stool chart’) or in a patient monitoring database. Adapted from Lewis SJ, Heaton KW. Stool form scale as a useful guide to intestinal transit time. Scand J Gastroenterol 1997; 32:920–924. Type 6 Fluffy pieces with ragged edges, a mushy stool Type 7 Watery, no solid pieces Entirely liquid Type 5 Soft blobs with clear-cut edges (passed easily) Type 4 Like a sausage or snake, smooth and soft Type 3 Like a sausage but with cracks on its surface Type 2 Sausage-shaped but lumpy Type 1 Separate hard lumps, like nuts (hard to pass) 11.14 Composition of oral rehydration solution and other replacement fluids* Fluid Na K Cl Energy WHO

Dioralyte

Pepsi 6.5 0.8 –

7UP 7.5 0.2 –

Apple juice 0.4

–

Orange juice 0.2

–

Breast milk

(WHO = World Health Organisation) *Values given in mmol/L for electrolyte and kcal/L for energy components.

230 • INFECTIOUS DISEASE that the pattern of infectious diseases seen in each country changes constantly, and travel history and information on countries previously lived in, particularly during childhood, are crucial. In general, the diversity of infectious diseases is greater in tropical than in temperate countries, and people in temperate countries have immunity to a narrower range of infections, reflecting less exposure in childhood and less ongoing boosting of immunity later in life, so that the most common travel-associated infections are those that are acquired by residents of temperate countries during visits to the tropics. In addition, those who have lived in tropical areas may lose immunity when they move to temperate countries and become susceptible when visiting their homeland. Most travel-associated infections can be prevented. Pretravel advice is tailored to the destination and the traveller (Box 11.15). It includes avoidance of insect bites (using at least 20% diethyltoluamide (DEET)), sun protection (sunscreen with a sun protection factor (SPF) of at least 15), food and water hygiene (‘Boil it, cook it, peel it or forget it!’), how to respond to travellers’ diarrhoea (seek medical advice if bloody or if it lasts more than 48 hrs) and, if relevant, safe sex (condom use). Fever acquired in the tropics Presentation with unexplained fever is common in travellers who are visiting or have recently travelled to tropical areas. Fever may also occur in those living in tropical regions if they have not developed immunity to the endemic pathogen or if this immunity is compromised by factors such as pregnancy. Frequent final diagnoses in such patients are malaria, typhoid fever, viral hepatitis and dengue fever. Travellers to affected areas may have viral haemorrhagic fevers (VHFs) such as Ebola, Lassa, Crimean–Congo and Marburg (see Box 11.36, p. 245), avian influenza (H5N1) or Middle East respiratory syndrome (MERS), which require special isolation precautions. Clinical assessment The approach to unexplained fever is as described above and key questions relating to infections acquired in tropical regions are listed in Box 11.16. Medicines purchased in some countries may have reduced efficacy, e.g. for malaria prophylaxis. Consult reliable up-to-date sources about resistance to antimalarial drugs Further information is available at fitfortravel.nhs.uk. 11.15 How to assess health needs in travellers before departure • Destination • Personal details, including previous travel experience • Dates of trip • Itinerary and purpose of trip • Personal medical history, including pregnancy, medication and allergies (e.g. to eggs, vaccines, antibiotics) • Past vaccinations: Childhood schedule followed? Diphtheria, tetanus, pertussis, polio, Neisseria meningitidis types B/C, Haemophilus influenzae B (HiB) Travel-related? Typhoid, yellow fever, hepatitis A, hepatitis B, meningococcal ACW135Y, rabies, Japanese B encephalitis, tick-borne encephalitis • Malaria prophylaxis: questions influencing the choice of antimalarial drugs are destination, past experience with antimalarials, history of epilepsy or psychiatric illness • Replacement of ongoing losses. The average adult’s diarrhoeal stool accounts for a loss of 200 mL of isotonic fluid. Stool losses should be carefully charted and an estimate of ongoing replacement fluid calculated. Commercially available rehydration sachets are conveniently produced to provide 200 mL of ORS; one sachet per diarrhoea stool is an appropriate estimate of supplementary replacement requirements. • Replacement of normal daily requirement. The average adult has a daily requirement of 1–1.5 L of fluid in addition to the calculations above. This will be increased substantially in fever or a hot environment. Antimicrobial agents In non-specific gastroenteritis, routine use of antimicrobials does not improve outcome and may lead to antimicrobial resistance or side-effects. They are usually used where there is systemic involvement, a host with immunocompromise or significant comorbidity. Evidence suggests that, in EHEC infections, the use of antibiotics may make the complication of haemolytic uraemic syndrome (HUS; p. 408) more likely due to increased toxin release. Antibiotics should therefore not be used in this condition. Conversely, antibiotics are indicated in Shigella dysenteriae infection and in invasive salmonellosis – in particular, typhoid fever. Antibiotics may also be advantageous in cholera epidemics, reducing infectivity and controlling the spread of infection. Antidiarrhoeal, antimotility and antisecretory agents These agents are not usually recommended in acute infective diarrhoea. Loperamide, diphenoxylate and opiates are potentially dangerous in dysentery in childhood, causing intussusception. Antisecretory agents, such as bismuth and chlorpromazine, may make the stools appear more bulky but do not reduce stool fluid losses and may cause significant sedation. Adsorbents, such as kaolin or charcoal, have little effect. Non-infectious causes of food poisoning While acute food poisoning and gastroenteritis are most frequently caused by infections, non-infectious causes must also be considered in the differential diagnosis. These are discussed on page 149. Antimicrobial-associated diarrhoea Antimicrobial-associated diarrhoea (AAD) is a common complication of antimicrobial therapy, especially with broadspectrum agents. It is most common in the elderly but can occur at all ages. Although the specific mechanism is unknown in most cases of AAD, C. difficile (p. 264) is implicated in 20–25% of cases and is the most common cause among patients with evidence of colitis. C. perfringens is a rarer cause that usually remains undiagnosed, and Klebsiella oxytoca may also cause antibiotic-associated haemorrhagic colitis. Infections acquired in the tropics Recent decades have seen unprecedented increases in longdistance business and holiday travel, as well as extensive migration. Although certain diseases retain their relatively fixed geographical distribution, being dependent on specific vectors or weather conditions, many travel with their human hosts and some may then be transmitted to other people. This means

Presenting problems in infectious diseases • 231

11.16 How to obtain a history from travellers to the tropics with fever Questions Factors to ascertain Countries visited and dates of travel Relate travel to known outbreaks of infection or antimicrobial resistance Determine the environment visited Travel to rural environments, forests, rivers or lakes Clarify where the person slept Sleeping in huts, use of bed nets, sleeping on the ground Establish what he/she was doing Exposure to people with medical illness, animals, soil, lakes and rivers History of insect bites Type of insect responsible, circumstances (location, time of day etc.), preventive measures Dietary history Ingestion of uncooked foods, salads and vegetables, meats (especially if under-cooked), shellfish, molluscs, unpasteurised dairy products, unbottled water and sites at which food prepared Sexual history History of sexual intercourse with commercial sex workers, local population or travellers from other countries Malaria prophylaxis Type of prophylaxis Vaccination history Receipt of pre-travel vaccines and appropriateness to area visited History of any treatments received while abroad Receipt of medicines, local remedies, blood transfusions or surgical procedures in the country visited. Vaccinations against yellow fever and hepatitis A and B are sufficiently effective to virtually exclude these infections. Oral and injectable typhoid vaccinations are 70–90% effective. The differential diagnosis is guided by the clinical scenario, presence of specific exposures (Box 11.17) and incubation period (Box 11.18). Falciparum malaria tends to present between 7 and 28 days after exposure in an endemic area. VHF, dengue and rickettsial infection can usually be excluded if more than 21 days have passed between leaving the area and onset of illness. Fig. 11.6 Approach to the patient with suspected viral haemorrhagic fever (VHF). See page 245. Epidemiological risk factors: staying with a febrile individual, caring for a sick individual, or contact with body fluids from a suspected human or animal case of VHF. (PCR = polymerase chain reaction) No Yes Signs of organ failure or epidemiological risk factors Isolation with full barrier protection Discuss with regional level 4 biosafety specialist unit PCR positive Proceed to standard investigation, isolation and treatment of traveller with fever or malaria Malaria positive Malaria negative PCR negative No Yes Patient has travelled within 7–21 days to an area endemic for VHF and has a fever Isolation with full barrier protection Take blood film for malaria test Send PCR to regional laboratory for VHF 11.17 Specific exposures and causes of fever in the tropics Exposure Infection or disease Mosquito bite Malaria, dengue fever, Chikungunya, filariasis, tularaemia Tsetse fly bite African trypanosomiasis Tick bite Rickettsial infections including typhus, Lyme disease, tularaemia, Crimean–Congo haemorrhagic fever, Kyasanur forest disease, babesiosis, tick-borne encephalitis Louse bite Typhus Flea bite Plague Sandfly bite Leishmaniasis, arbovirus infection Reduviid bug Chagas’ disease Animal contact Q fever, brucellosis, anthrax, plague, tularaemia, viral haemorrhagic fevers, rabies Fresh-water swimming Schistosomiasis, leptospirosis, Naegleria fowleri Exposure to soil Inhalation: dimorphic fungi Inhalation or inoculation: Burkholderia pseudomallei Inoculation (most often when barefoot): hookworms, Strongyloides stercoralis Raw or under-cooked fruit and vegetables Enteric bacterial infections, hepatitis A or E virus, Fasciola hepatica, Toxocara spp., Echinococcus granulosus (hydatid disease), Entamoeba histolytica Under-cooked pork Taenia solium (cysticercosis) Crustaceans or molluscs Paragonimiasis, gnathostomiasis, Angiostrongylus cantonensis infection, hepatitis A virus, cholera Unpasteurised dairy products Brucellosis, salmonellosis, abdominal tuberculosis, listeriosis Untreated water Enteric bacterial infections, giardiasis, Cryptosporidium spp. (chronic in immunocompromised), hepatitis A or E virus

232 • INFECTIOUS DISEASE Investigations and management Initial investigations should start with blood films for malaria parasites, FBC, urinalysis and chest X-ray if indicated. Box 11.19 lists diagnoses and investigations to consider in unexplained acute fever. Management is directed at the underlying cause. In patients with suspected VHF (p. 245), strict infection control measures with isolation and barrier nursing are implemented to prevent contact with the patient’s body fluids. The risk of VHF should be determined using epidemiological risk factors and clinical signs (Fig. 11.6), and further management undertaken as described on page 246. Diarrhoea acquired in the tropics Gastrointestinal illness is the most common infection amongst visitors to the tropics, with Salmonella spp., Campylobacter spp. and Cryptosporidium spp. infections prevalent worldwide (Box 11.20). Shigella spp. and Entamoeba histolytica (amoebiasis) are usually encountered in visitors to or residents of the Indian subcontinent or sub-Saharan and southern Africa. The approach to patients with acute diarrhoea is described on page 227. The benefits of treating travellers’ diarrhoea with antimicrobials are marginal, with slight reductions in stool Clinical examination is summarised on page 216. Particular attention should be paid to the skin, throat, eyes, nail beds, lymph nodes, abdomen and heart. Patients may be unaware of tick bites or eschars (p. 270). Body temperature should be measured at least twice daily. 11.19 Investigation of tropically acquired acute fever without localising signs Features on full blood count Further investigations Neutrophil leucocytosis Bacterial sepsis Blood culture Leptospirosis Culture of blood and urine, serology Borreliosis (tick- or louse-borne relapsing fever) Blood film Amoebic liver abscess Ultrasound Normal white cell count and differential Malaria (may have low platelets or anaemia) Blood film, antigen test Typhoid fever Blood and stool culture Typhus Serology Lymphocytosis Viral fevers, including VHF Serology, PCR Infectious mononucleosis Monospot test, serology Malaria Blood film, antigen test Rickettsial fevers Serology Atypical lymphocytes Dengue and other VHF Serology, antigen, PCR Infectious mononucleosis-like syndromes Serology, PCR HIV (acute retroviral syndrome) Serology, antigen Hepatitis viruses Serology, antigen, PCR Parasitic, malaria, trypanosomiasis Blood film, antigen test, PCR (PCR = polymerase chain reaction; VHF = viral haemorrhagic fever) 11.20 Most common causes of travellers’ diarrhoea • Enterotoxigenic E. coli (ETEC) • Shigella spp. • Campylobacter jejuni • Salmonella serovars • Plesiomonas shigelloides • Non-cholera Vibrio spp. • Aeromonas spp. 11.18 Incubation times and illnesses in travellers < 2 weeks Non-specific fever • Malaria • Chikungunya • Dengue • Scrub typhus • Spotted group rickettsiae • Acute HIV • Acute hepatitis C virus • Campylobacter • Salmonellosis • Shigellosis • East African trypanosomiasis • Leptospirosis • Relapsing fever • Influenza • Yellow fever Fever and coagulopathy (usually thrombocytopenia) • Malaria • VHF • Meningococcaemia • Enteroviruses • Leptospirosis and other bacterial pathogens associated with coagulopathy Fever and central nervous system involvement • Malaria • Typhoid fever • Rickettsial typhus (epidemic caused by Rickettsia prowazekii ) • Meningococcal meningitis • Arboviral encephalitis • East African trypanosomiasis • Other causes of encephalitis or meningitis • Angiostrongyliasis • Rabies Fever and pulmonary involvement • Influenza • Pneumonia, including Legionella pneumonia • Acute histoplasmosis • Acute coccidioidomycosis • Q fever • SARS Fever and rash • Viral exanthems (rubella, measles, varicella, mumps, HHV-6, enteroviruses • Chikungunya • Dengue • Spotted or typhus group rickettsiosis • Typhoid fever • Parvovirus B19 • HIV-1 2–6 weeks • Malaria • Tuberculosis • Hepatitis A, B, C and E viruses • Visceral leishmaniasis • Acute schistosomiasis • Amoebic liver abscess • Leptospirosis • African trypanosomiasis • VHF • Q fever • Acute American trypanosomiasis • Viral causes of mononucleosis syndromes

6 weeks • Non-falciparum malaria • Tuberculosis • Hepatitis B and E viruses • HIV-1 • Visceral leishmaniasis • Filariasis • Onchocerciasis • Schistosomiasis • Amoebic liver abscess • Chronic mycoses • African trypanosomiasis • Rabies • Typhoid fever (HHV-6 = human herpesvirus-6; SARS = severe acute respiratory syndrome; VHF = viral haemorrhagic fever) Adapted from Traveller’s Health Yellow Book, CDC Health Information for International Travel 2008.

Presenting problems in infectious diseases • 233

11.21 Causes of chronic diarrhoea acquired in the tropics • Giardia lamblia • Strongyloidiasis • Enteropathic Escherichia coli • HIV enteropathy • Intestinal flukes • Tropical sprue • Chronic intestinal schistosomiasis • Chronic calcific pancreatitis • Hypolactasia (primary and secondary) 11.22 Parasite infections that cause eosinophilia Infestation Pathogen Clinical syndrome with eosinophilia Strongyloidiasis Strongyloides stercoralis Larva currens Soil-transmitted helminthiases Hookworm Necator americanus Anaemia Ancylostoma duodenale Anaemia Ascariasis Ascaris lumbricoides Löffler’s syndrome Toxocariasis Toxocara canis Visceral larva migrans Schistosomiasis Schistosoma haematobium Katayama fever S. mansoni, S. japonicum Chronic infection Filariases Loiasis Loa loa Skin nodules Wuchereria bancrofti W. bancrofti Lymphangitis, lymphadenopathy, orchitis, intermittent bouts of cellulitis, lymphoedema and elephantiasis Brugia malayi B. malayi Brugian elephantiasis similar but typically less severe than that caused by W. bancrofti Mansonella perstans M. perstans Asymptomatic infection, occasionally subconjunctival nodules Onchocerciasis Onchocerca volvulus Visual disturbance, dermatitis Other nematode infections Trichinella spiralis Myositis Gnathostoma spinigerum Pruritus, migratory nodules, eosinophilic meningitis Cestode infections Taenia saginata, T. solium Usually asymptomatic; eosinophilia associated with migratory phase Echinococcus granulosus Lesions in liver or other organ; eosinophilia associated with leakage from cyst Liver flukes Fasciola hepatica Hepatic symptoms; eosinophilia associated with migratory phase Clonorchis sinensis As for fascioliasis Opisthorchis felineus As for fascioliasis Lung fluke Paragonimus westermani Lung lesions frequency and likelihood of cure at 72 hours offset by increased side-effects. The differential diagnosis of diarrhoea persisting for more than 14 days is wide (see Box 21.18, p. 784). Parasitic and bacterial causes, tropical malabsorption, inflammatory bowel disease and neoplasia should all be considered. Box 11.21 lists causes encountered particularly in visitors to or residents of the tropics. The workup should include tests for parasitic causes of chronic diarrhoea, such as examination of stool and duodenal aspirates for ova and parasites, and serological investigation. Tropical sprue is a malabsorption syndrome (p. 807) with no defined aetiology. It was typically associated with a long period of residence in the tropics or with overland travel but is now rarely seen. Giardia lamblia infection may progress to a malabsorption syndrome that mimics tropical sprue. If no cause is found, empirical treatment for Giardia lamblia infection with metronidazole is often helpful. HIV-1 has now emerged as a major cause of chronic diarrhoea. This may be due to HIV enteropathy or infection with agents such as Cryptosporidium spp., Cystoisospora belli (syn. Isospora belli ) or microsporidia (p. 316). However, many other causes of chronic AIDS-associated diarrhoea seen in the developed world are less common in tropical settings, e.g. CMV or disseminated Mycobacterium avium complex infections. Eosinophilia acquired in the tropics Eosinophilia occurs in a variety of haematological, allergic and inflammatory conditions discussed on page 927. It may also arise in HIV-1 and human T-cell lymphotropic virus (HTLV)-1 infection. However, eosinophils are important in the immune response to parasitic infections, in particular those involving parasites with a tissue migration phase. In the context of travel to or residence in the tropics, a patient with an eosinophil count of more than 0.4 × 109/L should be investigated for both non-parasitic (see Box 23.9, p. 926) and parasitic causes (Box 11.22). The response to parasite infections is often different when travellers to and residents of endemic areas are compared. Travellers often have recent and light infections associated with eosinophilia. Residents have often been infected for a long time, have evidence of chronic pathology and no longer have eosinophilia. Clinical assessment A history of travel to known endemic areas for schistosomiasis, onchocerciasis and the filariases will indicate possible causes. Assessment should establish how long patients have spent in endemic areas and the history should address all the elements in Box 11.16. Physical signs or symptoms that suggest a parasitic cause for eosinophilia include transient rashes (schistosomiasis or strongyloidiasis), fever (Katayama syndrome; p. 295), pruritus (onchocerciasis) or migrating subcutaneous swellings (loiasis, gnathostomiasis) (see Box 11.22). Paragonimiasis can give rise to haemoptysis, and the migratory phase of intestinal nematodes or lymphatic filariasis may cause cough, wheezing and transient pulmonary infiltrates. Schistosomiasis, strongyloidiasis and gnathostomiasis induce transient respiratory symptoms with infiltrates in the acute stages and, when eggs reach the pulmonary vasculature in chronic schistosomiasis infection, can

234 • INFECTIOUS DISEASE Skin biopsies are helpful in diagnosing aetiology. Culture of biopsy material may be needed to diagnose bacterial, fungal, parasitic and mycobacterial infections. Infections in adolescence Particular issues of relevance in adolescent patients are shown in Box 11.25. Infections in pregnancy Box 11.26 shows some of the infections encountered in pregnancy. result in shortness of breath with features of right heart failure due to pulmonary hypertension. Fever and hepatosplenomegaly are seen in schistosomiasis, Fasciola hepatica infection and toxocariasis (visceral larva migrans). Intestinal worms, such as Ascaris lumbricoides and Strongyloides stercoralis, can cause abdominal symptoms, including intestinal obstruction and diarrhoea. In the case of heavy infestation with Ascaris, this may be due to fat malabsorption and there may be associated nutritional deficits. Schistosoma haematobium can cause haematuria or haematospermia. Toxocara spp. can give rise to choroidal lesions with visual field defects. Angiostrongylus cantonensis and gnathostomiasis induce eosinophilic meningitis, and the hyperinfection syndrome caused by S. stercoralis in immunocompromised hosts induces meningitis due to Gramnegative bacteria. Myositis is a feature of trichinosis (trichinellosis) and cysticercosis, while periorbital oedema is found in trichinosis. Investigations The diagnosis of a parasitic infestation requires direct visualisation of adult worms, larvae or ova. Serum antibody detection may not distinguish between active and past infection and is often unhelpful in those born in endemic areas. Radiological investigations may provide circumstantial evidence of parasite infestation. Box 11.23 describes initial investigations for eosinophilia. Management A specific diagnosis guides therapy. In the absence of a specific diagnosis, many clinicians will give an empirical course of praziquantel if the individual has potentially been exposed to schistosomiasis, or with albendazole/ivermectin if strongyloidiasis or intestinal nematodes are likely causes. Skin conditions acquired in the tropics Community-based studies in the tropics consistently show that skin infections (bacterial and fungal), scabies and eczema are the most common skin problems (Box 11.24). Scabies and eczema are discussed on pages 1241 and 1244. Cutaneous leishmaniasis and onchocerciasis have defined geographical distributions (pp. 284 and 292). In travellers, secondarily infected insect bites, pyoderma, cutaneous larva migrans and non-specific dermatitis are common. During the investigation of skin lesions, enquiry should be made about habitation, activities undertaken and regions visited (see Box 11.16). Examples of skin lesions in tropical disease are shown in Figure 11.7. 11.23 Initial investigation of eosinophilia Investigation Pathogens sought Stool microscopy Ova, cysts and parasites Terminal urine Ova of Schistosoma haematobium Duodenal aspirate Filariform larvae of Strongyloides, liver fluke ova Day bloods Microfilariae Brugia malayi, Loa loa Night bloods Microfilariae Wuchereria bancrofti Skin snips Onchocerca volvulus Slit-lamp examination Onchocerca volvulus Serology Schistosomiasis, filariasis, strongyloidiasis, hydatid, trichinosis, gnathostomiasis etc. 11.24 Rash in tropical travellers/residents Maculopapular rash • Dengue • HIV-1 • Typhoid • Spirillum minus • Rickettsial infections • Measles Petechial or purpuric rash • Viral haemorrhagic fevers • Yellow fever • Meningococcal sepsis • Leptospirosis • Rickettsial spotted fevers • Malaria Vesicular rash • Monkeypox • Insect bites • Rickettsial pox Urticarial rash • Katayama fever (schistosomiasis) • Toxocara spp. • Strongyloides stercoralis • Fascioliasis Ulcers • Leishmaniasis • Mycobacterium ulcerans (Buruli ulcer) • Dracunculosis • Anthrax • Rickettsial eschar • Tropical ulcer (Fusobacterium ulcerans and Treponema vincentii ) • Ecthyma (staphylococci, streptococci) Papules • Scabies • Insect bites • Prickly heat • Ringworm • Onchocerciasis Nodules or plaques • Leprosy • Chromoblastomycosis • Dimorphic fungi • Trypanosomiasis • Onchocerciasis • Myiasis (larvae of tumbu fly or botfly) • Tungiasis (Tunga penetrans) Migratory linear rash • Cutaneous larva migrans (CLM; dog hookworms) • Strongyloides stercoralis (larva currens, more rapid than CLM) Migratory papules/nodules • Loa loa • Gnathostomiasis • Schistosomiasis Thickened skin • Mycetoma (actinomycetoma/ eumycetoma) • Elephantiasis (filariasis)

Presenting problems in infectious diseases • 235

Fig. 11.7 Examples of skin lesions in patients with fever in the tropics. A Subcutaneous nodule due to botfly infection. B Emerging larva after treatment with petroleum jelly. C Eschar of scrub typhus. D Rat bite fever. A, B and D, Courtesy of Dr Ravi Gowda, Royal Hallamshire Hospital, Sheffield. C, Courtesy of Dr Rattanaphone Phetsouvanh, Mahosot Hospital, Vientiane, PDR Laos. A B C D 11.25 Key issues in infectious diseases in adolescence • Common infectious syndromes: infectious mononucleosis, bacterial pharyngitis, whooping cough, pneumonia, staphylococcal skin/soft tissue infections, urinary tract infections, acute gastroenteritis. • Life-threatening infections: meningococcal infection (sepsis and/ or meningitis). • Sexually transmitted infections: human papillomavirus (HPV), HIV-1, hepatitis B virus and chlamydia. These may reflect either voluntary sexual activity or sexual coercion/abuse. • Travel-related infections: diarrhoea, malaria etc. are relatively common. • Infections in susceptible groups: patients with cystic fibrosis, congenital immunodeficiency, acute leukaemia and other adolescent malignancies are vulnerable to specific groups of infections. • Infections requiring prolonged antimicrobial use: adherence to chronic therapy is challenging, for both oral (antituberculous or antiretroviral) and systemic (osteomyelitis, septic arthritis or post-operative infections) treatments. Outpatient antimicrobial therapy is preferred to minimise hospitalisation. • Vaccination: engagement with age-specific vaccine programmes should be ensured, e.g. HPV, childhood booster vaccines and meningococcal vaccine. • Risk reduction: education relating to sexual health and alcohol and recreational drug usage is important. 11.26 Infections in pregnancy Infection Consequence Prevention and management Rubella Congenital malformation Childhood vaccination and vaccination of non-immune mothers post-delivery Cytomegalovirus Neonatal infection, congenital malformation Limited prevention strategies Zika virus Congenital malformation Avoidance of travel, delay in pregnancy if infected Varicella zoster virus Neonatal infection, congenital malformation, severe infection in mother VZ immunoglobulin (see Box 11.31) Herpes simplex virus (HSV) Congenital or neonatal infection Aciclovir and consideration of caesarean section for mothers who shed HSV from genital tract at time of delivery. Aciclovir for infected neonates Hepatitis B virus Chronic infection of neonate Hepatitis B immunoglobulin and active vaccination of newborn Hepatitis E virus Fulminant hepatitis, pre-term delivery, fetal loss Maintenance of standard food hygiene practices HIV-1 Chronic infection of neonate Antiretroviral drugs for mother and infant and consideration of caesarean section if HIV-1 viral load detectable. Avoidance of breastfeeding Parvovirus B19 Congenital infection Avoidance of individuals with acute infection if pregnant Measles More severe infection in mother and neonate, fetal loss Childhood vaccination, human normal immunoglobulin in non-immune pregnant contacts and vaccination post-delivery Dengue Neonatal dengue if mother has infection < 5 weeks prior to delivery Vector (mosquito) control Syphilis Congenital malformation Serological testing in pregnancy with prompt treatment of infected mothers Neisseria gonorrhoeae and Chlamydia trachomatis Neonatal conjunctivitis (ophthalmia neonatorum, p. 340) Treatment of infection in mother and neonate Listeriosis Neonatal meningitis or bacteraemia, bacteraemia or pyrexia of unknown origin in mother Avoidance of unpasteurised cheeses and other dietary sources Brucellosis Possibly increased incidence of fetal loss Avoidance of unpasteurised dairy products Group B streptococcal infection Neonatal meningitis and sepsis. Sepsis in mother after delivery Risk- or screening-based antimicrobial prophylaxis in labour (recommendations vary between countries) Toxoplasmosis Congenital malformation Diagnosis and prompt treatment of cases, avoidance of under-cooked meat while pregnant Malaria Fetal loss, intrauterine growth retardation, severe malaria in mother Avoidance of insect bites. Intermittent preventative treatment during pregnancy to decrease incidence in high-risk countries

236 • INFECTIOUS DISEASE Viral infections Systemic viral infections with exanthem Childhood exanthems are characterised by fever and widespread rash. Maternal antibody usually gives protection for the first 6–12 months of life. Comprehensive immunisation programmes have dramatically reduced the number of paediatric infections but incomplete uptake results in infections in later life. Measles The WHO has set the objective of eradicating measles globally using the live attenuated vaccine. However, vaccination of more than 95% of the population is required to prevent outbreaks. Natural illness produces life-long immunity. Clinical features Infection is by respiratory droplets with an incubation period of 6–19 days. A prodromal illness occurs, 1–3 days before the rash, with upper respiratory symptoms, conjunctivitis and the presence of the pathognomonic Koplik’s spots: small white spots surrounded by erythema on the buccal mucosa (Fig. 11.8A). As natural antibody develops, the maculopapular rash appears, spreading from the face to the extremities (Fig. 11.8B). Generalised lymphadenopathy and diarrhoea are common. Complications are more common in older children and adults, and include otitis media, bacterial pneumonia, transient hepatitis, pancreatitis and clinical encephalitis (approximately 0.1% of cases). A rare late complication is subacute sclerosing panencephalitis (SSPE), which occurs up to 7 years after infection. Diagnosis is clinical (although this has become unreliable in areas where measles is no longer common) and by detection of antibody (serum immunoglobulin M (IgM), seroconversion or salivary IgM). Measles is a serious disease in the malnourished, vitamindeficient or immunocompromised, in whom the typical rash may be missing and persistent infection with a giant cell pneumonitis or encephalitis may occur. In tuberculosis infection, measles suppresses cell-mediated immunity and may exacerbate disease; for this reason, measles vaccination should be deferred until after commencing antituberculous treatment. Measles does not cause congenital malformation but may be more severe in pregnant women. Mortality clusters at the extremes of age, averaging 1 : 1000 in developed countries and up to 1 : 4 in developing countries. Death usually results from a bacterial superinfection, occurring as a complication of measles: most often pneumonia, diarrhoeal disease or noma/cancrum oris, a gangrenous stomatitis. Death may also result from complications of measles encephalitis. Management and prevention Normal immunoglobulin attenuates the disease in the immunocompromised (regardless of vaccination status) and in non-immune pregnant women, but must be given within 6 days of exposure. Vaccination can be used in outbreaks and vitamin A may improve the outcome in uncomplicated disease. Antibiotic therapy is reserved for bacterial complications. All children aged 12–15 months should receive measles vaccination (as combined measles, mumps and rubella (MMR), a live attenuated vaccine), and a further MMR dose at age 4 years. Rubella (German measles) Rubella causes exanthem in the non-immunised. Clinical features Rubella is spread by respiratory droplet, with infectivity from up to 10 days before to 2 weeks after the onset of the rash. The incubation period is 15–20 days. In childhood, most cases are subclinical, although clinical features may include fever, maculopapular rash spreading from the face, and lymphadenopathy. Complications are rare but include thrombocytopenia and hepatitis. Encephalitis and haemorrhage are occasionally reported. In adults, arthritis involving hands or knees is relatively common, especially in women. If transplacental infection takes place in the first trimester or later, persistence of the virus is likely and severe congenital disease may result (Box 11.27). Even if normal at birth, the infant has an increased incidence of other diseases developing later, e.g. diabetes mellitus. Diagnosis Laboratory confirmation of rubella is required if there has been contact with a pregnant woman. This is achieved either by detection of rubella IgM in serum or by IgG seroconversion. In the exposed pregnant woman, absence of rubella-specific IgG confirms the potential for congenital infection. Prevention All children should be immunised with MMR vaccine. Congenital rubella syndrome may be controlled by testing women of childbearing age for rubella antibodies and offering vaccination if seronegative. Antenatal rubella screening was offered to pregnant mothers in the UK for many years for this reason. However, this Fig. 11.8 Measles. A Koplik’s spots (arrows) seen on buccal mucosa in the early stages of clinical measles. B Typical measles rash. A B

Viral infections • 237

Persistent viraemia in immunocompromised hosts may require immunoglobulin therapy to clear the virus. Pregnant women should avoid contact with cases of parvovirus B19 infection; if they are exposed, serology should be performed to establish whether they are non-immune. Passive prophylaxis with normal immunoglobulin has been suggested for non-immune pregnant women exposed to infection but there are limited data to support this recommendation. The pregnancy should be closely monitored by ultrasound scanning, so that hydrops fetalis can be treated by fetal transfusion. practice ceased in 2016 because: rubella is so rare in the UK as to be considered eliminated; pre-pregnancy MMR vaccination is considered to be a more effective method of protecting pregnant women; and the screening test may give inaccurate results, causing unnecessary stress to pregnant women. Parvovirus B19 Parvovirus B19 causes exanthem and other clinical syndromes. Some 50% of children and 60–90% of adults are seropositive. Most infections are spread by the respiratory route, although spread via contaminated blood is also possible. The virus has particular tropism for red cell precursors. Clinical features Many infections are subclinical. Clinical manifestations result after an incubation period of 14–21 days (Box 11.28). The classic exanthem (erythema infectiosum) is preceded by a prodromal fever and coryzal symptoms. A ‘slapped cheek’ rash is characteristic but the rash is very variable (Fig. 11.9). In adults, polyarthropathy is common. Infected individuals have a transient block in erythropoiesis for a few days, which is of no clinical consequence, except in individuals with increased red cell turnover due to haemoglobinopathy or haemolytic anaemia. These individuals develop an acute anaemia that may be severe (transient aplastic crisis; p. 968). Erythropoiesis usually recovers spontaneously after 10–14 days. Immunocompromised individuals, including those with congenital immunodeficiency or AIDS, can develop a more sustained block in erythropoiesis in response to the chronic viraemia that results from their inability to clear the infection. Infection during the first two trimesters of pregnancy can result in intrauterine infection and impact on fetal bone marrow; it causes 10–15% of non-immune (non-Rhesus-related) hydrops fetalis, a rare complication of pregnancy. Diagnosis IgM to parvovirus B19 suggests recent infection but may persist for months and false positives occur. Seroconversion to IgG positivity confirms infection but in isolation a positive IgG is of little diagnostic utility. Detection of parvovirus B19 DNA in blood is particularly useful in immunocompromised patients. Giant pronormoblasts or haemophagocytosis may be demonstrable in the bone marrow. Management Infection is usually self-limiting. Symptomatic relief for arthritic symptoms may be required. Severe anaemia requires transfusion. 11.27 Rubella infection: risk of congenital malformation Stage of gestation Likelihood of malformations 1–2 months 65–85% chance of illness, multiple defects/ spontaneous abortion 3 months 30–35% chance of illness, usually a single congenital defect (most frequently deafness, cataract, glaucoma, mental retardation or congenital heart disease, especially pulmonary stenosis or patent ductus arteriosus) 4 months 10% risk of congenital defects, most commonly deafness

20 weeks Occasional deafness 11.28 Clinical features of parvovirus B19 infection Affected age group Clinical manifestations Fifth disease (erythema infectiosum) Small children Three clinical stages: a ‘slapped cheek’ appearance, followed by a maculopapular rash progressing to a reticulate eruption on the body and limbs, then a final stage of resolution. Often the child is quite well throughout Gloves and socks syndrome Young adults Fever and an acral purpuric eruption with a clear margin at the wrists and ankles. Mucosal involvement also occurs Arthropathies Adults and occasionally children Symmetrical small-joint polyarthropathy. In children it tends to involve the larger joints in an asymmetrical distribution Impaired erythropoiesis Adults, those with haematological disease, the immunosuppressed Mild anaemia; in an individual with an underlying haematological abnormality it can precipitate transient aplastic crisis, or in the immunocompromised a more sustained but often milder pure red cell aplasia Hydrops fetalis Transplacental fetal infection Asymptomatic or symptomatic maternal infection that can cause fetal anaemia with an aplastic crisis, leading to non-immune hydrops fetalis and spontaneous abortion Fig. 11.9 Slapped cheek syndrome. The typical facial rash of parvovirus B19 infection.

238 • INFECTIOUS DISEASE HHV-7 is very closely related to HHV-6 and is believed to be responsible for a proportion of cases of exanthem subitum. Like HHV-6, HHV-7 causes an almost universal infection in childhood, with subsequent latent infection and occasional infection in the immunocompromised host. Clinical features Exanthem subitum is also known as roseola infantum or sixth disease (Box 11.29). A high fever is followed by a maculopapular rash as the fever resolves. Fever and/or febrile convulsions may also occur without a rash. Rarely, older children or adults may develop an infectious mononucleosis-like illness, hepatitis or rash. In the immunocompromised, infection is rare but can cause fever, rash, hepatitis, pneumonitis, cytopenia or encephalitis. Diagnosis and management Exanthem subitum is usually a clinical diagnosis but can be confirmed by antibody and/or DNA detection. The disease is self-limiting. Treatment with ganciclovir or foscarnet is used in immunocompromised hosts infected with HHV-6. Chickenpox (varicella) Varicella zoster virus (VZV) is a dermotropic and neurotropic virus that produces primary infection, usually in childhood, which may reactivate in later life. VZV is spread by aerosol and direct contact. It is highly infectious to non-immune individuals. Disease in children is usually well tolerated. Manifestations are more severe in adults, pregnant women and the immunocompromised. Clinical features The incubation period is 11–20 days, after which a vesicular eruption begins (Fig. 11.10), often on mucosal surfaces first, followed by rapid dissemination in a centripetal distribution (most dense on trunk and sparse on limbs). New lesions occur every 2–4 days and each crop is associated with fever. The rash progresses from small pink macules to vesicles and pustules within 24 hours. Infectivity lasts from up to 4 days (but usually 48 hours) before the lesions appear until the last vesicles crust over. Due to intense itching, secondary bacterial infection from scratching is the most common complication of primary chickenpox. Self-limiting cerebellar ataxia and encephalitis are rare complications. Adults, pregnant women and the immunocompromised are at increased risk of visceral involvement, which presents as pneumonitis, hepatitis or encephalitis. Pneumonitis can be fatal and is more likely to occur in smokers. Maternal infection in Human herpesvirus 6 and 7 Human herpesvirus 6 (HHV-6) is a lymphotropic virus that causes a childhood viral exanthem (exanthem subitum), rare cases of an infectious mononucleosis-like syndrome and infection in the immunocompromised host. Infection is almost universal, with approximately 95% of children acquiring this virus by 2 years of age. Transmission is via saliva. 11.29 Herpesvirus infections Virus Infection Herpes simplex virus (HSV) HSV-1 (p. 247) Herpes labialis (‘cold sores’) Stomatitis, pharyngitis Corneal ulceration Finger infections (‘whitlows’) Eczema herpeticum Encephalitis HSV-2 (p. 247) Genital ulceration and neonatal infection (acquired during vaginal delivery) Acute meningitis or transverse myelitis; rarely, encephalitis Varicella zoster virus (VZV) Chickenpox (varicella) Shingles (herpes zoster) Cytomegalovirus (CMV) (p. 242) Congenital infection Infectious mononucleosis (heterophile antibody-negative) Hepatitis Disease in immunocompromised patients: retinitis, encephalitis, pneumonitis, hepatitis, enteritis Fever with abnormalities in haematological parameters Epstein–Barr virus (EBV) (p. 241) Infectious mononucleosis Burkitt’s and other lymphomas Nasopharyngeal carcinoma Oral hairy leucoplakia (AIDS patients) Other lymphomas, post-transplant lymphoproliferative disorder (p. 225) Human herpesvirus 6 and 7 (HHV-6, HHV-7) Exanthem subitum Disease in immunocompromised patients Human herpesvirus 8 (HHV-8) (p. 248) Kaposi’s sarcoma, primary effusion lymphoma, multicentric Castleman’s disease Fig. 11.10 Varicella zoster virus infection. A Chickenpox. B Shingles in a thoracic dermatome. B A

Viral infections • 239

ipsilateral loss of taste and buccal ulceration, plus a rash in the external auditory canal. This may be mistaken for Bell’s palsy (p. 1082). Bowel and bladder dysfunction occur with sacral nerve root involvement. The virus occasionally causes cranial nerve palsy, myelitis or encephalitis. Granulomatous cerebral angiitis is a cerebrovascular complication that leads to a stroke-like syndrome in association with shingles, especially in an ophthalmic distribution. Post-herpetic neuralgia causes troublesome persistence of pain for 1–6 months or longer, following healing of the rash. It is more common with advanced age. early pregnancy carries a 3% risk of neonatal damage with developmental abnormalities of eyes, CNS and limbs. Chickenpox within 5 days of delivery leads to severe neonatal varicella with visceral involvement and haemorrhage. Diagnosis Diagnosis is primarily clinical, by recognition of the rash. If necessary, this can be confirmed by detection of antigen (direct immunofluorescence) or DNA (PCR) of aspirated vesicular fluid. Serology is used to identify seronegative individuals at risk of infection. Management and prevention The benefits of antivirals for uncomplicated primary VZV infection in children are marginal, shortening the duration of rash by only 1 day, and treatment is not normally required. Antivirals are, however, used for uncomplicated chickenpox in adults when the patient presents within 24–48 hours of onset of vesicles, in all patients with complications, and in those who are immunocompromised, including pregnant women, regardless of duration of vesicles (Box 11.30). More severe disease, particularly in immunocompromised hosts, requires initial parenteral therapy. Immunocompromised patients may have prolonged viral shedding and may require prolonged treatment until all lesions crust over. Human VZ immunoglobulin (VZIG) is used to attenuate infection in people who have had significant contact with VZV, are susceptible to infection (i.e. have no history of chickenpox or shingles and are seronegative for VZV IgG) and are at risk of severe disease (e.g. immunocompromised or pregnant) (Box 11.31). Ideally, VZIG should be given within 7 days of exposure, but it may attenuate disease even if given up to 10 days afterwards. Susceptible contacts who develop severe chickenpox after receiving VZIG should be treated with aciclovir. A live, attenuated VZV vaccine is available and in routine use in the USA and other countries, but in the UK its use has been restricted to non-immune health-care workers and household contacts of immunocompromised individuals. Children receive one dose after 1 year of age and a second dose at 4–6 years of age; seronegative adults receive two doses at least 1 month apart. The vaccine may also be used prior to planned iatrogenic immunosuppression, e.g. before transplant and for the elderly aged over 70 to prevent shingles. Shingles (herpes zoster) After initial infection, VZV persists in latent form in the dorsal root ganglion of sensory nerves and can reactivate in later life. Clinical features Burning discomfort occurs in the affected dermatome following reactivation and discrete vesicles appear 3–4 days later. This is associated with a brief viraemia, which can produce distant satellite ‘chickenpox’ lesions. Occasionally, paraesthesia occurs without rash (‘zoster sine herpete’). Severe disease, a prolonged duration of rash, multiple dermatomal involvement or recurrence suggests underlying immune deficiency, including HIV. Chickenpox may be contracted from a case of shingles but not vice versa. Although thoracic dermatomes are most commonly involved (Fig. 11.10B), the ophthalmic division of the trigeminal nerve is also frequently affected; vesicles may appear on the cornea and lead to ulceration. This condition can lead to blindness and urgent ophthalmology review is required. Geniculate ganglion involvement causes the Ramsay Hunt syndrome of facial palsy, 11.30 Therapy for herpes simplex and varicella zoster virus infection Disease state Treatment options Primary genital HSV Famciclovir 250 mg 3 times daily for 7–10 days Valaciclovir 1 g twice daily for 7–10 days Oral aciclovir 200 mg 5 times daily or 400 mg 3 times daily for 7–10 days Severe and preventing oral intake Aciclovir 5 mg/kg 3 times daily IV until patient can tolerate oral therapy Recurrent genital HSV-1 or 2 Oral aciclovir 200 mg 5 times daily or 400 mg 3 times daily for 5 days Famciclovir 125 mg twice daily for 5 days Valaciclovir 500 mg twice daily for 3–5 days or 2 g twice daily for 1 day. Shorter durations increasingly favoured Primary or recurrent oral HSV Usually no treatment If required, usually short duration, e.g. valaciclovir 2 g twice daily for 1 day Mucocutaneous HSV infection in immunocompromised host Aciclovir 5 mg/kg 3 times daily IV for 7–10 days Oral aciclovir 400 mg 4 times daily for 7–10 days Famciclovir 500 mg 3 times daily for 7–10 days Valaciclovir 1 g twice daily for 7–10 days Chickenpox in adult or child Oral aciclovir 800 mg 5 times daily for 5 days Famciclovir 500 mg 3 times daily for 5 days Valaciclovir 1 g 3 times daily for 5 days Immunocompromised host/pregnant woman Aciclovir 5 mg/kg 3 times daily IV until patient is improving, then complete therapy with oral therapy until all lesions are crusting over Shingles Treatment and doses as for chickenpox but duration typically 7–10 days Visceral involvement (non-CNS) in HSV Aciclovir IV 5 mg/kg 3 times daily for 14 days Visceral involvement (non-CNS) in VZV Aciclovir IV 5 mg/kg 3 times daily for 7 days Severe complications (encephalitis, disseminated infection) Aciclovir IV 10 mg/kg 3 times daily (up to 20 mg/kg in neonates) for 14–21 days HSV disease suppression Aciclovir 400 mg twice daily Famciclovir 250 mg twice daily Valaciclovir 500 mg daily (CNS = central nervous system; HSV = herpes simplex virus; VZV = varicella zoster virus)

240 • INFECTIOUS DISEASE time have led to outbreaks in young adults. Infection is spread by respiratory droplets. Clinical features The median incubation period is 19 days, with a range of 15–24 days. Classical tender parotid enlargement, which is bilateral in 75%, follows a prodrome of pyrexia and headache (Fig. 11.11). Meningitis complicates up to 10% of cases. The CSF reveals a lymphocytic pleocytosis or, less commonly, neutrophils. Rare complications include encephalitis, transient hearing loss, labyrinthitis, electrocardiographic abnormalities, pancreatitis and arthritis. Approximately 25% of post-pubertal males with mumps develop epididymo-orchitis but, although testicular atrophy occurs, sterility is unlikely. Oophoritis is less common. Abortion may occur if infection takes place in the first trimester of pregnancy. Complications may occur in the absence of parotitis. Diagnosis The diagnosis is usually clinical. In atypical presentations without parotitis, serology for mumps-specific IgM or IgG seroconversion (fourfold rise in IgG convalescent titre) confirms the diagnosis. Virus can also be cultured from urine in the first week of infection or detected by PCR in urine, saliva or CSF. Management and prevention Treatment is with analgesia. There is no evidence that glucocorticoids are of value for orchitis. Mumps vaccine is one of the components of the combined MMR vaccine. Influenza Influenza is an acute systemic viral infection that primarily affects the respiratory tract and carries a significant mortality. It is caused by influenza A virus or, in milder form, influenza B virus. Infection is seasonal, and variation in the haemagglutinin (H) and neuraminidase (N) glycoproteins on the surface of the virus leads to disease of variable intensity each year. Minor changes in haemagglutinin are known as ‘genetic drift’, whereas a switch in the haemagglutinin or neuraminidase antigen is termed ‘genetic shift’. Nomenclature of influenza strains is based on these glycoproteins, e.g. H1N1, H3N2 etc. Genetic shift results in the circulation of a new influenza strain within a community to Management Early therapy with aciclovir or related agents has been shown to reduce both early- and late-onset pain, especially in patients over 65 years. Post-herpetic neuralgia requires aggressive analgesia, along with agents such as amitriptyline 25–100 mg daily, gabapentin (commencing at 300 mg daily and building slowly to 300 mg twice daily or more) or pregabalin (commencing at 75 mg twice daily and building up to 100 mg or 200 mg 3 times daily if tolerated). Capsaicin cream (0.075%) may be helpful. Although controversial, glucocorticoids have not been demonstrated to reduce post-herpetic neuralgia to date. Enteroviral exanthems Coxsackie or echovirus infections can lead to a maculopapular eruption or roseola-like rash that occurs after fever falls. Enteroviral infections are discussed further under viral infections of the skin (see below). Systemic viral infections without exanthem Other systemic viral infections present with features other than a rash suggestive of exanthem. Rashes may occur in these conditions but differ from those seen in exanthems or are not the primary presenting feature. Mumps Mumps is a systemic viral infection characterised by swelling of the parotid glands. Infection is endemic worldwide and peaks at 5–9 years of age. Vaccination has reduced the incidence in children but incomplete coverage and waning immunity with Fig. 11.11 Typical unilateral mumps. A Note the loss of angle of the jaw on the affected (right) side. B Comparison showing normal (left) side. B A 11.31 Indications for varicella zoster immunoglobulin (VZIG) in adults An adult should satisfy all three of the following conditions:

  1. Significant contact Contact with chickenpox (any time from 48 hrs before the rash until crusting of lesions) or zoster (exposed, disseminated or, with immunocompromised contacts, localised zoster; between development of the rash until crusting) defined as: • Prolonged household contact, sharing a room for ≥ 15 mins or face-to-face contact (includes direct contact with zoster lesions) • Hospital contact with chickenpox in another patient, health-care worker or visitor • Intimate contact (e.g. touching) with person with shingles lesions • Newborn whose mother develops chickenpox no more than 5 days before delivery or 2 days after delivery
  2. Susceptible contact • Individual with no history of chickenpox, ideally confirmed by negative test for VZV IgG
  3. Predisposition to severe chickenpox • Immunocompromised due to disease (e.g. acute leukaemia, HIV, other primary or secondary immunodeficiency) • Medically immunosuppressed (e.g. following solid organ transplant; current or recent (< 6 months) cytotoxic chemotherapy or radiotherapy; current or recent (< 3 months) high-dose glucocorticoids; haematopoietic stem cell transplant) • Pregnant (any stage) • Infants: newborn whose mother has had chickenpox as above; premature infants < 28 weeks

Viral infections • 241

in the Indian subcontinent in 2014–16. Symptoms included more gastrointestinal symptoms than with seasonal influenza, respiratory failure and seizures or encephalitis. Severe disease was a feature of infants, adults less than 50 years, those with chronic lung or neurological disease, obese patients and pregnant women, but with time the clinical features have become indistinguishable from those of seasonal influenza. Infectious mononucleosis and Epstein–Barr virus Infectious mononucleosis (IM) is a clinical syndrome characterised by pharyngitis, cervical lymphadenopathy, fever and lymphocytosis (known colloquially as glandular fever). It is most often caused by Epstein–Barr virus (EBV) but other infections can produce a similar clinical syndrome (Box 11.32). EBV is a gamma herpesvirus. In developing countries, subclinical infection in childhood is virtually universal. In developed countries, primary infection may be delayed until adolescence or early adult life. Under these circumstances, about 50% of infections result in typical IM. The virus is usually acquired from asymptomatic excreters via saliva, either by droplet infection or environmental contamination in childhood, or by kissing among adolescents and adults. EBV is not highly contagious and isolation of cases is unnecessary. Clinical features EBV infection has a prolonged but undetermined incubation period, followed in some cases by a prodrome of fever, headache and malaise. This is followed by IM with severe pharyngitis, which may include tonsillar exudates and non-tender anterior and posterior cervical lymphadenopathy. Palatal petechiae, periorbital oedema, splenomegaly, inguinal or axillary lymphadenopathy, and macular, petechial or erythema multiforme rashes may occur. In most cases, fever resolves over 2 weeks, and fatigue and other abnormalities settle over a further few weeks. Complications are listed in Box 11.33. Death is rare but can occur due to respiratory obstruction, haemorrhage from splenic rupture, thrombocytopenia or encephalitis. The diagnosis of EBV infection outside the usual age in adolescence and young adulthood is more challenging. In children under 10 years the illness is mild and short-lived, but in adults over 30 years of age it can be severe and prolonged. In both groups, pharyngeal symptoms are often absent. EBV may present with jaundice, as a PUO or with a complication. Long-term complications of EBV infection Lymphoma complicates EBV infection in immunocompromised hosts, and some forms of Hodgkin lymphoma are EBV-associated (p. 961). The endemic form of Burkitt’s lymphoma complicates EBV infection in areas of sub-Saharan Africa where falciparum malaria is endemic. Nasopharyngeal carcinoma is a geographically restricted tumour seen in China and Alaska that is associated with EBV infection. X-linked lymphoproliferative (Duncan’s) syndrome is a familial lymphoproliferative disorder that follows primary EBV infection in boys without any other history of immunodeficiency; which few people are immune, potentially initiating an influenza epidemic or pandemic in which there is a high attack rate and there may be increased disease severity. Clinical features After an incubation period of 1–3 days, uncomplicated disease leads to fever, malaise and cough. Viral pneumonia may occur, although pulmonary complications are most often due to superinfection with Strep. pneumoniae, Staph. aureus or other bacteria. Rare extrapulmonary manifestations include myositis, myocarditis, pericarditis and neurological complications (Reye’s syndrome in children, encephalitis or transverse myelitis). Mortality is greatest in the elderly, those with medical comorbidities and pregnant women. Polymorphisms in the gene encoding an antiviral protein, interferon-induced transmembrane protein 3 (IFITM3), are associated with more severe influenza. Diagnosis Acute infection is diagnosed by viral antigen or RNA detection in a nasopharyngeal sample. The disease may also be diagnosed retrospectively by serology. Management and prevention Management involves early microbiological identification of cases and good infection control, with an emphasis on hand hygiene and preventing dissemination of infection by coughing and sneezing. Administration of neuraminidase inhibitor, oral oseltamivir (75 mg twice daily) or inhaled zanamivir (10 mg twice daily) for 5 days, can reduce the severity of symptoms if started within 48 hours of symptom onset (or possibly later in immunocompromised individuals). These agents have superseded routine use of amantadine and rimantadine. Antiviral drugs can also be used as prophylaxis in high-risk individuals during the ‘flu’ season. Resistance can emerge to all of these agents and so updated local advice should be followed with regard to the sensitivity to antivirals of the circulating strain. Prevention relies on seasonal vaccination of the elderly, children 2–7 years of age and individuals with chronic medical illnesses that place them at increased risk of the complications of influenza, such as chronic cardiopulmonary diseases or immune compromise, as well as their health-care workers. The vaccine composition changes each year to cover the ‘predicted’ seasonal strains but vaccination may fail when a new pandemic strain emerges. Avian influenza Avian influenza is caused by transmission of avian influenza A viruses to humans. Avian viruses, such as H5N1, possess alternative haemagglutinin antigens to seasonal influenza strains. Most cases have had contact with sick poultry, predominantly in South-east Asia, and person-to-person spread has been limited to date. Infections with H5N1 viruses have been severe, with enteric features and respiratory failure. Treatment depends on the resistance pattern but often involves oseltamivir. Vaccination against seasonal ‘flu’ does not adequately protect against avian influenza. There is a concern that adaptation of an avian strain to allow effective person-to-person transmission is likely to lead to a global pandemic of life-threatening influenza. Swine influenza Re-assortment of swine, avian and human influenza strains can occur in pigs and lead to outbreaks of swine ‘flu’ in humans, as occurred in 2009, when an outbreak of H1N1pdm2009 influenza spread around the world from Mexico. Cases were still occurring 11.32 Causes of infectious mononucleosis syndrome • Epstein–Barr virus infection • Cytomegalovirus • Human herpesvirus-6 or 7 • HIV-1 primary infection (p. 311) • Toxoplasmosis

242 • INFECTIOUS DISEASE of test serum to agglutinate sheep and horse red blood cells, respectively.). Sometimes antibody production is delayed, so an initially negative test should be repeated. However, many children and 10% of adolescents with IM do not produce heterophile antibody at any stage. Specific EBV serology confirms the diagnosis. Acute infection is characterised by IgM antibodies against the viral capsid, antibodies to EBV early antigen and the initial absence of antibodies to EBV nuclear antigen (anti-EBNA). Seroconversion of anti-EBNA at approximately 1 month after the initial illness may confirm the diagnosis in retrospect. CNS infections may be diagnosed by detection of viral DNA in CSF. Management Treatment is largely symptomatic. If a throat culture yields a β-haemolytic streptococcus, penicillin should be given. Administration of ampicillin or amoxicillin in this condition commonly causes an itchy macular rash and should be avoided (Fig. 11.12B). When pharyngeal oedema is severe, a short course of glucocorticoids, e.g. prednisolone 30 mg daily for 5 days, may help. Current antiviral drugs are not active against EBV. Return to work or school is governed by physical fitness rather than laboratory tests; contact sports should be avoided until splenomegaly has resolved because of the danger of splenic rupture. Unfortunately, about 10% of patients with IM suffer a chronic relapsing syndrome. Cytomegalovirus Cytomegalovirus (CMV), like EBV, circulates readily among children. A second period of virus acquisition occurs among teenagers and young adults, peaking between the ages of 25 and 35 years, rather later than with EBV infection. CMV infection is persistent, and is characterised by subclinical cycles of active virus replication and by persistent low-level virus shedding. Most post-childhood infections are therefore acquired from asymptomatic excreters who shed virus in saliva, urine, semen and genital secretions. Sexual transmission and oral spread are common among adults but infection may also be acquired by women caring for children with asymptomatic infections. Clinical features Most post-childhood CMV infections are subclinical, although some young adults develop an IM-like syndrome and some have a prolonged influenza-like illness lasting 2 weeks or more. Physical signs resemble those of IM but in CMV infections hepatomegaly is it is due to mutation of the SAP gene, causing failure of T-cell and NK-cell activation and inability to contain EBV infection. Investigations Atypical lymphocytes are common in EBV infection but also occur in other causes of IM, acute retroviral syndrome with HIV infection, viral hepatitis, mumps and rubella (Fig. 11.12A). They are also a feature of dengue, malaria and other geographically restricted infections (see Box 11.19). A ‘heterophile’ antibody is present during the acute illness and convalescence, which is detected by the Paul–Bunnell or ‘Monospot’ test. (A heterophile antibody is an antibody that has affinity for antigens other than the specific one, in this case animal immunoglobulins; the Paul–Bunnell and Monospot tests exploit this feature by detecting the ability Fig. 11.12 Features of infectious mononucleosis. A Atypical lymphocytes in peripheral blood. B Skin reaction to ampicillin. A B 11.33 Complications of Epstein–Barr virus infection Common • Severe pharyngeal oedema • Antibiotic-induced rash (80–90% with ampicillin) • Hepatitis (80%) • Prolonged post-viral fatigue (10%) • Jaundice (< 10%) Uncommon Neurological • Cranial nerve palsies • Polyneuritis • Transverse myelitis • Meningoencephalitis Haematological • Haemolytic anaemia • Thrombocytopenia Renal • Abnormalities on urinalysis • Interstitial nephritis Cardiac • Myocarditis • ECG abnormalities • Pericarditis Rare • Ruptured spleen • Respiratory obstruction • Agranulocytosis • X-linked lymphoproliferative syndrome EBV-associated malignancy • Nasopharyngeal carcinoma • Burkitt’s lymphoma • Hodgkin lymphoma (certain subtypes only) • Primary CNS lymphoma • Lymphoproliferative disease in immunocompromised

Viral infections • 243

in standing water; collections of water in containers, water-based air coolers and tyre dumps are a good environment for the vector in large cities. Aedes albopictus is a vector in some South-east Asian countries. There are four serotypes of dengue virus, all producing a similar clinical syndrome; type-specific immunity is life-long but immunity against the other serotypes lasts only a few months. Dengue haemorrhagic fever (DHF) and dengue shock syndrome (DSS) occur in individuals who are immune to one dengue virus serotype and are then infected with another. Prior immunity results in increased uptake of virus by cells expressing the antibody Fc receptor and increased T-cell activation with resultant cytokine release, causing capillary leak and disseminated intravascular coagulation (DIC; p. 978). Previously, dengue was seen in small children and DHF/DSS in children 2–15 years old, but these conditions are now being seen in children less than 2 years old, and most frequently in those 16–45 years of age or older, in whom severe organ dysfunction is more common. Other epidemiological changes include the spread of dengue into rural communities and greater case fatality in women. Clinical features Many cases of dengue infection are asymptomatic in children. Clinical disease presents with undifferentiated fever termed dengue-like illness. When dengue infection occurs with characteristic symptoms or signs it is termed ‘dengue’ (Box 11.34). A rash frequently follows the initial febrile phase as the fever settles. Laboratory features include leucopenia, neutropenia, more common, while lymphadenopathy, splenomegaly, pharyngitis and tonsillitis occur less often. Jaundice is uncommon and usually mild. Complications include meningoencephalitis, Guillain–Barré syndrome, autoimmune haemolytic anaemia, thrombocytopenia, myocarditis and skin eruptions, such as ampicillin-induced rash. Immunocompromised patients can develop hepatitis, oesophagitis, colitis, pneumonitis, retinitis, encephalitis and polyradiculitis. Women who develop a primary CMV infection during pregnancy have about a 40% chance of passing CMV to the fetus, causing congenital infection and disease at any stage of gestation. Features include petechial rashes, hepatosplenomegaly and jaundice; 10% of infected infants will have long-term CNS sequelae, such as microcephaly, cerebral calcifications, chorioretinitis and deafness. Infections in the newborn usually are asymptomatic or have features of an IM-like illness, although some studies suggest that subtle sequelae affecting hearing or mental development may occur. Investigations Atypical lymphocytosis is not as prominent as in EBV infection and heterophile antibody tests are usually negative. LFTs are often abnormal, with an alkaline phosphatase level raised out of proportion to transaminases. Serological diagnosis depends on the detection of CMV-specific IgM antibody plus a fourfold rise or seroconversion of IgG. In the immunocompromised, antibody detection is unreliable and detection of CMV in an involved organ by PCR, antigen detection, culture or histopathology establishes the diagnosis. Detection of CMV in the blood may be useful in transplant populations but not in HIV-positive individuals, since in HIV infection CMV reactivates at regular intervals, but these episodes do not correlate well with episodes of clinical disease. Detection of CMV in urine is not helpful in diagnosing infection, except in neonates, since CMV is intermittently shed in the urine throughout life following infection. Management Only symptomatic treatment is required in the immunocompetent patient. Immunocompromised individuals are treated with ganciclovir 5 mg/kg IV twice daily or with oral valganciclovir 900 mg twice daily for at least 14 days. Foscarnet or cidofovir is also used in CMV treatment of immunocompromised patients who are resistant to or intolerant of ganciclovir-based therapy. They can be given intravitreally if required. Dengue Dengue is a febrile illness caused by a flavivirus transmitted by mosquitoes. It is endemic in Asia, the Pacific, Africa and the Americas (Fig. 11.13). Approximately 400 million infections and 100 million clinically apparent infections occur annually, and dengue is the most rapidly spreading mosquito-borne viral illness. The principal vector is the mosquito Aedes aegypti, which breeds Fig. 11.13 Endemic zones of yellow fever and dengue. Dengue Yellow fever Dengue + yellow fever 11.34 Clinical features of dengue fever Incubation period • 2–7 days Prodrome • 2 days of malaise and headache Acute onset • Fever, backache, arthralgias, headache, generalised pains (‘break-bone fever’), pain on eye movement, lacrimation, scleral injection, anorexia, nausea, vomiting, pharyngitis, upper respiratory tract symptoms, relative bradycardia, prostration, depression, hyperaesthesia, dysgeusia, lymphadenopathy Fever • Continuous or ‘saddle-back’, with break on 4th or 5th day and then recrudescence; usually lasts 7–8 days Rash • Initial flushing faint macular rash in first 1–2 days. Maculopapular, scarlet morbilliform blanching rash from days 3–5 on trunk, spreading centrifugally and sparing palms and soles; onset often with fever defervescence. May desquamate on resolution or give rise to petechiae on extensor surfaces Convalescence • Slow and may be associated with prolonged fatigue syndrome, arthralgia or depression Complications • Dengue haemorrhagic fever and disseminated intravascular coagulation • Dengue shock syndrome • Severe organ involvement • Vertical transmission if infection within 5 weeks of delivery

244 • INFECTIOUS DISEASE effusions and ascites. This may progress to metabolic acidosis and multi-organ failure, including acute respiratory distress syndrome (ARDS; p. 198). Minor (petechiae, ecchymoses, epistaxis) or major (gastrointestinal or vaginal) haemorrhage, a feature of DHF, may occur. Cerebrovascular bleeding may be a complication of severe dengue. Diagnosis In endemic areas, mild dengue must be distinguished from other viral infections. The diagnosis can be confirmed by seroconversion of IgM or a fourfold rise in IgG antibody titres. Serological tests may detect cross-reacting antibodies from infection or vaccination against other flaviviruses, including yellow fever virus, Japanese encephalitis virus and West Nile virus. Isolation of dengue virus or detection of dengue virus RNA by PCR (p. 106) in blood or CSF is available in specialist laboratories. Commercial enzymelinked immunosorbent assay (ELISA) kits to detect the NS1 viral antigen, although less sensitive than PCR, are available in many endemic areas. Management and prevention Treatment is supportive, emphasising fluid replacement and appropriate management of shock and organ dysfunction, which is a major determinant of morbidity and mortality. With intensive care support, mortality rates are 1% or less. Aspirin should be avoided due to bleeding risk. Glucocorticoids have not been shown to help. No existing antivirals are effective. Breeding places of Aedes mosquitoes should be abolished and the adults destroyed by insecticides. A recently licensed vaccine is available. Yellow fever Yellow fever is a haemorrhagic fever of the tropics, caused by a flavivirus. It is a zoonosis of monkeys in West and Central African, and South and Central American tropical rainforests, where it may cause devastating epidemics (Fig. 11.13). Transmission is by tree-top mosquitoes, Aedes africanus (Africa) and Haemagogus spp. (America). The infection is introduced to humans either by infected mosquitoes when trees are felled, or by monkeys raiding human settlements. In towns, yellow fever may be transmitted between humans by Aedes aegypti, which breeds efficiently in small collections of water. The distribution of this mosquito is far wider than that of yellow fever, and more widespread infection is a continued threat. Yellow fever causes approximately 200 000 infections each year, mainly in sub-Saharan Africa, and the number is increasing. Overall mortality is around 15%, although this varies widely. Humans are infectious during the viraemic phase, which starts 3–6 days after the bite of the infected mosquito and lasts for 4–5 days. Clinical features After an incubation period of 3–6 days, yellow fever is often a mild febrile illness lasting less than 1 week, with headache, myalgia, conjunctival erythema and bradycardia. This is followed by fever resolution (defervescence) but, in some cases, fever recurs after a few hours to days. In more severe disease, fever recrudescence is associated with lower back pain, abdominal pain and somnolence, prominent nausea and vomiting, bradycardia and jaundice. Liver damage and DIC lead to bleeding with petechiae, mucosal haemorrhages and gastrointestinal bleeding. Shock, hepatic failure, renal failure, seizures and coma may ensue. thrombocytopenia and elevated alanine aminotransferase (ALT) or aspartate aminotransferase (AST). Many symptomatic infections run an uncomplicated course but complications or a protracted convalescence may ensue. Warning signs justify intense medical management and monitoring for progression to severe dengue. Atypical clinical features of dengue are increasingly common, especially in infants or older patients (Box 11.35). These, along with DHF or DSS, are recognised as features of severe dengue in the 2015 case definition. The period 3–7 days after onset of fever is termed the ‘critical’ phase, during which signs of DHF or DSS may develop. In mild forms, petechiae occur in the arm when a blood pressure cuff is inflated to a point between systolic and diastolic blood pressure and left for 5 minutes (the positive ‘tourniquet test’) – a non-specific test of capillary fragility and thrombocytopenia. As the extent of capillary leak increases, DSS develops, with a raised haematocrit, tachycardia and hypotension, pleural Adapted from https://wwwn.cdc.gov/nndss/conditions/dengue-virus-infections/ case-definition/2015/ 11.35 WHO case definitions of dengue, 2015 Probable dengue fever • Exposure in an endemic area • Fever • Two of: Nausea/vomiting Rash Aches/pains Positive tourniquet test Leucopenia Any warning sign Laboratory confirmation important Needs regular medical observation and instruction in the warning signs If there are no warning signs, need for hospitalisation is influenced by age, comorbidities, pregnancy and social factors Dengue with warning signs • Probable dengue plus one of: Abdominal pain or tenderness Persistent vomiting Signs of fluid accumulation, e.g. pleural effusion or ascites Mucosal bleed Hepatomegaly > 2 cm Rapid increase in haematocrit with fall in platelet count Needs medical intervention, e.g. intravenous fluid Severe dengue • Severe plasma leakage leading to: Shock (dengue shock syndrome) Fluid accumulation with respiratory distress • Severe haemorrhagic manifestations, e.g. gastrointestinal haemorrhage • Severe organ involvement (atypical features): Liver AST or ALT ≥ 1000 U/L CNS: impaired consciousness, meningoencephalitis, seizures Cardiomyopathy, conduction defects, arrhythmias Other organs, e.g. acute kidney injury, pancreatitis, acute lung injury, disseminated intravascular coagulopathy, rhabdomyolysis Needs emergency medical treatment and specialist care with intensive care input (ALT = alanine aminotransferase; AST = aspartate aminotransferase)

Viral infections • 245

11.36 Viral haemorrhagic fevers Disease Reservoir Transmission Incubation period Geography Mortality rate Clinical features of severe disease1 Lassa fever Multimammate rats (Mastomys natalensis) Urine from rat Body fluids from patients 6–21 days West Africa 15% Haemorrhage, shock, encephalopathy, ARDS (responds to ribavirin), deafness in survivors Ebola fever Fruit bats (Pteropodidae family) and bush meat Body fluids from patients Handling infected primates 2–21 days Central Africa Outbreaks as far north as Sudan 25–90% Haemorrhage and/or diarrhoea, hepatic failure and acute kidney injury Marburg fever Undefined Body fluids from patients Handling infected primates 3–9 days Central Africa Outbreak in Angola 25–90% Haemorrhage, diarrhoea, encephalopathy, orchitis Yellow fever Monkeys Mosquitoes 3–6 days See Figure 11.13 ~15% Hepatic failure, acute kidney injury, haemorrhage Dengue Humans Aedes aegypti 2–7 days See Figure 11.13 < 10%2 Haemorrhage, shock Crimean–Congo haemorrhagic fever Small vertebrates Ixodes tick 1–3 days up to 9 days Africa, Asia, Eastern Europe 30% Encephalopathy, early haemorrhage, hepatic failure, acute kidney injury, ARDS Domestic and wild animals Body fluids 3–6 days up to 13 days Rift Valley fever Domestic livestock Contact with animals, mosquito or other insect bites 2–6 days Africa, Arabian peninsula 1% Haemorrhage, blindness, meningoencephalitis (complications only in a minority) Kyasanur fever Monkeys Ticks 3–8 days Karnataka State, India 5–10% Haemorrhage, pulmonary oedema, neurological features, iridokeratitis in survivors Bolivian and Argentinian haemorrhagic fever (Junin and Machupo viruses) Rodents (Calomys spp.) Urine, aerosols Body fluids from case (rare) 5–19 days (3–6 days for parenteral) South America 15–30% Haemorrhage, shock, cerebellar signs (may respond to ribavirin) Haemorrhagic fever with renal syndrome (Hantaan fever) Rodents Aerosols from faeces 5–42 days (typically 14 days) Northern Asia, northern Europe, Balkans 5% Acute kidney injury, cerebrovascular accidents, pulmonary oedema, shock (hepatic failure and haemorrhagic features only in some variants) 1All potentially have circulatory failure. 2Mortality of uncomplicated and haemorrhagic dengue fever, respectively. (ARDS = acute respiratory distress syndrome) Diagnosis The differential diagnosis includes malaria, typhoid, viral hepatitis, leptospirosis, haemorrhagic fevers and aflatoxin poisoning. Diagnosis of yellow fever can be confirmed by detection of virus in the blood in the first 3–4 days of illness (e.g. by culture or reverse transcription polymerase chain reaction (RT-PCR)), the presence of IgM or a fourfold rise in IgG antibody titre. Leucopenia is characteristic. Liver biopsy should be avoided in life due to the risk of fatal bleeding. Postmortem features, such as acute mid-zonal necrosis and Councilman bodies with minimal inflammation in the liver, are suggestive but not specific. Immunohistochemistry for viral antigens improves specificity. Management and prevention Treatment is supportive, with meticulous attention to fluid and electrolyte balance, urine output and blood pressure. Blood transfusions, plasma expanders and peritoneal dialysis may be necessary. Patients should be isolated, as their blood and body products may contain virus particles. A single vaccination with a live attenuated vaccine gives full protection for at least 10 years and many travellers do not require a booster unless specified by individual countries’ travel requirements. Potential side-effects include hypersensitivity, encephalitis and systemic features of yellow fever (viscerotropic disease) caused by the attenuated virus. Vaccination is not recommended in people who are significantly immunosuppressed. The risk of vaccine side-effects must be balanced against the risk of infection for less immunocompromised hosts, pregnant women and older patients. An internationally recognised certificate of vaccination is sometimes necessary when crossing borders. Viral haemorrhagic fevers Viral haemorrhagic fevers (VHFs) are zoonoses caused by several different viruses (Box 11.36). They are geographically restricted and previously occurred in rural settings or in health-care facilities. The largest outbreak of VHF to date started in 2014, with Ebola

246 • INFECTIOUS DISEASE treated as being at high risk of VHF; appropriate infection control measures must be implemented and the patient transferred to a centre with biosafety level (BSL) 4 facilities if testing positive. Individuals with a history of travel within 21 days and fever, but without the relevant epidemiological features or signs of VHF, are classified as medium-risk and should have an initial blood sample tested to exclude malaria. If this is negative, relevant specimens (blood, throat swab, urine and pleural fluid, if available) are collected and sent to an appropriate reference laboratory for nucleic acid detection (PCR), virus isolation and serology. If patients are still felt to be at significant risk of VHF or if infection is confirmed, they should be transferred to a specialised high-security infectious disease unit. All further laboratory tests should be performed at BSL 4. Transport requires an ambulance with BSL 3 facilities. In addition to general supportive measures, ribavirin is given intravenously (100 mg/kg, then 25 mg/kg daily for 3 days and 12.5 mg/kg daily for 4 days) when Lassa fever or South American haemorrhagic fevers are suspected. Prevention Ribavirin has been used as prophylaxis in close contacts in Lassa fever but there are no formal trials of its efficacy. Ebola virus disease (EVD) Ebola virus disease (EVD) is thought to spread to human populations from fruit bats, sometimes indirectly via contact with infected primates or other animals. Person-to-person spread, via contact with blood, secretions or body parts, establishes EVD in populations. Family members, health-care workers and people performing traditional burials are at particular risk. The 2014 outbreak involved the Zaire strain of Ebola virus. Clinical features The incubation period is 2–21 days but typically 8–10 days. Fever and non-specific signs are accompanied by abdominal pain, diarrhoea, vomiting and hiccups. A maculopapular rash occurs after 5–7 days in some. Although bleeding from the gums or venepuncture sites or in the stool occurs, haemorrhage may be less prominent than in other VHFs and is often a terminal event, as observed in the 2014 epidemic. In contrast, fluid losses from diarrhoea are more marked and reach 10 L a day. Complications include meningoencephalitis, uveitis and miscarriages in pregnant women. Investigations Lymphopenia occurs, followed by neutrophilia, atypical lymphocytes, thrombocytopenia and coagulation abnormalities. Elevations of AST/ALT, features of acute kidney injury, electrolyte disturbances and proteinuria are also observed. The virus is detected by a PCR in blood or body fluids, but may need retesting if the duration of symptoms is less than 3 days. Serology provides a retrospective diagnosis. Management Treatment is supportive and aimed at fluid replacement. Bacterial super-infections should be promptly treated. A cocktail of monoclonal antibodies against Ebola virus, ZMapp, has been used in a few cases, but efficacy requires further studies. Mortality is approximately 40%. Survivors recover from the second week of illness but experience late sequelae, including arthritis (76%), uveitis (60%) and deafness (24%), while skin sloughing is common. Relapse with meningitis is reported months after recovery. circulating in Guinea, Liberia and Sierra Leone. The outbreak resulted in over 28 000 cases by 2016. Serological surveys have shown that Lassa fever is widespread in West Africa and may lead to up to 500 000 infections annually. Mortality overall may be low, as 80% of cases are asymptomatic, but in hospitalised cases mortality averages 15%. Ebola outbreaks have occurred at a rate of approximately one per year in Africa, involving up to a few hundred cases prior to the 2014 outbreak. Marburg has been documented less frequently, with outbreaks in the Democratic Republic of Congo and Uganda, but the largest outbreak to date involved 163 cases in Angola in 2005. Mortality rates of Ebola and Marburg are high. VHFs have extended into Europe, with an outbreak of Congo– Crimean haemorrhagic fever (CCHF) in Turkey in 2006, and cases of haemorrhagic fever with renal syndrome in the Balkans and Russia. An outbreak of CCHF in 2011 in Gujarat, India, involved several health-care workers and emphasised the importance of maintaining a high index of suspicion for VHF and implementing appropriate infection control measures at the first opportunity. Kyasanur forest disease is a tick-borne VHF currently confined to a small focus in Karnataka, India; there are about 500 cases annually. Monkeys are the principal hosts but, with forest felling, there are fears that this disease will increase. New outbreaks and new agents are identified sporadically. Details on recent disease outbreaks can be found at the WHO website (see ‘Further information’). Clinical features VHFs present with non-specific fever, malaise, body pains, sore throat and headache. On examination, conjunctivitis, throat injection, an erythematous or petechial rash, haemorrhage, lymphadenopathy and bradycardia may be noted. The viruses cause endothelial dysfunction with the development of capillary leak. Bleeding is due to endothelial damage and platelet dysfunction. Hypovolaemic shock and ARDS may develop (p. 198). Haemorrhage is a late feature of most VHFs and most patients present with earlier features. In Lassa fever, joint and abdominal pain is prominent. A macular blanching rash may be present but bleeding is unusual, occurring in only 20% of hospitalised patients. Encephalopathy may develop and deafness affects 30% of survivors. In CCHF, bleeding, manifest by haematemesis or bleeding per rectum, may be an early feature, accompanied by derangement of LFTs. The clue to the viral aetiology comes from the travel and exposure history. Travel to an outbreak area, activity in a rural environment and contact with sick individuals or animals within 21 days all increase the risk of VHF. Enquiry should be made about insect bites, hospital visits and attendance at ritual funerals (Ebola virus infection). For Lassa fever, retrosternal pain, pharyngitis and proteinuria have a positive predictive value of 80% in West Africa. Investigations and management Non-specific findings include leucopenia, thrombocytopenia and proteinuria. In Lassa fever, an AST of > 150 U/L is associated with a 50% mortality. It is important to exclude other causes of fever, especially malaria, typhoid and respiratory tract infections. Most patients suspected of having a VHF in the UK turn out to have malaria. A febrile patient from an endemic area within the 21-day incubation period, who has specific epidemiological risk factors (see Fig. 11.6) or signs of organ failure or haemorrhage, should be

Viral infections • 247

Prevention Prevention focuses on avoiding mosquito bites. Since Zika virus may be found in the semen or genital secretions for prolonged periods, infected individuals should practise safe sex for at least 6 months and planned pregnancy should be postponed for at least 6 months. Individuals who have travelled to an endemic area but are asymptomatic should practise safe sex and avoid pregnancy for at least 2 months. As this is an evolving area, updated guidance should be sought. There is currently no vaccine. Viral infections of the skin Herpes simplex virus 1 and 2 Herpes simplex viruses (HSVs) cause recurrent mucocutaneous infection; HSV-1 typically involves the mucocutaneous surfaces of the head and neck (Fig. 11.14), while HSV-2 predominantly involves the genital mucosa (pp. 333 and 336), although there is overlap (see Box 11.29). The seroprevalence of HSV-1 is 30–100%, varying by socioeconomic status, while that of HSV-2 is 20–60%. Infection is acquired by inoculation of viruses shed by an infected individual on to a mucosal surface in a susceptible person. The virus infects sensory and autonomic neurons and establishes latent infection in the nerve ganglia. Primary infection is followed by episodes of reactivation throughout life. Clinical features Primary HSV-1 or 2 infection is more likely to be symptomatic later in life, causing gingivostomatitis, pharyngitis or painful genital tract lesions. The primary attack may be associated with fever and regional lymphadenopathy. Recurrence Recurrent attacks occur throughout life, most often in association with concomitant medical illness, menstruation, mechanical trauma, immunosuppression, psychological stress or, for oral lesions, ultraviolet light exposure. HSV reactivation in the oral mucosa produces the classical ‘cold sore’ or ‘herpes labialis’. Prodromal hyperaesthesia is followed by rapid vesiculation, pustulation and crusting. Recurrent HSV genital disease is a common cause of recurrent painful ulceration (pp. 333 and 336). An inoculation lesion on the finger gives rise to a paronychia, termed a ‘whitlow’, in contacts of patients with herpetic lesions (Fig. 11.14B). Prevention Ebola virus may be detected in the semen months after recovery. Male survivors are therefore encouraged to practise safe sex for 12 months after symptom onset or until semen tests negative on two occasions, but recommendations are evolving. Public health measures are essential for outbreak control and involve contact surveillance and monitoring through the incubation period, separating healthy from sick individuals, practising safe burial methods and ensuring appropriate infection control measures to protect health-care and laboratory workers, including provision of personal protective equipment such as gloves, gowns and full-face protection (face shield or masks combined with goggles). An Ebola glycoprotein vaccine, rVZV-ZEBOV, was shown to be effective in 2016 after a trial in West Africa. Zika virus Zika virus is a flavivirus spread from primate hosts by Aedes aegypti and Aedes albopictus, which bite during the day. Described in Africa and Asia since 2015, it has been epidemic in the Caribbean and Central and South America, where a mosquito–man–mosquito transmission cycle is established. It also can be transmitted in semen. Clinical features The incubation period is 3–12 days. Infection is asymptomatic or mild, resembling dengue with fever, arthralgia, conjunctivitis and maculopapular rash. Complications include increased reports of Guillain–Barré syndrome. The major concern has been a marked increase in microcephaly in pregnant women infected with Zika virus, as well as increased rates of cerebral calcification, deafness, visual problems such as chorioretinal scarring, joint contractures (arthrogryposis), hydrops fetalis and growth retardation. Zika virus appears to infect neural progenitor cells. Investigations Routine blood tests are usually normal but may show leucopenia, thrombocytopenia or increased transaminases. PCR detects virus in the first week of illness or in urine up to 14 days. Serology provides a retrospective diagnosis but cross-reacts with other flaviruses. Plaque-reduction neutralisation testing can be used to detect virus-specific neutralising antibodies and distinguish between cross-reacting antibodies in primary flavivirus infections. Fig. 11.14 Cutaneous manifestations of herpes simplex virus 1 (HSV-1). A Acute HSV-1. There were also vesicles in the mouth – herpetic stomatitis. B Herpetic whitlow. C Eczema herpeticum. HSV-1 infection spreads rapidly in eczematous skin. A B C

248 • INFECTIOUS DISEASE appear on buttocks and thighs. Antiviral treatment is not available and management consists of symptom relief with analgesics. Herpangina This infection, caused by Coxsackie viruses, primarily affects children and teenagers in the summer months. It is characterised by a small number of vesicles at the soft/hard palate junction, often associated with high fever, an extremely sore throat and headache. The lesions are short-lived, rupturing after 2–3 days and rarely persisting for more than 1 week. Treatment is with analgesics if required. Culture of the virus from vesicles or DNA detection by PCR differentiates herpangina from HSV. Poxviruses These DNA viruses are rare but potentially important pathogens. Smallpox (variola) Smallpox, which has high mortality, was eradicated worldwide by a global vaccination programme but interest has re-emerged due to its potential as a bioweapon. The virus is spread by the respiratory route or contact with lesions, and is highly infectious. The incubation period is 7–17 days. A prodrome with fever, headache and prostration leads, in 1–2 days, to the rash, which develops through macules and papules to vesicles and pustules, worst on the face and distal extremities. Lesions in one area are all at the same stage of development with no cropping (unlike chickenpox). Vaccination can lead to a modified course of disease with milder rash and lower mortality. If a case of smallpox is suspected, national public health authorities must be contacted. Electron micrography (like Fig. 11.15) and DNA detection tests (PCR) are used to confirm diagnosis. Monkeypox Despite the name, the animal reservoirs for this virus are probably small squirrels and rodents. It causes a rare zoonotic infection in communities in the rainforest belt of Central Africa, producing a vesicular rash that is indistinguishable from smallpox, but differentiated by the presence of lymphadenopathy. Little person-to-person transmission occurs. Outbreaks outside Complications Disseminated cutaneous lesions can occur in individuals with underlying dermatological diseases, such as eczema (eczema herpeticum) (Fig. 11.14C). Herpes keratitis presents with pain and blurring of vision; characteristic dendritic ulcers are visible on slit-lamp examination and may produce corneal scarring and permanent visual impairment. Primary HSV-2 can cause meningitis or transverse myelitis. HSV is the leading cause of sporadic viral encephalitis (p. 1121); this follows either primary or secondary disease, usually with HSV-1. A haemorrhagic necrotising temporal lobe cerebritis produces temporal lobe epilepsy and altered consciousness/ coma. Without treatment, mortality is 80%. HSV is also implicated in the pathogenesis of Bell’s palsy with a lower motor neuron 7th nerve palsy, although antivirals have not been demonstrated to improve outcome. Neonatal HSV disease is usually associated with primary infection of the mother at term (see Box 11.26). In excess of two-thirds of cases develop disseminated disease with cutaneous lesions, hepatitis, pneumonitis and frequently encephalitis. Immunocompromised hosts can develop visceral disease with oesophagitis, hepatitis, pneumonitis, encephalitis or retinitis. Diagnosis Differentiation from other vesicular eruptions is achieved by demonstration of virus in vesicular fluid, usually by direct immunofluorescence or PCR. HSV encephalitis is diagnosed by a positive PCR for HSV in CSF. Serology is of limited value. Management Therapy of localised disease must commence in the first 48 hours of clinical disease (primary or recurrent); thereafter it is unlikely to influence clinical outcome. Oral lesions in an immunocompetent individual may be treated with topical aciclovir. All severe manifestations should be treated, regardless of the time of presentation (see Box 11.30). Suspicion of HSV encephalopathy requires immediate empirical antiviral therapy. Aciclovir resistance is encountered occasionally in immunocompromised hosts, in which case foscarnet is the treatment of choice. Human herpesvirus 8 Human herpesvirus 8 (HHV-8) (see Box 11.29) causes Kaposi’s sarcoma in both AIDS-related and endemic non-AIDS-related forms (p. 314). HHV-8 is spread via saliva, and men who have sex with men have an increased incidence of infection. Seroprevalence varies widely, being highest in sub-Saharan Africa. HHV-8 also causes two rare haematological malignancies: primary effusion lymphoma and multicentric Castleman’s disease. Current antivirals are not effective. Enterovirus infections Hand, foot and mouth disease This systemic infection is caused by Coxsackie viruses usually, or occasionally by echoviruses. It affects children and occasionally adults, resulting in local or household outbreaks, particularly in the summer months. A relatively mild illness with fever and lymphadenopathy develops after an incubation period of approximately 10 days; 2–3 days later, a painful papular or vesicular rash appears on palmoplantar surfaces of hands and feet, with associated oral lesions on the buccal mucosa and tongue that ulcerate rapidly. A papular erythematous rash may Fig. 11.15 Electron micrograph of molluscum contagiosum, a poxvirus. Courtesy of Prof. Goura Kudesia, Northern General Hospital, Sheffield.

Viral infections • 249

Respiratory viral infections These infections are described on page 581. Adenoviruses, rhinoviruses and enteroviruses (Coxsackie viruses and echoviruses) often produce non-specific upper respiratory tract symptoms but may cause viral pneumonia. Parainfluenza and respiratory syncytial viruses cause upper respiratory tract disease, croup and bronchiolitis in small children and pneumonia in the immunocompromised. Respiratory syncytial virus also causes pneumonia in nursing home residents and may be associated with nosocomial pneumonia. Metapneumovirus and bocavirus cause upper and occasionally lower respiratory tract infection, especially in immunosuppressed individuals. The severe acute respiratory syndrome (SARS), caused by the SARS coronavirus, emerged as a major respiratory pathogen during an outbreak in 2002–2003, with 8000 cases and 10% mortality (p. 582). Middle East respiratory syndrome coronavirus (MERS-CoV) In 2012, a novel coronavirus, distantly related to the SARS coronavirus, caused several deaths connected with pneumonia in patients originating from the Middle East. The Middle East respiratory syndrome coronavirus (MERS-CoV) appears to be a zoonosis, involving transmission from bats to camels and then to humans. Over 20 countries have reported cases, although most cases have a history of travel to Saudi Arabia or other countries in the Arabian Peninsula. By 2016 there had been over 1700 reported cases. Clinical features The incubation period in person-to-person transmission is 2–14 (average 5) days. Any age may be infected but the severe form of MERS-CoV mainly occurs in patients over 50 with medical comorbidities. Initial symptoms are fever, chills, headache, myalgia, dry cough and dyspnoea. Abdominal pain and diarrhoea may be prominent. The mean period from symptom onset to hospitalisation is 4 days, and 5 days to intensive care unit admission. Illness is complicated by rapid development of respiratory failure and features of ARDS and multi-organ failure. Mortality is 35%. Diagnosis and management Laboratory features include lymphopenia, thrombocytopenia and raised lactate dehydrogenase (LDH). Diagnosis is confirmed by PCR of serum, nasopharyngeal or other respiratory samples. Serology may also be useful. Treatment is supportive. Strict infection control measures should be implemented for anyone with fever, severe respiratory illness and epidemiological risk factors. Patients should be managed in an airborne infection isolation room with contact and airborne infection control measures, including personal protective equipment for health-care workers. Viral infections with neurological involvement See also page 1121. Japanese B encephalitis This flavivirus is an important cause of endemic encephalitis in Japan, China, Russia, South-east Asia, India and Pakistan; outbreaks also occur elsewhere. There are 10 000–20 000 cases reported to the WHO annually. Pigs and aquatic birds are the Africa have been linked to importation of African animals as exotic pets. Diagnosis is by electron micrography or DNA detection (PCR). Cowpox Humans in contact with infected cows develop large vesicles, usually on the hands or arms and associated with fever and regional lymphadenitis. The reservoir is thought to be wild rodents. Vaccinia virus This laboratory strain is the basis of the existing vaccine to prevent smallpox. Widespread vaccination is no longer recommended due to the likelihood of local spread from the vaccination site (potentially life-threatening in those with eczema (eczema vaccinatum) or immune deficiency) and of encephalitis. However, vaccination may still be recommended for key medical staff. Other poxviruses: orf and molluscum contagiosum See page 1239 and Figure 11.15. Gastrointestinal viral infections Norovirus (Norwalk agent) Norovirus is the most common cause of infectious gastroenteritis in the UK and leads to outbreaks in hospital wards, cruise ships and military camps. Food handlers may transmit this virus, which is relatively resistant to decontamination procedures. The incubation period is 24–48 hours. High attack rates and prominent vomiting are characteristic. Diagnosis may be achieved by electron microscopy, antigen or DNA detection (PCR) in stool samples, although the characteristic clinical and epidemiological features mean that microbiological confirmation is not always necessary. The virus is highly infectious and cases should be isolated and environmental surfaces cleaned with detergents and disinfected with bleach. Astrovirus Astroviruses cause diarrhoea in small children and occasionally in immunocompromised adults. Rotavirus Rotaviruses infect enterocytes and are a major cause of diarrhoeal illness in young children worldwide. There are winter epidemics in developed countries, particularly in nurseries. Adults in close contact with cases may develop disease. The incubation period is 48 hours and patients present with watery diarrhoea, vomiting, fever and abdominal pain. Dehydration is prominent. Diagnosis is aided by commercially available enzyme immunoassay kits, which require fresh or refrigerated stool samples. Immunity develops to natural infection. Monovalent and multivalent vaccines have been licensed in many countries and have now demonstrated efficacy in large trials in Africa and the Americas. Hepatitis viruses (A–E) See Chapter 22. Other viruses Adenoviruses are frequently identified from stool culture and implicated as a cause of diarrhoea in children. They have also been linked to cases of intussusception.

250 • INFECTIOUS DISEASE (HAM) in a subset of those infected (see Box 23.57, p. 964). It is found mainly in Japan, the Caribbean, Central and South America, and the Seychelles. HAM or tropical spastic paraparesis occurs in less than 5% of those with chronic infection, and presents with gait disturbance, spasticity of the lower extremities, urinary incontinence, impotence and sensory disturbance. Myositis and uveitis may also occur with HTLV-1 infection. Serology, sometimes confirmed with PCR, establishes the diagnosis. Treatment is usually supportive. Viral infections with rheumatological involvement Rheumatological syndromes characterise a variety of viral infections ranging from exanthems, such as rubella and parvovirus B19 (p. 237), to blood-borne viruses, such as HBV and HIV-1 and the sequelae of EVD. Chikungunya virus Chikungunya is an alphavirus that causes fever, rash and arthropathy. It is found principally in Africa and Asia, including India. Humans and non-human primates are the main reservoir and the main vector is the Aedes aegypti mosquito. Cases occur in epidemics on a background of sporadic cases. In 2007, an outbreak extended as far north as Italy. The incubation period is 2–12 days. A period of fever may be followed by an afebrile phase and then recrudescence of fever. Children may develop a maculopapular rash. Adults are susceptible to arthritis, which causes early morning pain and swelling, most often in the small joints. Arthritis can persist for months and may become chronic in individuals who are positive for human leucocyte antigen (HLA)-B27. Related alphaviruses causing similar syndromes include Sindbis virus (Scandinavia and Africa), O’nyong-nyong virus (Central Africa), Ross River virus (Australia) and Mayaro virus (Caribbean and South America). Diagnosis is by serology but cross-reactivity between alphaviruses occurs. Treatment is symptomatic. Prion diseases Prions cause transmissible spongiform encephalopathies and are discussed on page 1126. Bacterial infections Bacterial infections of the skin, soft tissues and bones Most infections of the skin, soft tissues and bone are caused by either Staph. aureus or streptococci (mainly Strep. pyogenes) (see pp. 1019 and 1237). Staphylococcal infections Staphylococci are usually found colonising the anterior nares and skin. Some staphylococci produce coagulase, an enzyme that converts fibrinogen to fibrin in rabbit plasma, causing it to clot. Staph. aureus is coagulase-positive, and most other species are coagulase-negative. In modern laboratory practice, however, the identification of Staph. aureus rarely involves the coagulase test. virus reservoirs and transmission is by mosquitoes. Exposure to rice paddies is a recognised risk factor. Clinical features The incubation period is 4–21 days. Most infections are subclinical in childhood and 1% or less of infections lead to encephalitis. Initial systemic illness with fever, malaise and anorexia is followed by headache, photophobia, vomiting and changes in brainstem function. Other neurological features include meningism, seizures, cranial nerve palsies, flaccid or spastic paralysis and extrapyramidal syndromes. Mortality with neurological disease is 25%. Most children die from respiratory failure. Some 50% of survivors have neurological sequelae. Investigations, management and prevention Other infectious causes of encephalitis should be excluded (p. 1121). There is neutrophilia and often hyponatraemia. CSF analysis reveals lymphocytosis and elevated protein. Serological testing of serum and CSF aids diagnosis but may cross-react with dengue and other flaviviruses. Treatment is supportive. Vaccination is recommended for travellers to endemic areas during the monsoon. Some endemic countries include vaccination in their childhood schedules. West Nile virus This flavivirus is an important cause of neurological disease in an area that extends from Australia, India and Russia through Africa and Southern Europe and across to North America. The disease has an avian reservoir and a mosquito vector. Older people are at increased risk of neurological disease. Clinical features Most infections are asymptomatic. After 2–6 days’ incubation, a mild febrile illness and arthralgia may occur. A prolonged incubation may be seen in immunocompromised individuals. Children may develop a maculopapular rash. Neurological disease is seen in 1% and is characterised by encephalitis, meningitis or asymmetric flaccid paralysis with 10% mortality. Diagnosis and management Diagnosis is by serology or detection of viral RNA in blood or CSF. Serological tests may show cross-reactivity with other flaviviruses, including vaccine strains. Treatment is supportive. Enterovirus 71 Enterovirus 71 has caused outbreaks around the globe of enteroviral disease with hand, foot and mouth disease (p. 248) and aseptic meningitis. Some cases have been complicated by encephalitis with flaccid paralysis or by brainstem involvement and death. The virus can be isolated from vesicle fluid, stool or CSF, and viral RNA can be detected in CSF by RT-PCR. Nipah virus encephalitis Nipah virus is a paramyxovirus in the Henipavirus genus, which caused an epidemic of encephalitis amongst Malaysian pig farmers in 1999 and subsequently caused outbreaks in Bangladesh and India. Mortality is around 30%. Diagnosis is by PCR or serology. Human T-cell lymphotropic virus type I Human T-cell lymphotropic virus type I (HTLV-1) is a retrovirus that causes chronic infection with development of adult T-cell leukaemia/lymphoma (ATL) or HTLV-1-associated myelopathy

Bacterial infections • 251

(Fig. 11.17A). Prevention involves careful attention to hand hygiene, skin preparation and aseptic technique, and the use of topical and systemic antibiotic prophylaxis. Treatment is by drainage of any abscesses plus adequate dosage of antistaphylococcal antibiotics, done early, particularly if prosthetic implants have been inserted. Cannula-related infection Staphylococcal infection associated with cannula sepsis (Fig. 11.17B and p. 196) and thrombophlebitis is an important and common reason for morbidity following hospital admission. The Visual Infusion Phlebitis (VIP) score aids cannula evaluation (Box 11.37). Staphylococci have a predilection for plastic, rapidly Staph. aureus is the main cause of staphylococcal infections. Staph. intermedius is another coagulase-positive staphylococcus, which causes infection following dog bites. Among coagulasenegative organisms, Staph. epidermidis is the predominant commensal organism of the skin, and can cause severe infections in those with central venous catheters or implanted prosthetic materials. Staph. saprophyticus is part of the normal vaginal flora and causes urinary tract infections in sexually active young women. Others implicated in human infections include Staph. lugdunensis, Staph. schleiferi, Staph. haemolyticus and Staph. caprae. Coagulase-negative staphylococci are not usually identified to species level. Staphylococci are particularly dangerous if they gain access to the blood stream, having the potential to disseminate widely (Fig. 11.16). In any patient with staphylococcal bacteraemia, especially injection drug-users, the possibility of endocarditis must be considered (p. 527). Growth of Staph. aureus in blood cultures should not be dismissed as a ‘contaminant’ unless all possible underlying sources have been excluded and repeated blood culture is negative. Any evidence of spreading cellulitis indicates the urgent need for an antistaphylococcal antibiotic, such as flucloxacillin (unless there is a likely risk of MRSA). This is particularly true for mid-facial cellulitis, which can result in cavernous sinus thrombophlebitis. In addition, Staph. aureus can cause severe systemic disease due to the effects of toxin produced at superficial sites in the absence of tissue invasion by bacteria. Skin infections Staphylococcal infections cause ecthyma, folliculitis, furuncles, carbuncles, bullous impetigo and the scalded skin syndrome (pp. 1235–1237). They may also be involved in necrotising infections of the skin and subcutaneous tissues (p. 226). Wound infections Many wound infections are caused by staphylococci, which may significantly prolong post-operative hospital stays Fig. 11.16 Infections caused by Staphylococcus aureus. CNS Meningitis Brain abscess (neurosurgical infections in particular) Respiratory Pneumonia Lung abscess Empyema Cardiac Endocarditis Pericarditis Blood stream Blood-stream infection Metastatic abscesses Bone and joint Osteomyelitis Septic arthritis Intestinal Enterocolitis Multisystem Toxic shock syndrome Skin Wound infections Boils, styes, carbuncles, abscesses Fig. 11.17 Manifestations of skin infection with Staphylococcus aureus. A Wound infection. B Cannula-related infection. B A Adapted from Jackson A. Nursing Times 1997; 94:68–71. 11.37 How to assess an intravenous cannula using the Visual Infusion Phlebitis (VIP) score Clinical features Score Assessment and management IV site appears healthy

No signs of phlebitis Observe cannula One of the following is evident: Slight pain near IV site Slight redness near IV site

Possible first signs of phlebitis Observe cannula Two of the following are evident: Pain near IV site Erythema Swelling

Early stage of phlebitis Resite cannula ALL of the following are evident and extensive: Pain along path of cannula Erythema Induration

Medium stage of phlebitis Resite cannula Consider treatment ALL of the following are evident and extensive: Pain along path of cannula Erythema Induration Palpable venous cord

Advanced stage of phlebitis or start of thrombophlebitis Resite cannula Consider treatment ALL of the following are evident: Pain along path of cannula Erythema Induration Palpable venous cord Pyrexia

Advanced stage of thrombophlebitis Initiate treatment Resite cannula

252 • INFECTIOUS DISEASE Streptococcal infections Streptococci are oropharyngeal and gut commensals, which appear as Gram-positive cocci in chains (see Fig. 6.3, p. 102). They are classified by the pattern of haemolysis they produce on blood agar (see Fig. 6.4, p. 102), by their ‘Lancefield groups’ (Box 11.38) and more recently by speciation on matrix-assisted laser desorption/ionisation time-of-flight (MALDI-TOF) mass spectometry. Some streptococci (e.g. Strep. milleri group) defy simple classification. Group A streptococci (GAS) are the leading cause of bacterial pharyngitis. Although the presence of fever, tender anterior lymphadenopathy and purulent tonsillar exudate and the absence of cough make streptococcal pharyngitis more likely than viral infection, clinical features alone are unreliable for diagnosing streptococcal pharyngitis. GAS are also the major cause of cellulitis, erysipelas and impetigo (pp. 1237 and 1235). Groups C and G streptococci cause cellulitis, particularly in elderly, diabetic or immunocompromised patients. Group B streptococci (GBS) colonise the gut and vagina. They cause post-partum and neonatal sepsis, as well as other deep infections (infective endocarditis, septic arthritis, osteomyelitis etc.), especially in the elderly. Streptococcal scarlet fever Group A (or occasionally groups C and G) streptococci causing pharyngitis, tonsillitis or other infection may lead to scarlet fever, if the infecting strain produces a streptococcal pyrogenic exotoxin. Scarlet fever is most common in school-age children, but can also occur in young adults who have contact with young children. A diffuse erythematous rash occurs, which blanches on pressure (Fig. 11.19A), classically with circumoral pallor. The tongue, initially coated, becomes red and swollen (‘strawberry tongue’, Fig. 11.19B). The disease lasts about 7 days, the rash disappearing in 7–10 days, followed by a fine desquamation. Residual petechial lesions in the antecubital fossa may be seen (‘Pastia’s sign’, Fig. 11.19C). Treatment involves intravenous benzylpenicillin or an oral penicillin plus symptomatic measures. forming a biofilm on cannulae, which remains as a source of bacteraemia. Local poultice application may relieve symptoms but cannula removal and antibiotic treatment with flucloxacillin (or a glycopeptide if MRSA is suspected) are necessary if there is any suggestion of spreading infection. Meticillin-resistant Staph. aureus Resistance to meticillin is due to a penicillin-binding protein mutation in Staph. aureus. Resistance to vancomycin/teicoplanin (glycopeptides) in either glycopeptide intermediate Staph. aureus (GISA) or, rarely, vancomycin-resistant (VRSA) strains threatens the ability to manage serious infections produced by such organisms. Meticillin-resistant Staph. aureus (MRSA) is now a major worldwide health care-acquired pathogen, accounting for up to 40% of staphylococcal bacteraemia in developed countries. Community-acquired MRSA (c-MRSA) currently accounts for 50% of all MRSA infections in the USA. These organisms have also acquired other toxins, such as Panton–Valentine leukocidin (PVL), and cause rapidly fatal infection in young people. Clinicians must be aware of the potential danger of these infections and be prepared to take whatever appropriate infection control measures are locally advised (p. 111). Treatment options for MRSA are shown in Box 6.16 (p. 117). Treatment should always be based on the results of antimicrobial susceptibility testing, since resistance to all these agents occurs. Milder MRSA infections may be treated with clindamycin, tetracyclines or co-trimoxazole. Glycopeptides, linezolid and daptomycin are reserved for treatment of more severe infections. Toxin-producing MRSA infections should be treated with protein-inhibiting antibiotics (clindamycin, linezolid). Staphylococcal toxic shock syndrome Staphylococcal toxic shock syndrome (TSS) is a serious and life-threatening disease associated with infection by Staph. aureus, which produces a specific toxin (toxic shock syndrome toxin 1, TSST1). It was formerly seen in young women in association with the use of highly absorbent intravaginal tampons but can occur with any Staph. aureus infection involving a relevant toxin-producing strain. The toxin acts as a ‘superantigen’, triggering significant T-cell activation and massive cytokine release. TSS has an abrupt onset with high fever, generalised systemic upset (myalgia, headache, sore throat and vomiting), a widespread erythematous blanching rash resembling scarlet fever, and hypotension. It rapidly progresses over a few hours to multi-organ failure, leading to death in 10–20%. Recovery is accompanied at 7–10 days by desquamation (Fig. 11.18). The diagnosis is clinical and may be confirmed in menstrual cases by finding a retained tampon with staphylococci on Gram stain. Subsequent culture and demonstration of toxin production are confirmatory. Management Treatment is with immediate and aggressive fluid resuscitation and an intravenous antistaphylococcal antimicrobial (flucloxacillin or vancomycin), usually with the addition of a protein synthesis inhibitor (e.g. clindamycin) to inhibit toxin production. Intravenous immunoglobulin is occasionally added in the most severe cases. Women who recover from tampon-associated TSS should avoid tampons for at least 1 year and be advised that the condition can recur. Fig. 11.18 Full-thickness desquamation after staphylococcal toxic shock syndrome.

Bacterial infections • 253

11.38 Streptococcal and related infections β-haemolytic group A (Strep. pyogenes) • Skin and soft tissue infection (including erysipelas, impetigo, necrotising fasciitis) • Streptococcal toxic shock syndrome • Puerperal sepsis • Scarlet fever • Glomerulonephritis • Rheumatic fever • Bone and joint infection • Tonsillitis β-haemolytic group B (Strep. agalactiae) • Neonatal infections, including meningitis • Female pelvic infections • Cellulitis β-haemolytic group C (various zoonotic streptococci) • Cellulitis • Endocarditis • Pharyngitis • Septic arthritis α-, β- or non-haemolytic group D (Enterococcus faecalis, E. faecium) • Endocarditis • Intra-abdominal infections • Urinary tract infection α- or non-haemolytic group D (Strep. gallolyticus subsp. gallolyticus/S. bovis biotype I) • Bacteraemia/endocarditis associated with large bowel malignancy β-haemolytic group G streptococci • Cellulitis • Endocarditis • Liver abscess • Septic arthritis α-haemolytic optochin-resistant (viridans streptococci – Strep. mitis, Strep. sanguis, Strep. mutans, Strep. salivarius) • Sepsis in immunosuppressed • Endocarditis α-haemolytic optochin-sensitive (Strep. pneumoniae) • Pneumonia • Meningitis • Endocarditis • Otitis media • Sepsis • Spontaneous bacterial peritonitis • Sinusitis Variable haemolysis (Strep. milleri group – Strep. anginosus, Strep. intermedius, Strep. constellatus) • Endocarditis • Intra-abdominal infections • Urinary tract infection Anaerobic streptococci (Peptostreptococcus spp.) • Sepsis in immunosuppressed • Endocarditis N.B. All streptococci can cause sepsis. Fig. 11.19 Clinical features of scarlet fever. A Characteristic rash with blanching on pressure. B ‘Strawberry tongue’. C Pastia’s sign: a petechial rash in the cubital fossa. C B A Streptococcal toxic shock syndrome Group A (or occasionally group C or G) streptococci can produce one of a variety of toxins, such as pyogenic exotoxin A. Like staphylococcal TSST1 (see above), these act as super-antigens. Initially, an influenza-like illness occurs, with signs of localised infection in 50% of cases, most often involving the skin and soft tissues. A faint erythematous rash, mainly on the chest, rapidly progresses to circulatory shock. Without aggressive management, multi-organ failure will develop. Fluid resuscitation must be undertaken, along with parenteral antistreptococcal antibiotic therapy, usually with benzylpenicillin and clindamycin, to inhibit toxin production. Intravenous immunoglobulin is often administered. If necrotising fasciitis is present, it should be treated as described on page 227 with urgent débridement. Treponematoses Syphilis This disease is described on page 337. Endemic treponematoses Yaws Yaws is a granulomatous disease, mainly involving the skin and bones; it is caused by Treponema pertenue, morphologically and serologically indistinguishable from the causative organisms of syphilis and pinta. It is important to establish the geographical origin and sexual history of patients to exclude false-positive syphilis serology due to endemic treponemal infections. Between 1950 and 1960, WHO campaigns treated over 60 million people and eradicated yaws from many areas, but the disease has persisted patchily throughout the tropics; there was a resurgence in the 1980s and 1990s in West and Central Africa and the South Pacific. Organisms are transmitted by bodily contact from a patient with infectious yaws through minor abrasions of the skin of another patient, usually a child. After an incubation period of 3–4 weeks, a proliferative granuloma containing numerous treponemes develops at the site of inoculation. This primary lesion is followed by secondary eruptions. In addition, there may be hypertrophic periosteal lesions of many bones, with underlying cortical rarefaction. Lesions of late yaws are characterised

254 • INFECTIOUS DISEASE after 6 months but granuloma formation and the accompanying fibrosis cause contractures and deformity. Clumps of acid-fast bacilli can be detected in the ulcer floor. A combination of rifampicin and streptomycin can cure the infection. Infected tissue should be removed surgically. Health campaigns in Ghana have successfully focused on early removal of the small, pre-ulcerative nodules. Systemic bacterial infections Brucellosis Brucellosis is an enzootic infection (i.e. endemic in animals) caused by Gram-negative bacilli. The four species causing human disease and their animal hosts are: Brucella melitensis (goats, sheep and camels in Europe, especially the Mediterranean basin, the Middle East, Africa, India, Central Asia and South America), B. abortus (cattle, mainly in Africa, Asia and South America), B. suis (pigs in South Asia) and B. canis (dogs). B. melitensis causes the most severe disease; B. suis is often associated with abscess formation. Infected animals may excrete Brucella spp. in their milk for prolonged periods and human infection is acquired by ingesting contaminated dairy products (especially unpasteurised milk), uncooked meat or offal. Animal urine, faeces, vaginal discharge and uterine products may transmit infection through abraded skin or via splashes and aerosols to the respiratory tract and conjunctiva. Clinical features Brucella spp. are intracellular organisms that survive for long periods within the reticulo-endothelial system. This explains the disease chronicity and tendency to relapse, even after antimicrobial therapy. Acute illness is characterised by a high swinging temperature, rigors, lethargy, headache, joint and muscle pains, and scrotal pain. Occasionally, there is delirium, abdominal pain and constipation. Physical signs are non-specific, e.g. enlarged lymph nodes. Splenomegaly may cause thrombocytopenia. Localised infection (Fig. 11.20), which occurs in about 30% of patients, is more likely if diagnosis and treatment are delayed. Diagnosis Definitive diagnosis depends on culture of the organism. Blood cultures are positive in 75–80% of B. melitensis and 50% of B. abortus infections. Bone marrow culture is not routine but may increase the diagnostic yield if antibiotics have been used prior to culture. CSF culture in neurobrucellosis is positive in about 30% of cases. The laboratory should be alerted to a suspected diagnosis of brucellosis, as the organism may infect laboratory workers and must be cultured at the appropriate biosafety level. Serology may also aid diagnosis. In endemic areas, a single high antibody titre of more than 1/320 or a fourfold rise in titre is needed to support a diagnosis of acute infection. The test usually takes several weeks to become positive but should eventually detect 95% of acute infections. Management Aminoglycosides show synergistic activity with tetracyclines against brucellae. Treatment regimens for different forms of brucellosis are outlined in Box 11.40. by destructive changes that closely resemble the osteitis and gummas of tertiary syphilis and that heal with scarring and deformity. Investigations and management are outlined in Box 11.39. Improved housing and hygiene, combined with mass chemotherapy programmes, have achieved dramatic success in the control of yaws. Pinta and bejel These two treponemal infections occur in poor rural populations with low standards of domestic hygiene but are found in separate parts of the world. They have features in common, notably that they are transmitted by contact, usually within the family and not sexually, and in the case of bejel, through common eating and drinking utensils. Their diagnosis and management are as for yaws (Box 11.39). • Pinta. Pinta is found only in South and Central America, where its incidence is declining. The infection is confined to the skin. The early lesions are scaly papules or dyschromic patches on the skin. The late lesions are often depigmented and disfiguring. • Bejel. Bejel is the Middle Eastern name for non-venereal syphilis, which has a patchy distribution across subSaharan Africa, the Middle East, Central Asia and Australia. It has been eradicated from Eastern Europe. Transmission is most commonly from the mouth of the mother or child and the primary mucosal lesion is seldom seen. The early and late lesions resemble those of secondary and tertiary syphilis (p. 337) but cardiovascular and neurological disease is rare. Tropical ulcer Tropical ulcer is due to a synergistic bacterial infection caused by a fusobacterium (F. ulcerans, an anaerobe) and Treponema vincentii. It is common in hot, humid regions. The ulcer is most common on the lower legs and develops as a papule that rapidly breaks down to a sharply defined, painful ulcer. The base of the ulcer has a foul slough. Penicillin and metronidazole are useful in the early stages but rest, elevation and dressings are the mainstays of treatment. Buruli ulcer This ulcer is caused by Mycobacterium ulcerans and occurs widely in tropical rainforests. In 1999, a survey in Ghana found 6500 cases; there are an estimated 10 000 cases in West Africa as a whole. The initial lesion is a small subcutaneous nodule on the arm or leg. This breaks down to form a shallow, necrotic ulcer with deeply undermined edges, which extends rapidly. Healing may occur 11.39 Diagnosis and treatment of yaws, pinta and bejel Diagnosis of early stages • Detection of spirochaetes in exudate of lesions by dark ground microscopy Diagnosis of latent and early stages • Positive serological tests, as for syphilis (see Box 13.8, p. 339) Treatment of all stages • Single intramuscular injection of 1.2 g long-acting penicillin, e.g. benzathine benzylpenicillin

Bacterial infections • 255

Borrelia infections Borrelia are flagellated spirochaetal bacteria that infect humans after bites from ticks or lice. They cause a variety of human infections worldwide (Box 11.41). Lyme disease Lyme disease (named after the town of Old Lyme in Connecticut, USA) is caused by B. burgdorferi, which occurs in the USA, Europe, Russia, China, Japan and Australia. In Europe, two additional genospecies are also encountered, B. afzelii and B. garinii. The reservoir of infection is ixodid (hard) ticks that feed on a variety of large mammals, particularly deer. Birds may spread ticks over a wide area. The organism is transmitted to humans via the bite of infected ticks; larval, nymphal and adult forms are all capable of spreading infection. Ehrlichiosis is a common co-infection with Lyme disease. Two forms occur: Anaplasma phagocytophilum, human granulocytic anaplasmosis (HGA); and Ehrlichia chaffeensis, human monocytic ehrlichiosis (HME). Clinical features There are three stages of disease. Progression may be arrested at any stage. • Early localised disease. The characteristic feature is a skin reaction around the site of the tick bite, known as erythema migrans (Fig. 11.21). Initially, a red ‘bull’s eye’ macule or papule appears 2–30 days after the bite. It then enlarges peripherally with central clearing and may persist for months. Atypical forms are common. The lesion is not pathognomonic of Lyme disease since similar lesions can occur after tick bites. Acute manifestations, such as fever, headache and regional lymphadenopathy, may develop with or without the rash. Fig. 11.20 Clinical features of brucellosis. Malodorous perspiration Suppurative arthritis Synovitis, bursitis Osteomyelitis Spinal spondylitis or sacroiliitis Paravertebral or psoas abscess Meningitis Intracranial or subarachnoid haemorrhage Stroke Myelopathy Radiculopathy Cranial nerve palsies Uveitis Retinal thrombophlebitis Myocarditis Endocarditis Pneumonitis or abscesses Hilar lymphadenopathy Splenic abscesses or calcification Hepatitis Epididymo-orchitis Pancytopenia 11.40 Treatment of brucellosis Adults with non-localised disease • Doxycycline 100 mg twice daily orally for 6 weeks plus gentamicin 5 mg/kg IV once daily for 7 days or • Doxycycline 100 mg twice daily plus rifampicin 600–900 mg orally once daily for 6 weeks Bone disease • Doxycycline 100 mg twice daily plus rifampicin 600–900 mg once daily orally for 6 weeks plus gentamicin 5 mg/kg IV once daily for 7 days or • Ciprofloxacin 750 mg twice daily orally plus rifampicin 600–900 mg orally once daily for 3 months Neurobrucellosis • Doxycycline 100 mg twice daily plus rifampicin 600–900 mg orally once daily for 6 weeks plus ceftriaxone 2vg IV twice daily until the cerebrospinal fluid is clear (though susceptibility should be confirmed because sensitivity to third-generation cephalosporins varies among strains) Endocarditis • Almost always needs surgical intervention plus • Doxycycline 100 mg twice daily, rifampicin 600–900 mg orally once daily and co-trimoxazole 5 mg/kg of trimethoprim component for 6 months plus gentamicin 5 mg/kg IV once daily for 2–4 weeks Pregnancy • Rifampicin 600–900 mg orally once daily and co-trimoxazole 5 mg/ kg of trimethoprim component for 4 weeks, but caution in last week of pregnancy due to displacement of bilirubin from albumin by drugs and risk of kernicterus to the fetus

256 • INFECTIOUS DISEASE after initial infection. Carditis, sometimes accompanied by atrioventricular conduction defects, occurs in the USA but is rare in Europe. • Late disease. Late manifestations include arthritis, polyneuritis and encephalopathy. Prolonged arthritis, particularly affecting large joints, and brain parenchymal involvement, causing neuropsychiatric abnormalities, may occur but are rare in the UK. Acrodermatitis chronica atrophicans is an uncommon late complication seen more frequently in Europe than North America. Doughy, patchy discoloration occurs on the peripheries, eventually leading to shiny atrophic skin. The lesions are easily mistaken for those of peripheral vascular disease. In patients coming from an endemic area or having risk factors, who have facial nerve palsy, Lyme disease should be considered. Diagnosis The diagnosis of early Lyme borreliosis is often clinical. Culture from biopsy material is not generally available, has a low yield and may take longer than 6 weeks. Antibody detection is frequently negative early in the course of the disease but sensitivity increases to 90–100% in disseminated or late disease. Immunofluorescence or ELISA can give false-positive reactions in a number of conditions, including other spirochaetal infections, infectious mononucleosis, rheumatoid arthritis and systemic lupus erythematosus (SLE). Immunoblot (Western blot) techniques are more specific and, although technically demanding, should be used to confirm the diagnosis. Microorganism DNA detection by PCR has been applied to blood, urine, CSF and biopsies of skin and synovium. Management Recent evidence suggests that asymptomatic patients with positive antibody tests should not be treated. However, erythema migrans always requires therapy because organisms may persist and cause progressive disease, even if the skin lesions resolve. Standard therapy consists of a 14-day course of doxycycline (200 mg daily) or amoxicillin (500 mg 3 times daily). Some 15% of patients with early disease will develop a mild Jarisch–Herxheimer reaction (JHR) during the first 24 hours of therapy (p. 339). In pregnant women and small children with penicillin allergy, or in those allergic to amoxicillin and doxycycline, 14-day treatment with cefuroxime axetil (500 mg twice daily) or erythromycin (250 mg 4 times daily) may be used. Disseminated disease and arthritis require therapy for a minimum of 28 days. Arthritis may respond poorly and prolonged or repeated courses may be necessary. Neuroborreliosis is treated with parenteral β-lactam antibiotics for 3–4 weeks; thirdgeneration cephalosporins such as ceftriaxone are the preferred therapy. Prevention Protective clothing and insect repellents should be used in tick-infested areas. Since the risk of borrelial transmission is lower in the first few hours of a blood feed, prompt removal of ticks is advisable. Unfortunately, larval and nymphal ticks are tiny and may not be noticed. Where risk of transmission is high, a single 200 mg dose of doxycycline, given within 72 hours of exposure, has been shown to prevent erythema migrans. Fig. 11.21 Rash of erythema migrans in Lyme disease with metastatic secondary lesions. Courtesy of Dr Ravi Gowda, Royal Hallamshire Hospital, Sheffield. 11.41 Clinical diseases caused by Borrelia spp. Species Vector Geographical distribution Lyme disease B. burgdorferi sensu stricto Tick: Ixodes scapularis Northern and eastern USA I. pacificus Western USA B. afzelii I. ricinus Europe I. persulcatus Asia B. garinii I. ricinus Europe I. persulcatus Asia Louse-borne relapsing fever B. recurrentis Human louse: Pediculus humanus corporis Worldwide Tick-borne relapsing fever B. hermsii Tick: Ornithodoros hermsii Western North America B. turicatae O. turicatae South-western North America and northern Mexico B. venezuelensis O. rudis Central America and northern South America B. hispanica O. erraticus Iberian peninsula and north-western Africa B. crocidurae O. erraticus North Africa and Mediterranean region B. duttonii O. moubata Central, eastern and southern Africa B. persica O. tholozani Western China, India, Central Asia, Middle East B. latyschewii O. tartakovskyi Tajikistan, Uzbekistan • Early disseminated disease. Dissemination occurs via the blood stream and lymphatics. There may be a systemic reaction with malaise, arthralgia and, occasionally, metastatic areas of erythema migrans (Fig. 11.21). Neurological involvement may follow weeks or months after infection. Common features include lymphocytic meningitis, cranial nerve palsies (especially unilateral or bilateral facial nerve palsy) and peripheral neuropathy. Radiculopathy, often painful, may present a year or more

Bacterial infections • 257

Tick-borne relapsing fever Soft ticks (Ornithodoros spp.) transmit B. duttonii (and other Borrelia species) through saliva while feeding on their host. People sleeping in mud houses are at risk, as the tick hides in crevices during the day and feeds on humans during the night. Rodents are the reservoir in all parts of the world except East Africa, where humans are the reservoir. Clinical manifestations are similar to those seen with the louse-borne disease but microorganisms are detected in fewer patients on dark field microscopy. A 7-day course (due to a higher relapse rate than in louse-borne relapsing fever) of treatment with either tetracycline (500 mg 4 times daily) or erythromycin (500 mg 4 times daily) is needed. Leptospirosis Microbiology and epidemiology Leptospirosis is one of the most common zoonotic diseases, favoured by a tropical climate and flooding during the monsoon but occurring worldwide. Leptospires are tightly coiled, thread-like organisms about 5–7 μm in length, which are actively motile; each end is bent into a hook. Leptospira interrogans is pathogenic for humans. The genus can be separated into more than 200 serovars (subtypes) belonging to 23 serogroups. Leptospirosis appears to be ubiquitous in wildlife and in many domestic animals. The organisms persist indefinitely in the convoluted tubules of the kidney and are shed into the urine in massive numbers, but infection is asymptomatic in the host. The most frequent hosts are rodents, especially the common rat (Rattus norvegicus). Particular leptospiral serogroups are associated with characteristic animal hosts; for example, L. ictero-haemorrhagiae is the classical parasite of rats and L. canicola of dogs. There is nevertheless considerable overlap in host–serogroup associations. Leptospires can enter their human hosts through intact skin or mucous membranes but entry is facilitated by cuts and abrasions. Prolonged immersion in contaminated water will also favour invasion, as the spirochaete can survive in water for months. Leptospirosis is common in the tropics and also in freshwater sports enthusiasts. Clinical features After a relatively brief bacteraemia, invading organisms are distributed throughout the body, mainly in kidneys, liver, meninges and brain. The incubation period averages 1–2 weeks. Four main clinical syndromes can be discerned and clinical features can involve multiple different organ systems (Fig. 11.23). Bacteraemic leptospirosis Bacteraemia with any serogroup can produce a non-specific illness with high fever, weakness, muscle pain and tenderness (especially of the calf and back), intense headache and photophobia, and sometimes diarrhoea and vomiting. Conjunctival congestion is the only notable physical sign. The illness comes to an end after about 1 week, or else merges into one of the other forms of infection. Aseptic meningitis Classically associated with L. canicola infection, this illness is very difficult to distinguish from viral meningitis. The conjunctivae may be congested but there are no other differentiating signs. Laboratory clues include a neutrophil leucocytosis, abnormal LFTs, and the occasional presence of albumin and casts in the urine. Louse-borne relapsing fever The human body louse, Pediculus humanus, causes itching. Borreliae (B. recurrentis) are liberated from infected lice when they are crushed during scratching, which also inoculates the borreliae into the skin. The disease occurs worldwide, with epidemic relapsing fever most often seen in Central/East Africa and South America. The borreliae multiply in the blood, where they are abundant in the febrile phases, and invade most tissues, especially the liver, spleen and meninges. Clinical features Onset is sudden with fever. The temperature rises to 39.5–40.5°C, accompanied by a tachycardia, headache, generalised aching, injected conjunctivae (Fig. 11.22) and herpes labialis. Thrombocytopenia is associated with a petechial rash and epistaxis. As the disease progresses tender hepatosplenomegaly, accompanied by jaundice and elevated transaminases, is common. There may be severe serosal and intestinal haemorrhage, delirium and meningism. The fever ends in crisis between the fourth and tenth days, often associated with profuse sweating, hypotension and circulatory and cardiac failure. There may be no further fever but, in a proportion of patients, after an afebrile period of about 7 days, there are one or more relapses, which are usually milder and less prolonged. In the absence of specific treatment, the mortality rate is up to 40%, especially among the elderly and malnourished. Investigations and management Dark ground microscopy of a wet film or Wright–Giemsa stained thick and thin films demonstrate the organism in blood from a febrile patient. Treatment aims to eradicate the organism and prevent relapses, while minimising the severe JHR that inevitably follows successful chemotherapy. The safest treatment is procaine penicillin 300 mg IM, followed the next day by 0.5 g tetracycline. Tetracycline alone is effective and prevents relapse, but may give rise to a worse reaction. Doxycycline 200 mg once orally in place of tetracycline has the advantage of also being curative for typhus, which often accompanies epidemics of relapsing fever. JHR is best managed in a high-dependency unit with expert nursing and medical care. The patient, clothing and all contacts must be freed from lice, as in epidemic typhus. Fig. 11.22 Louse-borne relapsing fever. Injected conjunctivae.

258 • INFECTIOUS DISEASE elevated protein level and normal glucose content. Acute kidney injury due to interstitial nephritis is common. In the tropics, dengue, malaria, typhoid fever, scrub typhus and hantavirus infection are important differential diagnoses. Definitive diagnosis of leptospirosis depends on isolation of the organism, serological tests or detection of specific DNA. In general, however, it is probably under-diagnosed. • Blood cultures are most likely to be positive if taken before the 10th day of illness. Special media are required and cultures may have to be incubated for several weeks. • Leptospires appear in the urine during the second week of illness, and in untreated patients may be recovered on culture for several months. • Serological tests are diagnostic if seroconversion or a fourfold increase in titre is demonstrated. The microscopic agglutination test (MAT) is the investigation of choice and can become positive by the end of the first week. IgM ELISA and immunofluorescent techniques are easier to perform, however, while rapid immunochromatographic tests are specific but of only moderate sensitivity in the first week of illness. • Detection of leptospiral DNA by PCR is possible in blood in early symptomatic disease, and in urine from the eighth day of illness and for many months thereafter. Management and prevention The general care of the patient is critically important. Blood transfusion for haemorrhage and careful attention to renal function, the usual cause of death, are especially important. Acute kidney injury is potentially reversible with adequate support, such as dialysis. Most infections are self-limiting. Therapy with either oral doxycycline (100 mg twice daily for 1 week) or intravenous penicillin (900 mg 4 times daily for 1 week) is effective but may not prevent the development of renal failure. Parenteral ceftriaxone (1 g daily) is as effective as penicillin. JHR may occur but is usually Icteric leptospirosis (Weil’s disease) Fewer than 10% of symptomatic infections result in severe icteric illness. Weil’s disease is a dramatic life-threatening event, characterised by fever, haemorrhages, jaundice and acute kidney injury. Conjunctival hyperaemia is a frequent feature. The patient may have a transient macular erythematous rash but the characteristic skin changes are purpura and large areas of bruising. In severe cases there may be epistaxis, haematemesis and melaena, or bleeding into the pleural, pericardial or subarachnoid spaces. Thrombocytopenia, probably related to activation of endothelial cells with platelet adhesion and aggregation, is present in 50% of cases. Jaundice is deep and the liver is enlarged but there is usually little evidence of hepatic failure or encephalopathy. Acute kidney injury, primarily caused by impaired renal perfusion and acute tubular necrosis, manifests as oliguria or anuria, with the presence of albumin, blood and casts in the urine. Weil’s disease may also be associated with myocarditis, encephalitis and aseptic meningitis. Uveitis and iritis may appear months after apparent clinical recovery. Pulmonary syndrome This syndrome has long been recognised in the Far East and has been described during an outbreak of leptospirosis in Nicaragua. It is characterised by haemoptysis, patchy lung infiltrates on chest X-ray, and respiratory failure. Total bilateral lung consolidation and ARDS (p. 324) with multi-organ dysfunction may develop, with a high mortality (over 50%). Diagnosis A polymorphonuclear leucocytosis is accompanied in severe infection by thrombocytopenia and elevated blood levels of creatine kinase. In jaundiced patients, there is hepatitis and the prothrombin time may be prolonged. The CSF in leptospiral meningitis shows a variable cellular response, a moderately Fig. 11.23 Clinical syndromes of leptospirosis. (ARDS = acute respiratory distress syndrome) Headache Photophobia Aseptic meningitis Bacteraemic leptospirosis Pulmonary syndrome Weil’s disease Epistaxis Haematemesis Conjunctivitis Uveitis Jaundice Pericarditis/ myocarditis/ vasculiitis Myositis Diarrhoea Vomiting Haemoptysis Pulmonary haemorrhage ARDS Hepatomegaly Renal failure Transient macular rash Purpura Bruising

Bacterial infections • 259

The patient is toxic and may have gastrointestinal symptoms, such as nausea, vomiting, abdominal pain and diarrhoea. DIC may occur, manifested by bleeding from various orifices or puncture sites, along with ecchymoses. Hypotension, shock, renal failure and ARDS may lead to further deterioration. Meningitis, pneumonia and expectoration of blood-stained sputum containing Y. pestis may complicate septicaemic, or occasionally bubonic, plague. Pneumonic plague Following primary infection in the lung, the onset of disease is very sudden, with cough and dyspnoea. The patient soon expectorates copious blood-stained, frothy, highly infective sputum, becomes cyanosed and dies. Chest radiology reveals bilateral infiltrates, which may be nodular and progress to an ARDS-like picture. Investigations The organism may be cultured from blood, sputum and bubo aspirates. For rapid diagnosis, Gram, Giemsa and Wayson’s stains (the latter containing methylene blue) are applied to smears from these sites. Y. pestis is seen as bipolar staining coccobacilli, sometimes referred to as having a ‘safety pin’ appearance. Smears are also subjected to antigen detection by immunofluorescence, using Y. pestis F1 antigen-specific antibodies. The diagnosis may be confirmed by seroconversion or a single high titre (> 128) of anti-F1 antibodies in serum. DNA detection by PCR is under evaluation. Plague is a notifiable disease under international health regulations (p. 114). Management If the diagnosis is suspected on clinical and epidemiological grounds, treatment must be started as soon as, or even before, samples have been collected for laboratory diagnosis. Streptomycin (1 g twice daily) or gentamicin (1 mg/kg 3 times daily) is the drug of choice. Tetracycline (500 mg 4 times daily) and chloramphenicol (12.5 mg/kg 4 times daily) are alternatives. Fluoroquinolones (ciprofloxacin and levofloxacin) may be as effective but there is less clinical experience. Treatment may also be needed for acute circulatory failure, DIC and hypoxia. Prevention and infection control Rats and fleas should be controlled. In endemic areas, people should avoid handling and skinning wild animals. The patient should be isolated for the first 48 hours or until clinical improvement begins. Attendants must wear gowns, masks and gloves. Exposed symptomatic or asymptomatic people who have been in close contact with a patient with pneumonic plague should receive post-exposure antibiotic prophylaxis (doxycycline 100 mg or ciprofloxacin 500 mg twice daily) for 7 days. A recombinant subunit vaccine (protein antigens F1 + V) is in development. Listeriosis Listeria monocytogenes is an environmental Gram-positive bacillus that can contaminate food. Outbreaks have been associated with raw vegetables, soft cheeses, under-cooked chicken, fish, meat and pâtés. The bacterium demonstrates ‘cold enrichment’, outgrowing other contaminating bacteria during refrigeration. Although food-borne outbreaks of gastroenteritis have been reported in immunocompetent individuals, Listeria causes more significant invasive infection, especially in pregnant women, older adults (over 55 years) and the immunocompromised. mild. Uveitis is treated with a combination of systemic antibiotics and local glucocorticoids. There is no role for the routine use of glucocorticoids in the management of leptospirosis. Trials in military personnel have shown that infection with L. interrogans can be prevented by taking prophylactic doxycycline 200 mg weekly. Plague Plague is caused by Yersinia pestis, a small Gram-negative bacillus that is spread between rodents by their fleas. If domestic rats become infected, infected fleas may bite humans. Hunters and trappers can contract plague from handling rodents. In the late stages of human plague, Y. pestis may be expectorated and spread between humans by droplets, causing ‘pneumonic plague’. Epidemics of plague, such as the ‘Black Death’, have occurred since ancient times. It is often said that the first sign of plague is the appearance of dead rats. Plague foci are widely distributed throughout the world, including the USA; human cases are reported from about 10 countries per year (Fig. 11.24). Y. pestis is a potential bioweapon because of the possibility of person-to-person spread and the high fatality rate associated with pneumonic plague. Clinical features Organisms inoculated through the skin are transported rapidly to the draining lymph nodes, where they elicit a severe inflammatory response that may be haemorrhagic. If the infection is not contained, sepsis ensues and necrotic, purulent or haemorrhagic lesions develop in many organs. Oliguria and shock follow, and disseminated intravascular coagulation may result in widespread haemorrhage. Inhalation of Y. pestis causes alveolitis. The incubation period is 3–6 days but shorter in pneumonic plague. Bubonic plague In this, the most common form of the disease, onset is usually sudden, with a rigor, high fever, dry skin and severe headache. Soon, aching and swelling at the site of the affected lymph nodes begin. The groin is the most common site of this ‘bubo’, made up of the swollen lymph nodes and surrounding tissue. Some infections are relatively mild but, in the majority of patients, toxaemia quickly increases, with a rapid pulse, hypotension and delirium. The spleen is usually palpable. Septicaemic plague Those not exhibiting a bubo usually deteriorate rapidly and have a high mortality. The elderly are more prone to this form of illness. Fig. 11.24 Foci of the transmission of plague. Reproduced by permission of the World Health Organisation. Frequent transmission Infrequent or suspected transmission

260 • INFECTIOUS DISEASE children diarrhoea and vomiting may be prominent early in the illness. The pulse is often slower than would be expected from the height of the temperature, i.e. a relative bradycardia. At the end of the first week, a rash may appear on the upper abdomen and on the back as sparse, slightly raised, rose-red spots, which fade on pressure. It is usually visible only on white skin. Cough and epistaxis occur. Around the 7th–10th day, the spleen becomes palpable. Constipation is followed by diarrhoea and abdominal distension with tenderness. Bronchitis and delirium may develop. If untreated, by the end of the second week the patient may be profoundly ill. Paratyphoid fever The course tends to be shorter and milder than that of typhoid fever and the onset is often more abrupt with acute enteritis. The rash may be more abundant and the intestinal complications less frequent. Complications These are given in Box 11.43. Haemorrhage from, or a perforation of, the ulcerated Peyer’s patches may occur at the end of the second week or during the third week of the illness. A drop in temperature to normal or subnormal levels may be falsely reassuring in patients with intestinal haemorrhage. Additional complications may involve almost any viscus or system because of the bacteraemia present during the first week. Bone and joint infection is common in children with sickle-cell disease. Investigations In the first week, diagnosis may be difficult because, in this invasive stage with bacteraemia, the symptoms are those of a generalised infection without localising features. Typically, there is a leucopenia. Blood culture establishes the diagnosis and multiple cultures increase the yield. Stool cultures are often positive in the second and third weeks. The Widal test detects antibodies to the O and H antigens but is not specific. Management Antibiotic therapy must be guided by in vitro sensitivity testing. Chloramphenicol (500 mg 4 times daily), ampicillin (750 mg 4 times daily) and co-trimoxazole (2 tablets or IV equivalent twice daily) are losing their effect due to resistance in many areas of the world, especially India and South-east Asia. Fluoroquinolones are the drugs of choice (e.g. ciprofloxacin 500 mg twice daily), if nalidixic acid screening predicts susceptibility, but resistance is common, especially in the Indian subcontinent and also in the UK. Extended-spectrum cephalosporins (ceftriaxone and cefotaxime) are useful alternatives but have a slightly increased In pregnancy, in addition to systemic symptoms of fever and myalgia, listeriosis causes chorioamnionitis, fetal deaths, abortions and neonatal infection. In other susceptible individuals, it causes systemic illness due to bacteraemia without focal symptoms. Meningitis, similar to other bacterial meningitis but with normal CSF glucose, is the next most common presentation; CSF usually shows increased neutrophils but occasionally only the mononuclear cells are increased (see Box 25.6, p. 1078). Investigations and management Diagnosis is made by blood and CSF culture. The organism grows readily in culture media. The most effective regimen consists of a combination of intravenous amoxicillin or ampicillin plus an aminoglycoside. A sulfamethoxazole/trimethoprim combination can be used in those with penicillin allergy. Cephalosporins are of no use in this infection, as the organism is inherently resistant, an important consideration when treating meningitis empirically. Proper treatment of foods before eating is the key to preventing listeriosis. Pregnant women are advised to avoid high-risk products, including soft cheeses. Typhoid and paratyphoid (enteric) fevers Typhoid and paratyphoid fevers, which are transmitted by the faecal–oral route, are important causes of fever in the Indian subcontinent, sub-Saharan Africa and Latin America. Elsewhere, they are relatively rare. Enteric fevers are caused by infection with Salmonella Typhi and Salmonella Paratyphi A and B. After a few days of bacteraemia, the bacilli localise, mainly in the lymphoid tissue of the small intestine, resulting in typical lesions in the Peyer’s patches and follicles. These swell at first, then ulcerate and usually heal. After clinical recovery, about 5% of patients become chronic carriers (i.e. continue to excrete the bacteria after 1 year); the bacilli may live in the gallbladder for months or years and pass intermittently in the stool and, less commonly, in the urine. Clinical features Typhoid fever Clinical features are outlined in Box 11.42. The incubation period is typically about 10–14 days but can be longer, and the onset may be insidious. The temperature rises in a stepladder fashion for 4 or 5 days with malaise, increasing headache, drowsiness and aching in the limbs. Constipation may be caused by swelling of lymphoid tissue around the ileocaecal junction, although in 11.42 Clinical features of typhoid fever First week • Fever • Headache • Myalgia • Relative bradycardia • Constipation • Diarrhoea and vomiting in children End of first week • Rose spots on trunk • Splenomegaly • Cough • Abdominal distension • Diarrhoea End of second week • Delirium, complications, then coma and death (if untreated) 11.43 Complications of typhoid fever Bowel • Perforation • Haemorrhage Septic foci • Bone and joint infection • Meningitis • Cholecystitis Toxic phenomena • Myocarditis • Nephritis Chronic carriage • Persistent gallbladder carriage

Bacterial infections • 261

Clinical features Pneumonia is the most common feature but localised skin nodules and abscesses, or sepsis, especially in diabetics, may occur. Diarrhoea and hepatosplenomegaly may be observed. The chest X-ray can resemble cavitatory tuberculosis. In chronic forms, multiple abscesses occur in subcutaneous tissue, liver, spleen and bone, accompanied by profound weight loss. Investigations and management Culture of blood, sputum or pus on selective media, e.g. Ashdown agar, may yield B. pseudomallei. Latex agglutination has been developed as a rapid diagnostic test in Thailand and PCR-based tests are also available. Indirect haemagglutination testing can be helpful in travellers; however, most people in endemic areas are seropositive. In the acute illness, prompt initiation of empirical therapy is lifesaving. Ceftazidime 100 mg/kg (2 g 3 times daily) or meropenem (0.5–1 g 3 times daily) is given for 2–3 weeks, followed by maintenance therapy of co-trimoxazole (sulfamethoxazole 1600 mg plus trimethoprim 320 mg twice daily) or doxycycline 200 mg daily for 3–6 months. Abscesses should be drained surgically. Actinomycete infections Nocardiosis Nocardiosis is an uncommon infection caused by aerobic Actinomycetes of the genus Nocardia, which are found in the soil. Infection occurs most frequently by direct traumatic inoculation or occasionally via inhalation or ingestion. Nocardiosis can result in localised cutaneous ulcers or nodules, most often in the lower limbs. Chronic destructive infection in tropical countries can result in actinomycetoma, involving soft tissues with occasional penetration to the bone. Actinomycetoma may also be caused by other aerobic Actinomycetes, and a similar clinical syndrome, eumycetoma, is caused by filamentous fungi. Both conditions are discussed on page 301. Systemic Nocardia infection, most commonly in immunocompromised individuals, results in suppurative disease with lung and brain abscesses. On microscopy, Nocardia spp. appear as long, filamentous, branching Gram-positive rods, which are also weakly acidfast. They are easily grown in culture but require prolonged incubation. Treatment of systemic infection is guided by sensitivity testing and typically requires combinations of imipenem with ceftriaxone, amikacin or co-trimoxazole, often for 6–12 months or longer. Meropenem, tigecycline, linezolid and minocycline may also be used with severe disease or with allergy, or when intolerance prevents use of the preferred agents. Abscesses are drained surgically when this is feasible. Localised cutaneous infection is usually treated with a single agent for 1–3 months. Treatment of actinomycetoma is discussed on page 301. Actinomyces spp. Actinomyces are anaerobic Actinomycetes, which are predominantly commensals of the oral cavity. They are capable of causing deep, suppurating infection in the head and neck (cervicofacial actinomycosis) and the lungs (thoracic actinomycosis). They also cause suppurating disease in the pelvis, associated with intrauterine contraceptive devices (IUCDs). Modern diagnostic techniques demonstrate that actinomycosis treatment failure rate. Azithromycin (500 mg once daily) is an alternative when fluoroquinolone resistance is present but has not been validated in severe disease. Treatment should be continued for 14 days. Pyrexia may persist for up to 5 days after the start of specific therapy. Even with effective chemotherapy, there is still a danger of complications, recrudescence of the disease and the development of a carrier state. Chronic carriers were formerly treated for 4 weeks with ciprofloxacin but may require an alternative agent and duration, as guided by antimicrobial sensitivity testing. Cholecystectomy may be necessary. Prevention Improved sanitation and living conditions reduce the incidence of typhoid. Travellers to countries where enteric infections are endemic should be inoculated with one of the three available typhoid vaccines (two inactivated injectable and one oral live attenuated). Tularaemia Tularaemia is primarily a zoonotic disease of the northern hemisphere. It is caused by a highly infectious Gram-negative bacillus, Francisella tularensis. F. tularensis is passed transovarially (ensuring transmission from parent to progeny) in ticks, which allows persistence in nature without the absolute requirement for an infected animal reservoir. It is a potential weapon for bioterrorism. Wild rabbits, rodents and domestic dogs or cats are potential reservoirs, and ticks, mosquitoes or other biting flies are the vectors. Infection is introduced either through an arthropod or animal bite or via contact with infected animals, soil or water through skin abrasions. The most common ‘ulceroglandular’ variety of the disease (70–80%) is characterised by skin ulceration with regional lymphadenopathy. There is also a purely ‘glandular’ form. Alternatively, inhalation of the infected aerosols may result in pulmonary tularaemia, presenting as pneumonia. Rarely, the portal of entry of infection may be the conjunctiva, leading to a nodular, ulcerated conjunctivitis with regional lymphadenopathy (an ‘oculoglandular’ form). Typhoidal tularaemia is a rare and serious form of tularaemia with vomiting, diarrhoea and hepatosplenomegaly, which may be complicated by pneumonia and meningitis. Investigations and management Demonstration of a single high titre (≥ 1 : 160) or a fourfold rise in 2–3 weeks in the tularaemia tube agglutination test confirms the diagnosis. Bacterial yield from the lesions is extremely poor. DNA detection methods to enable rapid diagnosis are in development. Treatment consists of a 10–21-day course of parenteral aminoglycosides, streptomycin (7.5–10 mg/kg twice daily) or gentamicin (1.7 mg/kg 3 times daily), with doxycycline or ciprofloxacin offered as alternatives. Melioidosis Melioidosis is caused by Burkholderia pseudomallei, a saprophyte found in soil and water (rice paddy fields). Infection is by inoculation or inhalation, leading to bacteraemia, which is followed by the formation of abscesses in the lungs, liver and spleen. Patients with diabetes, renal stones, thalassaemia or severe burns are particularly susceptible. The disease is most common in Southeast Asia and northern Australia, and carries a significant mortality. Disease may present years or decades after the initial exposure.

262 • INFECTIOUS DISEASE Campylobacter jejuni infection This infection is essentially a zoonosis, although contaminated water may be implicated, as the organism can survive for many weeks in fresh water. The most common sources of the infection are chicken, beef and contaminated milk products. Pet puppies have also been sources. Campylobacter infection is now the most common cause of bacterial gastroenteritis in the UK, accounting for some 100 000 cases per annum, most of which are sporadic. The incubation period is 2–5 days. Colicky abdominal pain may be severe and mimic acute appendicitis or other surgical pathology. Nausea, vomiting and significant diarrhoea, frequently containing blood, are common features. The majority of Campylobacter infections affect fit young adults and are self-limiting after 5–7 days. About 10–20% will have prolonged symptomatology, occasionally meriting treatment with a macrolide, most often azithromycin, as many organisms are resistant to ciprofloxacin. Approximately 1% of cases will develop bacteraemia and possible distant foci of infection. Campylobacter spp. have been linked to Guillain–Barré syndrome and post-infectious reactive arthritis (pp. 1140 and 1031). Salmonella spp. infection Salmonella enterica serovars other than Salmonella Typhi and Paratyphi (p. 260), of which there are more than 2000, can cause gastroenteritis. They are widely distributed throughout the animal kingdom. Two serovars are most important worldwide: Salmonella Enteritidis phage type 4 and Salmonella Typhimurium dt.104. The is caused by many different Actinomyces species, the most common of which is Actinomyces israelii. Treatment of established disease requires prolonged (about 6–12 months) of penicillin or doxycycline. Early disease may respond to shorter antibiotic courses. Gastrointestinal bacterial infections The approach to patients presenting with acute gastroenteritis is described on page 227. Staphylococcal food poisoning Staph. aureus is transmitted via the hands of food handlers to foodstuffs such as dairy products, including cheese, and cooked meats. Inappropriate storage of these foods allows growth of the organism and production of one or more heat-stable enterotoxins that cause the symptoms. Nausea and profuse vomiting develop within 1–6 hours. Diarrhoea may not be marked. The toxins that cause the syndrome act as ‘super-antigens’ and induce a significant neutrophil leucocytosis that may be clinically misleading. Most cases settle rapidly but severe dehydration can occasionally be life-threatening. Antiemetics and appropriate fluid replacement are the mainstays of treatment. Suspect food should be cultured for staphylococci and demonstration of toxin production. The public health authorities should be notified if food vending is involved. Bacillus cereus food poisoning Ingestion of the pre-formed heat-stable exotoxins of B. cereus causes rapid onset of vomiting and some diarrhoea within hours of food consumption, which resolves within 24 hours. Fried rice and freshly made sauces are frequent sources; the organism grows and produces enterotoxin during storage (Fig. 11.25). If viable bacteria are ingested and toxin formation takes place within the gut lumen, then the incubation period is longer (12–24 hours) and watery diarrhoea and cramps are the predominant symptoms. The disease is self-limiting but can be quite severe. Rapid and judicious fluid replacement and appropriate notification of the public health authorities are all that is required. Clostridium perfringens food poisoning Spores of C. perfringens are widespread in the guts of large animals and in soil. If contaminated meat products are incompletely cooked and stored in anaerobic conditions, C. perfringens spores germinate and viable organisms multiply. Subsequent reheating of the food causes release of enterotoxin. Symptoms (diarrhoea and cramps) occur some 6–12 hours following ingestion. The illness is usually self-limiting. Clostridial enterotoxins are potent and most people who ingest them will be symptomatic. ‘Point source’ outbreaks, in which a number of cases all become symptomatic following ingestion, classically occur after school or canteen lunches where meat stews are served. Clostridial necrotising enteritis (CNE) or pigbel is an often-fatal type of food poisoning caused by a β-toxin of C. perfringens, type C. The toxin is normally inactivated by certain proteases or by normal cooking. Pigbel is more likely in protein malnutrition or in the presence of trypsin inhibitors, either in foods such as sweet potatoes or during infection with Ascaris sp. roundworms. Fig. 11.25 Bacillus cereus food poisoning. Spores contaminate uncooked cereals, e.g. rice 2° contamination Parboiled (insufficient to kill spores) Storage at warm temperature allows germination Rapid deep-fry kills bacteria not toxins Ingestion of toxin Ingestion of spores or viable bacteria Acute vomiting ± diarrhoea 2 – 4 hours after ingestion Enterocolitis12 – 24 hours after ingestion Bacteria multiply in gut and elute toxin Inadequate reheating Viable bacteria remain

Bacterial infections • 263

Entero-aggregative E. coli Entero-aggregative E. coli (EAEC) strains adhere to the mucosa but also produce a locally active enterotoxin and demonstrate a particular ‘stacked brick’ aggregation to tissue culture cells when viewed by microscopy. They have been associated with prolonged diarrhoea in children in South America, South-east Asia and India. Enterohaemorrhagic E. coli A number of distinct ‘O’ serotypes of E. coli possess both the genes necessary for adherence (see ‘EPEC’ above) and plasmids encoding two distinct enterotoxins (verotoxins), which are identical to the toxins produced by Shigella (‘shiga toxins 1 and 2’). E. coli O157:H7 is perhaps the best known of these verotoxin-producing E. coli (VTEC) but others, including types O126 and O11, are also implicated. In 2011, an outbreak of food-borne illness linked to fenugreek seeds occurred in Germany and was due to E. coli O104:H4, an EAEC strain that had acquired genes encoding shiga toxin 2a. Although the incidence of enterohaemorrhagic E. coli (EHEC) is considerably lower than that of Campylobacter and Salmonella infection, it is increasing in the developing world. The reservoir of infection is in the gut of herbivores. The organism has an extremely low infecting dose (10–100 organisms). Runoff water from pasture lands where cattle have grazed, which is used to irrigate vegetable crops, as well as contaminated milk, meat products (especially hamburgers that have been incompletely cooked), lettuce, radish shoots and apple juice have all been implicated as sources (Fig. 11.26). The incubation period is between 1 and 7 days. Initial watery diarrhoea becomes uniformly blood-stained in 70% of cases and latter may be resistant to commonly used antibiotics such as ciprofloxacin. Some strains have a clear relationship to particular animal species, e.g. Salmonella Arizonae and pet reptiles. Transmission is by contaminated water or food, particularly poultry, egg products and minced beef, direct person-to-person spread or the handling of exotic pets such as salamanders, lizards or turtles. The incidence of Salmonella enteritis is falling in the UK due to an aggressive culling policy in broiler chicken stocks, coupled with vaccination. The incubation period of Salmonella gastroenteritis is 12–72 hours and the predominant feature is diarrhoea, sometimes with passage of blood. Vomiting may be present at the outset. Approximately 5% of cases are bacteraemic and invasive nontyphoidal salmonellosis is a leading cause of bacteraemia in sub-Saharan Africa. Reactive (post-infective) arthritis occurs in approximately 2%. Antibiotics are not indicated for uncomplicated Salmonella gastroenteritis but are prescribed for bacteraemia. Salmonellae are notorious for persistent infection and can seed endothelial surfaces such as an atherosclerotic aorta. Mortality, as with other forms of gastroenteritis, is higher in the elderly (see Box 11.12, p. 228). Escherichia coli infection Many serotypes of E. coli constitute part of the human gut microbiome. Clinical disease requires either colonisation with a new or previously unrecognised strain, or the acquisition by current colonising bacteria of a particular pathogenicity factor for mucosal attachment or toxin production. Travel to unfamiliar areas of the world allows contact with different strains of endemic E. coli and the development of travellers’ diarrhoea. Enteropathogenic strains may be found in the gut of healthy individuals and, if these people move to a new environment, close contacts may develop symptoms. At least five different clinico-pathological patterns of diarrhoea are associated with specific strains of E. coli with characteristic virulence factors. Enterotoxigenic E. coli Enterotoxigenic E. coli (ETEC) is the most common cause of travellers’ diarrhoea, although there are other causes (see Box 11.20, p. 232). The organisms produce either a heat-labile or a heat-stable enterotoxin, causing marked secretory diarrhoea and vomiting after 1–2 days’ incubation. The illness is usually mild and self-limiting after 3–4 days. Antibiotics are of questionable value (p. 232). Entero-invasive E. coli Illness caused by entero-invasive E. coli (EIEC) is very similar to Shigella dysentery (p. 265) and is caused by invasion and destruction of colonic mucosal cells. No enterotoxin is produced. Acute watery diarrhoea, abdominal cramps and some scanty blood-staining of the stool are common. The symptoms are rarely severe and are usually self-limiting. Enteropathogenic E. coli Enteropathogenic E. coli (EPEC) organisms are very important in infant diarrhoea. They are able to attach to the gut mucosa, inducing a specific ‘attachment and effacement’ lesion and causing destruction of microvilli and disruption of normal absorptive capacity. The symptoms vary from mild non-bloody diarrhoea to quite severe illness, but without bacteraemia. Fig. 11.26 Verocytotoxigenic Escherichia coli (VTEC) infections. Normal reservoir 2.5% British cattle excrete VTEC Meat products surface contamination Children camping/ playing on soiled pasture Farm contacts/ visits Water supplies (runoff) contaminated Contaminated milk Poor kitchen hygiene Poor hand hygiene Lack of washing facilities Mincing/ processing Irrigation of vegetables Inadequate pasteurisation Eaten unwashed or uncooked Disease Very low infecting dose < 100 organisms/g food

264 • INFECTIOUS DISEASE fluids and bowel rest. First-line antimicrobial therapy involves metronidazole (500 mg orally 3 times daily for 10 days) or vancomycin (125 mg orally 4 times daily for 7–10 days). Although vancomycin is more effective than metronidazole against hypervirulent C. difficile strains (e.g. ribotype 027), it is more expensive and may drive the emergence of vancomycin resistance in other organisms (e.g. enterococci, Staph. aureus). For these reasons, some authorities reserve its use for relapse (15–30% of patients), failure of initial response or severe infection. Fidaxomicin is associated with a lower relapse rate than vancomycin but is more expensive. Intravenous immunoglobulin and/or glucocorticoids are sometimes given in the most severe or refractory cases, and faecal transplantation from a healthy donor is increasingly used to manage relapses by restoring a more advantageous gut microbiome profile. Surgical intervention needs to be considered early in severe cases. Yersinia enterocolitica infection Yersinia enterocolitica, commonly found in pork, causes mild to moderate gastroenteritis and can produce significant mesenteric adenitis after an incubation period of 3–7 days. It predominantly causes disease in children but adults may also be affected. The illness resolves slowly. Complications include reactive arthritis (p. 1031; 10–13% of cases), which may be persistent, and anterior uveitis. Cholera Cholera, caused by Vibrio cholerae serotype O1, is the archetypal toxin-mediated bacterial cause of acute watery diarrhoea. The enterotoxin activates adenylate cyclase in the intestinal epithelium, inducing net secretion of chloride and water. V. cholerae O1 has two biotypes, classical and El Tor, and each of these has two distinct serotypes, Inaba and Ogawa. Following its origin in the Ganges valley, devastating epidemics have occurred, often in association with large religious festivals, and pandemics have spread worldwide. The seventh pandemic, due to the El Tor biotype, began in 1961 and spread via the Middle East to become endemic in Africa, subsequently spreading throughout South and Central America. Numbers of cases of cholera have been increasing, with outbreaks in Ghana in 2014 and Tanzania in 2015. El Tor is more resistant to commonly used antimicrobials than classical Vibrio, and causes prolonged carriage in 5% of is associated with severe abdominal pain. There is little systemic upset, vomiting or fever. Enterotoxins have both a local effect on the bowel and a distant effect on particular body tissues, such as glomerular apparatus, heart and brain. The potentially life-threatening haemolytic uraemic syndrome (HUS, p. 408) occurs in 10–15% of sufferers from this infection, arising 5–7 days after the onset of symptoms. It is most likely at the extremes of age, is heralded by a high peripheral leucocyte count, and may be induced, particularly in children, by antibiotic therapy. HUS is treated by dialysis if necessary and may be averted by plasma exchange. Antibiotics should be avoided since they can stimulate toxin release. Clostridium difficile infection C. difficile is the most commonly diagnosed cause of antibioticassociated diarrhoea (p. 230), and is an occasional constituent of the gut microbiome. C. difficile can produce two toxins (A and B). C. difficile infection (CDI) usually follows antimicrobial therapy, which alters the composition of the gastrointestinal flora and may result in colonisation with toxigenic C. difficile, if the patient is exposed to C. difficile spores. The combination of toxin production and the ability to produce environmentally stable spores accounts for the clinical features and transmissibility of CDI. A hypervirulent strain of C. difficile, ribotype 027, has emerged, which produces more toxin and more severe disease than other C. difficile strains. Clinical features Disease manifestations range from diarrhoea to life-threatening pseudomembranous colitis. Around 80% of cases occur in people over 65 years of age, many of whom are frail with comorbid diseases. Symptoms usually begin in the first week of antibiotic therapy but can occur at any time up to 6 weeks after treatment has finished. The onset is often insidious, with lower abdominal pain and diarrhoea that may become profuse and watery. The presentation may resemble acute ulcerative colitis with bloody diarrhoea, fever and even toxic dilatation and perforation. Ileus is also seen in pseudomembranous colitis. Investigations C. difficile can be isolated from stool culture in 30% of patients with antibiotic-associated diarrhoea and over 90% of those with pseudomembranous colitis, but also from 5% of healthy adults and up to 20% of elderly patients in residential care. The diagnosis of CDI therefore rests on detection of toxins A or B in the stool. Current practice in the UK is to screen stool from patients with a compatible clinical syndrome by detection either of glutamate dehydrogenase (GDH), an enzyme produced by C. difficile, or of C. difficile nucleic acid (e.g. by PCR); if screening is positive, a C. difficile toxin ELISA or a tissue culture cytotoxicity assay is performed. The rectal appearances at sigmoidoscopy may be characteristic, with erythema, white plaques or an adherent pseudomembrane (Fig. 11.27), or may resemble ulcerative colitis. In some cases, the rectum is spared and abnormalities are observed in the proximal colon. Patients who are ill require abdominal and erect chest X-rays to exclude perforation or toxic dilatation. CT may be useful when the diagnosis is in doubt. Management The precipitating antibiotic should be stopped and the patient should be isolated. Supportive therapy includes intravenous Fig. 11.27 Clostridium difficile infection. Colonoscopic view showing numerous adherent ‘pseudomembranes’ on the mucosa.

Bacterial infections • 265

seafood is widespread (e.g. Japan). After an incubation period of approximately 20 hours, explosive diarrhoea, abdominal cramps and vomiting occur. Systemic symptoms of headache and fever are frequent but the illness is self-limiting after 4–7 days. Rarely, a severe septic illness arises; in this case, V. parahaemolyticus can be isolated using specific halophilic culture. Bacillary dysentery (shigellosis) Shigellae are Gram-negative rods, closely related to E. coli, that invade the colonic mucosa. There are four main groups: Sh. dysenteriae, flexneri, boydii and sonnei. In the tropics, bacillary dysentery is usually caused by Sh. flexneri, while in the UK most cases are caused by Sh. sonnei. Shigellae are often resistant to multiple antibiotics, especially in tropical countries. The organism only infects humans and its spread is facilitated by its low infecting dose of around 10 organisms. Spread may occur via contaminated food or flies, but personto-person transmission by unwashed hands after defaecation is the most important factor. Outbreaks occur in psychiatric hospitals, residential schools and other closed institutions, and dysentery is a constant accompaniment of wars and natural catastrophes, which bring crowding and poor sanitation in their wake. Shigella infection may spread rapidly among men who have sex with men. Clinical features Disease severity varies from mild Sh. sonnei infections that may escape detection to more severe Sh. flexneri infections, while those due to Sh. dysenteriae may be fulminating and cause death within 48 hours. In a moderately severe illness, the patient complains of diarrhoea, colicky abdominal pain and tenesmus. Stools are small, and after a few evacuations contain blood and purulent exudate with little faecal material. Fever, dehydration and weakness occur, with tenderness over the colon. Reactive arthritis or iritis may occasionally complicate bacillary dysentery (p. 1031). Management and prevention Oral rehydration therapy or, if diarrhoea is severe, intravenous replacement of water and electrolyte loss is necessary. Antibiotic therapy is with ciprofloxacin (500 mg twice daily for 3 days) Azithromycin and ceftriaxone are alternatives but resistance occurs to all agents, especially in Asia. The use of antidiarrhoeal medication should be avoided. The prevention of faecal contamination of food and milk and the isolation of cases may be difficult, except in limited outbreaks. Hand-washing is very important. Respiratory bacterial infections Most of these infections are described in Chapter 17. Diphtheria Infection with Corynebacterium diphtheriae occurs most commonly in the upper respiratory tract and is usually spread by droplet infection. Infection may also complicate skin lesions, especially in alcoholics. The organisms remain localised at the site of infection but release of a soluble exotoxin damages the heart muscle and the nervous system. Diphtheria has been eradicated from many parts of the world by mass vaccination using a modified exotoxin but remains infections. An atypical serotype, O139, has been responsible for localised outbreaks in Bangladesh. Infection spreads via the stools or vomit of symptomatic patients or of the much larger number of subclinical cases. Organisms survive for up to 2 weeks in fresh water and 8 weeks in salt water. Transmission is normally through infected drinking water, shellfish and food contaminated by flies, or on the hands of carriers. Clinical features Severe diarrhoea without pain or colic begins suddenly and is followed by vomiting. Following the evacuation of normal gut faecal contents, typical ‘rice water’ material is passed, consisting of clear fluid with flecks of mucus. Classical cholera produces enormous loss of fluid and electrolytes, leading to intense dehydration with muscular cramps. Shock and oliguria develop but mental clarity remains. Death from acute circulatory failure may occur rapidly unless fluid and electrolytes are replaced. Improvement is rapid with proper treatment. The majority of infections, however, cause mild illness with slight diarrhoea. Occasionally, a very intense illness, ‘cholera sicca’, occurs, with loss of fluid into dilated bowel, killing the patient before typical gastrointestinal symptoms appear. The disease is more dangerous in children. Diagnosis and management Clinical diagnosis is easy during an epidemic. Otherwise, the diagnosis should be confirmed bacteriologically. Stool darkfield microscopy shows the typical ‘shooting star’ motility of V. cholerae. Rectal swab or stool cultures allow identification. Cholera is notifiable under international health regulations. Maintenance of circulation by replacement of water and electrolytes is paramount (p. 229). Ringer-Lactate is the best fluid for intravenous replacement. Vomiting usually stops once the patient is rehydrated, and fluid should then be given orally up to 500 mL hourly. Early intervention with oral rehydration solutions that include resistant starch, based on either rice or cereal, shortens the duration of diarrhoea and improves prognosis. Severe dehydration, as indicated by altered consciousness, skin tenting, very dry tongue, decreased pulses, low blood pressure or minimal urine output, mandates intravenous replacement. Total fluid requirements may exceed 50 L over a period of 2–5 days. Accurate records are greatly facilitated by the use of a ‘cholera cot’, which has a reinforced hole under the patient’s buttocks, beneath which a graded bucket is placed. Three days’ treatment with tetracycline 250 mg 4 times daily, a single dose of doxycycline 300 mg or ciprofloxacin 1 g in adults reduces the duration of excretion of V. cholerae and the total volume of fluid needed for replacement. Prevention Strict personal hygiene is vital and drinking water should come from a clean piped supply or be boiled. Flies must be denied access to food. Oral vaccines containing killed V. cholerae with or without the B subunit of cholera toxin are used in specific settings. In epidemics, improvements in sanitation and access to clean water, public education and control of population movement are vital. Mass single-dose vaccination and treatment with tetracycline are valuable. Disinfection of discharges and soiled clothing, and scrupulous hand-washing by medical attendants reduce spread. Vibrio parahaemolyticus infection This marine organism produces a disease similar to enterotoxigenic E. coli (see above). It is very common where ingestion of raw

266 • INFECTIOUS DISEASE should be given half an hour before the full dose in every patient. Adrenaline (epinephrine) solution must be available to deal with any immediate type of reaction (0.5–1.0 mL of 1/1000 solution IM). An antihistamine is also given. In a severely ill patient, the risk of anaphylactic shock is outweighed by the mortal danger of diphtheritic toxaemia. A dose of up to 100 000 IU of antitoxin is injected intravenously if the test dose is tolerated. For disease of moderate severity, 16 000–40 000 IU IM will suffice, and for mild cases 4000–8000 IU. Penicillin (1200 mg 4 times daily IV) or amoxicillin (500 mg 3 times daily) should be administered for 2 weeks to eliminate C. diphtheriae. Patients allergic to penicillin can be given erythromycin. Due to poor immunogenicity of primary infection, all sufferers should be immunised with diphtheria toxoid following recovery. Patients must be managed in strict isolation and attended by staff with a clearly documented immunisation history until three swabs 24 hours apart are culture-negative. Prevention Active immunisation should be given to all children. If diphtheria occurs in a closed community, contacts should be given erythromycin, which is more effective than penicillin in eradicating the organism in carriers. All contacts should also be immunised or given a booster dose of toxoid. Booster doses are required every 10 years to maintain immunity. Pneumococcal infection Strep. pneumoniae (the pneumococcus) is the leading cause of community-acquired pneumonia globally (p. 582) and one of the leading causes of infection-related mortality. Otitis media, meningitis and sinusitis are also frequently caused by Strep. pneumoniae. Occasional patients present with bacteraemia without obvious focus. Asplenic individuals are at risk of fulminant pneumococcal disease with purpuric rash. Increasing rates of penicillin resistance have been reported around the world for Strep. pneumoniae, although they remain low in the UK. Strains with cephalosporin resistance causing meningitis require treatment with a combination of cephalosporins, glycopeptides and rifampicin. Macrolide resistance is also increasing. Newer quinolones are also used (e.g. levofloxacin) but rates of resistance are rising. Vaccination of infants with the protein conjugate pneumococcal vaccine decreases Strep. pneumoniae infection in infants and in their relatives. The polysaccharide pneumococcal vaccine is used in individuals predisposed to Strep. pneumoniae infection and the elderly, but only modestly reduces pneumococcal bacteraemia and does not prevent pneumonia. All asplenic individuals should receive vaccination against Strep. pneumoniae. Anthrax Anthrax is an endemic zoonosis in many countries; it causes human disease following inoculation of the spores of Bacillus anthracis. B. anthracis was the first bacterial pathogen described by Koch and the model pathogen for ‘Koch’s postulates’ (see Box 6.1, p. 100). It is a Gram-positive organism with a central spore. The spores can survive for years in soil. Infection is commonly acquired from contact with animals, particularly herbivores. The ease of production of B. anthracis spores makes this infection a candidate for biological warfare or bioterrorism. B. anthracis produces a number of toxins that mediate the clinical features of disease. important in areas where vaccination has been incomplete, e.g. in Russia and South-east Asia. The disease is notifiable in all countries of Europe and North America, and international guidelines have been issued by the WHO for the management of infection. Clinical features The average incubation period is 2–4 days. The disease begins insidiously with a sore throat (Box 11.44). Despite modest fever, there is usually marked tachycardia. The diagnostic feature is the ‘wash-leather’ elevated, greyish-green membrane on the tonsils. It has a well-defined edge, is firm and adherent, and is surrounded by a zone of inflammation. There may be swelling of the neck (‘bull neck’) and tender enlargement of the lymph nodes. In the mildest infections, especially where there is a high degree of immunity, a membrane may not appear and inflammation is minimal. With anterior nasal infection there is nasal discharge, frequently blood-stained. In laryngeal diphtheria, a husky voice and highpitched cough signal potential respiratory obstruction requiring urgent tracheostomy. If infection spreads to the uvula, fauces and nasopharynx, the patient is gravely ill. Death from acute circulatory failure may occur within the first 10 days. Late complications arise as a result of toxin action on the heart or nervous system. About 25% of survivors of the early toxaemia may later develop myocarditis with arrhythmias or cardiac failure. These are usually reversible, with no permanent damage other than heart block in survivors. Neurological involvement occurs in 75% of cases. After tonsillar or pharyngeal diphtheria, it usually starts after 10 days with palatal palsy. Paralysis of accommodation often follows, manifest by difficulty in reading small print. Generalised polyneuritis with weakness and paraesthesia may follow in the next 10–14 days. Recovery from such neuritis is always ultimately complete. Management A clinical diagnosis of diphtheria must be notified to the public health authorities and the patient sent urgently to a specialist infectious diseases unit. Empirical treatment should commence after collection of appropriate swabs. Diphtheria antitoxin is produced from hyperimmune horse serum. It neutralises circulating toxin but has no effect on toxin already fixed to tissues, so it must be injected intramuscularly without awaiting the result of a throat swab. However, reactions to this foreign protein include a potentially lethal immediate anaphylactic reaction (p. 75) and a ‘serum sickness’ with fever, urticaria and joint pains, which occurs 7–12 days after injection. A careful history of previous horse serum injections or allergic reactions should be taken and a small test injection of serum 11.44 Clinical features of diphtheria Acute infection • Membranous tonsillitis • or Nasal infection • or Laryngeal infection • or Skin/wound/conjunctival infection (rare) Complications • Laryngeal obstruction or paralysis • Myocarditis • Peripheral neuropathy

Bacterial infections • 267

Leprosy Leprosy (Hansen’s disease) is a chronic granulomatous disease affecting skin and nerves and caused by Mycobacterium leprae, a slow-growing mycobacterium that cannot be cultured in vitro. The clinical manifestations are determined by the degree of the patient’s cell-mediated immunity (CMI; p. 69) towards M. leprae (Fig. 11.28). High levels of CMI with elimination of leprosy bacilli produces tuberculoid leprosy, whereas absent CMI results in lepromatous leprosy. Complications arise due to nerve damage, immunological reactions and bacillary infiltration. People with leprosy are frequently stigmatised and using the word ‘leper’ is inappropriate. Epidemiology and transmission Some 4 million people have leprosy and around 750 000 new cases are detected annually. About 70% of the world’s leprosy patients live in India, with the disease endemic in Brazil, Indonesia, Mozambique, Madagascar, Tanzania and Nepal. Untreated lepromatous patients discharge bacilli from the nose. Infection occurs through the nose, followed by haematogenous spread to skin and nerve. The incubation period is 2–5 years for tuberculoid cases and 8–12 years for lepromatous cases. Leprosy incidence peaks at 10–14 years, and is more common in males and in household contacts of leprosy cases. Pathogenesis M. leprae has tropism for Schwann cells and skin macrophages. In tuberculoid leprosy, effective CMI controls bacillary multiplication (‘paucibacillary’) and organised epithelioid granulomata form. In lepromatous leprosy, there is abundant bacillary multiplication (‘multibacillary’), e.g. in Schwann cells and perineurium. Between these two extremes is a continuum, varying from patients with Clinical features These depend on the route of entry of the anthrax spores. Cutaneous anthrax This skin lesion is associated with occupational exposure to anthrax spores during processing of hides and bone products. It accounts for the vast majority of clinical cases. Animal infection is a serious problem in Africa, India, Pakistan and the Middle East. Spores are inoculated into exposed skin. A single lesion develops as an irritable papule on an oedematous haemorrhagic base. This progresses to a depressed black eschar. Despite extensive oedema, pain is infrequent. Gastrointestinal anthrax This is associated with the ingestion of contaminated meat. The caecum becomes infected, which produces nausea, vomiting, anorexia and fever, followed in 2–3 days by severe abdominal pain and bloody diarrhoea. Toxaemia and death can develop rapidly thereafter. Inhalational anthrax This form of the disease is extremely rare but has been associated with bioterrorism. Without rapid and aggressive therapy at the onset of symptoms, the mortality is 50–90%. Fever, dyspnoea, cough, headache and sepsis develop 3–14 days following exposure. Typically, the chest X-ray shows only widening of the mediastinum and pleural effusions, which are haemorrhagic. Meningitis may occur. Management B. anthracis can be cultured from skin swabs from lesions. Skin lesions are readily curable with early antibiotic therapy. Treatment is with ciprofloxacin (500 mg twice daily) until penicillin susceptibility is confirmed; the regimen can then be changed to benzylpenicillin with doses up to 2.4 g IV given 6 times daily or phenoxymethylpenicillin 500–1000 mg 4 times daily administered for 10 days. The addition of an aminoglycoside may improve the outlook in severe disease. In view of concerns about concomitant inhalational exposure, particularly in the era of bioterrorism, a further 2-month course of ciprofloxacin 500 mg twice daily or doxycycline 100 mg twice daily orally is added to eradicate inhaled spores. Inhalational anthrax is treated with ciprofloxacin and clindamycin for at least 14 days, followed by therapy to eradicate spores. Monoclonal antibodies against B. anthracis protective antigen can be added for systemic infection. Prophylaxis with ciprofloxacin (500 mg twice daily for 2 months) is recommended for anyone at high risk of inhalational exposure to anthrax spores and should be combined with three doses of anthrax vaccine adsorbed (AVA). Bacterial infections with neurological involvement Infections affecting the CNS, including bacterial meningitis, botulism and tetanus, are described on page 1117. Mycobacterial infections Tuberculosis Tuberculosis is predominantly, although by no means exclusively, a respiratory disease and is described on page 588. Fig. 11.28 Leprosy: mechanisms of damage and tissue affected. Mechanisms under the broken line are characteristic of disease near the lepromatous end of the spectrum, and those under the solid line are characteristic of the tuberculoid end. They overlap in the centre where, in addition, instability predisposes to type 1 lepra reactions. At the peak in the centre, neither bacillary growth nor cell-mediated immunity has the upper hand. (BL = borderline lepromatous; BT = borderline tuberculoid) Adapted from Bryceson ADM, Pfaltzgraff RE. Leprosy, 3rd edn. Churchill Livingstone, Elsevier Ltd; 1990.

High Zero Cell-mediated immunity Bacillary index Chronic exaggerated cellular hypersensitivity Nerves, skin Acute changes in cellullar hypersensitivity (type 1 lepra reactions) Nerves, skin Complications of nerve damage (anaesthesia, dryness, paralysis, contracture, misuse, tissue destruction) Face, hands, feet Lepromatous Borderline Tuberculoid LL BL BT TT Bacillary invasion Nerves, skin, muscle, bone, mucosae, eye, testis Immune complexes (type 2 lepra reactions) Nerves, skin, eye, testis, kidney

268 • INFECTIOUS DISEASE • Anaesthesia. In skin lesions, the small dermal sensory and autonomic nerve fibres are damaged, causing localised sensory loss and loss of sweating. Anaesthesia can occur in the distribution of a damaged large peripheral nerve. A ‘glove and stocking’ sensory neuropathy is also common in lepromatous leprosy. • Nerve damage. Peripheral nerve trunks are affected at ‘sites of predilection’. These are the ulnar (elbow), median (wrist), radial (humerus), radial cutaneous (wrist), common peroneal (knee), posterior tibial and sural nerves (ankle), facial nerve (zygomatic arch) and great auricular nerve (posterior triangle of the neck). Damage to peripheral nerve trunks produces characteristic signs with regional sensory loss and muscle dysfunction (Fig. 11.29C). All these nerves should be examined for enlargement and tenderness, and tested for motor and sensory function. The CNS is not affected. • Eye involvement. Blindness is a devastating complication for a patient with anaesthetic hands and feet. Eyelid closure is impaired when the facial nerve is affected. Damage to the trigeminal nerve causes anaesthesia of the cornea and conjunctiva. The cornea is then susceptible to trauma and ulceration. • Other features. Many organs can be affected. Nasal collapse occurs secondary to bacillary destruction of the nasal cartilage and bone. Diffuse infiltration of the testes causes testicular atrophy and the acute orchitis that occurs with type 2 reactions. This results in azoospermia and hypogonadism. Leprosy reactions Leprosy reactions (Box 11.47) are events superimposed on the cardinal features shown in Box 11.45. • Type 1 (reversal) reactions. These occur in 30% of borderline patients (BT, BB or BL – see below) and are delayed hypersensitivity reactions. Skin lesions become moderate CMI (borderline tuberculoid) to patients with little cellular response (borderline lepromatous). Immunological reactions evolve as the immune response develops and the bacillary antigenic stimulus varies, particularly in borderline patients. Delayed hypersensitivity reactions produce type 1 (reversal) reactions, while immune complexes contribute to type 2 (erythema nodosum leprosum) reactions. HIV/leprosy co-infected patients have typical lepromatous and tuberculoid leprosy skin lesions and typical leprosy histology and granuloma formation. Surprisingly, even with low circulating CD4 counts, tuberculoid leprosy may be observed and there is not an obvious shift to lepromatous leprosy. Clinical features Box 11.45 gives the cardinal features of leprosy. Types of leprosy are compared in Box 11.46. • Skin. The most common skin lesions are macules or plaques. Tuberculoid patients have few, hypopigmented lesions (Fig. 11.29A). In lepromatous leprosy, papules, nodules or diffuse infiltration of the skin occur. The earliest lesions are ill defined; gradually, the skin becomes infiltrated and thickened. Facial skin thickening leads to the characteristic leonine facies (Fig. 11.29B). 11.46 Clinical characteristics of the polar forms of leprosy Clinical and tissue-specific features Lepromatous Tuberculoid Skin and nerves Number and distribution Widely disseminated One or a few sites, asymmetrical Skin lesions Definition: Clarity of margin Poor Good Elevation of margin Never Common Colour: Dark skin Slight hypopigmentation Marked hypopigmentation Light skin Slight erythema Coppery or red Surface Smooth, shiny Dry, scaly Central healing None Common Sweat and hair growth Impaired late Impaired early Loss of sensation Late Early and marked Nerve enlargement and damage Late Early and marked Bacilli (bacterial index) Many (5 or 6+) Absent (0) Natural history Progressive Self-healing Other tissues Upper respiratory mucosa, eye, testes, bones, muscle None Reactions Immune complexes (type 2) Cell-mediated (type 1) 11.45 Cardinal features of leprosy • Skin lesions, typically anaesthetic at tuberculoid end of spectrum • Thickened peripheral nerves • Acid-fast bacilli on skin smears or biopsy 11.47 Reactions in leprosy Lepra reaction type 1 (reversal) Lepra reaction type 2 (erythema nodosum leprosum) Mechanism Cell-mediated hypersensitivity Immune complexes Clinical features Painful tender nerves, loss of function Swollen skin lesions New skin lesions Tender papules and nodules; may ulcerate Painful tender nerves, loss of function Iritis, orchitis, myositis, lymphadenitis Fever, oedema Management Prednisolone 40 mg, reducing over 3–6 months1 Moderate: prednisolone 40 mg daily Severe: thalidomide2 or prednisolone 40–80 mg daily, reducing over 1–6 months; local if eye involved3 1lndicated for any new impairment of nerve or eye function. 2Contraindicated in women who may become pregnant. 31% hydrocortisone drops or ointment and 1% atropine drops.

Bacterial infections • 269

are obtained by scraping dermal material on to a glass slide. The smears are then stained for acid-fast bacilli, the number counted per high-power field and a score derived on a logarithmic scale (0–6): the bacterial index (BI). Smears are useful for confirming the diagnosis and monitoring response to treatment. Neither serology nor PCR is sensitive or specific enough for diagnosis. Management The principles of treatment are outlined in Box 11.48. All leprosy patients require MDT with an approved first-line regimen (Box 11.49). Rifampicin is a potent bactericidal for M. leprae but should always be given in combination with other antileprotics, since a single-step mutation can confer resistance. Dapsone is bacteriostatic. It commonly causes mild haemolysis and rarely anaemia. Clofazimine is a red, fat-soluble crystalline dye, weakly bactericidal for M. leprae. Skin discoloration (red to purple–black) and ichthyosis are troublesome side-effects, particularly on pale skins. New bactericidal drugs against M. leprae have been identified, notably fluoroquinolones (pefloxacin and ofloxacin). Minocycline and clarithromycin may also be used. These agents are now established second-line drugs. Minocycline causes a grey pigmentation of skin lesions. Fig. 11.29 Clinical features of leprosy. A Tuberculoid leprosy. Single lesion with a well-defined active edge and anaesthesia within the lesion. B Lepromatous leprosy. Widespread nodules and infiltration, with loss of the eyebrows. This man also has early collapse of the nose. C Borderline tuberculoid leprosy with severe nerve damage. This boy has several well-defined, hypopigmented, macular, anaesthetic lesions. He has severe nerve damage affecting both ulnar and median nerves bilaterally and has sustained severe burns to his hands. D Reversal (type 1) reactions. Erythematous, oedematous lesions. A B C D erythematous (Fig. 11.29D). Peripheral nerves become tender and painful, with sudden loss of nerve function. These reactions may occur spontaneously, after starting treatment and also after completion of multidrug therapy (MDT). • Type 2 (erythema nodosum leprosum, ENL) reactions. These are partly due to immune complex deposition and occur in BL and LL patients who produce antibodies and have a high antigen load. They manifest with malaise, fever and crops of small pink nodules on the face and limbs. Iritis and episcleritis are common. Other signs are acute neuritis, lymphadenitis, orchitis, bone pain, dactylitis, arthritis and proteinuria. ENL may continue intermittently for several years. Borderline cases In borderline tuberculoid (BT) cases, skin lesions are more numerous than in tuberculoid (TT) cases, and there is more severe nerve damage and a risk of type 1 reactions. In borderline leprosy (BB) cases, skin lesions are numerous and vary in size, shape and distribution; annular lesions are characteristic and nerve damage is variable. In borderline lepromatous (BL) cases, there are widespread small macules in the skin and widespread nerve involvement; both type 1 and type 2 reactions occur. Pure neural leprosy (i.e. without skin lesions) occurs principally in India and accounts for 10% of patients. There is asymmetrical involvement of peripheral nerve trunks and no visible skin lesions. On nerve biopsy, all types of leprosy have been found. Investigations The diagnosis is clinical, made by finding a cardinal sign of leprosy and supported by detecting acid-fast bacilli in slit-skin smears or typical histology in a skin biopsy. Slit-skin smears 11.48 Principles of leprosy treatment • Stop the infection with chemotherapy • Treat reactions • Educate the patient about leprosy • Prevent disability • Support the patient socially and psychologically

270 • INFECTIOUS DISEASE Rickettsial and related intracellular bacterial infections Rickettsial fevers The rickettsial fevers are the most common tick-borne infections. It is important to ask potentially infected patients about contact with ticks, lice or fleas. There are two main groups of rickettsial fevers: spotted fevers and typhus (Box 11.50). Pathogenesis The rickettsiae are intracellular Gram-negative organisms that parasitise the intestinal canal of arthropods. Infection of humans through the skin occurs from the excreta of arthropods, but the saliva of some biting vectors is infected. The organisms multiply in capillary endothelial cells, producing lesions in the skin, CNS, heart, lungs, liver, kidneys and skeletal muscles. Endothelial proliferation, associated with a perivascular reaction, may cause thrombosis and purpura. In epidemic typhus, the brain is the target organ; in scrub typhus, the cardiovascular system and lungs in particular are attacked. An eschar, a black necrotic crusted sore, is often found in tick- and mite-borne typhus (see Fig. 11.7C, p. 235). This is due to vasculitis following immunological recognition of the inoculated organism. Regional lymph nodes often enlarge. Spotted fever group Rocky Mountain spotted fever Rickettsia rickettsii is transmitted by tick bites. It is widely distributed and increasing in western and south-eastern states of the USA and also in Central and South America. The incubation period is about 7 days. The rash appears on about the third or fourth day of illness, looking at first like measles, but in a few hours a typical maculopapular eruption develops. The rash spreads in 24–48 hours from wrists, forearms and ankles to the back, limbs and chest, and then to the abdomen, where it is least pronounced. Larger cutaneous and subcutaneous haemorrhages may appear in severe cases. The liver and spleen become palpable. At the extremes of life, the mortality is 2–12%. Other spotted fevers R. conorii (boutonneuse fever) and R. africae (African tick bite fever) cause Mediterranean and African tick typhus, which also occurs on the Indian subcontinent. The incubation period is approximately 7 days. Infected ticks may be picked up by walking on grasslands, or dogs may bring ticks into the house. Careful examination might reveal a diagnostic eschar, and the maculopapular rash on the trunk, limbs, palms and soles. There may be delirium and meningeal signs in severe infections but recovery is usual. R. africae can be associated with multiple eschars. Some cases, particularly those with R. africae, present without rash (‘spotless spotted fever’). Other spotted fevers are shown in Box 11.50. Typhus group Scrub typhus fever Scrub typhus is caused by Orientia tsutsugamushi (formerly Rickettsia tsutsugamushi), transmitted by mites. It occurs in the Far East, Myanmar, Pakistan, Bangladesh, India, Indonesia, the South Pacific islands and Queensland, particularly where patches of forest cleared for plantations have attracted rats and mites. In many patients, one eschar or more develops, surrounded by an area of cellulitis (see Fig. 11.7C, p. 235) and Although single-dose treatment is less effective than the conventional 6-month treatment for paucibacillary leprosy, it is an operationally attractive field regimen recommended by the WHO. Lepra reactions are treated as shown in Box 11.47. Chloroquine can also be used. Patient education This is essential and should patients should be informed that, after 3 days of chemotherapy, they are not infectious and can lead a normal social life. It should emphasise that gross deformities are not inevitable. Patients with anaesthetic hands or feet need to avoid and treat burns or other minor injuries. Good footwear is important. Physiotherapy helps maintain range of movement of affected muscles and neighbouring joints. Prognosis Untreated, tuberculoid leprosy has a good prognosis; it may self-heal and peripheral nerve damage is limited. Lepromatous leprosy (LL) is a progressive condition with high morbidity if untreated. After treatment, the majority of patients, especially those who have no nerve damage at the time of diagnosis, do well, with resolution of skin lesions. Borderline patients are at risk of developing type 1 reactions, which may result in devastating nerve damage. Prevention and control The previous strategy of centralised leprosy control campaigns has been superseded by integrated programmes, with primary health-care workers in many countries now responsible for case detection and provision of MDT. It is not yet clear how successful this will be, especially in the time-consuming area of disability prevention. BCG vaccination has been shown to give good but variable protection against leprosy; adding killed M. leprae to BCG does not enhance protection. 11.49 Modified WHO-recommended multidrug therapy (MDT) regimens in leprosy Type of leprosy1 Monthly supervised treatment Daily selfadministered treatment Duration of treatment2 Paucibacillary Rifampicin 600 mg Dapsone 100 mg 6 months Multibacillary Rifampicin 600 mg Clofazimine 50 mg 12 months Clofazimine 300 mg Dapsone 100 mg Paucibacillary single-lesion Ofloxacin 400 mg Rifampicin 600 mg Minocycline 100 mg Single dose 1Classification uses the bacillary index (BI) in slit-skin smears or, if BI is not available, the number of skin lesions: • paucibacillary single-lesion leprosy (1 skin lesion) • paucibacillary (2–5 skin lesions) • multibacillary (> 5 skin lesions). 2Studies from India have shown that multibacillary patients with an initial BI of

4 need longer treatment, for at least 24 months.

Bacterial infections • 271

confused. The rash appears on the 4th–6th day. In its early stages, it disappears on pressure but soon becomes petechial with subcutaneous mottling. It appears first on the anterior folds of the axillae, sides of the abdomen or backs of hands, then on the trunk and forearms. The neck and face are seldom affected. During the second week, symptoms increase in severity. Sores develop on the lips. The tongue becomes dry, brown, shrunken and tremulous. The spleen is palpable, the pulse feeble and the patient stuporous and delirious. The temperature falls rapidly at the end of the second week and the patient recovers gradually. In fatal cases, the patient usually dies in the second week from toxaemia, cardiac or renal failure, or pneumonia. Endemic (flea-borne) typhus Flea-borne or ‘endemic’ typhus caused by R. typhi is endemic worldwide. Humans are infected when the faeces or contents of a crushed flea, which has fed on an infected rat, are introduced into the skin. The incubation period is 8–14 days. The symptoms resemble those of a mild louse-borne typhus. The rash may be scanty and transient. Investigation of rickettsial infection Routine blood investigations are not diagnostic. There is usually hepatitis and thrombocytopenia. Diagnosis is made on clinical grounds and response to treatment, and may be confirmed by antibody detection or PCR in specialised laboratories. Differential diagnoses include malaria, which should be excluded, typhoid, meningococcal sepsis and leptospirosis. Management of rickettsial fevers The different rickettsial fevers vary in severity but all respond to tetracycline 500 mg 4 times daily, doxycycline 200 mg daily enlargement of regional lymph nodes. The incubation period is about 9 days. Mild or subclinical cases are common. The onset of symptoms is usually sudden, with headache (often retro-orbital), fever, malaise, weakness and cough. In severe illness, the general symptoms increase, with apathy and prostration. An erythematous maculopapular rash often appears on about the 5th–7th day and spreads to the trunk, face and limbs, including the palms and soles, with generalised painless lymphadenopathy. The rash fades by the 14th day. The temperature rises rapidly and continues as a remittent fever (i.e. the difference between maximum and minimum temperature exceeds 1°C), remaining above normal with sweating until it falls on the 12th–18th day. In severe infection, the patient is prostrate with cough, pneumonia, delirium and deafness. Cardiac failure, renal failure and haemorrhage may develop. Convalescence is often slow and tachycardia may persist for some weeks. Epidemic (louse-borne) typhus Epidemic typhus is caused by R. prowazekii and is transmitted by infected faeces of the human body louse, usually through scratching the skin. Patients suffering from epidemic typhus infect lice, which leave when the patient is febrile. In conditions of overcrowding, the disease spreads rapidly. It is prevalent in parts of Africa, especially Ethiopia and Rwanda, and in the South American Andes and Afghanistan. Large epidemics have occurred in Europe, usually as a sequel to war. The incubation period is usually 12–14 days. There may be a few days of malaise but the onset is more often sudden, with rigors, fever, frontal headaches, pains in the back and limbs, constipation and bronchitis. The face is flushed and cyanotic, the eyes are congested and the patient becomes 11.50 Features of rickettsial infections Disease Organism Reservoir Vector Geographical area Rash Gangrene Target organs Mortality Spotted fever group Rocky Mountain spotted fever R. rickettsii Rodents, dogs, ticks Ixodes tick North, Central and South America Morbilliform Haemorrhagic Often Bronchi, myocardium, brain, skin 2–12%2 Boutonneuse fever R. conorii Rodents, dogs, ticks Ixodes tick Mediterranean, Africa, South-west Asia, India Maculopapular – Skin, meninges 2.5%3 Siberian tick typhus R. sibirica Rodents, birds, domestic animals, ticks Various ticks Siberia, Mongolia, northern China Maculopapular – Skin, meninges Rare3 Australian tick typhus R. australis Rodents, ticks Ticks Australia Maculopapular – Skin, meninges Rare3 Oriental spotted fever R. japonica Rodents, dogs, ticks Ticks Japan Maculopapular – Skin, meninges Rare3 African tick bite fever1 R. africae Cattle, game, ticks Ixodes tick South Africa Can be spotless – Skin, meninges Rare3 Typhus group Scrub typhus Orientia tsutsugamushi Rodents Trombicula mite South-east Asia Maculopapular Unusual Bronchi, myocardium, brain, skin Rare3 Epidemic typhus R. prowazekii Humans Louse Worldwide Morbilliform Haemorrhagic Often Brain, skin, bronchi, myocardium Up to 40% Endemic typhus R. typhi Rats Flea Worldwide Slight – – Rare3 1Eschar at bite site and local lymphadenopathy. 2Highest in adult males. 3Except in infants, older people and the debilitated.

272 • INFECTIOUS DISEASE • Cat scratch disease. B. henselae causes this common benign lymphadenopathy in children and young adults. A vesicle or papule develops on the head, neck or arms after a cat scratch. The lesion resolves spontaneously but there may be regional lymphadenopathy that persists for up to 4 months before also resolving spontaneously. Rare complications include retinitis and encephalopathy. • Bacillary angiomatosis. This is an HIV-associated disease caused by B. quintana or B. henselae (p. 316). • Oroya fever and verruga peruana (Carrion’s disease). This is endemic in areas of Peru. It is a biphasic disease caused by B. bacilliformis, transmitted by sandflies of the genus Phlebotomus. Fever, haemolytic anaemia and microvascular thrombosis with end-organ ischaemia are features. It is frequently fatal if untreated. Investigations and management Bartonellae can be cultured in specialised laboratories but PCR is often used to diagnose infection. Serum antibody detection is possible but cross-reactions occur with Chlamydia and Coxiella spp. Bartonella spp. are typically treated with macrolides or tetracyclines. Antibiotic use is guided by clinical need. Cat scratch disease usually resolves spontaneously but Bartonella endocarditis requires valve replacement and combination antibiotic therapy with doxycycline and gentamicin. Chlamydial infections These are listed in Box 11.52 and are also described on pages 340 and 582. or chloramphenicol 500 mg 4 times daily for 7 days. Louseborne typhus and scrub typhus can be treated with a single dose of 200 mg doxycycline, repeated for 2–3 days to prevent relapse. Chloramphenicol- and doxycycline-resistant strains of O. tsutsugamushi have been reported from Thailand and patients here may need treatment with rifampicin. Nursing care is important, especially in epidemic typhus. Sedation may be required for delirium and blood transfusion for haemorrhage. Relapsing fever and typhoid are common intercurrent infections in epidemic typhus, and pneumonia in scrub typhus, which require diagnosis and treatment. Convalescence is usually protracted, especially in older people. To prevent rickettsial infection, lice, fleas, ticks and mites need to be controlled with insecticides. Q fever Q fever occurs worldwide and is caused by the rickettsia-like organism Coxiella burnetii, an obligate intracellular organism that survives in the extracellular environment. Cattle, sheep and goats are important reservoirs and the organism is transmitted by inhalation of aerosolised particles. An important characteristic of C. burnetii is its antigenic variation, called phase variation, due to a change of lipopolysaccharide (LPS). When isolated from animals or humans, C. burnetii expresses phase I antigen and is very infectious (a single bacterium is sufficient to infect a human). In culture, there is an antigenic shift to the phase II form, which is not infectious. Measurement of antigenic shift helps differentiate acute and chronic Q fever. Clinical features The incubation period is 3–4 weeks. The initial symptoms are non-specific with fever, headache and chills; in 20% of cases, a maculopapular rash occurs. Other presentations include pneumonia and hepatitis. Chronic Q fever may present with osteomyelitis, encephalitis and endocarditis. Investigations and management Diagnosis is usually serological and the stage of the infection can be distinguished by isotype tests and phase-specific antigens. Phase I and II IgM titres peak at 4–6 weeks. In chronic infections, IgG titres to phase I and II antigens may be raised. Prompt treatment of acute Q fever with doxycycline reduces fever duration. Treatment of Q fever endocarditis is problematic, requiring prolonged therapy with doxycycline and rifampicin or ciprofloxacin with hydroxychloroquine; even then, organisms are not always eradicated. Valve surgery is often required (p. 526). Bartonellosis This group of diseases is caused by intracellular Gram-negative bacilli closely related to the rickettsiae, which have been discovered to be important causes of ‘culture-negative’ endocarditis. They are found in many domestic pets, such as cats, although for several the host is undefined (Box 11.51). The principal human pathogens are Bartonella quintana, B. henselae and B. bacilliformis. Bartonella infections are associated with the following: • Trench fever. This is a relapsing fever with severe leg pain and is caused by B. quintana. The disease is not fatal but is very debilitating. • Bacteraemia and endocarditis in the homeless. Endocarditis due to B. quintana or B. henselae is associated with severe damage to the heart valves. 11.52 Chlamydial infections Organism Disease caused Chlamydia trachomatis Trachoma Lymphogranuloma venereum (see Box 13.12, p. 341) Cervicitis, urethritis, proctitis (p. 334) Chlamydia psittaci Psittacosis (see Box 17.36, p. 582) Chlamydophila (Chlamydia) pneumoniae Atypical pneumonia (see Box 17.36, p. 582) Acute/chronic sinusitis 11.51 Clinical diseases caused by Bartonella spp. Reservoir Vector Organism Disease Cats Flea B. henselae Cat scratch disease, bacillary angiomatosis, endocarditis Undefined Lice B. quintana Trench fever, bacillary angiomatosis, endocarditis Undefined Sandfly B. bacilliformis Carrion’s disease: Oroya fever and verruga peruana Undefined Flea B. rochalimae Fever, rash, anaemia, splenomegaly

Protozoal infections • 273

Protozoal infections Protozoa are responsible for many important infectious diseases. They can be categorised according to whether they cause systemic or local infection. Trichomoniasis is described on page 335. Systemic protozoal infections Malaria Malaria in humans is caused by Plasmodium falciparum, P. vivax, P. ovale (subspecies curtisi and wallikeri), P. malariae and the predominantly simian parasite P. knowlesi. It is transmitted by the bite of female anopheline mosquitoes and occurs throughout the tropics and subtropics at altitudes below 1500 metres (Fig. 11.31). The WHO estimates that 214 million cases of clinical malaria occurred in 2015, 88% of these in Africa, especially among children and pregnant women. WHO prevention and treatment campaigns reduced the incidence of malaria between 1950 and 1960, but since 1970 there has been resurgence. Furthermore, P. falciparum has now become resistant to chloroquine and sulfadoxine-pyrimethamine, initially in South-east Asia and now throughout Africa. The WHO’s Millennium Development Goal malaria target aimed to halt the spread of the disease by 2015 and this has been achieved. The ‘Roll Back Malaria’ campaign was designed to halve mortality by 2010 by utilising the ‘best evidence’ vector and disease control methods, such as artemisinin combination therapy (ACT). Travellers are susceptible to malaria (p. 230). Most cases are due to P. falciparum, usually from Africa, and of these 1% die because of late diagnosis. Migrants from endemic countries who spend long periods of time in non-endemic countries are particularly at risk if they visit friends and family in their country of origin. They have lost their partial immunity and frequently do not take malaria prophylaxis. A few people living near airports in Europe have acquired malaria from accidentally imported mosquitoes. Pathogenesis Life cycle of the malarial parasite The female anopheline mosquito becomes infected when it feeds on human blood containing gametocytes, the sexual forms of the malarial parasite (Figs 11.32 and 11.33). Development in the mosquito takes 7–20 days, and results in sporozoites accumulating in the salivary glands and being inoculated into the human blood stream. Sporozoites disappear from human blood within half an hour and enter the liver. After some days, merozoites leave the liver and invade red blood cells, where further asexual cycles of multiplication take place, producing schizonts. Fig. 11.30 Trachoma. Trachoma is characterised by hyperaemia and numerous pale follicles. Courtesy of Institute of Ophthalmology, Moorfields Eye Hospital, London. Trachoma Trachoma is a chronic keratoconjunctivitis caused by Chlamydia trachomatis and is the most common cause of avoidable blindness. The classic trachoma environment is dry and dirty, causing children to have eye and nose discharges. Transmission occurs through flies, on fingers and within families. In endemic areas, the disease is most common in children. Pathology and clinical features The onset is usually insidious. Infection may be asymptomatic, lasts for years, may be latent over long periods and may recrudesce. The conjunctiva of the upper lid is first affected with vascularisation and cellular infiltration. Early symptoms include conjunctival irritation and blepharospasm. The early follicles are characteristic (Fig. 11.30) but clinical differentiation from conjunctivitis due to other causes may be difficult. Scarring causes inversion of the lids (entropion) so that the lashes rub against the cornea (trichiasis). The cornea becomes vascularised and opaque. The problem may not be detected until vision begins to fail. Investigations and management Intracellular inclusions may be demonstrated in conjunctival scrapings by staining with iodine or immunofluorescence. Although chlamydiae may, in theory, be isolated in chick embryo or cell culture or detected by nucleic acid amplification tests, these methods are rarely available in the areas where trachoma is encountered, and in any case their sensitivity and specificity are poorly established. Diagnosis of trachoma is therefore based on clinical and epidemiological features. A single dose of azithromycin (20 mg/kg) has been shown to be superior to 6 weeks of tetracycline eye ointment twice daily for individuals in mass treatment programmes. Deformity and scarring of the lids, and corneal opacities, ulceration and scarring require surgical treatment after control of local infection. Prevention Personal and family hygiene should be improved. Proper care of the eyes of newborn and young children is essential. Family contacts should be examined. The WHO is promoting the SAFE strategy for trachoma control (surgery, antibiotics, facial cleanliness and environmental improvement). Fig. 11.31 Distribution of malaria. (For up-to-date information see the Malaria Atlas Project (MAP): map.ox.ac.uk.)

274 • INFECTIOUS DISEASE from multiplication of parasites in red cells that have not been eliminated by treatment and immune processes (Box 11.53). Pathology Red cells infected with malaria are prone to haemolysis. This is most severe with P. falciparum, which invades red cells of all ages but especially young cells; P. vivax and P. ovale invade reticulocytes, and P. malariae normoblasts, so that infections Fig. 11.32 Scanning electron micrograph of Plasmodium falciparum oöcysts lining an anopheline mosquito’s stomach. Fig. 11.33 Malarial parasites: life cycle. Hypnozoites(*) are present only in Plasmodium vivax and P. ovale infections. (RBC = red blood cell) IN FEMALE ANOPHELINE MOSQUITO IN HUMANS Primary exo-erythrocytic cycle (liver) Sexual differentiation (RBCs) Bite Bite Female gametocyte being fertilised by male gamete Maturation of female gamete Exflagellating male gametocyte Zygote Stomach wall Young oöcyst Segmenting oöcyst Ruptured oöcyst Sporozoites invading salivary glands Hypnozoite∗ Trophozoite Schizont Immature gametocytes Male and female gametocytes Merozoites Ring form Merozoites Oökinete Sexual cycle Erythrocytic (asexual) cycle (RBCs) 11.53 Relationships between life cycle of parasite and clinical features of malaria Cycle/ feature Plasmodium vivax, P. ovale P. malariae P. falciparum Pre-patent period (minimum incubation) 8–25 days 15–30 days 8–25 days Exoerythrocytic cycle Persistent as hypnozoites Pre-erythrocytic only Pre-erythrocytic only Asexual cycle 48 hrs synchronous 72 hrs synchronous < 48 hrs asynchronous Fever periodicity Alternate days Every third day None Delayed onset Common Rare Rare Relapses Common up to 2 years Recrudescence many years later Recrudescence up to 1 year Rupture of the schizont releases more merozoites into the blood and causes fever, the periodicity of which depends on the species of parasite. P. vivax and P. ovale may persist in liver cells as dormant forms, hypnozoites, capable of developing into merozoites months or years later. Thus the first attack of clinical malaria may occur long after the patient has left the endemic area, and the disease may relapse after treatment with drugs that only kill the erythrocytic stage of the parasite. P. falciparum, P. knowlesi and P. malariae have no persistent exo-erythrocytic phase but recrudescence of fever may result

Protozoal infections • 275

P. falciparum infection This is the most dangerous of the malarias. The onset is often insidious, with malaise, headache and vomiting. Cough and mild diarrhoea are also common. The fever has no particular pattern. Jaundice is common due to haemolysis and hepatic dysfunction. The liver and spleen enlarge and may become tender. Anaemia develops rapidly, as does thrombocytopenia. A patient with falciparum malaria, apparently not seriously ill, may rapidly develop dangerous complications (Fig. 11.34 and Box 11.54). Cerebral malaria is manifested by delirium, seizures or coma, usually without localising signs. Children die rapidly without any specific symptoms other than fever. Immunity is impaired in pregnancy and the parasite can preferentially bind to the placental protein chondroitin sulphate A. Abortion and intrauterine growth retardation from parasitisation of the maternal side of the placenta are frequent. Previous splenectomy increases the risk of severe malaria. P. vivax and P. ovale infection In many cases, the illness starts with several days of continued fever before the development of classical bouts of fever on alternate days. Fever starts with a rigor. The patient feels cold and the temperature rises to about 40°C. After half an hour to remain lighter. Anaemia may be profound and is worsened by dyserythropoiesis, splenomegaly and depletion of folate stores. In P. falciparum malaria, red cells containing trophozoites adhere to vascular endothelium in post-capillary venules in brain, kidney, liver, lungs and gut by the formation of ‘knob’ proteins. They also form ‘rosettes’ and rouleaux with uninfected red cells. Vessel congestion results in organ damage, which is exacerbated by rupture of schizonts, liberating toxic and antigenic substances (Fig. 11.33). P. falciparum has influenced human evolution, with the appearance of protective mutations such as sickle-cell (HbS; p. 951), thalassaemia (p. 953), glucose-6-phosphate dehydrogenase (G6PD) deficiency (p. 948) and HLA-B53. P. falciparum does not grow well in red cells that contain haemoglobin F, C or especially S. Haemoglobin S heterozygotes (AS) are protected against the lethal complications of malaria. P. vivax cannot enter red cells that lack the Duffy blood group; therefore many West Africans and African Americans are protected. Clinical features The clinical features of malaria are non-specific and the diagnosis must be suspected in anyone returning from an endemic area who has features of infection. Fig. 11.34 Features of Plasmodium falciparum infection. (RBC = red blood cell) Insets (malaria retinopathy) Courtesy of Dr Nicholas Beare, Royal Liverpool University Hospital; (blood films of P. vivax and P. falciparum) Courtesy of Dr Kamolrat Silamut, Mahidol Oxford Research Unit, Bangkok, Thailand. Neurological Coma Hypoglycaemia Seizures Cranial nerve palsies Opisthotonus Respiratory Pulmonary oedema Secondary bacterial pneumonia Abdomen Jaundice Tender liver edge with hepatitis Pain in left upper quadrant with splenomegaly Fever Cardiovascular Shock Cardiac failure (‘algid malaria’) Dysrhythmias with quinine Renal Acute kidney injury Severe haemolysis resulting in haemoglobinuria (‘blackwater fever’) Optic fundi Blood Parasitaemia Anaemia Thrombocytopenia Coagulopathy Disconjugate gaze due to cranial nerve palsy Malaria retinopathy with Roth’s spots Ring form Ring form in RBCs Trophozoite Schizont P. vivax in RBCs Blood film showing parasitaemia P. falciparum

276 • INFECTIOUS DISEASE to quantify the parasite load (by counting the percentage of infected erythrocytes). P. falciparum parasites may be very scanty, especially in patients who have been partially treated. With P. falciparum, only ring forms are normally seen in the early stages (Fig. 11.34); with the other species, all stages of the erythrocytic cycle may be found. Gametocytes appear after about 2 weeks, persist after treatment and are harmless, except that they are the source by which more mosquitoes become infected. Immunochromatographic rapid diagnostic tests (RDTs) for malaria antigens, such as OptiMAL (which detects the Plasmodium LDH of P. falciparum and vivax) and Parasight-F (which detects the P. falciparum histidine-rich protein 2), are extremely sensitive and specific for falciparum malaria but less so for other species. They should be used in parallel with blood film examination but are especially useful where the microscopist is less experienced in examining blood films (e.g. in the UK). They are less sensitive for low-level parasitaemia and positivity may persist for a month or more in some individuals. The QBC Malaria Test is a fluorescence microscopy-based malaria diagnostic test that is also widely used. DNA detection (PCR) is used mainly in research and is useful for determining whether a patient has a recrudescence of the same malaria parasite or a reinfection with a new parasite. an hour, the hot or flush phase begins. It lasts several hours and gives way to profuse perspiration and a gradual fall in temperature. The cycle is repeated 48 hours later. Gradually, the spleen and liver enlarge and may become tender. Anaemia develops slowly. Relapses are frequent in the first 2 years after leaving the malarious area and infection may be acquired from blood transfusion. P. malariae and P. knowlesi infection This is usually associated with mild symptoms and bouts of fever every third day. Parasitaemia may persist for many years, with the occasional recrudescence of fever or without producing any symptoms. Chronic P. malariae infection causes glomerulonephritis and long-term nephrotic syndrome in children. P. knowlesi is usually mild but can deteriorate rapidly. Investigations Giemsa-stained thick and thin blood films should be examined whenever malaria is suspected. In the thick film, erythrocytes are lysed, releasing all blood stages of the parasite. This, as well as the fact that more blood is used in thick films, facilitates the diagnosis of low-level parasitaemia. A thin film is essential to confirm the diagnosis, species and, in P. falciparum infections, Coma (cerebral malaria) • Maintain airway • Nurse on side • Exclude other treatable causes of coma (e.g. hypoglycaemia, bacterial meningitis) • Avoid harmful ancillary treatments such as glucocorticoids, heparin and adrenaline (epinephrine) • Intubate if necessary Hyperpyrexia • Tepid sponging, fanning, cooling blanket • Antipyretic drug (paracetamol) Convulsions • Maintain airway • Treat promptly with diazepam or paraldehyde injection Hypoglycaemia • Measure blood glucose • Give 50% dextrose injection followed by 10% dextrose infusion (glucagon may be ineffective) Severe anaemia (packed cell volume < 15%) • Transfuse fresh whole blood or packed cells if pathogen screening of donor blood is available Acute pulmonary oedema • Nurse at 45°, give oxygen, venesect 250 mL of blood, give diuretic, stop intravenous fluids • Intubate and add PEEP/CPAP (p. 202) in life-threatening hypoxaemia • Haemofilter Acute kidney injury • Exclude pre-renal causes • Fluid resuscitation if appropriate • Peritoneal dialysis (haemofiltration or haemodialysis if available) Spontaneous bleeding and coagulopathy • Transfuse screened fresh whole blood (cryoprecipitate/fresh frozen plasma and platelets if available) • Vitamin K injection Metabolic acidosis • Exclude or treat hypoglycaemia, hypovolaemia and Gram-negative sepsis • Fluid resuscitation • Give oxygen Shock (‘algid malaria’) • Suspect Gram-negative sepsis • Take blood cultures • Give parenteral antimicrobials • Correct haemodynamic disturbances Aspiration pneumonia • Give parenteral antimicrobial drugs • Change position • Physiotherapy • Give oxygen Hyperparasitaemia • Consider exchange transfusion (e.g. > 10% of circulating erythrocytes parasitised in non-immune patient with severe disease) Specific therapy • Intravenous artesunate • Mefloquine should be avoided due to increased risk of post-malaria neurological syndrome From WHO. Severe falciparum malaria. In: Severe and complicated malaria, 3rd edn. Trans Roy Soc Trop Med Hyg 2000; 94 (suppl. 1):S1–41. (CPAP = continuous positive airway pressure; PEEP = positive end-expiratory pressure) 11.54 Severe manifestations/complications of falciparum malaria and their immediate management

Protozoal infections • 277

Complicated P. falciparum malaria Severe malaria should be considered in any non-immune patient with a parasite count greater than 2% or with complications, and is a medical emergency (see Box 11.54). Management includes early and appropriate antimalarial chemotherapy, active treatment of complications, correction of fluid, electrolyte and acid–base balance, and avoidance of harmful ancillary treatments. The treatment of choice is intravenous artesunate. Late haemolysis is a treatment side-effect in some patients. Rectal administration of artesunate is also being developed to allow administration in remote rural areas. Quinine salt is the alternative. Exchange transfusion has not been tested in randomised controlled trials but may be beneficial for non-immune patients with persisting high parasitaemias (> 10% circulating erythrocytes). Non-falciparum malaria P. vivax, P. ovale, P. knowlesi and P. malariae infections should be treated with oral chloroquine but some chloroquine resistance has been reported from Indonesia. ‘Radical cure’ is achieved in patients with P. vivax or P. ovale malaria using a course of primaquine, which destroys the hypnozoite phase in the liver. Haemolysis may develop in those who are G6PD-deficient. Cyanosis due to the formation of methaemoglobin in the red cells is more common but not dangerous (see Fig. 7.1, p. 135). All are sensitive to ACTs. Prevention Clinical attacks of malaria may be preventable with chemoprophylaxis using chloroquine, atovaquone plus proguanil (Malarone), doxycycline or mefloquine. Box 11.56 gives the recommended doses for protection of the non-immune. The risk of malaria in the area to be visited and the degree of chloroquine resistance guide the recommendations for prophylaxis. Updated recommendations are summarised at fitfortravel.nhs.uk. Fansidar should not be used for chemoprophylaxis, as deaths have occurred from agranulocytosis or Stevens–Johnson syndrome (pp. 1224 and 1254). Mefloquine is useful in areas of multiple drug resistance, such as East and Central Africa and Papua New Guinea. Experience shows it to be safe for at least 2 years but there are several contraindications to its use (Box 11.56). Expert advice is required for individuals unable to tolerate the first-line agents listed or in whom they are contraindicated. Mefloquine should be started 2–3 weeks before travel to give time for assessment of side-effects. Chloroquine should not be taken continuously as a prophylactic for more than 5 years without regular ophthalmic examination, as it may cause irreversible retinopathy. Pregnant and lactating women may take proguanil or chloroquine safely. Prevention also involves advice about the use of highpercentage diethyltoluamide (DEET), covering up extremities when out after dark, and sleeping under permethrin-impregnated mosquito nets. Malaria control in endemic areas There are major initiatives to reduce and eliminate malaria in endemic areas. Successful programmes combine vector control, including indoor residual spraying, use of long-lasting insecticide-treated bed nets (ITNs) and intermittent preventative therapy (IPT; repeated dose of prophylactic drugs in high-risk groups, such as children and pregnant women, which reduces malaria and anaemia). Research to produce a fully protective malaria vaccine is ongoing. Management Mild P. falciparum malaria Since P. falciparum is now resistant to chloroquine and sulfadoxine-pyrimethamine (Fansidar) almost worldwide, an artemisinin-based treatment is recommended (Box 11.55) and WHO policy in Africa recommends always using ACT, e.g. co-artemether or artesunate–amodiaquine. Unfortunately, artemisinin resistance has now been reported in South-east Asia. 11.55 Malaria treatment Mild malaria Preferred therapy • Co-artemether (CoArtem or Riamet); contains artemether and lumefantrine (4 tablets orally at 0, 8, 24, 36, 48 and 60 hrs) Alternative therapy • Quinine (600 mg of quinine salt 3 times daily orally for 5–7 days), together with or followed by doxycycline (200 mg once daily orally for 7 days) Use clindamycin not doxycycline if the patient is a pregnant woman or young child or • Atovaquone–proguanil (Malarone, 4 tablets orally once daily for 3 days) Pregnancy • Co-artemether but avoid in early pregnancy. • If not using co-artemether, use quinine plus clindamycin (450 mg 3 times daily orally for 7 days) Other regimens • Artesunate (200 mg orally daily for 3 days) and mefloquine (1 g orally on day 2 and 500 mg orally on day 3) Severe malaria Preferred therapy • Artesunate 2.4 mg/kg IV at 0, 12 and 24 hrs and then once daily for 7 days. Once the patient is able to recommence oral intake, switch to 2 mg/kg orally once daily, to complete a total cumulative dose of 17–18 mg/kg Alternative therapy • Quinine, loading dose 20 mg/kg IV over 4 hrs, up to a maximum of 1.4 g, then maintenance doses of 10 mg/kg quinine salt given as 4-hr infusions 3 times daily for the first 48 hrs then twice a day, up to a maximum of 700 mg per dose or until the patient can take drugs orally. Combine with doxycycline (or clindamycin if there are contraindications to doxycycline) • Note the loading dose should not be given if quinine, quinidine or mefloquine has been administered in the previous 24 hrs • Patients should be monitored by ECG while receiving quinine, with special attention to QRS duration and QT interval Non-falciparum malaria Preferred therapy • Chloroquine: 600 mg chloroquine base orally, followed by 300 mg base in 6 hrs, then 150 mg base twice daily for 2 more days plus primaquine (30 mg orally daily (for P. vivax) or 15 mg orally daily (for P. ovale) for 14 days) after confirming G6PD-negative Patients with mild to moderate G6PD deficiency and P. vivax or P. ovale • Chloroquine plus primaquine 0.75 mg/kg weekly orally for 8 weeks Chloroquine-resistant P. vivax • Co-artemether as for P. falciparum (G6PD = glucose-6-phosphate dehydrogenase)

278 • INFECTIOUS DISEASE the patient is usually severely ill and may have developed pleural effusions and signs of myocarditis or hepatitis. There may be a petechial rash. The patient may die before there are signs of involvement of the CNS. If the illness is less acute, drowsiness, tremors and coma develop. Babesiosis Babesiosis is a tick-borne intra-erythrocytic protozoon parasite. There are more than 100 species of Babesia, all of which have an animal reservoir, typically either rodents or cattle, and are transmitted to humans via the tick vector Ixodes scapularis. Most American cases of babesiosis are due to B. microti and most European cases to B. divergens. Patients present with fever and malaise 1–4 weeks after a tick bite. Illness may be complicated by haemolytic anaemia. Severe illness is seen in splenectomised patients. The diagnosis is made by blood-film examination. Treatment is with quinine and clindamycin. African trypanosomiasis (sleeping sickness) African sleeping sickness is caused by trypanosomes (Fig. 11.35) conveyed to humans by the bites of infected tsetse flies, and is unique to sub-Saharan Africa (Fig. 11.36). The incidence of sleeping sickness across Africa has declined by over 60% since 1990 due to better control measures. Trypanosoma brucei gambiense trypanosomiasis has a wide distribution in West and Central Africa and accounts for 90% of human African trypanosomiasis (HAT). T. brucei rhodesiense trypanosomiasis is found in parts of East and Central Africa. In West Africa, transmission is mainly at the riverside, where the fly rests in the shade of trees; no animal reservoir has been identified for T. gambiense. T. rhodesiense has a large reservoir in numerous wild animals and transmission takes place in the shade of woods bordering grasslands. Rural populations employed in agriculture, fishing and animal husbandry are susceptible. Local people and tourists visiting forests infested with tsetse flies and animal reservoirs may become infected. Clinical features A bite by a tsetse fly is painful and commonly becomes inflamed; if trypanosomes are introduced, the site may again become painful and swollen about 10 days later (‘trypanosomal chancre’), associated with regional lymphadenopathy. Within 2–3 weeks of infection, the trypanosomes invade the blood stream. The disease is characterised by an early haematolymphatic (stage 1) and a late encephalitic phase (stage 2), in which the parasite crosses the blood–brain barrier and chronic encephalopathy develops. Rhodesiense infections In these infections, the disease is more acute and severe than in gambiense infections, so that, within days or a few weeks, Fig. 11.35 Trypanosomiasis. Scanning electron micrograph showing trypanosomes swimming among erythrocytes. Fig. 11.36 Distribution of human African trypanosomiasis. Data are from 2009. From Simarro PP, Diarra A, Ruiz Postigo JA, et al. The human African trypanosomiasis control and surveillance programme of the World Health Organization 2000–2009: the way forward. PLoS Negl Trop Dis 2011; 5(2):e1007. Non-endemic None 1–100 101–500 501–1000

1000 No. of cases Antimalarial tablets Adult prophylactic dose Regimen Chloroquine resistance high Mefloquine2 250 mg weekly Started 2–3 weeks before travel and continued until 4 weeks after or Doxycycline3,4 100 mg daily Started 1 week before and continued until 4 weeks after travel or Malarone4 1 tablet daily From 1–2 days before travel until 1 week after return Chloroquine resistance absent Chloroquine5 and proguanil 300 mg base weekly 100–200 mg daily Started 1 week before and continued until 4 weeks after travel } 1Choice of regimen is determined by area to be visited, length of stay, level of malaria transmission, level of drug resistance, presence of underlying disease in the traveller and concomitant medication taken. 2Contraindicated in the first trimester of pregnancy, lactation, cardiac conduction disorders, epilepsy, psychiatric disorders; may cause neuropsychiatric disorders. 3Causes photosensitisation and sunburn if high-protection sunblock is not used. 4Avoid in pregnancy. 5British preparations of chloroquine usually contain 150 mg base, French preparations 100 mg base and American preparations 300 mg base. 11.56 Chemoprophylaxis of malaria1

Protozoal infections • 279

American trypanosomiasis (Chagas’ disease) Chagas’ disease occurs widely in South and Central America. The cause is Trypanosoma cruzi, transmitted to humans from the faeces of a reduviid (triatomine) bug, in which the trypanosomes develop before infecting humans. These bugs live in wild forests in crevices, burrows and palm trees. The Triatoma infestans bug has become domesticated in the Southern Cone countries (Argentina, Brazil, Chile, Paraguay and Uruguay). It lives in the mud and wattle walls and thatched roofs of simple rural houses and emerges at night to feed and defaecate on the sleeping occupants. Infected faeces are rubbed in through the conjunctiva, mucosa of mouth or nose, or abrasions of the skin. Over 100 species of mammal – domestic, peridomestic and wild – may serve as reservoirs of infection. In some areas, blood transfusion accounts for about 5% of cases. Congenital transmission occasionally occurs. Pathology The trypanosomes migrate via the blood stream, develop into amastigote forms in the tissues and multiply intracellularly by binary fission. In the acute phase (primarily cell-mediated), inflammation of parasitised, as well as non-parasitised, cardiac muscles and capillaries occurs, resulting in acute myocarditis. In the chronic phase, focal myocardial atrophy, signs of chronic passive congestion and thromboembolic phenomena, cardiomegaly and apical cardiac aneurysm are salient findings. In the digestive form of disease, focal myositis and discontinuous lesions of the intramural myenteric plexus are seen, predominantly in the oesophagus and colon. Clinical features Acute phase Clinical manifestations of the acute phase are seen in only 1–2% of individuals infected before the age of 15 years. Young children (1–5 years) are most commonly affected. The entrance of T. cruzi through an abrasion produces a dusky-red, firm swelling and enlargement of regional lymph nodes. A conjunctival lesion, although less common, is characteristic; the unilateral firm, reddish swelling of the lids may close the eye and constitutes ‘Romaña’s sign’. In a few patients, an acute generalised infection soon appears, with a transient morbilliform or urticarial rash, fever, lymphadenopathy and enlargement of the spleen and liver. In a small minority of patients, acute myocarditis and heart failure or neurological features, including personality changes and signs of meningoencephalitis, may be seen. The acute infection may be fatal to infants. Chronic phase About 50–70% of infected patients become seropositive and develop an indeterminate form when no parasitaemia is detectable. They have a normal lifespan with no symptoms but are a natural reservoir for the disease and maintain the life cycle of parasites. After a latent period of several years, 10–30% of chronic cases develop low-grade myocarditis and damage to conducting fibres, which causes cardiomyopathy characterised by cardiac dilatation, arrhythmias, partial or complete heart block and sudden death. In nearly 10% of patients, damage to Auerbach’s plexus results in dilatation of various parts of the alimentary canal, especially the colon and oesophagus, so-called ‘mega’ disease. Dilatation of the bile ducts and bronchi are also recognised sequelae. Autoimmune processes may be responsible for much of the damage. There are geographical variations of the basic pattern Gambiense infections The distinction between early and late stages may not be apparent in gambiense infections. The disease usually runs a slow course over months or years, with irregular bouts of fever and enlargement of lymph nodes. These are characteristically firm, discrete, rubbery and painless, and are particularly prominent in the posterior triangle of the neck (‘Winterbottom’s sign’). The spleen and liver may become palpable. After some months without treatment, the CNS is invaded. Patients develop headache, altered behaviour, blunting of higher mental functions, insomnia by night and sleepiness by day, delirium and eventually tremors, pareses, wasting, coma and death. Investigations Trypanosomiasis should be considered in any febrile patient from an endemic area. In rhodesiense infections, thick and thin malaria blood films will reveal trypanosomes. The trypanosomes may be seen in the blood or from puncture of the primary lesion in the earliest stages of gambiense infections, but it is usually easier to demonstrate them by aspiration of a lymph node. Concentration methods include buffy coat microscopy and miniature anion exchange chromatography. Due to the cyclical nature of parasitaemia, the diagnosis is often made by demonstration of antibodies using a simple, rapid screening card agglutination trypanosomiasis test (CATT) for gambiense HAT, followed by parasitological confirmation. No reliable serological test is available for rhodesiense HAT. PCR diagnosis is available, although technical requirements limit its availability in endemic regions. If the CNS is affected, the cell count (> 20 × 109 leucocytes/L) and protein content of the CSF are increased and the glucose is diminished. A very high level of serum IgM or the presence of IgM in the CSF is suggestive of trypanosomiasis. Recognition of CNS involvement is critical, as failure to treat it might be fatal. Management Therapeutic options for African trypanosomiasis are limited and most antitrypanosomal drugs are toxic and expensive. The prognosis is good if treatment is begun early, before the brain has been invaded. At this stage, intravenous suramin, after a test dose of 100–200 mg, should be given for rhodesiense infections, followed by five injections of 20 mg/kg every 7 days. For gambiense infections, deep intramuscular or intravenous pentamidine 4 mg/kg for 7 days is given. For the treatment of stage 2 (nervous system) infection caused by gambiense HAT, patients were previously treated with melarsoprol (an arsenical). Treatment-related mortality with melarsoprol is 4–12% due to reactive encephalopathy. Now eflornithine (DFMO), an irreversible inhibitor of ornithine decarboxylase (100 and 150 mg/kg IV 4 times daily for 14 days for adults and children, respectively), is a safer and cost-effective option. Combinations of eflornithine (400 mg daily for 7 days) with oral nifurtimox (15 mg/kg daily for 15 days) have been shown to decrease relapses, deaths and drug toxicity. Stage 2 rhodesiense infection is treated with melarsoprol 2.2 mg/kg IV for 10 days. Prevention In endemic gambiense areas, various measures are taken against tsetse flies, and field teams help detect and treat early HAT. In rhodesiense endemic areas, control is difficult.

280 • INFECTIOUS DISEASE Clinical features In most immunocompetent individuals, including children and pregnant women, the infection goes unnoticed. In approximately 10% of patients, it causes a self-limiting illness, most common in adults aged 25–35 years. The presenting feature is usually localised or generalised painless lymphadenopathy. The cervical nodes are primarily involved but mediastinal, mesenteric or retroperitoneal groups may be affected. The spleen is seldom palpable. Most patients have no systemic symptoms but some complain of malaise, fever, fatigue, muscle pain, sore throat and headache. Complete resolution usually occurs within a few months, although symptoms and lymphadenopathy tend to fluctuate unpredictably and some patients do not recover completely for a year or more. Encephalitis, myocarditis, polymyositis, pneumonitis or hepatitis occasionally occur in immunocompetent patients but are more frequent in immunocompromised hosts. Retinochoroiditis (Fig. 11.38) is usually the result of congenital infection but has also been reported in acquired disease. Congenital toxoplasmosis Acute toxoplasmosis, mostly subclinical, affects 0.3–1% of pregnant women, with an approximately 60% transmission rate to the fetus, which rises with increasing gestation. Seropositive females infected 6 months before conception have no risk of fetal transmission. Congenital disease affects approximately 40% of infected fetuses, and is more likely and more severe with infection early in gestation (see Box 11.26, p. 235). Many fetal infections are subclinical at birth but long-term sequelae include retinochoroiditis, microcephaly and hydrocephalus. of disease. Reactivation of Chagas’ disease can occur in patients with HIV if the CD4 count falls lower than 200 cells/mm3; this can cause space-occupying lesions with a presentation similar to Toxoplasma gondii, encephalitis, encephalitis, meningoencephalitis or myocarditis. Investigations T. cruzi is easily detectable in a blood film in the acute illness. In chronic disease, it may be recovered in up to 50% of cases by xenodiagnosis, in which infection-free, laboratory-bred reduviid bugs feed on the patient; subsequently, the hindgut or faeces of the bug are examined for parasites. Parasite DNA detection by PCR in the patient’s blood is a highly sensitive method for documentation of infection and, in addition, can be employed in faeces of bugs used in xenodiagnosis tests to improve sensitivity. Antibody detection is also highly sensitive. Management and prevention Parasiticidal agents are used to treat the acute phase, congenital disease and early chronic phase (within 10 years of infection). Nifurtimox is given orally. The dose, which has to be carefully supervised to minimise toxicity while preserving parasiticidal activity, is 10 mg/kg daily orally, divided into three equal doses for 90 days. The paediatric dose is 15 mg/kg daily. Cure rates of 80% in acute disease are obtained. Benznidazole is an alternative, given at a dose of 5 mg/kg daily orally, in two divided doses for 60 days; children receive 10 mg/kg daily. Both nifurtimox and benznidazole are toxic, with adverse reaction rates of 30–55%. Parasiticidal treatment of the chronic phase is usually performed but, in the cardiac or digestive ‘mega’ diseases, does not reverse tissue damage. Surgery may be needed. Preventative measures include improvement of housing and destruction of reduviid bugs by spraying of houses with insecticides. Blood and organ donors should be screened. Toxoplasmosis Toxoplasma gondii is an intracellular parasite. The sexual phase of the parasite’s life cycle (Fig. 11.37) occurs in the small intestinal epithelium of the domestic cat. Oöcysts are shed in cat faeces and are spread to intermediate hosts (pigs, sheep and also humans) through widespread contamination of soil. Oöcysts may survive in moist conditions for weeks or months. Once they are ingested, the parasite transforms into rapidly dividing tachyzoites through cycles of asexual multiplication. Microscopic tissue cysts develop containing bradyzoites, which persist for the lifetime of the host. Cats become infected or reinfected by ingesting tissue cysts in prey such as rodents and birds. Human infection occurs via oöcyst-contaminated soil, salads and vegetables, or by ingestion of raw or under-cooked meats containing tissue cysts. Sheep, pigs and rabbits are the most common meat sources. Outbreaks of toxoplasmosis have been linked to the consumption of unfiltered water. In developed countries, toxoplasmosis is the most common protozoal infection; around 22% of adults in the UK are seropositive. Most primary infections are subclinical; however, toxoplasmosis is thought to account for about 15% of heterophile antibody-negative infectious mononucleosis (p. 241). In India or Brazil, approximately 40–60% of pregnant females are seropositive for T. gondii. In HIV-1 infection (p. 320), toxoplasmosis is an important opportunistic infection with considerable morbidity and mortality. Generalised toxoplasmosis has been described after accidental laboratory infection with highly virulent strains. Fig. 11.37 Life cycle of Toxoplasma gondii. Cat Rodents Birds Oöcysts in faeces Contaminated food, water or soil Tissue cysts Oöcysts Oöcysts Tissue cysts Humans Vertical transmission Congenital infection Transfusion Transplantation Food animals

Protozoal infections • 281

plastidae). There are 21 leishmanial species that cause diverse clinical syndromes, which can be placed into three broad groups: • visceral leishmaniasis (VL, kala-azar) • cutaneous leishmaniasis (CL) • mucosal leishmaniasis (ML). Epidemiology and transmission Although most clinical syndromes are caused by zoonotic transmission of parasites from animals (chiefly canine and rodent reservoirs) to humans through phlebotomine sandfly vectors (Fig. 11.39A), humans are the only known reservoir (anthroponotic person-to-person transmission) in major VL foci in the Indian subcontinent and in injection drug-users (Fig. 11.39B and C). Leishmaniasis occurs in approximately 100 countries around the world, with an estimated annual incidence of 0.9–1.3 million new cases (25% VL). The life cycle of Leishmania is shown in Figure 11.40. Flagellar promastigotes (10–20 μm) are introduced by the feeding female sandfly. The promastigotes are taken up by neutrophils, which undergo apoptosis and are then engulfed by macrophages, in which the parasites transform into amastigotes (2–4 μm; Leishman–Donovan body). These multiply, causing macrophage Investigations In contrast to immunocompromised patients, in whom the diagnosis often requires direct detection of parasites, serology is often used in immunocompetent individuals. The Sabin–Feldman dye test (indirect fluorescent antibody test), which detects IgG antibody, is most commonly used. Recent infection induces a fourfold or greater increase in titre when paired sera are tested in parallel. Peak titres of 1/1000 or more are reached within 1–2 months of the onset of infection, and serology then becomes an unreliable indicator of recent infection. The detection of significant levels of Toxoplasma-specific IgM antibody may be useful in confirming acute infection. A false-positive result or persistence of IgM antibodies for years after infection makes interpretation difficult; however, negative IgM antibodies virtually rule out acute infection. During pregnancy, it is critical to differentiate recent from past infection; the presence of high-avidity IgG antibodies excludes infection acquired in the preceding 3–4 months. If necessary, the presence of Toxoplasma organisms in a lymph node biopsy or other tissue can be detected histochemically with T. gondii antiserum, or by the use of PCR to detect Toxoplasmaspecific DNA. Management In immunocompetent subjects, uncomplicated toxoplasmosis is self-limiting and responds poorly to antimicrobial therapy. Treatment with sulfadiazine, pyrimethamine and folinic acid is usually reserved for severe or progressive disease, and for infection in immunocompromised patients. In pregnant women with established recent infection, spiramycin (3 g daily in divided doses) is given until term. Once fetal infection is established, treatment with sulfadiazine and pyrimethamine plus calcium folinate is recommended (spiramycin does not cross the placental barrier). The cost/benefit of routine Toxoplasma screening and treatment in pregnancy is being debated in many countries. There is insufficient evidence to determine the effects on mother or baby of current antiparasitic treatment for women who seroconvert in pregnancy. Leishmaniasis Leishmaniasis is caused by unicellular, flagellate, intracellular protozoa belonging to the genus Leishmania (order KinetoFig. 11.38 Retinochoroiditis due to toxoplasmosis. Fig. 11.39 Transmission of leishmaniasis. A Zoonotic transmission. B Anthroponotic transmission. C Anthroponotic transmission in the injection drug-user. (CL = cutaneous leishmaniasis; VL = visceral leishmaniasis) Zoonotic VL, CL L. infantum L. major L. mexicana complex L. (V.) brasiliensis complex Anthroponotic VL, CL L. donovani L. tropica Anthroponotic in injection drug-users HIV-VL co-infection L. infantum A B C

282 • INFECTIOUS DISEASE may become afebrile for intervening periods ranging from weeks to months. This is followed by a relapse of fever, often of lesser intensity. Splenomegaly develops quickly in the first few weeks and becomes massive as the disease progresses. Moderate hepatomegaly occurs later. Lymphadenopathy is common in Africa, the Mediterranean and South America but is rare in the Indian subcontinent. Blackish discoloration of the skin, from which the disease derived its name, kala-azar (the Hindi word for ‘black fever’), is a feature of advanced illness but is now rarely seen. Pancytopenia is common. Moderate to severe anaemia develops rapidly and can cause cardiac failure. Thrombocytopenia, often compounded by hepatic dysfunction, may result in bleeding from the retina, gastrointestinal tract and nose. In advanced illness, hypoalbuminaemia may manifest as pedal oedema, ascites and anasarca (gross generalised oedema and swelling). As disease progresses, there is profound immunosuppression and secondary infections are very common. These include tuberculosis, pneumonia, gastroenteritis, severe amoebic or bacillary dysentery, boils, cellulitis, chickenpox, shingles and scabies. Without adequate treatment, most patients with clinical VL die. Investigations Pancytopenia is the dominant feature, with granulocytopenia and monocytosis. Polyclonal hypergammaglobulinaemia, chiefly IgG followed by IgM, and hypoalbuminaemia are seen later. Demonstration of amastigotes (Leishman–Donovan bodies) in splenic smears is the most efficient means of diagnosis, with 98% sensitivity (Fig. 11.42); however, it carries a risk of serious haemorrhage in inexperienced hands. Safer methods, such as bone marrow or lymph node smears, are not as sensitive but lysis and infection of other cells. Sandflies pick up amastigotes when feeding on infected patients or animal reservoirs. In the sandfly, the parasite transforms into a flagellar promastigote, which multiplies by binary fission in the gut of the vector and migrates to the proboscis to infect a new host. Sandflies live in hot and humid climates in the cracks and crevices of mud or straw houses and lay eggs in organic matter. People living in such conditions are more prone to leishmaniasis. Female sandflies bite during the night and preferentially feed on animals; humans are incidental hosts. Visceral leishmaniasis (kala-azar) VL is caused by the protozoon Leishmania donovani complex (comprising L. donovani, L. infantum and L. chagasi). India, Sudan, Bangladesh and Brazil account for 90% of cases of VL. Other affected regions include the Mediterranean, East Africa, China, Arabia, Israel and other South American countries (Fig. 11.41). In addition to sandfly transmission, VL has also been reported to follow blood transfusion, and disease can present unexpectedly in immunosuppressed patients – for example, after renal transplantation and in HIV infection. The majority of people infected remain asymptomatic. In visceral disease, the spleen, liver, bone marrow and lymph nodes are primarily involved. Clinical features In the Indian subcontinent, adults and children are equally affected; elsewhere, VL is mainly a disease of small children and infants, except in adults with HIV co-infection. The incubation period ranges from weeks to months (occasionally, several years). The first sign of infection is high fever, usually accompanied by rigor and chills. Fever intensity decreases over time and patients Fig. 11.40 Life cycle of Leishmania. From Knight R. Parasitic disease in man. Churchill Livingstone, Elsevier Ltd; 1982. Sandfly (Phlebotomus in eastern hemisphere, Lutzomyia and Psychodopygus in western hemisphere) Stomach Pharynx Bite Proboscis Macrophage Promastigote Amastigote Amastigote Dermis only L. tropica L. mexicana etc. Dermis and mucosae (sometimes) L. brasiliensis Viscera and dermis (sometimes) L. donovani Fig. 11.41 World distribution of visceral leishmaniasis. L. chagasi L. infantum L. donovani Fig. 11.42 Splenic smear showing numerous intracellular, and a few extracellular, amastigotes. Courtesy of Dr S. Sundar and Dr H.W. Murray.

Protozoal infections • 283

of 10 mg/kg of AmBisome cured 96% of Indian patients. The manufacturer of AmBisome has donated a large quantity of the drug for use in the Kala-azar Elimination Programme in India, Nepal and Bangladesh, leading to its adoption as the first-line drug in treatment. Other drugs The oral drug miltefosine, an alkyl phospholipid, has been approved in several countries for the treatment of VL. A daily dose of 50 mg (patient’s body weight < 25 kg) to 100 mg (≥ 25 kg), or 2.5 mg/kg for children, for 28 days cures over 90% of patients. Side-effects include mild to moderate vomiting and diarrhoea, and rarely skin allergy or renal or liver toxicity. Since it is a teratogenic drug, it cannot be used in pregnancy; female patients are advised not to become pregnant for the duration of treatment and 3 months thereafter because of its half-life of nearly 1 week. Paromomycin is an aminoglycoside that has undergone trials in India and Africa, and is highly effective if given intramuscularly at 11 mg/kg of paromomycin base, daily for 3 weeks. No significant auditory or renal toxicity is seen. The drug is approved in India for VL treatment. Pentamidine isethionate was used to treat Sb-refractory patients with VL. However, declining efficacy and serious side-effects, such as type 1 diabetes mellitus, hypoglycaemia and hypotension, have led to it being abandoned. Multidrug therapy of VL is likely to be used increasingly to prevent emergence of drug resistance, and in India short-course combinations (a single dose of AmBisome 5 mg/kg with either 7 days of miltefosine or 10 days of paromomycin, or 10 days each of miltefosine and paromomycin) were as effective as standard therapy. In India, in treatment centres where the cold chain (a temperature-controlled supply chain) is not maintained, 10 days of paromomycin combined with miltefosine is an alternative treatment regimen. Response to treatment A good response results in fever resolution, improved well-being, reduction in splenomegaly, weight gain and recovery of blood counts. Patients should be followed regularly for 6–12 months, as some may experience relapse irrespective of the treatment regimen. HIV–visceral leishmaniasis co-infection HIV-induced immunosuppression (Ch. 12) increases the risk of contracting VL 100–1000 times. Most cases of HIV–VL co-infection have been reported from Spain, France, Italy and Portugal. Antiretroviral therapy (ART) has led to a remarkable decline in the incidence of VL co-infection in Europe. However, numbers are increasing in Africa (mainly Ethiopia), Brazil and the Indian subcontinent. Although the clinical triad of fever, splenomegaly and hepatomegaly is found in the majority of co-infected patients, those with low CD4 count may have atypical clinical presentations. VL may present with gastrointestinal involvement (stomach, duodenum or colon), ascites, pleural or pericardial effusion, or involvement of lungs, tonsil, oral mucosa or skin. Diagnostic principles remain the same as those in non-HIV patients. Parasites are numerous and easily demonstrable, even in buffy coat preparations. Sometimes amastigotes are found in unusual sites, such as bronchoalveolar lavage fluid, pleural fluid or biopsies of the gastrointestinal tract. Serological tests have low sensitivity. DNA detection by PCR of the blood or its buffy coat is at least 95% sensitive and accurately tracks recovery and relapse. are frequently employed. Parasites may be demonstrated in buffy coat smears, especially in immunosuppressed patients. Sensitivity is improved by culturing the aspirate material or by using PCR for DNA detection and species identification, but these tests can only be performed in specialised laboratories. Serodiagnosis, by ELISA or immunofluorescence antibody test, is employed in developed countries. In endemic regions, a highly sensitive direct agglutination test using stained promastigotes and an equally efficient rapid immunochromatographic k39 strip test have become popular. These tests remain positive for several months after cure has been achieved, so do not predict response to treatment or relapse. The vast majority of people exposed to the parasite do not develop clinical illness but may have positive serological tests thereafter. Formal gel (aldehyde) or other similar tests based on the detection of raised globulin have limited value and should not be employed for the diagnosis of VL. Differential diagnosis This includes malaria, typhoid, tuberculosis, schistosomiasis and many other infectious and neoplastic conditions, some of which may coexist with VL. Fever, splenomegaly, pancytopenia and non-response to antimalarial therapy may provide clues before specific laboratory diagnosis is made. Management Pentavalent antimonials Antimony (Sb) compounds were the first drugs to be used for the treatment of leishmaniasis and remain the mainstay of treatment in most parts of the world. The exception is the Indian subcontinent, especially Bihar state, where almost two-thirds of cases are refractory to Sb treatment. Traditionally, pentavalent antimony is available as sodium stibogluconate (100 mg/mL) in English-speaking countries and meglumine antimoniate (85 mg/mL) in French-speaking ones. The daily dose is 20 mg/ kg body weight, intravenously or intramuscularly, for 28–30 days. Side-effects are common and include arthralgia, myalgia, raised hepatic transaminases, pancreatitis (especially in patients co-infected with HIV) and ECG changes (T-wave inversion and reduced amplitude). Severe cardiotoxicity, manifest by concave ST segment elevation, prolongation of QTc greater than 0.5 msec and ventricular dysrhythmias, is not uncommon. The incidence of cardiotoxicity and death is particularly high with improperly manufactured Sb. Amphotericin B Amphotericin B deoxycholate, given once daily or on alternate days at a dose of 0.75–1.00 mg/kg for 15–20 doses, is used as the first-line drug in many regions where there is a significant level of Sb unresponsiveness. It has a cure rate of nearly 100%. Infusion-related side-effects, such as high fever with rigor, thrombophlebitis, diarrhoea and vomiting, are extremely common. Serious side-effects, including renal or hepatic toxicity, hypokalaemia and thrombocytopenia, are observed frequently. Lipid formulations of amphotericin B (p. 126) are less toxic. AmBisome is first-line therapy in Europe for VL. Dosing recommendations vary according to geographical region. In the Indian subcontinent, a total dose of 10 or 15 mg/kg, administered in a single dose or as multiple doses over several days, respectively, is considered adequate, whereas in Africa 14–18 mg/kg, and in South America and Europe 21–24 mg/kg, in divided doses, typically spread over 10 days, is recommended for immunocompetent patients. High daily doses of the lipid formulations are well tolerated, and in one study a single dose

284 • INFECTIOUS DISEASE Treatment of PKDL is difficult. In India, Sb for 120 days, several courses of amphotericin B infusions, or miltefosine for 12 weeks is required. In Sudan, Sb for 2 months is considered adequate. In the absence of a physical handicap, most patients are reluctant to complete the treatment. PKDL patients are a human reservoir, and focal outbreaks have been linked to patients with PKDL in areas previously free of VL. Prevention and control Sandfly control through insecticide spray is very important. Mosquito nets or curtains treated with insecticides will keep out the tiny sandflies. In endemic areas with zoonotic transmission, infected or stray dogs should be destroyed. In areas with anthroponotic transmission, early diagnosis and treatment of human infections, to reduce the reservoir and control epidemics of VL, is extremely important. Serology is useful in diagnosis of suspected cases in the field. No vaccine is currently available. Cutaneous and mucosal leishmaniasis Cutaneous leishmaniasis CL (oriental sore) occurs in both the Old World (Asia, Africa and Europe) and the New World (the Americas). Transmission is described on page 281. In the Old World, CL is mild. It is found around the Mediterranean basin, throughout the Middle East and Central Asia as far as Pakistan, and in sub-Saharan West Africa and Sudan (Fig. 11.44). The causative organisms for Old World zoonotic CL are L. major, L. tropica and L. aethiopica (Box 11.57). Anthroponotic CL is caused by L. tropica, and is confined to urban or suburban areas of the Old World. Afghanistan is currently the biggest focus but infection is endemic in Pakistan, the western deserts of India, Iran, Iraq, Syria and other areas of the Middle East. In recent years, there has been an increase in the incidence of zoonotic CL in both the Old and the New Worlds due to urbanisation and deforestation, which led to peridomestic transmission (in and around human dwellings). Treatment of VL with HIV co-infection is essentially the same as in immunocompetent patients but there are some differences in outcome. Conventional amphotericin B (0.7 mg/kg/day for 28 days) may be more effective in achieving initial cure than Sb (20 mg/kg/day for 28 days). Using high-dose liposomal amphotericin B (4 mg/kg on days 1–5, 10, 17, 24, 31 and 38), a high cure rate is possible. However, co-infected patients have a tendency to relapse within 1 year and maintenance chemotherapy with monthly liposomal amphotericin B is useful. Post-kala-azar dermal leishmaniasis After treatment and apparent recovery from VL in India and Sudan, some patients develop dermatological manifestations due to local parasitic infection. Clinical features In India, dermatological changes occur in a small minority of patients 6 months to at least 3 years after the initial infection. They are seen as macules, papules, nodules (most frequently) and plaques, which have a predilection for the face, especially the area around the chin. The face often appears erythematous (Fig. 11.43A). Hypopigmented macules can occur over all parts of the body and are highly variable in extent. There are no systemic symptoms and little spontaneous healing occurs. In Sudan, approximately 50% of patients with VL develop post-kala-azar dermal leishmaniasis (PKDL), experiencing skin manifestations concurrently with VL or within the following 6 months. In addition to the dermatological features, a measles-like micropapular rash (Fig. 11.43B) may be seen all over the body. In Sudan, children are more frequently affected than in India. Spontaneous healing occurs in about three-quarters of cases within 1 year. Investigations and management The diagnosis is clinical, supported by demonstration of scanty parasites in lesions by slit-skin smear and culture. Immunofluorescence and immunohistochemistry may demonstrate the parasite in skin tissues. In the majority of patients, serological tests (direct agglutination test or k39 strip tests) are positive. Fig. 11.43 Post-kala-azar dermal leishmaniasis. A In India, with macules, papules, nodules and plaques. B In Sudan, with micronodular rash. A, From Sundar S, Kumar K, Chakravarty J, et al. Cure of antimony-unresponsive Indian post-kala-azar dermal leishmaniasis with oral miltefosine. Trans R Soc Trop Med Hyg 2006; 100(7):698–700. B, Courtesy of Dr E.E. Zijlstra. A B

Protozoal infections • 285

the vector bite. The small, red papules may be single or multiple and increase gradually in size, reaching 2–10 cm in diameter. A crust forms, overlying an ulcer with a granular base and with raised borders (Fig. 11.45). These ulcers develop a few weeks or months after the bite. There can be satellite lesions, especially in L. major and occasionally in L. tropica infections. Regional lymphadenopathy, pain, pruritus and secondary bacterial infections may occur. Lesions of L. mexicana and L. peruviana closely resemble those seen in the Old World, but lesions on the pinna of the ear are common and are chronic and destructive. L. mexicana is responsible for chiclero ulcers, the self-healing sores of Mexico. If immunity is effective, there is usually spontaneous healing in L. tropica, L. major and L. mexicana lesions. In some patients with anergy to Leishmania, the skin lesions of L. aethiopica, L. mexicana and L. amazonensis infections progress to the development of diffuse CL; this is characterised by spread of the infection from the initial ulcer, usually on the face, to involve the whole body in the form of non-ulcerative nodules. Occasionally, in L. tropica infections, sores that have apparently healed relapse persistently (recidivans or lupoid leishmaniasis). Mucosal leishmaniasis The Viannia subgenus extends widely from the Amazon basin as far as Paraguay and Costa Rica, and is responsible for deep sores and ML. In L. (V.) brasiliensis complex infections, cutaneous lesions may be followed by mucosal spread of the disease simultaneously or even years later. Young men with chronic lesions are particularly at risk, and 2–40% of infected persons develop ‘espundia’, metastatic lesions in the mucosa of the nose or mouth. This is characterised by thickening and erythema of the nasal mucosa, typically starting at the junction of the nose and upper lip. Later, ulceration develops. The lips, soft palate, fauces and larynx may also be invaded and destroyed, leading to considerable suffering and deformity. There is no spontaneous healing, and death may result from severe respiratory tract infections due to massive destruction of the pharynx. Investigations in CL and ML CL is often diagnosed on the basis of the lesions’ clinical characteristics. Parasitological confirmation is important, however, because clinical manifestations may be mimicked by other infections. Amastigotes can be demonstrated on a slit-skin smear with Giemsa staining; alternatively, they can be cultured from the sores early during the infection. Parasites seem to be particularly New World CL is a more significant disease, which may disfigure the nose, ears and mouth, and is caused by the L. mexicana complex (comprising L. mexicana, L. amazonensis and L. venezuelensis) and by the Viannia subgenus L. (V.) brasiliensis complex (comprising L. (V.) guyanensis, L. (V.) panamensis, L. (V.) brasiliensis and L. (V.) peruviana). CL is commonly imported and should be considered in the differential diagnosis of an ulcerating skin lesion, especially in travellers who have visited endemic areas of the Old World or forests in Central and South America. Pathogenesis Inoculated parasites are taken up by dermal macrophages, in which they multiply and form a focus for lymphocytes, epithelioid cells and plasma cells. Self-healing may occur with necrosis of infected macrophages, or the lesion may become chronic with ulceration of the overlying epidermis, depending on the aetiological pathogen. Clinical features The incubation period is typically 2–3 months (range 2 weeks to 5 years). In all types of CL a papule develops at the site of Fig. 11.44 World distribution of cutaneous leishmaniasis. L. mexicana L. brasiliensis L. infantum L. tropica L. major L. aethiopica 11.57 Types of Old World cutaneous leishmaniasis Leishmania spp. Host Clinical features L. tropica Dogs Slow evolution, less severe L. major Gerbils, desert rodents Rapid necrosis, wet sores L. aethiopica Hyraxes Solitary facial lesions with satellites Fig. 11.45 Cutaneous leishmaniasis. A Papule. B Ulcer. B, Courtesy of Dr Ravi Gowda, Royal Hallamshire Hospital, Sheffield. A B

286 • INFECTIOUS DISEASE effective in New World CL caused by L. guyanensis. In ML, 8 injections of pentamidine (4 mg/kg on alternate days) cure the majority of patients. Ketoconazole (600 mg daily for 4 weeks) has shown some potential against L. mexicana infection. In Saudi Arabia, fluconazole (200 mg daily for 6 weeks) reduced healing times and cured 79% of patients with CL caused by L. major. In India, itraconazole (200 mg daily for 6 weeks) produced good results in CL. Prevention of CL and ML Personal protection against sandfly bites is important. No effective vaccine is yet available. Gastrointestinal protozoal infections Amoebiasis Amoebiasis is caused by Entamoeba histolytica, which is spread between humans by its cysts. It is one of the leading parasitic causes of morbidity and mortality in the tropics and is occasionally acquired in non-tropical countries. Two nonpathogenic Entamoeba species (E. dispar and E. moshkovskii) are morphologically identical to E. histolytica, and are distinguishable only by molecular techniques, isoenzyme studies or monoclonal antibody typing. However, only E. histolytica causes amoebic dysentery or liver abscess. The life cycle of the amoeba is shown in Figure 11.46A. Pathology Cysts of E. histolytica are ingested in water or uncooked foods contaminated by human faeces. Infection may also be acquired through anal/oral sexual practices. In the colon, trophozoite forms emerge from the cysts. The parasite invades the mucous membrane of the large bowel, producing lesions that are maximal difficult to isolate from sores caused by L. brasiliensis, responsible for the vast majority of cases in Brazil. Touch preparations from biopsies and histopathology usually have a low sensitivity. Culture of fine needle aspiration material has been reported to be the most sensitive method. ML is more difficult to diagnose parasitologically. The leishmanin skin test measures delayed-type hypersensitivity to killed Leishmania organisms. A positive test is defined as induration of more than 5 mm, 48 hours after intradermal injection. The test is positive, except in diffuse CL and during active VL. PCR is used increasingly for diagnosis and speciation, which is useful in selecting therapy. Management of CL and ML Small lesions may self-heal or are treated by freezing with liquid nitrogen or curettage. There is no ideal antimicrobial therapy. Treatment should be individualised on the basis of the causative organism, severity of the lesions, availability of drugs, tolerance of the patient for toxicity, and local resistance patterns. In CL, topical application of paromomycin 15% plus methylbenzethonium chloride 12% is beneficial. Intralesional antimony (Sb 0.2–0.8 mL/lesion) up to 2 g seems to be rapidly effective in suitable cases; it is well tolerated and economic, and is safe in patients with cardiac, liver or renal diseases. In ML, and in CL when the lesions are multiple or in a disfiguring site, it is better to treat with parenteral Sb in a dose of 20 mg/ kg/day (usually given for 20 days for CL and 28 days for ML), or with conventional or liposomal amphotericin B (see treatment of VL above). Sb is also indicated to prevent the development of mucosal disease, if there is any chance that a lesion acquired in South America is due to an L. brasiliensis strain. Refractory CL or ML should be treated with an amphotericin B preparation. Other regimens may be effective. Two to four doses of pentamidine (2–4 mg/kg), administered on alternate days, are Fig. 11.46 Amoebiasis. A The life cycle of Entamoeba histolytica. B The chocolate-brown appearance of aspirated material from an amoebic liver abscess. A, From Knight R. Parasitic disease in man. Churchill Livingstone, Elsevier Ltd; 1982. B, Courtesy of Dr Ravi Gowda, Royal Hallamshire Hospital, Sheffield. B Trophozoite in faeces (do not encyst) Cyst maturation in distal colon and faeces Ingested mature cyst Encystment in colon Excystment in small bowel Lumen Colonic mucosa Ulcer Amoeboma Amoebic abscess Ingested erythrocytes Tissue trophozoite A trophozoite

Protozoal infections • 287

Management Intestinal and early hepatic amoebiasis responds quickly to oral metronidazole (800 mg 3 times daily for 5–10 days) or other long-acting nitroimidazoles like tinidazole or ornidazole (both in doses of 2 g daily for 3 days). Nitazoxanide (500 mg twice daily for 3 days) is an alternative drug. Either diloxanide furoate or paromomycin, in doses of 500 mg orally 3 times daily for 10 days after treatment, should be given to eliminate luminal cysts. If a liver abscess is large or threatens to burst, or if the response to chemotherapy is not prompt, aspiration is required and is repeated if necessary. Rupture of an abscess into the pleural cavity, pericardial sac or peritoneal cavity necessitates immediate aspiration or surgical drainage. Small serous effusions resolve without drainage. Prevention Personal precautions against contracting amoebiasis include not eating fresh, uncooked vegetables or drinking unclean water. Giardiasis Infection with Giardia lamblia is found worldwide and is common in the tropics. It particularly affects children, tourists and immunosuppressed individuals, and is the parasite most commonly imported into the UK. In cystic form, it remains viable in water for up to 3 months and infection usually occurs by ingesting contaminated water. Its flagellar trophozoite form attaches to the duodenal and jejunal mucosa, causing inflammation. Clinical features and investigations After an incubation period of 1–3 weeks, there is diarrhoea, abdominal pain, weakness, anorexia, nausea and vomiting. On examination, there may be abdominal distension and tenderness. Chronic diarrhoea and malabsorption may occur, with bulky stools that float. Stools obtained at 2–3-day intervals should be examined for cysts. Duodenal or jejunal aspiration by endoscopy gives a higher diagnostic yield. The ‘string test’ may be used, in which one end of a piece of string is passed into the duodenum by swallowing and retrieved after an overnight fast; expressed fluid is then examined for the presence of G. lamblia trophozoites. A number of stool antigen detection tests are available. Jejunal biopsy specimens may show G. lamblia on the epithelial surface. Management Treatment is with a single dose of tinidazole 2 g, metronidazole 400 mg 3 times daily for 10 days, or nitazoxanide 500 mg orally twice daily for 3 days. Cryptosporidiosis Cryptosporidium spp. are coccidian protozoal parasites of humans and domestic animals. Infection is acquired by the faecal–oral route through contaminated water supplies. The incubation period is approximately 7–10 days and is followed by watery diarrhoea and abdominal cramps. The illness is usually self-limiting but in immunocompromised patients, especially those with HIV, the illness can be devastating, with persistent severe diarrhoea and substantial weight loss (p. 317). Cyclosporiasis Cyclospora cayetanensis is a globally distributed coccidian protozoal parasite of humans. Infection is acquired by ingestion in the caecum but extend to the anal canal. These are flaskshaped ulcers, varying greatly in size and surrounded by healthy mucosa. A localised granuloma (amoeboma), presenting as a palpable mass in the rectum or a filling defect in the colon on radiography, is a rare complication that should be differentiated from carcinoma. Amoebic ulcers may cause severe haemorrhage but rarely perforate the bowel wall. Amoebic trophozoites can emerge from the vegetative cyst from the bowel and be carried to the liver in a portal venule. They can multiply rapidly and destroy the liver parenchyma, causing an abscess (see also p. 879). The liquid contents at first have a characteristic pinkish colour, which may later change to chocolate-brown (said to resemble anchovy sauce). Cutaneous amoebiasis, though rare, causes progressive genital, perianal or peri-abdominal surgical wound ulceration. Clinical features Intestinal amoebiasis – amoebic dysentery Most amoebic infections are asymptomatic. The incubation period of amoebiasis ranges from 2 weeks to many years, followed by a chronic course with abdominal pains and two or more unformed stools a day. Offensive diarrhoea, alternating with constipation, and blood or mucus in the stool are common. There may be abdominal pain, especially in the right lower quadrant (which may mimic acute appendicitis). A dysenteric presentation with passage of blood, simulating bacillary dysentery or ulcerative colitis, occurs particularly in older people, in the puerperium and with super-added pyogenic infection of the ulcers. Amoebic liver abscess The abscess is usually found in the right hepatic lobe. There may not be associated diarrhoea. Early symptoms may be only local discomfort and malaise; later, a swinging temperature and sweating may develop, usually without marked systemic symptoms or signs. An enlarged, tender liver, cough and pain in the right shoulder are characteristic but symptoms may remain vague and signs minimal. A large abscess may penetrate the diaphragm, rupturing into the lung, and may be coughed up through a hepatobronchial fistula. Rupture into the pleural or peritoneal cavity, or rupture of a left lobe abscess in the pericardial sac, is less common but more serious. Investigations The stool and any exudate should undergo prompt microscopic examination for motile trophozoites containing red blood cells. Movements cease rapidly as the stool preparation cools. Several stools may need to be examined in chronic amoebiasis before cysts are found. Sigmoidoscopy may reveal typical flask-shaped ulcers, which should be scraped and examined immediately for E. histolytica. In endemic areas, one-third of the population are symptomless passers of amoebic cysts. An amoebic abscess of the liver is suspected on clinical grounds; there is often a neutrophil leucocytosis and a raised right hemidiaphragm on chest X-ray. Confirmation is by ultrasonic scanning. Aspirated pus from an amoebic abscess has the characteristic chocolate-brown appearance but only rarely contains free amoebae (Fig. 11.46B). Serum antibodies are detectable by immunofluorescence in over 95% of patients with hepatic amoebiasis and intestinal amoeboma, but in only about 60% of dysenteric amoebiasis. DNA detection by PCR has been shown to be useful in diagnosis of E. histolytica infections but is not generally available.

288 • INFECTIOUS DISEASE adult hookworm is 1 cm long and lives in the duodenum and upper jejunum. Eggs are passed in the faeces. In warm, moist, shady soil, the larvae develop into rhabditiform and then the infective filariform stages; they then penetrate human skin and are carried to the lungs. After entering the alveoli, they ascend the bronchi, are swallowed and mature in the small intestine, reaching maturity 4–7 weeks after infection. The worms attach to the mucosa of the small intestine by their buccal capsule (Fig. 11.48) and withdraw blood. The mean daily blood loss from one A. duodenale is 0.15 mL and that from N. americanus 0.03 mL. Hookworm infection is a leading cause of anaemia in the tropics and subtropics. A. duodenale is endemic in the Far East and Mediterranean coastal regions, and is also present in Africa, while N. americanus is endemic in West, East and Central Africa, and Central and South America, as well as in the Far East. of contaminated water and recent food-borne outbreaks have been associated with raspberries and coriander (cilantro). The incubation period of approximately 2–11 days is followed by diarrhoea with abdominal cramps, which may remit and relapse. Although usually self-limiting, the illness may last as long as 6 weeks, with significant weight loss and malabsorption, and is more severe in immunocompromised individuals. Diagnosis is by detection of oöcysts on faecal microscopy or PCR of stool. Treatment may be necessary in a few cases, using co-trimoxazole 960 mg twice daily for 7 days. Infections caused by helminths Helminths (from the Greek helmins, meaning worm) include three groups of parasitic worm (Box 11.58), large multicellular organisms with complex tissues and organs. Intestinal human nematodes Adult nematodes living in the human gut can cause disease. There are two types: • the hookworms, which have a soil stage in which they develop into larvae that then penetrate the host • a group of nematodes that survive in the soil merely as eggs, which have to be ingested for their life cycle to continue. The geographical distribution of hookworms is limited by the larval requirement for warmth and humidity. Soil-transmitted nematode infections can be prevented by avoidance of faecal soil contamination (adequate sewerage disposal) or skin contact (wearing shoes), and by strict personal hygiene. Ancylostomiasis (hookworm) Ancylostomiasis is caused by Ancylostoma duodenale or Necator americanus. The complex life cycle is shown in Figure 11.47. The 11.58 Classes of helminth that parasitise humans Nematodes or roundworms • Intestinal human nematodes: Ancylostoma duodenale, Necator americanus, Strongyloides stercoralis, Ascaris lumbricoides, Enterobius vermicularis, Trichuris trichiura • Tissue-dwelling human nematodes: Wuchereria bancrofti, Brugia malayi, Loa loa, Onchocerca volvulus, Dracunculus medinensis, Mansonella perstans, Dirofilaria immitis • Zoonotic nematodes: Trichinella spiralis Trematodes or flukes • Blood flukes: Schistosoma haematobium, S. mansoni, S. japonicum, S. mekongi, S. intercalatum • Lung flukes: Paragonimus spp. • Hepatobiliary flukes: Clonorchis sinensis, Fasciola hepatica, Opisthorchis felineus • Intestinal flukes: Fasciolopsis buski Cestodes or tapeworms • Intestinal tapeworms: Taenia saginata, T. solium, Diphyllobothrium latum, Hymenolepis nana • Tissue-dwelling cysts or worms: Taenia solium, Echinococcus granulosus Fig. 11.47 Ancylostomiasis. Life cycle of Ancylostoma. Warm, moist shady soil Pharynx Bronchi Lungs Eosinophilia Duodenum Adult worm Blood loss Faecal eggs Blood stream Larvae Ova Fig. 11.48 Ancylostoma duodenale. Electron micrograph showing the ventral teeth. From Gibbons LM. SEM guide to the morphology of nematode parasites of vertebrates. Farnham Royal, Slough: Commonwealth Agricultural Bureau International; 1986.

Infections caused by helminths • 289

manifestations, either urticaria or larva currens (a highly characteristic pruritic, elevated, erythematous lesion, rapidly advancing along the course of larval migration), are characteristic and occur in 66% of patients. Systemic strongyloidiasis (the Strongyloides hyperinfection syndrome), with dissemination of larvae throughout the body, occurs with immune suppression (HIV or HTLV-1 infection, immunosuppressant treatment). Patients present with severe, generalised abdominal pain, abdominal distension and shock. Massive larval invasion of the lungs causes cough, wheeze and dyspnoea; cerebral involvement has manifestations ranging from subtle neurological signs to coma. Gram-negative sepsis frequently complicates the picture. Investigations There is eosinophilia. Serology (ELISA) is helpful but definitive diagnosis depends on finding the larvae. The faeces should be examined microscopically for motile larvae; excretion is intermittent and so repeated examinations are necessary. Larvae may be found in jejunal aspirates or detected using the string test (p. 287). Larvae may also be cultured from faeces. Management A course of two doses of ivermectin (200 μg/kg), administered on successive days, is effective. Alternatively, albendazole is given orally (15 mg/kg twice daily for 3 days). A second course may be required. For the Strongyloides hyperinfection syndrome, ivermectin is given at 200 μg/kg for 5–7 days. Ascaris lumbricoides (roundworm) This pale yellow nematode is 20–35 cm long. Humans are infected by eating food contaminated with mature ova. Ascaris larvae hatch in the duodenum, migrate through the lungs, ascend the bronchial tree, are swallowed and mature in the small intestine. This tissue migration can provoke both local and general hypersensitivity reactions, with pneumonitis, eosinophilic granulomas, wheezing and urticaria. Clinical features Intestinal ascariasis causes symptoms ranging from vague abdominal pain to malnutrition. The large size of the adult worm and its tendency to aggregate and migrate cause obstructive complications. Tropical and subtropical areas are endemic for ascariasis, and here it causes up to 35% of all intestinal obstructions, most commonly in the terminal ileum. Obstruction can be complicated further by intussusception, volvulus, haemorrhagic infarction and perforation. Other complications include blockage of the bile or pancreatic duct and obstruction of the appendix by adult worms. Ascariasis in non-endemic areas has been associated with pig husbandry and may be caused by Ascaris suum, which is indistinguishable from (and possibly the same species as) Ascaris lumbricoides. Investigations The diagnosis is made microscopically by finding ova in the faeces. Adult worms are frequently expelled rectally or orally. Occasionally, the worms are demonstrated radiographically by a barium examination. There is eosinophilia. Management A single dose of albendazole (400 mg), pyrantel pamoate (11 mg/kg; maximum 1 g), or ivermectin (150–200 μg/kg), or alternatively mebendazole (100 mg twice daily for 3 days) Clinical features An allergic dermatitis, usually on the feet (ground itch), may be experienced at the time of infection. The passage of the larvae through the lungs in a heavy infection causes a paroxysmal cough with blood-stained sputum, associated with patchy pulmonary consolidation and eosinophilia. When the worms reach the small intestine, vomiting and epigastric pain resembling peptic ulcer disease may occur. Sometimes, frequent loose stools are passed. The degree of iron and protein deficiency depends not only on the worm burden but also on patient nutrition and iron stores. Anaemia with high-output cardiac failure may result. The mental and physical development of children may be delayed in severe infection. Investigations There is eosinophilia. The characteristic ovum can be recognised in the stool. If hookworms are present in numbers sufficient to cause anaemia, faecal occult blood testing will be positive. Management A single dose of albendazole (400 mg) is the treatment of choice. Alternatively, mebendazole 100 mg twice daily for 3 days may be used. Anaemia and heart failure associated with hookworm infection respond well to oral iron, even when severe; blood transfusion is rarely required. Strongyloidiasis (threadworm) Strongyloides stercoralis is a small nematode (2 mm × 0.4 mm) that parasitises the mucosa of the upper part of the small intestine, often in large numbers, causing persistent eosinophilia. The eggs hatch in the bowel but only larvae are passed in the faeces. In moist soil, they moult and become the infective filariform larvae. After penetrating human skin, they undergo a development cycle similar to that of hookworms, except that the female worms burrow into the intestinal mucosa and submucosa. Some larvae in the intestine may develop into filariform larvae, which may then penetrate the mucosa or the perianal skin and lead to autoinfection and persistent infection. Patients with Strongyloides infection persisting for more than 35 years have been described. Strongyloidiasis occurs in the tropics and subtropics, and is especially prevalent in the Far East. Clinical features These are shown in Box 11.59. The classic triad of symptoms consists of abdominal pain, diarrhoea and urticaria. Cutaneous 11.59 Clinical features of strongyloidiasis Penetration of skin by infective larvae • Itchy rash Presence of worms in gut • Abdominal pain, diarrhoea, steatorrhoea, weight loss Allergic phenomena • Urticarial plaques and papules, wheezing, arthralgia Autoinfection • Transient itchy, linear, urticarial weals across abdomen and buttocks (larva currens) Systemic (super-)infection • Diarrhoea, pneumonia, meningoencephalitis, death

290 • INFECTIOUS DISEASE Trichuris trichiura (whipworm) Whipworm infections are common worldwide with poor hygiene. Infection follows ingestion of earth or food contaminated with ova, which have become infective after lying for 3 weeks or more in moist soil. The adult worm is 3–5 cm long and has a coiled anterior end resembling a whip. Whipworms inhabit the caecum, lower ileum, appendix, colon and anal canal. There are usually no symptoms, but intense infections in children may cause persistent diarrhoea or rectal prolapse, and growth retardation. The diagnosis is readily made by identifying ova in faeces. Treatment is with mebendazole in doses of 100 mg twice daily or albendazole 400 mg daily for 3 days for patients with light infections, and for 5–7 days for those with heavy infections. Tissue-dwelling human nematodes Filarial worms are tissue-dwelling nematodes. The larval stages are inoculated by biting mosquitoes or flies, each specific to a particular filarial species. The larvae develop into adult worms (2–50 cm long), which, after mating, produce millions of microfilariae (170–320 μm long) that migrate in blood or skin. The life cycle is completed when the vector takes up microfilariae by biting humans. In the insect, ingested microfilariae develop into infective larvae for inoculation in humans, normally the only host. Disease is due to the host’s immune response to the worms (both adult and microfilariae), particularly dying worms, and its pattern and severity vary with the site and stage of each species (Box 11.60). The worms are long-lived: microfilariae survive 2–3 years and adult worms 10–15 years. The infections are chronic and worst in individuals constantly reinfected. Lymphatic filariasis The filarial worms Wuchereria bancrofti and Brugia malayi infect approximately 120 million people globally and cause clinical outcomes ranging from subclinical infection to hydrocele and elephantiasis. W. bancrofti is usually transmitted by night-biting culicine or anopheline mosquitoes (Fig. 11.50). The adult worms, 4–10 cm in length, live in the lymphatics, and the females produce microfilariae that circulate in large numbers in the peripheral blood, usually at night. The infection is widespread in tropical Africa, on the North African coast, in coastal areas of Asia, Indonesia and northern Australia, the South Pacific islands, the West Indies and also in North and South America. treats intestinal ascariasis. Patients should be warned that they might expel numerous whole, large worms. Obstruction due to ascariasis should be treated with nasogastric suction, piperazine and intravenous fluids. Complete intestinal obstruction and its complications require urgent surgical intervention. Prevention Community chemotherapy programmes reduce Ascaris infection. The whole community can be treated every 3 months for several years. Alternatively, schoolchildren are targeted; treating them lowers the prevalence of ascariasis in the community. Enterobius vermicularis (threadworm) This helminth is common worldwide and affects mainly children. After the ova are swallowed, development takes place in the small intestine but the adult worms are found chiefly in the colon. Clinical features The female lays ova around the anus, causing intense itching, especially at night. The ova are often carried to the mouth on the fingers and so reinfection or human-to-human infection occurs (Fig. 11.49). In females, the genitalia may be involved. The adult worms may be seen moving on the buttocks or in the stool. Investigations Ova are detected in stool samples or by applying the adhesive surface of cellophane tape to the perianal skin in the morning. This is then examined on a glass slide under the microscope. A perianal swab, moistened with saline, also allows diagnosis. Management A single dose of mebendazole (100 mg), albendazole (400 mg), pyrantel pamoate (11 mg/kg) or piperazine (4 g) treats infection and is repeated after 2 weeks to control auto-reinfection. If infection recurs in a family, each member should be treated. All nightclothes and bed linen are laundered during treatment. Fingernails must be kept short and hands washed carefully before meals. Subsequent therapy is reserved for family members with recurrent infection. Fig. 11.49 Threadworm. Life cycle of Enterobius vermicularis. Adult worm in colon Itch Ova 11.60 Pathogenicity of filarial infections depending on site and stage of worms Worm species Adult worm Microfilariae Wuchereria bancrofti and Brugia malayi Lymphatic vessels+++ Blood− Pulmonary capillaries++ Loa loa Subcutaneous+ Blood+ Onchocerca volvulus Subcutaneous+ Skin+++ Eye+++ Mansonella perstans Retroperitoneal− Blood− Mansonella streptocerca Skin+ Skin++ (+++ severe; ++ moderate; + mild; − rarely pathogenic)

Infections caused by helminths • 291

of the lymphatic system. Silicates absorbed from volcanic soil can also cause non-filarial elephantiasis. Tropical pulmonary eosinophilia is a complication, seen mainly in India, due to microfilariae trapped in the pulmonary capillaries that are destroyed by allergic inflammation. Patients present with paroxysmal cough, wheeze and fever. If untreated, this may progress to debilitating chronic interstitial lung disease. Investigations In the earliest stages of lymphangitis, the diagnosis is made on clinical grounds, supported by eosinophilia and sometimes by positive filarial serology. Filarial infections cause the highest eosinophil counts of all helminthic infections. Microfilariae can be found in the peripheral blood at night, and either are seen moving in a wet blood film or are detected by microfiltration of a sample of lysed blood. They are usually present in hydrocele fluid, which may occasionally yield an adult filaria. By the time elephantiasis develops, microfilariae become difficult to find. Calcified filariae may sometimes be demonstrable by radiography. Movement of adult worms can be seen on scrotal ultrasound. PCR-based tests for detection of W. bancrofti and B. malayi DNA from blood have been developed. Indirect fluorescence and ELISA detect antibodies in over 95% of active cases and 70% of established elephantiasis. The test becomes negative 1–2 years after cure. Serological tests cannot distinguish the different filarial infections. Highly sensitive and specific, commercially available, immunochromatographic card tests detect circulating W. bancrofti antigen using fingerprick blood samples taken at any time of the day. In tropical pulmonary eosinophilia, serology is strongly positive and IgE levels are massively elevated but circulating microfilariae are not found. The chest X-ray shows miliary changes or mottled opacities. Pulmonary function tests show a restrictive picture. Management Treatment is aimed at halting and reversing disease progression. Diethylcarbamazine (DEC, 2 mg/kg orally 3 times daily for 12 days, or 6 mg/kg as a single dose) kills microfilariae and adult worms. Most adverse effects seen with DEC treatment are due to the host response to dying microfilariae, which is directly proportional to the microfilarial load. The main symptoms are fever, headache, nausea, vomiting, arthralgia and prostration. These usually occur within 24–36 hours of the first dose of DEC. Antihistamines or glucocorticoids treat these allergic phenomena. Combining albendazole (400 mg) with ivermectin (200 μg/kg) in a single dose, with or without DEC (300 mg), is also highly effective in clearing the parasites. Treatment of Wolbachia with doxycycline (200 mg/day) for 4–8 weeks provides additional benefit by eliminating the bacteria; this leads to interruption of parasite embryogenesis. For tropical pulmonary eosinophilia, DEC for 14 days is the treatment of choice. Chronic lymphatic pathology Experience in India and Brazil shows that active management of chronic lymphatic pathology can alleviate symptoms. Patients should be taught meticulous skin care of their lymphoedematous limbs to prevent secondary bacterial and fungal infections. Tight bandaging, massage and bed rest with elevation of the affected limb help to control the lymphoedema. Prompt diagnosis and antibiotic therapy of bacterial cellulitis prevent further lymphatic damage and worsening of existing elephantiasis. Plastic surgery may be indicated in established elephantiasis. Relief can be obtained by removal of excess tissue but recurrences are probable B. malayi usually causes less severe disease than W. bancrofti and is transmitted by Mansonia or Anopheles mosquitoes in Indonesia, Borneo, Malaysia, Vietnam, South China, South India and Sri Lanka. Pathology Several factors contribute to the pathogenesis of lymphatic filariasis. Toxins released by adult worms cause lymphangiectasia; this dilatation of the lymphatic vessels leads to lymphatic dysfunction and the chronic clinical manifestations of lymphatic filariasis, lymphoedema and hydrocele. Death of the adult worm results in acute filarial lymphangitis. The filariae are symbiotically infected with rickettsia-like bacteria (Wolbachia spp.), and lipopolysaccharide released from Wolbachia triggers inflammation. Lymphatic obstruction persists after death of the adult worm. Secondary bacterial infections cause tissue destruction. The host response to microfilariae is central to the pathogenesis of tropical pulmonary eosinophilia. Clinical features Acute filarial lymphangitis presents with fever, pain, tenderness and erythema along the course of inflamed lymphatic vessels. Inflammation of the spermatic cord, epididymis and testis is common. Episodes last a few days but may recur several times a year. Temporary oedema becomes more persistent and regional lymph nodes enlarge. Progressive enlargement, coarsening, corrugation, fissuring and bacterial infection of the skin and subcutaneous tissue develop gradually, causing irreversible ‘elephantiasis’. The scrotum may reach an enormous size. Chyluria and chylous effusions are milky and opalescent; on standing, fat globules rise to the top. Acute lymphatic manifestations of filariasis must be differentiated from thrombophlebitis and infection. Oedema and lymphatic obstructive changes must be distinguished from congestive cardiac failure, malignancy, trauma and idiopathic abnormalities Fig. 11.50 Wuchereria bancrofti and Brugia malayi. Life cycle of organisms and pathogenesis of lymphatic filariasis. Microfilariae in blood and trapped in pulmonary capillaries Infective larva Mosquito Microfilariae Adult worm in lymphatics Epididymo-orchitis and hydrocele Lymphangitis and lymphoedema

292 • INFECTIOUS DISEASE feeding, they pick up the microfilariae, which mature into the infective larva and are transmitted to a new host in subsequent bites. Humans are the only known hosts (Fig. 11.51). Onchocerciasis is endemic in sub-Saharan Africa, Yemen and a few foci in Central and South America. It is estimated that 26 million people are infected, of whom 500 000 are visually impaired and 270 000 blind. Due to onchocerciasis, huge tracts of fertile land lie virtually untilled and individuals and communities are impoverished. Pathology After inoculation of larvae by a bite, the worms mature in 2–4 months and live for up to 17 years in subcutaneous and connective tissues. At sites of trauma, over bony prominences and around joints, fibrosis may form nodules around adult worms, which otherwise cause no direct damage. Innumerable microfilariae, discharged by the female O. volvulus, move actively in these nodules and in the adjacent tissues. The microfilariae are widely distributed in the skin and may invade the eye. Live microfilariae elicit little tissue reaction but dead ones may cause severe allergic inflammation, leading to hyaline necrosis and loss of collagen and elastin. Death of microfilariae in the eye causes inflammation and may lead to blindness. Clinical features The infection may remain symptomless for months or years. The first symptom is usually itching, localised to one quadrant of the body and later becoming generalised and involving the eyes. Transient oedema of part or all of a limb is an early sign, followed by papular urticaria spreading gradually from the site of infection. This is difficult to see on dark skins, in which the most common signs are papules excoriated by scratching, spotty hyperpigmentation from resolving inflammation, and chronic changes of a rough, thickened or inelastic, wrinkled skin. Both infected and uninfected superficial lymph nodes enlarge and may hang down in folds of loose skin in the groin. Hydrocele, femoral hernias and scrotal elephantiasis can occur. Firm subcutaneous nodules of more than 1 cm in diameter (onchocercomas) occur in chronic infection. unless new lymphatic drainage is established. Hydroceles and chyluria can be repaired surgically. Prevention Treatment of the whole population in endemic areas with annual single-dose DEC (6 mg/kg), either alone or in combination with albendazole or ivermectin, can reduce filarial transmission. Mass treatment should be combined with mosquito control programmes. Loiasis Loiasis is caused by infection with the filaria Loa loa. The disease is endemic in forested and swampy parts of Western and Central Africa. The adult worms, 3–7 cm × 4 mm, chiefly parasitise the subcutaneous tissue of humans, releasing larval microfilariae into the peripheral blood in the daytime. The vector is Chrysops, a forest-dwelling, day-biting fly. The host response to Loa loa is usually absent or mild, so that the infection may be harmless. From time to time a shortlived, inflammatory, oedematous swelling (a Calabar swelling) is produced around an adult worm. Heavy infections, especially when treated, may cause encephalitis. Clinical features The infection is often symptomless. The incubation period is commonly over a year but may be just 3 months. The first sign is usually a Calabar swelling: an irritating, tense, localised swelling that may be painful, especially if it is near a joint. The swelling is generally on a limb; it measures a few centimetres in diameter but may be diffuse and extensive. It usually disappears after a few days but may persist for 2–3 weeks. Several swellings may appear at irregular intervals, often in adjacent sites. Sometimes, there is urticaria and pruritus elsewhere. Occasionally, a worm may be seen wriggling under the skin, especially that of an eyelid, and may cross the eye under the conjunctiva, taking many minutes to do so. Investigations Diagnosis is by demonstrating microfilariae in blood taken during the day, but they may not always be found in patients with Calabar swellings. Antifilarial antibodies are positive in 95% of patients and there is massive eosinophilia. Occasionally, a calcified worm may be seen on X-ray. Management DEC (see above) is curative, in a dose of 9–12 mg/kg daily, continued for 21 days. Treatment may precipitate a severe reaction in patients with a heavy microfilaraemia, characterised by fever, joint and muscle pain, and encephalitis; microfilaraemic patients should be given glucocorticoid cover. Prevention Building houses away from trees and having dwellings wirescreened reduce infections. Protective clothing and insect repellents are also useful. DEC in a dose of 5 mg/kg daily for 3 days each month is partially protective. Onchocerciasis (river blindness) Onchocerciasis results from infection by the filarial Onchocerca volvulus. The infection is conveyed by flies of the genus Simulium, which breed in rapidly flowing, well-aerated water. Adult flies inflict painful bites during the day, both inside and outside houses. While Fig. 11.51 Onchocerca volvulus. Life cycle of organism and pathogenesis of onchocerciasis. Adult worm in subcutaneous nodule Microfilariae in dermis: dermatitis Microfilariae in eyes: 'river blindness' Infective larva Simulium fly Microfilariae

Infections caused by helminths • 293

be broken. Antibiotics for secondary infection and prophylaxis of tetanus are also required. A global eradication campaign aims to provide clean drinking water and eradicate water fleas from drinking water by simple filtration of water through a plastic mesh filter and chemical treatment of water supplies. Other filariases Mansonella perstans This filarial worm is transmitted by the midges Culicoides austeni and C. grahami. It is common throughout equatorial Africa, as far south as Zambia, and also in Trinidad and parts of northern and eastern South America. M. perstans has never been proven to cause disease but it may be responsible for a persistent eosinophilia and occasional allergic manifestations. M. perstans is resistant to ivermectin and DEC, and the infection may persist for many years. Dirofilaria immitis This dog heartworm infects humans, causing skin and lung lesions. It is not uncommon in the USA, Japan and Australia. Zoonotic nematodes Trichinosis (trichinellosis) Trichinella spiralis is a nematode that parasitises rats and pigs, and is transmitted to humans by ingestion of partially cooked infected pork, particularly sausage or ham, or occasionally by bear meat. Symptoms result from invasion of intestinal submucosa by ingested larvae, which develop into adult worms, and the secondary invasion of striated muscle by fresh larvae produced by these adult worms. Outbreaks have occurred in countries where pork is eaten. Clinical features The clinical features of trichinosis are determined by the larval numbers. A light infection with a few worms may be asymptomatic; a heavy infection causes nausea and diarrhoea 24–48 hours after the infected meal. A few days later, the symptoms associated with larval invasion predominate: there is fever and oedema of the face, eyelids and conjunctivae; invasion of the diaphragm may cause pain, cough and dyspnoea; and involvement of the muscles of the limbs, chest and mouth causes stiffness, pain and tenderness in affected muscles. Larval migration may cause acute myocarditis and encephalitis. Eosinophilia is observed after the second week. An intense infection may prove fatal but those who survive recover completely. Investigations Frequently, people who have eaten infected pork from a common source develop symptoms at about the same time. Biopsy from the deltoid or gastrocnemius muscle after the third week of symptoms may reveal encysted larvae. Serological tests are also helpful. Management Treatment is with albendazole (400 mg twice daily for 8–14 days) or mebendazole (200–400 mg three times daily for 3 days, followed by 400–500 mg three times daily for 10 days). Treatment commenced early in infection kills newly formed adult worms in the submucosa and reduces the number of larvae reaching the Eye disease is most common in highly endemic areas and is associated with chronic heavy infections and nodules on the head. Early manifestations include itching, lacrimation and conjunctival injection. These cause conjunctivitis; sclerosing keratitis with pannus formation; uveitis, which may lead to glaucoma and cataract; and, less commonly, choroiditis and optic neuritis. Classically, ‘snowflake’ deposits are seen in the edges of the cornea. Investigations The finding of nodules or characteristic lesions of the skin or eyes in a patient from an endemic area, associated with eosinophilia, is suggestive. Skin snips or shavings, taken with a corneoscleral punch or scalpel blade from calf, buttock and shoulder, are placed in saline under a cover slip on a microscope slide and examined after 4 hours. Microfilariae are seen wriggling free in all but the lightest infections. Slit-lamp examination may reveal microfilariae moving in the anterior chamber of the eye or trapped in the cornea. A nodule may be removed and incised, showing the coiled, thread-like adult worm. Filarial antibodies are positive in up to 95% of patients. Rapid strip tests to detect antibody or antigen are under clinical evaluation. When there is a strong suspicion of onchocerciasis but tests are negative, a provocative Mazzotti test, in which administration of 0.5–1.0 mg/kg of DEC exacerbates pruritus or dermatitis, strongly suggests onchocerciasis. Management Ivermectin is recommended, in a single dose of 100–200 μg/kg, repeated several times at 3-monthly intervals to prevent relapses. It kills microfilariae and has minimal toxicity. In the rare event of a severe reaction causing oedema or postural hypotension, prednisolone 20–30 mg may be given daily for 2 or 3 days. Ivermectin has little macrofilaricidal effect so that, 1 year after ivermectin treatment, skin microfilarial densities regain at least 20% of pre-treatment levels; repeated treatments are required for the lifespan of the adult worm. Eradication of Wolbachia with doxycycline (100 mg daily for 6 weeks) prevents worm reproduction. Prevention Mass treatment with ivermectin reduces community morbidity and slows the progression of eye disease but it does not clear worm infection. Simulium can be destroyed in its larval stage by the application of insecticide to streams. Long trousers, skirts and sleeves discourage the fly from biting. Dracunculiasis (Guinea worm) Infestation with the Guinea worm Dracunculus medinensis manifests when the female worm, over a metre long, emerges from the skin. Humans are infected by ingesting a small crustacean, Cyclops, which inhabits wells and ponds, and contains the infective larval stage of the worm. The worm was widely distributed across Africa and the Middle East but successful global eradication programmes have limited the infection to a few countries in sub-Saharan Africa. However, recent findings of dog dracunculiasis in Chad and Ethiopia pose a new threat to eradication efforts. Management and prevention Traditionally, the protruding worm is extracted by winding it out gently over several days on a matchstick. The worm must never

294 • INFECTIOUS DISEASE Gnathostomiasis Gnathostomiasis is a nematode infection that occurs predominantly in South-east Asia and is due to Gnathostoma spinigerum. It also occurs in other parts of Asia, Central and South America, and Africa. Humans are infected by the larvae from intermediate hosts (raw or under-cooked freshwater fish, shrimps and frogs) and are not definitive hosts, so the life cycle is incomplete. Pruritic, painful, migratory nodules appear 3–4 weeks after ingestion due to larval migration. Complications include cough, visual disturbance, eosinophilic meningitis or encephalitis. Serology confirms diagnosis and the preferred treatment is albendazole (400 mg twice daily) for 21 days, but its role in visual or neurological disease is uncertain as it may increase larval migration. Trematodes (flukes) These leaf-shaped worms are parasitic to humans and animals. Their complex life cycles may involve one or more intermediate hosts, often freshwater molluscs. Schistosomiasis Schistosomiasis is a major cause of morbidity in the tropics. The species commonly causing disease in humans are: Schistosoma haematobium, S. mansoni, S. japonicum, S. mekongi and S. intercalatum. S. haematobium is sometimes called bilharzia or bilharziasis. Schistosome eggs have been found in Egyptian mummies. The life cycle is shown in Figure 11.53A. The ovum is passed in the urine or faeces of infected individuals and gains access to fresh water, where the ciliated miracidium inside it is liberated; it enters its intermediate host, a species of freshwater snail, and multiplies. Large numbers of fork-tailed cercariae are then liberated into the water, where they may survive for 2–3 days. Cercariae can penetrate the skin or the mucous membrane of the mouth of humans. They transform into schistosomulae and moult as they pass through the lungs; then they are carried by the blood stream to the liver, and so to the portal vein, where they mature. The male worm is up to 20 mm in length and the more slender cylindrical female, usually enfolded longitudinally by the male, is longer (Fig. 11.53B). Within 4–6 weeks of infection, they migrate to the venules draining the pelvic viscera, where the females deposit ova. Pathology Disease is usually due to passage of eggs through mucosa and to the granulomatous reaction to eggs deposited in tissues. The eggs of S. haematobium pass mainly through the bladder wall but may also involve the rectum, seminal vesicles, vagina, cervix and uterine tubes. S. mansoni and S. japonicum eggs pass mainly through the wall of the lower bowel or are carried to the liver. The most serious, although rare, site of ectopic egg deposition is the CNS. Granulomas are composed of macrophages, eosinophils, and epithelioid and giant cells around an ovum. Later, there is fibrosis and eggs calcify, which is often visible radiologically. Eggs of S. haematobium may leave the vesical plexus and be carried directly to the lung. Those of S. mansoni and S. japonicum may also reach the lungs after the development of portal hypertension and consequent portasystemic collateral circulation. Egg deposition in the pulmonary vasculature, and the resultant host response, can lead to pulmonary hypertension. muscles. Glucocorticoids are necessary to control the serious effects of acute inflammation. Anisakiasis (herring worm) This infection is caused by the larvae of a fish nematode (Anisakis simplex or Pseudoterranova decipiens) and is associated with consumption of under-cooked fish or squid. The parasite cannot complete its life cycle in humans but larval ingestion is associated with pharyngeal tingling, abdominal pain, diarrhoea and vomiting. Diagnosis is made by identification of the larva by patients or endoscopists, and albendazole (400 mg twice a day for 5 days) can be used in treatment if larvae are not removed. Cutaneous larva migrans Cutaneous larva migrans (CLM) is the most common linear lesion seen in travellers (Fig. 11.52). Intensely pruritic, linear, serpiginous lesions result from the larval migration of the dog hookworm (Ancylostoma caninum). The track moves across the skin at a rate of 2–3 cm/day. This contrasts with the fast-moving transient rash of Strongyloides (p. 289). Although the larvae of dog hookworms frequently infect humans, they do not usually develop into the adult form. The most common site for CLM is the foot but elbows, breasts and buttocks may be affected. Most patients with CLM have recently visited a beach where the affected part was exposed. The diagnosis is clinical. Treatment may be local with 12-hourly application of 15% thiabendazole cream, or systemic with a single dose of albendazole (400 mg) or ivermectin (150–200 μg/kg). Angiostrongylus cantonensis The rat lungworm infects humans in Asia and the Pacific basin, via infected snails or contaminated water. It causes eosinophilic meningitis. The role of combination therapy with glucocorticoids and albendazole remains controversial. Fig. 11.52 Cutaneous larva migrans. Courtesy of Dr Ravi Gowda, Royal Hallamshire Hospital, Sheffield.

Infections caused by helminths • 295

association of S. haematobium infection with squamous cell carcinoma of the bladder. Disease of the seminal vesicles may lead to haematospermia. Females may develop schistosomal papillomas of the vulva, and schistosomal lesions of the cervix may be mistaken for cancer. Intestinal symptoms may follow Clinical features Recent travellers, especially those overlanding through Africa, may present with allergic manifestations and eosinophilia; residents of schistosomiasis-endemic areas are more likely to present with chronic urinary tract pathology or portal hypertension. During the early stages of infection, there may be itching lasting 1–2 days at the site of cercarial penetration (‘swimmer’s itch’). After a symptom-free period of 3–5 weeks, acute schistosomiasis (Katayama syndrome) may present with allergic manifestations, such as urticaria, fever, muscle aches, abdominal pain, headaches, cough and sweating. On examination, hepatomegaly, splenomegaly, lymphadenopathy and pneumonia may be present. These allergic phenomena may be severe in infections with S. mansoni and S. japonicum, but are rare with S. haematobium. The features subside after 1–2 weeks. Chronic schistosomiasis is due to egg deposition and occurs months to years after infection. The symptoms and signs depend on the intensity of infection and the species of infecting schistosome (Box 11.61). Schistosoma haematobium Humans are the only natural hosts of S. haematobium, which is highly endemic in Egypt and East Africa, and occurs throughout Africa and the Middle East (Fig. 11.54). Infection can be acquired after a brief exposure, such as swimming in freshwater lakes in Africa. Painless terminal haematuria is usually the first and most common symptom. Frequency of micturition follows, due to bladder neck obstruction. Later, frequent urinary tract infections, bladder or ureteric stones, hydronephrosis, and ultimately renal failure with a contracted calcified bladder may occur. Pain is often felt in the iliac fossa or in the loin, and radiates to the groin. In several endemic areas, there is a strong epidemiological Fig. 11.53 Schistosoma. A Life cycle. B Scanning electron micrograph of adult schistosome worms, showing the larger male worm embracing the thinner female.

Lungs Portal vein Blood stream Adult worm in vesical and rectal veins River Nile etc. Miracidium Snail Cercariae Ovum A B 11.61 Pathogenesis of schistosomiasis Time Schistosoma haematobium S. mansoni and S. japonicum Cercarial penetration Days Papular dermatitis at site of penetration As for S. haematobium Larval migration and maturation Weeks Pneumonitis, myositis, hepatitis, fever, ‘serum sickness’, eosinophilia, seroconversion As for S. haematobium Early egg deposition Months Cystitis, haematuria Colitis, granulomatous hepatitis, acute portal hypertension Ectopic granulomatous lesions: skin, CNS etc. Immune complex glomerulonephritis As for S. haematobium Late egg deposition Years Fibrosis and calcification of ureters, bladder: bacterial infection, calculi, hydronephrosis, carcinoma Colonic polyposis and strictures, periportal fibrosis, portal hypertension Pulmonary granulomas and pulmonary hypertension As for S. haematobium

296 • INFECTIOUS DISEASE fibrosis with splenic enlargement is usual. Deposition of eggs or worms in the CNS, especially in the brain or spinal cord, causes symptoms in about 5% of infections, notably epilepsy, blindness, hemiplegia or paraplegia. Investigations There is marked eosinophilia. Serological tests (ELISA) are useful as screening tests but remain positive after treatment. In S. haematobium infection, dipstick urine testing shows blood and albumin. The eggs can be found by microscopic examination of the centrifuged deposit of terminal stream urine (Fig. 11.55). Ultrasound assesses the urinary tract; bladder wall thickening, hydronephrosis and bladder calcification can be detected. Cystoscopy reveals ‘sandy’ patches, bleeding mucosa and later distortion. In a heavy infection with S. mansoni or S. japonicum, the characteristic egg with its lateral spine can usually be found in the stool. When the infection is light or of long duration, a rectal biopsy can be examined. Sigmoidoscopy may show inflammation or bleeding. Biopsies should be examined for ova. Management The object of therapy is to kill the adult schistosomes and stop egg-laying. Praziquantel (20 mg/kg orally twice daily for 1 day) is the drug of choice for all forms of schistosomiasis except S. japonicum and S. mekongi, for which 60 mg/kg (20 mg for 3 doses) is recommended. The drug produces parasitological cure in 80% of treated individuals and over 90% reduction in egg counts in the remainder. Side-effects are uncommon but include nausea and abdominal pain. Praziquantel therapy in early infection reverses hepatomegaly, bladder wall thickening and granulomas. Surgery may be required to deal with residual lesions such as ureteric stricture, small fibrotic urinary bladders, or granulomatous masses in the brain or spinal cord. Removal of rectal papillomas by diathermy or by other means may provide symptomatic relief. Prevention No single means of controlling schistosomiasis has been established to date. The life cycle is terminated if fresh water containing the snail host is not contaminated by ova-containing urine or faeces. The provision of latrines and of a safe water supply, however, remains a major problem in rural areas throughout the Fig. 11.54 Geographical distribution of schistosomiasis. From Cook GC, ed. Manson’s tropical diseases, 20th edn. Saunders, Elsevier Inc.; 1995. } S. mansoni S. haematobium S. japonicum S. mekongi S. intercalatum Fig. 11.55 Ova of Schistosoma haematobium in urine. Note the terminal spike. involvement of the bowel wall. Ectopic worms cause skin or spinal cord lesions. The severity of S. haematobium infection varies greatly and many with a light infection are asymptomatic. However, as adult worms can live for 20 years or more and lesions may progress, these patients should always be treated. Schistosoma mansoni S. mansoni is endemic throughout Africa, the Middle East, Venezuela, Brazil and the Caribbean (Fig. 11.54). Characteristic symptoms begin 2 months or more after infection. They may be slight – no more than malaise – or consist of abdominal pain and frequent stools that contain blood-stained mucus. With severe advanced disease, increased discomfort from rectal polyps may be experienced. The early hepatomegaly is reversible but portal hypertension may cause massive splenomegaly, fatal haematemesis from oesophageal varices, or progressive ascites (p. 868). Liver function is initially preserved because the pathology is fibrotic rather than cirrhotic. S. mansoni and other schistosome infections predispose to the carriage of Salmonella, in part because Salmonella may attach to the schistosomes and in part because shared antigens on schistosomes may induce immunological tolerance to Salmonella. Schistosoma japonicum, S. mekongi and S. intercalatum In addition to humans, the adult worm of S. japonicum infects the dog, rat, field mouse, water buffalo, ox, cat, pig, horse and sheep. Although other Schistosoma spp. can infect species other than humans, the non-human reservoir seems to be particularly important only in transmission for S. japonicum. S. japonicum is prevalent in the Yellow River and Yangtze–Jiang basins in China, where the infection is a major public health problem. It also has a focal distribution in the Philippines, Indonesia and Thailand (Fig. 11.54). The related S. mekongi occurs in Laos, Thailand and Myanmar, and S. intercalatum in West and Central Africa. The pathology of S. japonicum is similar to that of S. mansoni, but as this worm produces more eggs, the lesions tend to be more extensive and widespread. The clinical features resemble those of severe infection with S. mansoni, with added neurological features. The small and large bowel may be affected, and hepatic

Infections caused by helminths • 297

is ingested, and cysticercosis (systemic infection from larval migration) if ova are ingested. Echinococcus granulosus (dog tapeworm) does not cause human intestinal infection, but causes hydatid disease (which is analogous to cysticercosis) following ingestion of ova and subsequent larval migration. tropics. Furthermore, S. japonicum has so many hosts besides humans that latrines would have little impact. Population mass treatment annually helps prevent S. haematobium and S. mansoni infection but so far has had little success with S. japonicum. Targeting the intermediate host, the snail, is problematic and has not, on its own, proved successful. For personal protection, contact with infected water must be avoided. Liver flukes Liver flukes infect at least 20 million people and remain an important public health problem in endemic areas. They are associated with abdominal pain, hepatomegaly and relapsing cholangitis. Clonorchis sinensis and Opisthorchis felineus are major aetiological agents of bile duct cancer. The three major liver flukes have similar life cycles and pathologies, as outlined in Box 11.62. Other flukes of medical importance include lung and intestinal flukes (see Box 11.58). Cestodes (tapeworms) Cestodes are ribbon-shaped worms that inhabit the intestinal tract. They have no alimentary system and absorb nutrients through the tegumental surface. The anterior end, or scolex, has suckers for attaching to the host. From the scolex, a series of progressively developing segments arise, the proglottides, which may continue to show active movements when shed. Cross-fertilisation takes place between segments. Ova, present in large numbers in mature proglottides, remain viable for weeks, and during this period they may be consumed by the intermediate host. Larvae liberated from the ingested ova pass into the tissues of the intermediate host, forming larval cysticerci. Tapeworms cause two distinct patterns of disease: either intestinal infection or systemic cysticercosis (Fig. 11.56). Taenia saginata (beef tapeworm), Taenia asiatica and Diphyllobothrium latum (fish tapeworm) cause only intestinal infection in humans, following ingestion of intermediate hosts. Taenia solium causes intestinal infection if a cysticerci-containing intermediate host 11.62 Diseases caused by flukes in the bile duct Clonorchiasis Opisthorchiasis Fascioliasis Parasite Clonorchis sinensis Opisthorchis felineus Fasciola hepatica Other mammalian hosts Dogs, cats, pigs Dogs, cats, foxes, pigs Sheep, cattle Mode of spread Ova in faeces, water As for C. sinensis Ova in faeces on to wet pasture 1st intermediate host Snails Snails Snails 2nd intermediate host Freshwater fish Freshwater fish Encysts on vegetation Geographical distribution Far East, especially South China Far East, especially North-east Thailand Cosmopolitan, including UK Pathology Escherichia coli cholangitis, abscesses, biliary carcinoma As for C. sinensis Toxaemia, cholangitis, eosinophilia Symptoms Often symptom-free, recurrent jaundice As for C. sinensis Unexplained fever, tender liver, may be ectopic, e.g. subcutaneous fluke Diagnosis Ova in stool or duodenal aspirate As for C. sinensis As for C. sinensis, also serology Prevention Cook fish Cook fish Avoid contaminated watercress Treatment Praziquantel 25 mg/kg 3 times daily for 2 days As for C. sinensis but for 1 day only Triclabendazole 10 mg/kg single dose; repeat treatment may be required* *In the UK, available from the Hospital for Tropical Diseases, London. Fig. 11.56 Cysticercosis. Life cycle of Taenia solium. Adult worms in gut Pig Eggs passed in human faeces Human pork tapeworm infection results from eating undercooked pork containing cysticerci Eggs ingested by pig become cysticerci in muscles If cysticerci are swallowed they develop to adult tapeworms in the human intestine Ingestion of meat Faecal–oral route Human cysticercosis results from ingestion of the tapeworm eggs as a result of faecal contamination of food If eggs are swallowed by humans they develop to cysticerci in various sites, e.g. brain, muscle Cysticerci

298 • INFECTIOUS DISEASE Heavy brain infections, especially in children, may cause features of encephalitis. More commonly, however, cerebral signs do not occur until the larvae die, 5–20 years later. Epilepsy, including new-onset focal seizures, personality changes, staggering gait and signs of hydrocephalus are the most common features. Investigations Calcified cysts in muscles can be recognised radiologically. In the brain, however, less calcification takes place and larvae are only occasionally visible by plain X-ray; CT or magnetic resonance imaging (MRI) will usually show them. Epileptic fits starting in adult life suggest the possibility of cysticercosis if the patient has lived in or travelled to an endemic area. The subcutaneous tissue should be palpated and any nodule excised for histology. Radiological examination of the skeletal muscles may be helpful. Antibody detection is available for serodiagnosis. Management and prevention Albendazole (15 mg/kg daily for a minimum of 8 days) has now become the drug of choice for parenchymal neurocysticercosis. Praziquantel (50 mg/kg in 3 divided doses daily for 10 days) is another option. Prednisolone (10 mg 3 times daily) is also given for 14 days, starting 1 day before the albendazole or praziquantel. In addition, antiepileptic drugs should be given until the reaction in the brain has subsided. Operative intervention is indicated for hydrocephalus. Studies from India and Peru suggest that most small, solitary cerebral cysts will resolve without treatment. Echinococcus granulosus (Taenia echinococcus) and hydatid disease Dogs are the definitive hosts of the tiny tapeworm E. granulosus. The larval stage, a hydatid cyst, normally occurs in sheep, cattle, Intestinal tapeworm Humans acquire tapeworm by eating under-cooked beef infected with the larval stage of T. saginata, under-cooked pork containing the larval stage of T. solium or T. asiatica, or under-cooked freshwater fish containing larvae of D. latum. Usually, only one adult tapeworm is present in the gut but up to 10 have been reported. The ova of all the three Taenia are indistinguishable microscopically. However, examination of scolex and proglottides can differentiate them: T. solium has a rostellum and two rows of hooklets on the scolex, and discharges multiple proglottides (3–5) attached together with lower degrees of uterine branching (approximately 10); T. saginata has only four suckers in its scolex, and discharges single proglottids with greater uterine branching (up to 30); T. asiatica has a rostellum without hooks on its scolex and is difficult to differentiate from T. saginata, except that there are fewer uterine branches (16–21). Taenia solium T. solium, the pork tapeworm, is common in central Europe, South Africa, South America and parts of Asia. It is not as large as T. saginata. The adult worm is found only in humans following the ingestion of pork containing cysticerci. Intestinal infection is treated with praziquantel (5–10 mg/kg) or niclosamide (2 g), both as a single dose, or alternatively with nitazoxanide (500 mg twice daily for 3 days). These are followed by a mild laxative (after 1–2 hours) to prevent retrograde intestinal autoinfection. Cooking pork well prevents intestinal infection. Great care must be taken while attending a patient harbouring an adult worm to avoid ingestion of ova or segments. Taenia saginata Infection with T. saginata occurs in all parts of the world. The adult worm may be several metres long and produces little or no intestinal upset in human beings, but identification of segments in the faeces or on underclothing may distress the patient. Ova may be found in the stool. Praziquantel is the drug of choice; niclosamide or nitazoxanide is an alternative. Prevention depends on efficient meat inspection and the thorough cooking of beef. Taenia asiatica T. asiatica is a newly recognised species of Taenia, restricted to Asia. It is acquired by eating uncooked meat or viscera of pigs. Clinical features and treatment are similar to those of T. saginata. Cysticercosis Human cysticercosis is acquired by ingesting T. solium tapeworm ova, from either contaminated fingers or food (Fig. 11.56). The larvae are liberated from eggs in the stomach, penetrate the intestinal mucosa and are carried to many parts of the body, where they develop and form cysticerci, 0.5–1 cm cysts that contain the head of a young worm. They do not grow further or migrate. Common locations are the subcutaneous tissue, skeletal muscles and brain (Fig. 11.57). Clinical features Superficial cysts can be palpated under the skin or mucosa as pea-like ovoid bodies, but cause few or no symptoms and will eventually die and become calcified. Fig. 11.57 Neurocysticercosis. T2-weighted axial image of the brain showing multiple lesions of neurocysticercosis (large arrows show the largest lesions).

Ectoparasites • 299

Management and prevention Hydatid cysts should be excised wherever possible. Great care is taken to avoid spillage and cavities are sterilised with 0.5% silver nitrate or 2.7% sodium chloride. Albendazole (400 mg twice daily for 3 months) should also be used and is often combined with PAIR (percutaneous puncture, aspiration, injection of scolicidal agent and re-aspiration). Praziquantel (20 mg/kg twice daily for 14 days) also kills protoscolices perioperatively. Prevention is difficult when there is a close association with dogs. Personal hygiene, satisfactory disposal of carcasses, meat inspection and deworming of dogs reduces the prevalence of disease. Other tapeworms Other cestodes’ adult or larval stages may infect humans. Sparganosis is a condition in which an immature worm develops in humans, usually subcutaneously, as a result of eating or applying to the skin the secondary or tertiary intermediate host, such as frogs or snakes. Ectoparasites Ectoparasites only interact with the outermost surfaces of the host; see also page 1241. Jiggers (tungiasis) This is widespread in tropical America and Africa, and is caused by the sand flea Tunga penetrans. The pregnant flea burrows into the skin around toes and produces large numbers of eggs. Fig. 11.58 Hydatid disease. A Life cycle of Echinococcus granulosus. B Daughter cysts removed at surgery. C Within the daughter cysts are the protoscolices. Human Hydatid cysts in liver, lung etc. Sheep etc. Hydatid cysts in liver, lung etc. Ova Faeces Dog etc. Worms in gut A B C camels and other animals that are infected from contaminated pastures or water. By handling a dog or drinking contaminated water, humans may ingest eggs (Fig. 11.58). The embryo is liberated from the ovum in the small intestine and invades the blood stream, spreading to the liver. The resultant cyst grows very slowly, sometimes intermittently. It is composed of an enveloping fibrous pericyst, laminated hyaline membrane (ectocyst) and inner germinal layers (endocyst) that give rise to daughter cysts, or a germinating cystic brood capsule in which larvae (protoscolices) develop. Over time, some cysts calcify and become non-viable. The disease is common in the Middle East, North and East Africa, Australia and Argentina. Foci of infection persist in the UK in rural Wales and Scotland. E. multilocularis, which has a cycle between foxes and voles, causes a similar but more severe infection, ‘alveolar hydatid disease’, which invades the liver like cancer. Clinical features A hydatid cyst is typically acquired in childhood and, after growing for years, may cause pressure symptoms. These vary, depending on the site involved. In nearly 75% of patients with hydatid disease, the right lobe of the liver is invaded and contains a single cyst. In others, a cyst may be found in lung, bone, brain or elsewhere. Investigations The diagnosis depends on the clinical, radiological and ultrasound findings in a patient that has close contact with dogs in an endemic area. Complement fixation and ELISA are positive in 70–90% of patients.

300 • INFECTIOUS DISEASE Candidiasis (thrush) Superficial candidiasis is caused by Candida spp., mainly C. albicans. Manifestations include oropharyngeal (pp. 790 and 1240) and vaginal candidiasis (‘thrush’), intertrigo and chronic paronychia. Superficial candidiasis often follows antibiotic therapy. Intertrigo is characterised by inflammation in skin folds with surrounding ‘satellite lesions’. Chronic paronychia is associated with frequent wetting of the hands. Superficial candidiasis is treated mainly with topical azoles (p. 126), oral azoles being reserved for refractory or recurrent disease. Severe oropharyngeal and oesophageal candidiasis is a consequence of CD4+ T-lymphocyte depletion/ dysfunction, as in HIV infection (p. 316). Recurrent vaginal or penile candidiasis may be a manifestation of diabetes mellitus. Rarely, mutations in the autoimmune regulator gene (AIRE) or signal transducer and activator of transcription 1 (STAT1) cause a syndrome of chronic mucocutaneous candidiasis (p. 689). This is characterised by Candida infections of skin, mucosa and nails, with hyperkeratotic nails and erythematous periungual skin. Patients have cell-mediated immune defects against Candida and may have polyendocrinopathy and autoimmune features. Subcutaneous mycoses Chromoblastomycosis Chromoblastomycosis is a predominantly tropical or subtropical disease caused by environmental dematiaceous (dark-pigmented) fungi, most commonly Fonsecaea pedrosoi. Other causes include F. compacta, Cladophialophora carrionii and Phialophora verrucosa. The disease is a cutaneous/subcutaneous mycosis acquired by traumatic inoculation. Commonly affected areas The burrows are intensely irritating and the whole inflammatory nodule should be removed with a sterile needle. Secondary infection of lesions is common. Myiasis Myiasis is due to skin infestation with larvae of the South American botfly, Dermatobia hominis, or the African tumbu fly, Cordylobia anthropophaga. The larvae develop in a subcutaneous space with a central sinus. This orifice is the air source for the larvae, and periodically the larval respiratory spiracles protrude through the sinus. Patients with myiasis feel movement within the larval burrow and can experience intermittent sharp, lancinating pains. Myiasis is diagnosed clinically and should be suspected with any furuncular lesion accompanied by pain and a crawling sensation in the skin. The larva may be suffocated by blocking the respiratory orifice with petroleum jelly and gently removing it with tweezers. Secondary infection of myiasis is rare and rapid healing follows removal of intact larvae. Fungal infections Fungal infections, or mycoses, are classified as superficial, subcutaneous or systemic (deep), depending on the degree of tissue invasion. They are caused by filamentous fungi (moulds), by yeasts or by fungi that vary between these two forms, depending on environmental conditions (dimorphic fungi; Fig. 11.59). Superficial mycoses Superficial cutaneous fungal infections caused by dermatophyte fungi are described in Chapter 29. Fig. 11.59 Classification of medically important fungi. Fungal classification is based on simple morphological characteristics. Pneumocystis jirovecii is morphologically distinct from other fungi and does not fit into this classification. Although Candida albicans exists in a number of forms, including filamentous (hyphae and pseudohyphae), it is generally encountered in its yeast form so is classified in this category. Insets (dimorphic fungi) Courtesy of Beatriz Gomez and Angela Restrepo, CIB, Medellín, Colombia. Filamentous fungi (moulds) Characterised by the production of elongated, cylindrical, often septate cells (hyphae) and conidia (spores) Examples: • Aspergillus spp. (A. fumigatus shown here) • Fusarium spp. • Dermatophyte fungi (Tricophyton spp., Microsporum spp. etc.) • Mucorales Dimorphic fungi Yeasts Exist in filamentous (top) or yeast (bottom) form, depending on environmental conditions Examples: • Histoplasma capsulatum, Coccidioides immitis, Paracoccidioides brasiliensis (shown here), Blastomyces dermatidis • Sporothrix schenkii • Talaromyces marneffei • Malassezia spp. Characterised by the production of oval or round cells, which reproduce by binary fission (budding) Examples: • Candida spp. • Cryptococcus spp. (C. neoformans shown here)

Fungal infections • 301

disease. Success has also been reported wth co-trimoxazole plus amikacin, with rifampicin added in difficult cases and to prevent recurrence. Phaeohyphomycosis Phaeohyphomycoses are a heterogeneous group of fungal diseases caused by a large number (more than 70) of dematiaceous fungi. In phaeohyphomycosis, the tissue form of the fungus is predominantly mycelial (filamentous), as opposed to eumycetoma (grain) or chromoblastomycosis (sclerotic body). Disease may be superficial, subcutaneous or deep. The most serious manifestation is cerebral phaeohyphomycosis, which presents with a ring-enhancing, space-occupying cerebral lesion. Optimal therapy for this condition has not been established but usually consists of neurosurgical intervention and antifungal (usually triazole) therapy. Causative agents are Cladophialophora bantiana, Fonsecaea spp. and Rhinocladiella mackenziei, which occurs mainly in the Middle East and is usually fatal. Sporotrichosis Sporotrichosis is caused by Sporothrix schenckii, a dimorphic fungal saprophyte of plants in tropical and subtropical regions. Disease is caused by dermal inoculation of the fungus, usually from a thorn (occasionally from a cat scratch). In fixed cutaneous sporotrichosis, a subcutaneous nodule develops at the site of infection and subsequently ulcerates, with a purulent discharge. The disease may then spread along the cutaneous lymphatic channels, resulting in multiple cutaneous nodules that ulcerate and discharge (lymphocutaneous sporotrichosis). Rarer forms include cutaneous disease presenting with arthritis. Later, draining sinuses may form. Pulmonary sporotrichosis occurs as a result of inhalation of the conidia (spores) and causes chronic cavitary fibronodular disease with haemoptysis and constitutional symptoms. Disseminated disease may occur, especially in patients with HIV. Investigations Typical yeast forms detected on histology confirm diagnosis but are rarely seen; the fungus can also be cultured from biopsy specimen. A latex agglutination test detects S. schenckii antibodies in serum. Management Cutaneous and lymphocutaneous disease is treated with itraconazole (200–400 mg daily, prescribed as the oral solution, which has better bioavailability than the capsule formulation) for 3–6 months. Alternative agents include a saturated solution of potassium iodide (SSKI, given orally), initiated with 5 drops and increased to 40–50 drops 3 times daily, or terbinafine (500 mg twice daily). Localised hyperthermia may be used in pregnancy (to avoid azole use). Osteoarticular disease requires a longer course of therapy (at least 12 months). Severe or lifethreatening disease is treated with amphotericin B (lipid formulation preferred). Systemic mycoses Aspergillosis Aspergillosis is an opportunistic systemic mycosis, which affects the respiratory tract predominantly. It is described on page 596. include the foot, ankle and lower leg. Lesions may start several months after the initial injury, and medical attention is often sought several years later. The initial lesion is a papule. Further papules develop and coalesce to form irregular plaques. Nodular lesions may produce a characteristic ‘cauliflower’ appearance. Diagnosis is by histopathological examination of infected material, which shows dematiaceous, rounded, thick-walled ‘sclerotic bodies’ with septa at right angles to each other. The aetiological agent is confirmed by culture. Therapeutic approaches include antifungal agents, cryosurgery and surgical excision, alone or in combination, but the optimal therapy is unknown. Itraconazole and terbinafine are the most effective antifungal agents. However, posaconazole has also been used with a good outcome. Mycetoma (eumycetoma and actinomycetoma) Mycetoma is a chronic suppurative infection of the deep soft tissues and bones, most commonly of the limbs but also of the abdominal or chest wall or head. It is caused by either filamentous fungi, Eumyces (eumycetoma – 40%) or aerobic Actinomycetes (actinomycetoma – 60%). Many fungi cause eumycetomas, the most common being Madurella mycetomatis, M. grisea, Leptosphaeria senegalensis and Scedosporium apiospermum; causes of actinomycetoma include Nocardia, Streptomyces and Actinomadura spp. Both groups produce characteristically coloured ‘grains’ (microcolonies), the colour depending on the organism (black grains – eumycetoma, red and yellow grains – actinomycetoma, white grains – either). The disease occurs mostly in the tropics and subtropics. Clinical features The disease is acquired by inoculation (e.g. from a thorn) and most commonly affects the foot (Madura foot). Mycetoma begins as a painless swelling at the implantation site, which becomes chronic and progressive, grows and spreads steadily within the soft tissues, eventually extending into bone. Nodules develop under the epidermis and these rupture, revealing sinuses through which grains may be discharged. Sinuses heal with scarring, while fresh sinuses appear elsewhere. Deeper tissue invasion and bone involvement are less rapid and extensive in eumycetoma than actinomycetoma. There is little pain and usually no fever or lymphadenopathy, but there is progressive disability. Investigations Diagnosis of mycetoma involves identification of grains in pus, and/ or histopathological examination of tissue. Culture is necessary for species identification and susceptibility testing. Serological tests are not available. Management Eumycetoma is usually treated with a combination of surgery and antifungal therapy. Antifungal susceptibility testing, if available, is recommended, although clinical outcome does not necessarily correspond to in vitro test results. Itraconazole and ketoconazole (both 200–400 mg/day) are used most commonly. Success has also been reported with terbinafine monotherapy, and refractory cases have responded to voriconazole or posaconazole. Amphotericin B is not usually effective. Therapy is continued for 6–12 months or longer. In extreme cases, amputation may be required. Actinomycetoma is treated with prolonged antibiotic combinations, most commonly streptomycin and dapsone. Dapsone is replaced by co-trimoxazole in intolerance or refractory

302 • INFECTIOUS DISEASE Cryptococcosis Cryptococcosis is a systemic mycosis caused by two environmental yeast species, Cr. neoformans and Cr. gattii. Cr. neoformans is distributed worldwide and is primarily an opportunistic pathogen, most commonly associated with HIV infection (p. 321). Cr. gattii is a primary pathogen with a widespread distribution that includes Australasia, Africa, Canada (Vancouver Island) and the north-western USA. Cryptococcosis is acquired by inhalation of yeasts. These may disseminate to any organ, most commonly the CNS and skin. The manifestations of Cr. neoformans are most severe in immunocompromised individuals. Conversely, Cr. gattii causes severe disease in immunocompetent hosts. Disseminated cryptococcosis (sepsis with cryptococci present in the blood stream or at multiple sites) is largely restricted to immunocompromised patients. CNS manifestations of cryptococcosis include meningitis (p. 321) and cryptococcoma (Fig. 11.60), the latter more likely with Cr. gattii infection. Manifestations of pulmonary cryptococcosis range from severe pneumonia (in more immunocompromised patients) to asymptomatic disease with single or multiple pulmonary nodules, sometimes exhibiting cavitation (in patients with lesser immunosuppression). Cryptococcal nodules may mimic other causes of lung pathology, such as tuberculosis or malignancy, and diagnosis requires histopathology and/or culture. Treatment of severe cryptococcosis is the same as for cryptococcal meningitis, initially with liposomal amphotericin B (p. 321). Mild pulmonary disease is usually treated with fluconazole, although for asymptomatic nodules resection of the lesions is likely to be sufficient. Fusariosis Fusarium spp. cause disseminated disease in patients with prolonged neutropenia. The disease presents with Candidiasis Systemic candidiasis is an opportunistic mycosis caused by Candida spp. The most common cause is C. albicans. Other agents include C. dubliniensis, C. glabrata, C. krusei, C. parapsilosis and C. tropicalis. Candida species identification often predicts susceptibility to fluconazole: C. krusei is universally resistant, many C. glabrata isolates have reduced susceptibility or are resistant, and other species are mostly susceptible. Candidiasis is usually an endogenous disease that originates from oropharyngeal, genitourinary or skin colonisation, although nosocomial spread occurs. C. auris is an emerging species, which has a particular propensity for nosocomial transmission. Syndromes of systemic candidiasis Acute disseminated candidiasis This usually presents as candidaemia (isolation of Candida spp. from the blood). The main predisposing factor is the presence of a central venous catheter. Other major factors include recent abdominal surgery, total parenteral nutrition (TPN), recent antimicrobial therapy and localised Candida colonisation. Up to 40% of cases will have ophthalmic involvement, with characteristic retinal ‘cotton wool’ exudates. As this is a sightthreatening condition, candidaemic patients should have a full ophthalmoscopy review. Skin lesions (non-tender pink/ red nodules) may be seen. Although predominantly a disease of intensive care and surgical patients, acute disseminated candidiasis and/or Candida endophthalmitis is seen occasionally in injection drug-users, due to candidal contamination of citric acid or lemon juice used to dissolve heroin. Chronic disseminated candidiasis (hepatosplenic candidiasis) Persistent fever in a neutropenic patient, despite antibacterial therapy and neutrophil recovery, associated with the development of abdominal pain, raised alkaline phosphatase and multiple lesions in abdominal organs (e.g. liver, spleen and/or kidneys) on radiological imaging, suggests a diagnosis of hepatosplenic candidiasis. This represents a form of immune reconstitution syndrome (p. 104) in patients recovering from neutropenia and usually lasts for several months, despite appropriate therapy. Other manifestations Renal tract candidiasis, osteomyelitis, septic arthritis, peritonitis, meningitis and endocarditis are all well recognised and are usually sequelae of acute disseminated disease. Diagnosis and treatment of these conditions require specialist mycological advice. Management Blood cultures positive for Candida spp. must never be ignored. Acute disseminated candidiasis is treated with antifungal therapy, removal of any in-dwelling central venous catheter (whether known to be the source of infection or not) and removal of any documented source. Candidaemia should be treated initially with an echinocandin (p. 126), with subsequent adjustment (usually to intravenous or oral fluconazole) guided by clinical response, species identification and susceptibility testing. Treatment should continue for a minimum of 14 days. Alternative therapies include voriconazole and amphotericin B formulations. Chronic disseminated candidiasis requires prolonged treatment over several months with fluconazole or other agents, depending on species and clinical response. The duration of the condition may be reduced by adjuvant therapy with systemic glucocorticoids. Fig. 11.60 Cryptococcal disease. A 23-year-old HIV-positive male developed headache and left-sided weakness. A MRI scan of the brain showed a space-occupying lesion (arrow) with surrounding oedema. B Histopathological examination of the lesion stained with Grocott’s silver stain showed encapsulated yeasts. Cryptococcus neoformans was cultured. A B

Fungal infections • 303

Talaromyces (formerly Penicillium) marneffei infection T. marneffei is a thermally dimorphic pathogen (filamentous in environmental conditions and yeast at body temperature), which causes disease in South-east Asia, mainly in association with HIV infection (although immunocompetent patients may also be infected). Acquisition is usually by inhalation of environmental spores, with primary lung infection followed by haematogenous dissemination. A generalised papular rash, which progresses to widespread necrosis and ulceration, is a characteristic feature. Skin lesions may resemble molluscum contagiosum. Diagnosis is by histopathology and/or culture of respiratory secretions, blood or any infected clinical material (e.g. skin lesions, bone marrow, biopsies). Treatment involves an amphotericin B formulation followed by itraconazole (in severe infection), or itraconazole alone. Histoplasmosis Histoplasmosis is a primary systemic mycosis caused by the dimorphic fungus Histoplasma capsulatum. H. capsulatum var. capsulatum is endemic to east-central USA (especially the Mississippi and Ohio river valleys), parts of Canada, Latin America, the Caribbean, East and South-east Asia, and Africa. It occurs sporadically in Australia and India, and is very rare in Europe. H. capsulatum var. duboisii is found in West Africa and Madagascar. The primary reservoir of H. capsulatum is soil enriched by bird and bat droppings, in which the fungus remains viable for many years. Infection is by inhalation of infected dust. Natural infections are found in bats, which represent a secondary reservoir of infection. Histoplasmosis is a specific hazard for explorers of caves and people who clear out bird (including chicken) roosts. Pathology The organism is inhaled in the form of conidia or hyphal fragments and transforms to the yeast phase during infection. Conidia or yeasts are phagocytosed by alveolar macrophages and neutrophils, and this may be followed by haematogenous dissemination to any organ. Subsequent development of a T-lymphocyte response brings the infection under control, resulting in a latent state in most exposed individuals. Clinical features Disease severity depends on the quantity of spores inhaled and the immune status of the host. In most cases, infection is asymptomatic. Pulmonary symptoms are the most common presentation, with fever, non-productive cough and an influenzalike illness. Erythema nodosum, myalgia and joint pain frequently occur, and chest radiography may reveal a pneumonitis with hilar or mediastinal lymphadenopathy. Patients with pre-existing lung disease, such as chronic obstructive pulmonary disease (COPD) or emphysema, may develop chronic pulmonary histoplasmosis (CPH). The predominant features of this condition, which may easily be mistaken for tuberculosis, are fever, cough, dyspnoea, weight loss and night sweats. Radiological findings include fibrosis, nodules, cavitation and hilar/mediastinal lymphadenopathy. Disease caused by H. capsulatum var. duboisii presents more commonly with papulonodular and ulcerating lesions of the skin and underlying subcutaneous tissue and bone (sometimes referred to as ‘African histoplasmosis’). Multiple lesions of the ribs are common and the bones of the limbs may be affected. Lung involvement is relatively rare. Radiological examination may show rounded foci of bone destruction, sometimes associated Fig. 11.61 Fusarium infection. A patient presented with fever and skin nodules after developing neutropenia secondary to haematopoietic stem cell transplantation and chemotherapy for relapsed leukaemia. Fusarium solani was cultured from skin lesions and blood cultures. A Tender, erythematous papules/nodules on upper arm. B Gram stain of Fusarium in blood culture medium. A B antibiotic-resistant fever and evidence of dissemination (e.g. skin nodules, endophthalmitis, septic arthritis, pulmonary disease; Fig. 11.61). In contrast to Aspergillus spp., Fusarium spp. is often recovered from blood cultures. Treatment is challenging because of resistance to antifungal agents; voriconazole, posaconazole or lipid-formulated amphotericin B is most often prescribed. Mucormycosis Mucormycosis is a severe but uncommon opportunistic systemic mycosis caused by a number of ‘mucoraceous’ moulds, most commonly Lichtheimia (formerly Absidia) spp., Rhizomucor spp., Mucor spp. and Rhizopus spp. Disease patterns include rhinocerebral/craniofacial, pulmonary, cutaneous and systemic disease. All are characterised by the rapid development of severe tissue necrosis, which is almost always fatal if left untreated. The most common predisposing factors are profound immunosuppression from neutropenia and/or haematopoietic stem cell transplantation, uncontrolled diabetes mellitus, iron chelation therapy with desferrioxamine and severe burns. Definitive diagnosis is by culture but histopathological confirmation is required, as the fungi may be environmental contaminants. Treatment requires a combination of antifungal therapy and surgical débridement, with correction of predisposing factor(s) if possible. High-dose lipid-formulated amphotericin B is most commonly used. Posaconazole is active against many mucoraceous moulds in vitro and may be used as a second-line agent or as oral ‘step-down’ therapy.

304 • INFECTIOUS DISEASE Coccidioides meningitis (which may be associated with CSF eosinophils) is the most severe disease manifestation; it is fatal if untreated and requires life-long suppressive therapy with antifungal azoles. Investigations and management Diagnosis is by direct histopathological detection in specimens, culture of infected tissue or fluids, or antibody detection. IgM may be detected after 1–3 weeks of disease by precipitin tests. IgG appears later and is detected with the complement fixation test. Change in IgG titre may be used to monitor clinical progress. Treatment depends on specific disease manifestations and ranges from regular clinical reassessment without antifungal therapy (in mild pulmonary, asymptomatic cavitary or single nodular disease) to high-dose treatment with an antifungal azole, which may be continued indefinitely (e.g. in meningitis). Amphotericin B is used in diffuse pneumonia, disseminated disease and, intrathecally, in meningitis. Posaconazole has been used successfully in refractory disease. Paracoccidioidomycosis This is a primary systemic mycosis caused by inhalation of the dimorphic fungus Paracoccidioides brasiliensis, which is restricted to South America. The disease affects the lungs, mucous membranes (painful destructive ulceration in 50% of cases), skin, lymph nodes and adrenal glands (hypoadrenalism). Diagnosis is by microscopy and culture of lesions, and antibody detection. Oral itraconazole solution (200 mg/day) has demonstrated 98% efficacy and is currently the treatment of choice (mean duration 6 months). Ketoconazole, fluconazole, voriconazole and 2–3-year courses of sulphonamides are alternatives. Amphotericin B is used in severe or refractory disease, followed by an azole or sulphonamide. Blastomycosis Blastomyces dermatitidis is a dimorphic fungus endemic to restricted parts of North America, mainly around the Mississippi and Ohio rivers. Very occasionally, it is reported from Africa. The disease usually presents as a chronic pneumonia similar to pulmonary tuberculosis. Bones, skin and the genitourinary tract may also be affected. Diagnosis is by culture of the organism or identification of the characteristic yeast form in a clinical specimen. Antibody detection is rarely helpful. Treatment is with amphotericin B (severe disease) or itraconazole. Further information Websites britishinfection.org British Infection Association; source of general information on communicable diseases. cdc.gov Centers for Disease Control, USA; source of general information about infectious diseases. fitfortravel.nhs.uk Scottish site with valuable information for travellers. https://www.gov.uk/government/organisations/public-health-england Public Health England; information on infectious diseases in the UK. idsociety.org Infectious Diseases Society of America; source of general information relating to infectious diseases and of authoritative practice guidelines. who.int. especially www.who.int/csr/don World Health Organisation; invaluable links on travel medicine with updates on outbreaks of infections, changing resistance patterns and vaccination requirements. with abscess formation. Other disease patterns include a visceral form with liver and splenic invasion, and disseminated disease. Acute disseminated histoplasmosis is seen with immunocompromise, including HIV infection. Features include fever, pancytopenia, hepatosplenomegaly, lymphadenopathy and often a papular skin eruption. Chronic disseminated disease presents with fever, anorexia and weight loss. Cutaneous and mucosal lesions, lymphadenopathy, hepatosplenomegaly and meningitis may develop. Emergomyces africanus (formerly Emmonsia sp.) is a dimorphic fungus recently described in South Africa, which causes a disseminated histoplasmosis-like illness, mainly associated with HIV infection. Histopathologically, yeast forms appear similar to histoplasmosis and can be distinguished only by PCR. Investigations Histoplasmosis should be suspected in endemic areas with every undiagnosed infection in which there are pulmonary signs, enlarged lymph nodes, hepatosplenomegaly or characteristic cutaneous/bony lesions. Radiological examination in long-standing cases may show calcified lesions in the lungs, spleen or other organs. In the more acute phases of the disease, single or multiple soft pulmonary shadows with enlarged tracheobronchial nodes are seen on chest X-ray. Laboratory diagnosis is by direct detection (histopathology or antigen detection), culture and serology; although antigen detection is the most effective method, it is not widely available. Serology utilises complement fixation testing or immunodiffusion; interpretation is complex and requires a specialist. Histoplasma antigen may be detectable in blood or urine. Culture is definitive but slow (up to 12 weeks). Histopathology may show characteristic intracellular yeasts. Diagnosis of subcutaneous or bony infection is mainly by histopathological examination and/or culture. Management Mild pulmonary disease does not require treatment. However, if prolonged, it may be treated with itraconazole. More severe pulmonary disease is treated with an amphotericin B formulation for 2 weeks, followed by itraconazole for 12 weeks, with methylprednisolone added for the first 2 weeks of therapy if there is hypoxia or ARDS. CPH is treated with itraconazole oral solution for 12–24 months, and disseminated histoplasmosis with an amphotericin B formulation followed by itraconazole. Lipid formulations of amphotericin B are preferred but their use is subject to availability. In subcutaneous and bone infection, patterns of remission and relapse are more common than cure. A solitary bony lesion may require local surgical treatment only. Coccidioidomycosis This is a primary systemic mycosis caused by the dimorphic fungi Coccidioides immitis and C. posadasii, found in the south-western USA and Central and South America. The disease is acquired by inhalation of conidia (arthrospores). In 60% of cases it is asymptomatic but in the remainder it affects the lungs, lymph nodes and skin. Rarely (in approximately 0.5%), it may spread haematogenously to bones, adrenal glands, meninges and other organs, particularly in those with immunocompromise. Pulmonary coccidioidomycosis has two forms: primary and progressive. If symptomatic, primary coccidioidomycosis presents with cough, fever, chest pain, dyspnoea and (commonly) arthritis and a rash (erythema multiforme). Progressive disease presents with systemic upset (e.g. fever, weight loss, anorexia) and features of lobar pneumonia, and may resemble tuberculosis.

Ch04-3 Clinical Medicine

02-12 HIV infection and AIDS

12 HIV infection and AIDS

HIV infection and AIDS G Maartens Clinical examination in HIV disease 306 Epidemiology 308 Global and regional epidemics 308 Modes of transmission 308 Virology and immunology 309 Diagnosis and investigations 310 Diagnosing HIV infection 310 Viral load and CD4 counts 311 Clinical manifestations of HIV 311 Presenting problems in HIV infection 312 Lymphadenopathy 313 Weight loss 313 Fever 313 Mucocutaneous disease 314 Gastrointestinal disease 316 Hepatobiliary disease 317 Respiratory disease 318 Nervous system and eye disease 319 Rheumatological disease 321 Haematological abnormalities 322 Renal disease 322 Cardiac disease 322 HIV-related cancers 322 Prevention of opportunistic infections 323 Preventing exposure 323 Chemoprophylaxis 323 Immunisation 324 Antiretroviral therapy 324 ART complications 325 ART in special situations 326 Prevention of HIV 327

306 • HIV INFECTION AND AIDS Clinical examination in HIV disease Inset (oral hairy leucoplakia) Courtesy of Audiovisual Dept, St Mary’s Hospital, London. Observation Oropharynx Mucous membranes Neck Lymph node enlargement Tuberculosis Lymphoma Kaposi’s sarcoma Persistent generalised lymphadenopathy Parotidomegaly Eyes Retina Toxoplasmosis HIV retinopathy Progressive outer retinal necrosis • Weight loss • Tachypnoea • Fevers and sweats Skin Abdomen Hepatosplenomegaly Chest Lungs Pleural effusion Tuberculosis Kaposi’s sarcoma Parapneumonic Central nervous system Higher mental function HIV dementia Progressive multifocal leucoencephalopathy Focal signs Toxoplasmosis Primary CNS lymphoma Neck stiffness Cryptococcal meningitis Tuberculous meningitis Pneumococcal meningitis Anogenital region Rashes Legs Peripheral nerve examination Spastic paraparesis Peripheral neuropathy Kaposi’s sarcoma Molluscum contagiosum Gingivitis/periodontitis Cervical lymphadenopathy Oropharyngeal candidiasis Teeth Oral hairy leucoplakia Cytomegalovirus retinitis Anal cancer Papular pruritic eruption

Herpes zoster Seborrhoeic dermatitis Herpes simplex Aphthous ulcers Kaposi’s sarcoma Condylomas Herpes simplex Ulcers

Clinical examination in HIV disease • 307

HIV clinical staging classifications World Health Organisation (WHO) clinical stage (used in low- and middle-income countries) Centers for Disease Control (CDC) clinical categories (used in high-income countries) Stage 1 Category A Asymptomatic Persistent generalised lymphadenopathy Primary HIV infection Asymptomatic Persistent generalised lymphadenopathy Stage 2 Category B Unexplained moderate weight loss (< 10% of body weight) Recurrent upper respiratory tract infections Herpes zoster Angular cheilitis Recurrent oral ulceration Papular pruritic eruptions Seborrhoeic dermatitis Fungal nail infections Bacillary angiomatosis Candidiasis, oropharyngeal (thrush) Candidiasis, vulvovaginal; persistent, frequent or poorly responsive to therapy Cervical dysplasia (moderate or severe)/cervical carcinoma in situ Constitutional symptoms, such as fever (38.5°C) or diarrhoea lasting > 1 month Oral hairy leucoplakia Herpes zoster, involving two distinct episodes or more than one dermatome Idiopathic thrombocytopenic purpura Listeriosis Pelvic inflammatory disease, particularly if complicated by tubo-ovarian abscess Peripheral neuropathy Stage 3 Unexplained severe weight loss (> 10% of body weight) Unexplained chronic diarrhoea for > 1 month Unexplained persistent fever (> 37.5°C for > 1 month) Persistent oral candidiasis Oral hairy leucoplakia Pulmonary tuberculosis Severe bacterial infections Acute necrotising ulcerative stomatitis, gingivitis or periodontitis Unexplained anaemia (< 80 g/L (8 g/dL)), neutropenia (< 0.5 × 109/L) and/or chronic thrombocytopenia (< 50 × 109/L) Stage 4 Category C Candidiasis of oesophagus, trachea, bronchi or lungs Cervical carcinoma – invasive Cryptococcosis – extrapulmonary Cryptosporidiosis, chronic (> 1 month) Cytomegalovirus disease (outside liver, spleen and nodes) Herpes simplex chronic (> 1 month) ulcers or visceral HIV encephalopathy HIV wasting syndrome Cystoisosporiasis (formerly known as isosporiasis), chronic (> 1 month) Kaposi’s sarcoma Lymphoma (cerebral or B-cell non-Hodgkin) Mycobacterial infection, non-tuberculous, extrapulmonary or disseminated Mycosis – disseminated endemic (e.g. coccidioidomycosis, talaromycosis (formerly penicilliosis), histoplasmosis) Pneumocystis pneumonia Pneumonia, recurrent bacterial Progressive multifocal leucoencephalopathy Toxoplasmosis – cerebral Tuberculosis – extrapulmonary (CDC includes pulmonary) Sepsis, recurrent (including non-typhoidal Salmonella) (CDC only includes Salmonella) Symptomatic HIV-associated nephropathy* Symptomatic HIV-associated cardiomyopathy* Leishmaniasis, atypical disseminated* *These conditions are in WHO stage 4 but not in CDC category C.

308 • HIV INFECTION AND AIDS particularly in southern Africa, where average life expectancy of the general population fell to below 40 years before the introduction of ART. Modes of transmission HIV is transmitted by sexual contact, by exposure to blood (e.g. injection drug use, occupational exposure in health-care workers) and blood products, or to infants of HIV-infected mothers (who may be infected in utero, perinatally or via breastfeeding). Worldwide, the major route of transmission is heterosexual. The risk of contracting HIV after exposure to infected body fluid is dependent on the integrity of the exposed site, the type and volume of fluid, and the level of viraemia in the source person. The approximate transmission risk after exposure is given in Box 12.2. Factors that increase the risk of transmission are listed in Box 12.3. A high proportion of patients with haemophilia in high-income countries had been infected through contaminated blood products by the time HIV antibody screening was adopted in 1985. Routine screening of blood and blood products for HIV infection has virtually eliminated this as a mode of transmission. However, the World Health Organisation (WHO) estimates that, because of the lack of adequate screening facilities in resource-poor countries, 5–10% of blood transfusions globally are with HIV-infected blood. Epidemiology The acquired immunodeficiency syndrome (AIDS) was first recognised in 1981, although the earliest documented case of HIV infection has been traced to a blood sample from the Democratic Republic of Congo in 1959. AIDS is caused by the human immunodeficiency virus (HIV), which progressively impairs cellular immunity. The origin of HIV is a zoonotic infection with simian immunodeficiency viruses (SIV) from African primates, probably first infecting local hunters. SIVs do not cause disease in their natural primate hosts. HIV-1 was transmitted from chimpanzees and HIV-2 from sooty mangabey monkeys. HIV-1 is the cause of the global HIV pandemic, while HIV-2, which causes a similar illness to HIV-1 but progresses more slowly and is less transmissible, is restricted mainly to western Africa. It has been estimated that both HIV-1 and HIV-2 first infected humans about 100 years ago. HIV-2 will not be discussed further in this chapter. There are three groups of HIV-1, representing three separate transmission events from chimpanzees: M (‘major’, worldwide distribution), O (‘outlier’) and N (‘non-major and non-outlier’). Groups O and N are restricted to West Africa. Group M consists of nine subtypes: A–D, F–H, J and K (subtypes E and I were subsequently shown to be recombinants of other subtypes). Globally, subtype C (which predominates in sub-Saharan Africa and India) accounts for half of infections and appears to be more readily transmitted. Subtype B predominates in Western Europe, the Americas and Australia. In Europe, the prevalence of non-B subtypes is increasing because of migration. Subtypes A and D are associated with slower and faster disease progression, respectively. Global and regional epidemics In 2015 it was estimated that there were 36.7 million people living with HIV/AIDS, 2.1 million new infections and 1.1 million AIDS-related deaths. The global epidemiology of HIV has been changed by expanding access to combination antiretroviral therapy (ART), which reached 17 million people in 2015: the annual number of AIDS-related deaths has almost halved since the peak in 2005, the number of new infections has decreased by 40% since the peak in 1997, and the number of people living with HIV has increased. Regions have marked differences in HIV prevalence, incidence and dominant modes of transmission (Box 12.1). HIV has had a devastating impact in sub-Saharan Africa, 12.2 Risk of HIV transmission after single exposure to an HIV-infected source HIV exposure Approximate risk Sexual Vaginal intercourse: female to male 0.05% Vaginal intercourse: male to female 0.1% Anal intercourse: insertive 0.05% Anal intercourse: receptive 0.5% Oral intercourse: insertive 0.005% Oral intercourse: receptive 0.01% Blood exposure Blood transfusion 90% Intravenous drug-users sharing needles 0.67% Percutaneous needlestick injury 0.3% Mucous membrane splash 0.09% Mother to child Vaginal delivery 15% Breastfeeding (per month) 0.5% 12.1 Regional HIV prevalence in 2015, incidence trend and dominant mode of transmission Region People living with HIV (millions) HIV incidence trend (2011–2015) Dominant transmission Sub-Saharan Africa 25.5 Decreasing Heterosexual Asia and Pacific 5.1 Stable IDU, heterosexual Latin America and Caribbean

Stable MSM, heterosexual Western and Central Europe, and North America 2.4 Stable MSM Eastern Europe and Central Asia 1.5 Increasing IDU Middle East and North Africa 0.23 Stable IDU, MSM (IDU = injection drug-users; MSM = men who have sex with men)

Virology and immunology • 309

Fig. 12.1 Life cycle of HIV. Red arrows indicate sites of action of antiretroviral drugs. Proviral DNA Cell nucleus Integration Double-stranded DNA Fusion Fusion inhibitors Binding to co-receptor CCR5 or CXCR4 Attachment to CD4 receptor Maturation Viral release Reverse transcriptase inhibitors Chemokine receptor antagonist Chemokine co-receptor (CCR5 or CXCR4) Genomic RNA Reverse transcription of viral RNA genome Reverse transcription Integrase inhibitors Transcription Translation Viral proteins Viral mRNA Protease inhibitors Cleavage of polypeptides and assembly 12.3 Factors increasing the risk of transmission of HIV Common to all transmission categories • High viral load Sexual transmission • STIs, especially genital ulcers • Cervical ectopy • Rectal or vaginal lacerations • Menstruation • Uncircumcised male partner • Receptive anal intercourse • Depot intramuscular progesterone contraceptive use Injection drug use transmission • Sharing equipment • Linked commercial sex • Intravenous use • Concomitant cocaine use • Incarceration Occupational transmission • Deep injury • Visible blood on device • Needle was in a blood vessel Vertical transmission • Prolonged rupture of membranes • Older gestational age (STIs = sexually transmitted infections) Virology and immunology HIV is an enveloped ribonucleic acid (RNA) retrovirus from the lentivirus family. After mucosal exposure, HIV is transported via dendritic cells to the lymph nodes, where infection becomes established. This is followed by viraemia and dissemination to lymphoid organs, which are the main sites of viral replication. Each mature virion has a lipid membrane lined by a matrix protein that is studded with glycoprotein (gp) 120 and gp41 spikes. The inner cone-shaped protein core (p24) houses two copies of the single-stranded RNA genome and viral enzymes. The HIV genome consists of three characteristic retroviral genes – gag (encodes a polyprotein that is processed into structural proteins, including p24), pol (codes for the enzymes reverse transcriptase, integrase and protease) and env (codes for envelope proteins gp120 and gp41) – as well as six regulatory genes. HIV infects cells bearing the CD4 receptor; these are T-helper lymphocytes, monocyte–macrophages, dendritic cells, and microglial cells in the central nervous system (CNS). Entry into the cell commences with binding of gp120 to the CD4 receptor (Fig. 12.1), which results in a conformational change in gp120 that permits binding to one of two chemokine co-receptors (CXCR4 or CCR5). The chemokine co-receptor CCR5 is utilised during initial infection, but later on the virus may adapt to use CXCR4. Individuals who are homozygous for the CCR5 delta

310 • HIV INFECTION AND AIDS Diagnosis and investigations Diagnosing HIV infection Globally, the trend is towards universal HIV testing, rather than testing only those patients at high risk or those with manifestations of HIV infection. However, in the UK, testing is still targeted to high-risk groups (Box 12.4). HIV is diagnosed by detecting host antibodies either with rapid point-of-care tests or in the laboratory, where enzyme-linked immunosorbent assay (ELISA) tests are usually done. Most tests detect antibodies to both HIV-1 and HIV-2. A positive antibody test from two different immunoassays is sufficient to confirm infection. Western blot assays can also be used to confirm infection but they are expensive and sometimes yield indeterminate results. Screening tests often include an assay for p24 antigen in addition to antibodies, in order to detect patients with primary infection before the antibody response occurs. Nucleic acid amplification tests (usually polymerase chain reaction, PCR) to detect HIV RNA are used to diagnose infections in infants of HIV-infected mothers, who carry maternal antibodies to HIV for up to 15 months irrespective of whether they are infected, and to diagnose primary infection before 32 mutation do not express CCR5 on CD4 cells and are immune to HIV infection. Chemokine co-receptor binding is followed by membrane fusion and cellular entry involving gp41. After penetrating the cell and uncoating, a deoxyribonucleic acid (DNA) copy is transcribed from the RNA genome by the reverse transcriptase enzyme, which is carried by the infecting virion. Reverse transcription is an error-prone process and multiple mutations arise with ongoing replication, which results in considerable viral genetic heterogeneity. Viral DNA is transported into the nucleus and integrated within the host cell genome by the integrase enzyme. Integrated virus is known as proviral DNA and persists for the life of the cell. Cells infected with proviral HIV DNA produce new virions only if they undergo cellular activation, resulting in the transcription of viral messenger RNA (mRNA) copies, which are then translated into viral peptide chains. The precursor polyproteins are then cleaved by the viral protease enzyme to form new viral structural proteins and enzymes that migrate to the cell surface and are assembled using the host cellular apparatus to produce infectious viral particles; these bud from the cell surface, incorporating the host cell membrane into the viral envelope. The mature virion then infects other CD4 cells and the process is repeated. CD4 lymphocytes that are replicating HIV have a very short survival time of about 1 day. It has been estimated that in asymptomatic HIV-infected people, more than 1010 virions are produced and 109 CD4 lymphocytes destroyed each day. The CD4 lymphocytes are destroyed primarily by the host immune response rather than by cytopathic effects of HIV. A small percentage of T-helper lymphocytes enter a postintegration latent phase. Latently infected cells are important as sanctuary sites from antiretroviral drugs, which act only on replicating virus. Current ART is unable to eradicate HIV infection due to the persistence of proviral DNA in long-lived latent CD4 cells. The host immune response to HIV infection is both humoral, with the development of antibodies to a wide range of antigens, and cellular, with a dramatic expansion of HIV-specific CD8 cytotoxic T lymphocytes, resulting in a CD8 lymphocytosis and reversal of the usual CD4:CD8 ratio. CD8 cytotoxic T lymphocytes kill activated CD4 cells that are replicating HIV, but not latently infected CD4 cells. HIV evades destruction despite this vigorous immune response, in part because the highly conserved regions of gp120 and gp41 that are necessary for viral attachment and entry are covered by highly variable glycoprotein loops that change over time as a result of mutations selected for by the immune response. The initial peak of viraemia in primary infection settles to a plateau phase of persistent chronic viraemia. With time, there is gradual attrition of the T-helper lymphocyte population and, as these cells are pivotal in orchestrating the immune response, the patient becomes susceptible to opportunistic diseases. The predominant opportunist infections in HIV-infected people are the consequences of impaired cell-mediated rather than antibody-mediated immunity (e.g. mycobacteria, herpesviruses). However, there is also a B-lymphocyte defect with impaired antibody production to new antigens and dysregulated antibody production with a polyclonal increase in gamma globulins, resulting in an increased risk of infection with encapsulated bacteria, notably Streptococcus pneumoniae. The immune activation in response to HIV infection does not completely resolve on effective ART. This residual inflammatory state has been implicated in the pathogenesis of several non-AIDS morbidities that occur at a higher rate in HIV-infected people on ART than in the general population: cardiovascular, neurological and liver disease, chronic kidney disease and non-AIDS cancers. 12.4 Patients who should be offered and recommended HIV testing in the UK1 Patients accessing specialist sexual health services (including genitourinary medicine) • All patients who attend for testing or treatment Patients accessing primary care (including emergency care) and secondary care • All patients attending their first appointment at: Drug dependency programmes Pregnancy termination services Services treating hepatitis B or C, lymphoma or tuberculosis • All patients who: Have symptoms that may indicate HIV or for which HIV is part of the differential diagnosis Are from a country or group with high rate of HIV infection Are male, or trans women, who have sex with men Report sexual contact with someone from a country with high rate of HIV infection Disclose high-risk sexual practices, e.g. ‘chemsex’ (p. 332) Are diagnosed with, or request testing for, a sexually transmitted infection Report a history of injecting drug use Are the sexual partners of people known to be HIV-positive or at high risk of HIV • In areas of high2 and extremely high3 prevalence: All patients not previously diagnosed with HIV who register with a general practice or undergo blood testing for any reason • In areas of extremely high prevalence3: All emergency care and secondary care patients not previously diagnosed with HIV At each general practice consultation consider offering opportunistic HIV testing Prison inmates • All new inmates not previously diagnosed with HIV 1Adapted from National Institute for Health and Care Excellence NG60 – HIV testing: increasing uptake among people who may have undiagnosed HIV NICE guideline (Dec. 2016). 2Prevalence of diagnosed HIV is 2–5 per 1000 people aged 15–59. 3Prevalence of diagnosed HIV is ≥ 5 per 1000 people aged 15–59.

Clinical manifestations of HIV • 311

The CD4 count varies by up to 20% from day to day and is also transiently reduced by intercurrent infections. Due to this variability, major therapeutic decisions should not be taken on the basis of a single count. The percentage of lymphocytes that are CD4+, rather than the absolute count, is routinely used in paediatrics, as the normal CD4 counts in infants and young children are much higher than in adults. In adults, the CD4 percentage is occasionally useful when evaluating significant reductions in an individual’s CD4 count, which may be associated with transient lymphopenia due to intercurrent infection or pregnancy. In this case, the CD4 percentage will be unchanged. The normal CD4 count is over 500 cells/mm3. The rate of decline in CD4 count is highly variable. People with CD4 counts between 200 and 500 cells/mm3 have a low risk of developing major opportunistic infections. Morbidity due to inflammatory dermatoses, herpes zoster, oral candidiasis, tuberculosis, bacterial pneumonia and HIV-related immune disorders (e.g. immune thrombocytopenia) becomes increasingly common as CD4 counts decline. Once the count is below 200 cells/mm3, there is severe immune suppression and a high risk of AIDS-defining conditions. It is important to note that patients can be asymptomatic despite very low CD4 counts and that major opportunistic diseases occasionally present with high CD4 counts. The CD4 count should be performed every 3–6 months in patients on ART, together with measurement of the viral load. Viral load The level of viraemia is measured by quantitative PCR of HIV RNA, known as the viral load. Determining the viral load is crucial for monitoring responses to ART (p. 324). People with high viral loads (e.g. > 100 000 copies/mL) experience more rapid declines in CD4 count, while those with low viral loads (< 1000 copies/mL) usually have slow or even no decline in CD4 counts. Transient increases in viral load occur with intercurrent infections and immunisations, so the test should be done at least 2 weeks afterwards. Viral loads are variable; only changes in viral load of more than 0.5 log10 copies/mL are considered clinically significant. Clinical manifestations of HIV Clinical staging of patients should be done at the initial medical examination, as it provides prognostic information and is a key criterion for initiating prophylaxis against opportunistic infections. Two clinical staging systems are used internationally (p. 307). In both, patients are staged according to the most severe manifestation and do not improve their classification. For example, a patient who is asymptomatic following a major opportunistic disease (AIDS) remains at stage 4 or category C of the WHO and CDC systems, respectively, and never reverts to earlier stages. Finally, patients do not always progress steadily through all stages and may present with AIDS, having been asymptomatic. Primary HIV infection Primary infection is symptomatic in more than 50% of cases but the diagnosis is often missed. The incubation period is usually 2–4 weeks after exposure. The duration of symptoms is variable but is seldom longer than 2 weeks. The clinical manifestations (Box 12.8) resemble those of infectious mononucleosis/glandular fever (p. 241), but the presence of maculopapular rash or mucosal ulceration strongly suggests primary HIV infection antibodies have developed. PCR is more sensitive than p24 antigen detection for diagnosing primary infection. The purpose of HIV testing is not simply to identify infected individuals, but also to educate people about prevention and transmission of the virus. Counselling in the client’s home language is essential both before testing and after the result is obtained (Boxes 12.5 and 12.6). There are major advantages to using rapid point-of-care HIV tests in that pre- and post-test counselling can be done at the same visit. A number of baseline investigations should be done at the initial medical evaluation (Box 12.7). The extent of these investigations will depend on the resources available. Viral load and CD4 counts CD4 counts CD4 lymphocyte counts are usually determined by flow cytometry but cheaper methods have been developed for low-income countries. The CD4 count is the most clinically useful laboratory indicator of the degree of immune suppression; it is used, together with clinical staging, in decisions to start prophylaxis against opportunistic infections, and is of great value in the differential diagnosis of clinical problems. 12.6 How to carry out post-test counselling Test result negative • Discuss transmission and need for behaviour modification • Advise second test 3 months after last exposure Test result positive • Explain meaning of result • Organise medical follow-up • Assess coping strategy • Stress importance of disclosure • Explain value of antiretroviral therapy • Provide written information and useful Internet resources • Discuss confidentiality issues • Organise emotional and practical support (names/phone numbers) • Facilitate notification of sexual partners 12.5 How to carry out pre-test counselling • Discuss meaning of positive and negative test results • Realise importance of maintaining confidentiality • Identify person to whom positive result could be disclosed • Explore knowledge and explain natural history of HIV • Discuss transmission and risk reduction • Assess coping strategy • Explain test procedure • Obtain informed consent 12.7 Baseline investigations • CD4 count • Viral load • Hepatitis B surface antigen • Hepatitis C antibody • Liver function tests • Full blood count • Urinalysis, serum creatinine • Syphilis serology • Cervical smear in women • Serum cryptococcal antigen (if CD4 < 100) • Tuberculin skin test • Sexually transmitted infection screen

312 • HIV INFECTION AND AIDS response. The median time from infection to the development of AIDS in adults is about 9 years (see Fig. 12.2). A small proportion of untreated HIV-infected people are long-term non-progressors, with CD4 counts in the reference range for 10 years or more. Some long-term non-progressors have undetectable viral loads and are known as ‘elite controllers’. Minor HIV-associated disorders A wide range of disorders indicating some impairment of cellular immunity occur in most patients before they develop AIDS (CDC category B or WHO stages 2 and 3). Careful examination of the mouth is important when patients are being followed up, as oral candidiasis and oral hairy leucoplakia are common conditions that require initiation of prophylaxis against opportunistic infections, irrespective of the CD4 count. Acquired immunodeficiency syndrome AIDS is defined by the development of specified opportunistic infections, cancers and severe manifestations of HIV itself (p. 307). CDC category C is the most widely used definition of AIDS. WHO updated its classification more recently and added a few conditions of similar prognosis to its stage 4 disease. Presenting problems in HIV infection HIV itself is associated with a wide variety of clinical manifestations, and opportunistic diseases add many more. All body systems can be affected by HIV. The CD4 count is useful in differential diagnosis (Box 12.9): opportunistic diseases that may present at higher CD4 counts become increasingly common as CD4 counts decline, so the CD4 count helps to rule out certain disorders. For example, in a patient with a pulmonary infiltrate and a CD4 count of 350 cells/mm3, pulmonary tuberculosis is a likely diagnosis and PJP is very unlikely, but if the patient’s CD4 count is 50 cells/mm3, both PJP and tuberculosis are likely. Globally, tuberculosis is the most common cause of morbidity and mortality in HIV-infected patients. Tuberculosis should be considered in the differential diagnosis of most presenting problems in patients from communities where tuberculosis is common. rather than the other viral causes of infectious mononucleosis. In infectious mononucleosis due to Epstein–Barr virus (EBV) or in cytomegalovirus (CMV), rashes generally occur only if aminopenicillins are given. Atypical lymphocytosis occurs less frequently than in EBV infection. Transient lymphopenia, including CD4 lymphocytes, is found in most cases (Fig. 12.2), which may result in opportunistic infections, notably oropharyngeal candidiasis. Major opportunistic infections like Pneumocystis jirovecii pneumonia (PJP) may rarely occur. Thrombocytopenia and moderate elevation of liver enzymes are commonly present. The differential diagnosis of primary HIV includes acute EBV, primary CMV infection, rubella, primary toxoplasmosis and secondary syphilis. Early diagnosis is made by detecting HIV RNA by PCR or p24 antigenaemia. The appearance of specific anti-HIV antibodies in serum (seroconversion) occurs 2–12 weeks after the development of symptoms. The window period during which antibody tests may be false negative is prolonged when post-exposure prophylaxis has been used. Asymptomatic infection A prolonged period of clinical latency follows primary infection, during which infected individuals are asymptomatic. Persistent generalised lymphadenopathy with nodes typically < 2 cm diameter is a common finding. Eventually, the lymph nodes regress, with destruction of node architecture as disease advances. Viraemia peaks during primary infection and then drops as the immune response develops, to reach a plateau about 3 months later. The level of viraemia post seroconversion is a predictor of the rate of decline in CD4 counts, which is highly variable and explained in part by genetic factors affecting the immune Fig. 12.2 Virological and immunological progression of untreated HIV infection.

Clinical latency Constitutional symptoms Opportunistic diseases Death Primary infection Acute HIV syndrome Wide dissemination of virus Seeding of lymphoid organs

HIV RNA copies per mL plasma

CD4+ T–lymphocyte count (cells/mm3)

9 10

Weeks CD4 Viral load Years 9 12 12.8 Clinical features of primary infection • Fever • Maculopapular rash • Pharyngitis • Lymphadenopathy • Myalgia/arthralgia • Diarrhoea • Headache • Oral and genital ulceration • Meningo-encephalitis • Bell’s palsy

Presenting problems in HIV infection • 313

warrants further investigation. Lymph node needle aspiration (using a wide-bore needle such as 19G if tuberculosis is suspected) should be performed. One slide should be air-dried and sent for staining for acid-fast bacilli, which has about a 70% yield in tuberculosis. The other slide should be fixed and sent for cytology. If caseous liquid is aspirated, this should be sent for mycobacterial culture or PCR. If needle aspiration is unhelpful, or if lymphoma or Kaposi’s sarcoma is suspected, excision biopsy should be performed. Weight loss Weight loss is a very common finding in advanced HIV infection. The HIV wasting syndrome is an AIDS-defining condition and is defined as weight loss of more than 10% of body weight, plus either unexplained chronic diarrhoea (lasting over 1 month) or chronic weakness and unexplained prolonged fever (lasting over 1 month). This is a diagnosis of exclusion. If the weight loss is rapid (more than 1 kg a month), then major opportunistic infections or cancers become more likely. Painful oral conditions and nausea from drugs contribute by limiting intake. Depression is very common and can cause significant weight loss. Measurement of C-reactive protein is helpful in the work-up of weight loss, as this is markedly raised with most opportunistic diseases but not with HIV itself. Erythrocyte sedimentation rate (ESR) is elevated by HIV infection and is therefore not useful. The presence of fever or diarrhoea is helpful in the differential diagnosis of weight loss (Fig. 12.3). Fever Fever is a very common presenting feature. Common causes of prolonged fever with weight loss are listed in Figure 12.3. Non-typhoid Salmonella bacteraemia, which commonly presents with fever in low-income countries, is accompanied by diarrhoea in only about 50% of patients. Pyrexia of unknown origin (PUO) in HIV infection is defined as temperature over 38°C with no cause found after 4 weeks in outpatients or 3 days in inpatients, and initial investigations such as chest X-rays, urinalysis and Lymphadenopathy Persistent generalised lymphadenopathy due to HIV is described above under asymptomatic infection. Lymphadenopathy may also be due to malignancy (Kaposi’s sarcoma or lymphoma) or infections, especially tuberculosis, which is an extremely common cause in low- and middle-income countries. Tuberculous lymph nodes are often matted and may become fluctuant due to extensive caseous necrosis; inexperienced clinicians often perform incision and drainage inappropriately when simple aspiration is all that is required. Symmetrical generalised lymphadenopathy may occur in disseminated tuberculosis. Lymphoma typically presents with large, firm, asymmetric nodes. Rapid enlargement of a node, asymmetric enlargement or lymphadenopathy associated with constitutional symptoms (even if the nodes are symmetrical) Fig. 12.3 Presentation and differential diagnosis of weight loss. (ART = antiretroviral therapy; AZT = zidovudine; CMV = cytomegalovirus; d4T = stavudine; KS = Kaposi’s sarcoma; MAC = Mycobacterium avium complex; NHL = non-Hodgkin lymphoma; PI = protease inhibitor) Loss of weight Fever Diarrhoea Yes No Yes No Tuberculosis MAC Disseminated mycoses NHL CMV HIV wasting Depression HIV wasting Painful oral/oesophageal disorder Lipoatrophy (d4T and AZT) Symptomatic hyperlactataemia GI side-effects of ART Small bowel (large-volume, watery) Large bowel (small-volume, blood/mucus, tenesmus) Cryptosporidiosis Microsporidiosis Cystoisosporiasis HIV enteropathy PI-induced MAC CMV Salmonella Shigella Campylobacter Clostridium difficile 12.9 CD4 count and risk of common HIV-associated diseases < 500 cells/mm3 • Tuberculosis • Bacterial pneumonia • Herpes zoster • Oropharyngeal candidiasis • Non-typhoid salmonellosis • Kaposi’s sarcoma • Non-Hodgkin lymphoma • HIV-associated idiopathic thrombocytopenic purpura < 200 cells/mm3 • Pneumocystis jirovecii pneumonia • Chronic herpes simplex ulcers • Oesophageal candidiasis • Cystoisospora belli (syn. Isospora belli ) diarrhoea • HIV wasting syndrome • HIV-associated dementia • Peripheral neuropathy • Endemic mycoses < 100 cells/mm • Cerebral toxoplasmosis • Cryptococcal meningitis • Cryptosporidiosis and microsporidiosis • Primary CNS lymphoma • Cytomegalovirus • Disseminated Mycobacterium avium complex (MAC) • Progressive multifocal leucoencephalopathy

314 • HIV INFECTION AND AIDS be taken, and sent for histology and culture for mycobacteria and fungi, in patients with papular rashes or if there are constitutional symptoms coinciding with the development of the rash. Seborrhoeic dermatitis Seborrhoeic dermatitis is very common in HIV. The severity increases as the CD4 count falls. It presents as scaly red patches, typically in the nasolabial folds and in hairy areas. Fungal infections are thought to play a role in the pathogenesis of this condition. It responds well to a combined topical antifungal and glucocorticoid. Selenium sulphide shampoo is helpful for scalp involvement. blood cultures have failed to identify the cause. HIV itself can present with prolonged fever but this is a diagnosis of exclusion, as a treatable cause will be found in most patients. Abdominal imaging, preferably by computed tomography (CT), should be requested. Abdominal nodes (especially if they are hypodense in the centre) or splenic microabscesses strongly suggest tuberculosis. Mycobacterial blood cultures, which can also detect fungi, should be performed. Bone marrow aspirate and trephine biopsy are helpful if the full blood count shows cytopenias. Liver biopsy may be helpful if the liver enzymes are elevated but is invasive and seldom necessary. Mycobacterial and fungal stains and cultures should be done on all biopsies. Chest X-rays should be repeated after about a week, as micronodular or interstitial infiltrates may have become apparent (see p. 319 for differential diagnosis). Tuberculosis is by far the most common cause of PUO in low- and middle-income countries, and in these settings a trial of empirical therapy is warranted after cultures have been sent. In high-income countries, disseminated Mycobacterium avium complex (MAC) infection is an important cause of PUO, often also presenting with diarrhoea and splenomegaly. Disseminated endemic mycoses (e.g. histoplasmosis, coccidioidomycosis, talaromycosis) present with PUO, often with papular skin eruptions or mucosal ulcerations (Fig. 12.4). Skin biopsy for histology and fungal culture is often diagnostic. Mucocutaneous disease The skin and mouth must be carefully examined, as mucocutaneous manifestations are extremely common in HIV and many prognostically important conditions can be diagnosed by simple inspection. The differential diagnosis of dermatological conditions is simplified by categorising disorders according to the lesion type (Box 12.10). Some common dermatological diseases, notably psoriasis, are exacerbated by HIV. The risk of many drug rashes is increased in HIV-infected patients. Skin biopsy should Fig. 12.4. Disseminated histoplasmosis presenting with diffuse papular rash and fever. Skin biopsy was diagnostic. Courtesy of Professor Graeme Meintjes. Fig. 12.5 Severe mucocutaneous herpes simplex. Chronic anogenital or perioral ulcers are very common in advanced HIV infection. 12.10 Differential diagnosis of skin conditions by lesion type Scaly rashes • Seborrhoeic dermatitis • Psoriasis* (exacerbated by HIV) • Tinea corporis* • Dry skin/ichthyosis • Norwegian scabies* • Drug rashes* Pruritic papules • Pruritic papular eruption (‘itchy red bump disease’) • Eosinophilic folliculitis • Scabies* Papules and nodules (non-pruritic) • Molluscum contagiosum* • Secondary syphilis • Kaposi’s sarcoma • Bacillary angiomatosis • Cryptococcosis • Warts* • Disseminated endemic mycoses (histoplasmosis, coccidioidomycosis and talaromycosis) Blisters • Herpes simplex • Herpes zoster • Fixed drug eruptions • Drug rashes (especially toxic epidermal necrolysis) Mucocutaneous ulcers • Ecthyma • Herpes simplex • Aphthous ulcers (minor and major) • Histoplasmosis • Drug rashes (Stevens– Johnson syndrome) Hyperpigmentation • Post-inflammatory (especially pruritic papular eruption) • Zidovudine • Emtricitabine (palms and soles) *See Chapter 29 for more information.

Presenting problems in HIV infection • 315

• classic KS: rare, indolent and restricted largely to elderly Mediterranean or Jewish men • endemic KS: occurs in sub-Saharan Africa, is more aggressive, presents at earlier ages than classic KS, and affects men more than women • KS in patients on immunosuppressant drugs: usually transplant recipients, who experience disseminated disease • AIDS-associated KS. In Africa, the male-to-female ratio of AIDS-associated KS is much lower than is seen with endemic KS, but men are still more affected than women, despite the fact that the seroprevalence of human herpesvirus 8 is the same in both sexes. AIDS-associated KS is always a multicentric disease. Early mucocutaneous lesions are macular and may be difficult to diagnose. Subsequently, lesions become papular or nodular, and may ulcerate. KS lesions typically have a red–purple colour (Fig. 12.6 and p. 306) but may become hyperpigmented, especially in dark-skinned patients. As the disease progresses, the skin lesions become more numerous and larger. Lymphoedema is common, as lymphatic vessels are infiltrated. KS also commonly spreads to lymph nodes and viscerally, especially to the lungs and gastrointestinal tract. Visceral disease occasionally occurs in the absence of mucocutaneous involvement. B symptoms of fever, night sweats and weight loss may occur. KS may respond to ART. Chemotherapy should be reserved for those patients who fail to remit on ART, or be given together with ART if there are poor prognostic features such as visceral involvement, oedema, ulcerated lesions and B symptoms. Bacillary angiomatosis Bacillary angiomatosis is a bacterial infection caused by Bartonella henselae or B. quintana. Skin lesions range from solitary superficial red–purple lesions resembling KS or pyogenic granuloma, to Herpes simplex infections Recurrences of herpes simplex infection are very common and primarily affect the nasolabial and anogenital areas (Fig. 12.5). As immune suppression worsens, the ulcers take longer to heal and become more extensive. Ulcers that persist for more than 4 weeks are AIDS-defining. The diagnosis is clinical, but PCR of vesicle fluid or from ulcer swabs may be diagnostic with unusual presentations. Response to a course of antiviral drug such as aciclovir is good but relapses are common. Frequent relapses that persist despite ART should be treated with aciclovir 400 mg twice daily for 6–12 months (Box 12.11). Herpes zoster This usually presents with a pathognomonic vesicular rash on an erythematous base in a dermatomal distribution (p. 239). The median CD4 count at the first episode of zoster is 350 cells/mm3. In patients with advanced HIV disease, the rash may be multidermatomal and recurrent episodes may occur. Disseminated zoster is rare. In HIV-infected patients, zoster is generally more extensive and has a longer duration, and there is a higher risk of developing post-herpetic neuralgia. High doses of aciclovir or its congeners should be given for all cases with active disease, irrespective of the time since the onset of the rash. Post-herpetic neuralgia is difficult to manage. Analgesic adjuvants, e.g. amitriptyline and pregabalin, should be commenced in all patients with prolonged pain. Topical capsaicin has modest efficacy. Kaposi’s sarcoma Kaposi’s sarcoma (KS) is a spindle-cell tumour of lymphoendothelial origin. All forms of KS are due to sexually transmitted human herpesvirus 8, also known as KS-associated herpesvirus. KS occurs in four patterns: 12.11 Treatment of common opportunistic infections in adults with AIDS Opportunistic infection Treatment Alternative treatment Secondary prophylaxis* Pneumocystis jirovecii pneumonia Co-trimoxazole 20/100 mg/kg/day (in 4 divided doses) for 21 days; maximum per dose 320/1600 mg Early adjunctive prednisone 40 mg twice daily, if hypoxic Clindamycin 900 mg 3 times daily IV (switch to 600 mg 3 times daily PO once improving) plus primaquine 30 mg daily for 21 days Co-trimoxazole 160/800 mg daily Cerebral toxoplasmosis Sulfadiazine 15 mg/kg 4 times daily plus pyrimethamine 200 mg stat, then 75 mg daily plus folinic acid 15–25 mg daily for 6 weeks Co-trimoxazole 320/1600 mg twice daily for 4 weeks, then 160/800 mg twice daily for 3 months Co-trimoxazole 160/800 mg daily Cryptococcosis Liposomal amphotericin B 4 mg/kg/ day IV plus flucytosine 25 mg/kg 4 times daily for 14 days, followed by fluconazole 400 mg daily for 8 weeks Amphotericin B 1 mg/kg/day IV plus fluconazole 800 mg daily for 14 days, followed by fluconazole 400 mg daily for 8 weeks Fluconazole 200 mg daily (for minimum of 1 year) Oesophageal candidiasis Fluconazole 200 mg daily for 14 days Itraconazole 200 mg daily for 14–21 days Not usually recommended Disseminated Mycobacterium avium complex Clarithromycin 500 mg twice daily plus ethambutol 15 mg/kg daily Azithromycin 500 mg daily plus ethambutol 15 mg/kg daily Continue treatment for minimum of 1 year Herpes simplex ulcers Aciclovir 400 mg 3 times daily for 5–10 days Valaciclovir 500 mg or famciclovir 125 mg twice daily for 5–10 days Aciclovir 400 mg twice daily only if recurrences are frequent/severe Cystoisospora belli diarrhoea Co-trimoxazole 160/800 mg 4 times daily for 10 days Ciprofloxacin 500 mg twice daily for 10 days Co-trimoxazole 160/800 mg daily *Secondary prophylaxis may be discontinued once CD4 counts have increased to > 200 cells/mm3 on antiretroviral therapy for at least 3 months.

316 • HIV INFECTION AND AIDS (p. 306) that can be scraped off to reveal a red raw surface. Erythematous candidiasis is more difficult to diagnose and presents with a reddened mucosa and a smooth shiny tongue. Angular cheilitis due to Candida is a common manifestation. Topical antifungals are usually effective. Antifungal lozenges are more effective than antifungal solutions. Systemic azole therapy, usually fluconazole, should be given if topical therapy fails or if there are oesophageal symptoms. Oral hairy leucoplakia (p. 306) appears as corrugated white plaques running vertically on the side of the tongue and is virtually pathognomonic of HIV disease. It is usually asymptomatic and is due to EBV. Oral ulcers are common. Herpetiform oral ulcers occur in primary infection. Herpes simplex typically affects the nasolabial area but may cause oral ulcers. In early disease, minor aphthous ulcers are common. In advanced disease, giant aphthous ulcers occur. These destroy tissue, are painful and need to be differentiated from herpes simplex and CMV ulcers by biopsy. They respond to systemic glucocorticoids and ART. A number of disseminated endemic mycoses, notably histoplasmosis (p. 303), may cause oral ulcers, usually associated with constitutional symptoms. Finally, superficial oral ulcers may occur as part of the Stevens–Johnson syndrome, usually caused by sulphonamides or NNRTIs. KS often involves the mouth, especially the hard palate (see above and Fig. 12.6). Nodular oral lesions are associated with a worse prognosis. Gingivitis is very common. Good oral hygiene and regular dental check-ups are important. Acute necrotising ulcerative gingivitis and periostitis (p. 306) can result in loss of teeth; they should be treated with a course of metronidazole and a dental referral should be made. Nail disorders Fungal infections (onychomycosis, p. 1240) are very common and often involve multiple nails. Blue–black discoloration of nails is common and may be due to HIV or to the antiretroviral drug zidovudine. Gastrointestinal disease Oesophageal diseases Oesophageal candidiasis (Fig. 12.7) is the most common cause of pain on swallowing (odynophagia), dysphagia and regurgitation. Concomitant oral candidiasis is present in about 70% of patients. Systemic azole therapy, e.g. fluconazole 200 mg daily for 14 days, is usually curative but relapses are common (Box 12.11). Patients whose oesophageal symptoms fail to respond to azoles should be investigated with oesophagoscopy. Major aphthous ulceration and CMV ulcers are the most likely causes and need to be differentiated by biopsy. Occasionally, herpes simplex oesophagitis or KS is responsible. Diarrhoea Chronic diarrhoea is a very common presenting problem in patients with advanced HIV, especially in areas where there is no access to safe water. It is a major cause of wasting. The differential diagnosis of diarrhoea depends on whether the presentation is with large- or small-bowel symptoms (see Fig. 12.3). The presentation and aetiology of acute diarrhoea are similar to those in HIV-uninfected patients. multiple subcutaneous nodules or plaques. Lesions are painful and may bleed or ulcerate. The infection may become disseminated with fevers, lymphadenopathy and hepatosplenomegaly. Diagnosis is made by biopsy of a lesion and Warthin–Starry silver staining, which reveals aggregates of bacilli. Treatment with doxycycline or azithromycin is effective. Papular pruritic eruption Papular pruritic eruption (‘itchy red bump disease’) is an intensely itchy, symmetrical rash affecting the trunk and extremities. It is thought to be due to an allergic reaction to insect bites. In sub-Saharan Africa, it is the most common skin manifestation of HIV. Post-inflammatory hyperpigmentation is common. Topical glucocorticoids, emollients and antihistamines are useful but response is variable. Measures to reduce insect bites are logical but difficult to implement in low-income settings. Drug rashes Cutaneous hypersensitivity to drugs is said to occur 100 times more frequently in HIV infection. The most common type is an erythematous maculopapular rash, which may be scaly. The drugs most commonly associated with rashes are sulphonamides and non-nucleoside reverse transcriptase inhibitors (NNRTIs – see below). Severe, life-threatening features of drug rashes include blistering (when this affects more than 30% of surface area it is known as toxic epidermal necrolysis), involvement of mucous membranes (Stevens–Johnson syndrome, pp. 1224 and 1254), or systemic involvement with fever or organ dysfunction (especially hepatitis, which is often delayed for a week or two after the rash develops). Because sulphonamides are important in the treatment and prophylaxis of opportunistic infections, rechallenge or desensitisation is often attempted in patients who have previously experienced rashes, provided the reaction was not life-threatening. Details of rashes caused by ART are given below. Oral conditions Oropharyngeal candidiasis is very common. It is nearly always caused by C. albicans (p. 300), but azole-resistant Candida species may be selected for if there have been repeated courses of azole drugs. Pseudomembranous candidiasis is the most common manifestation, with white patches on the buccal mucosa Fig. 12.6 Oral Kaposi’s sarcoma. A full examination is important to detect disease that may affect the palate, gums, fauces or tongue.

Presenting problems in HIV infection • 317

fever, weight loss and diarrhoea, but the diarrhoea is seldom profuse. Hepatobiliary disease Chronic viral hepatitis Hepatitis B and/or C (HBV and HCV) co-infection is common in HIV-infected people due to shared risk factors for transmission. The natural history of both HBV and HCV is altered by HIV co-infection. In the ART era, chronic liver disease from viral hepatitis has emerged as a major cause of morbidity and mortality. HBV and HCV are further described on pages 873 and 877. Hepatitis B HBV infection is common in several groups of people at risk of HIV infection: residents of low- and middle-income countries, injection drug-users, haemophiliacs and MSM. HIV co-infection increases HBV viraemia, is associated with less elevation of transaminase (presumably due to immune suppression), and increases the risk of liver fibrosis and hepatocellular carcinoma. Several nucleoside reverse transcriptase inhibitors (NRTIs; lamivudine, emtricitabine and tenofovir) are also effective against HBV. HBV status should be checked at baseline in all HIV-infected patients. Treatment with anti-HBV drugs should be considered for all patients who have active HBV replication (HBeAg-positive or HBV DNA > 2000 IU/ mL) and/or evidence of inflammation or fibrosis on liver biopsy (see also p. 876). A flare of hepatitis may be associated with improved immune function after starting ART or discontinuing Large-bowel diarrhoea Acute diarrhoea caused by the bacterial enteric pathogens Campylobacter, Shigella and Salmonella occurs more frequently than in HIV-uninfected people and the illness is more severe. Bacteraemia is much more common, notably due to non-typhoid Salmonella (p. 262). Diarrhoea caused by Clostridium difficile should be considered if there has been prior exposure to antibiotics, as is often the case in patients with symptomatic HIV. CMV colitis presents with chronic large-bowel symptoms and fever in patients with CD4 counts below 100 cells/mm3. On colonoscopy, ulcers are seen, mostly involving the left side of the colon. Biopsy of ulcers shows typical ‘owl’s-eye’ inclusion bodies. Small-bowel diarrhoea Chronic small-bowel diarrhoea may be due to HIV enteropathy but this is a diagnosis of exclusion. It typically presents with chronic watery diarrhoea and wasting without fever. Infection with one of three unicellular organisms is responsible for most cases: cryptosporidiosis, microsporidiosis and cystoisosporiasis (formerly known as isosporiasis) (Box 12.12). All three organisms are intracellular parasites that invade enterocytes. If the diagnosis is not made by stool microscopy on at least two specimens, a duodenal biopsy should be performed (Fig. 12.8). Electron microscopy is essential for speciation of microsporidia. About 40% of patients with disseminated MAC infections have watery diarrhoea. Fever is a prominent feature of MAC infection, which helps differentiate it from cryptosporidiosis, microsporidiosis and cystoisosporiasis. Intestinal tuberculosis typically involves the ileocaecal area and may present with Fig. 12.7 Oesophageal candidiasis. Endoscopy showing typical pseudomembranous candidiasis. Fig. 12.8 Cryptosporidiosis. Duodenal biopsy may be necessary to confirm cryptosporidiosis or microsporidiosis. The arrow indicates an oöcyst. 12.12 Common causes of chronic watery diarrhoea Cryptosporidiosis Microsporidiosis Cystoisosporiasis (formerly isosporiasis) Organism Protozoan Fungus Protozoan Species Cryptosporidium parvum C. hominis Enterozoon bieneusi Encephalitozoon intestinalis etc. Cystoisospora belli Animal host Multiple Multiple No Distribution Global Global Tropics Stool examination Acid-fast stain Trichrome stain Polymerase chain reaction Acid-fast stain Specific treatment No established therapy Albendazole (some species) Co-trimoxazole

318 • HIV INFECTION AND AIDS regions (Fig. 12.9) but may be normal initially. High-resolution CT scan is more sensitive than chest X-ray, usually showing typical ‘ground-glass’ interstitial infiltrates. Pneumatoceles may occur and may rupture, resulting in a pneumothorax. The diagnosis is made with silver stains, PCR or immunofluorescence of broncho-alveolar lavage or induced sputum (note that spontaneously produced sputum should not be sent, as the yield is low). Treatment is with high-dose co-trimoxazole, together with adjunctive systemic glucocorticoids if the patient is hypoxic (see Box 12.11). Pulmonary tuberculosis Tuberculosis is the most common cause of admission in countries with a high tuberculosis incidence. Pulmonary tuberculosis in patients with mild immune suppression typically presents as in HIV-uninfected patients, with a chronic illness and apical pulmonary cavities (p. 588). However, in patients with CD4 counts below 200 cells/mm3, there are four important differences in the clinical presentation of pulmonary tuberculosis: • Tuberculosis progresses more rapidly, with a subacute or even acute presentation. The diagnosis therefore needs to be made and therapy commenced promptly. A trial of empirical therapy is often started while awaiting the results of mycobacterial cultures. • The chest X-ray appearance alters: cavities are rarely seen, pulmonary infiltrates are no longer predominantly in apical areas, and pleural effusions and hilar or mediastinal lymphadenopathy are common (Fig. 12.10). A normal chest X-ray is not unusual in symptomatic patients with tuberculosis confirmed on sputum culture. These atypical findings can result in a delayed or missed diagnosis. • Sputum smears, which are positive in most HIV-uninfected adults with pulmonary tuberculosis, are negative in more than half of patients. The main reason for this is the absence of pulmonary cavities. • Many patients have disseminated tuberculosis, sometimes with a classic miliary pattern on chest X-ray, but more antiretrovirals that have anti-HBV activity. HBV co-infection increases the risk of antiretroviral hepatotoxicity. Hepatitis C HCV infection is extremely common in injection drug-users and haemophiliacs. HIV co-infection increases HCV viraemia and increases the risk of liver fibrosis and hepatocellular carcinoma. Treatment for HCV should preferably be deferred in patients with CD4 counts < 200 cells/mm3 until they are stable on ART. As with HBV co-infection, a flare of hepatitis may be associated with improved immune function after starting ART, and there is an increased risk of antiretroviral hepatotoxicity. Response to anti-HCV therapy is similar to that seen in HIVuninfected people, but there are important drug–drug interactions between several antiretrovirals and the newer HCV protease inhibitors. HIV cholangiopathy HIV cholangiopathy, a form of secondary sclerosing cholangitis (p. 888), may occur in patients with severe immune suppression. In some patients, coexisting intestinal infection with CMV, cryptosporidiosis or microsporidiosis is present, but it is uncertain if these organisms play an aetiological role. Papillary stenosis is common and is amenable to cautery via endoscopic retrograde cholangiopancreatography (ERCP), which provides symptomatic relief. Acalculous cholecystitis is a common complication of cholangiopathy. ART may improve the condition. Respiratory disease Pulmonary disease is very common and is the major reason for hospital admission. Most patients who are admitted for respiratory diseases will have either bacterial pneumonia, pulmonary tuberculosis or PJP. PJP is more common in highincome countries, while tuberculosis is more common in low- and middle-income countries. An approach to the differential diagnosis of all three conditions is given in Box 12.13. Pneumocystis jirovecii pneumonia The key presenting feature of Pneumocystis jirovecii pneumonia (PJP) is progressive dyspnoea with a duration of less than 12 weeks. Dry cough and fever are common. The chest X-ray typically shows a bilateral interstitial infiltrate spreading out from the hilar Fig. 12.9 Pneumocystis pneumonia: typical chest X-ray appearance. Note the interstitial bilateral infiltrate. 12.13 Comparative features of bacterial pneumonia, Pneumocystis jirovecii pneumonia and pulmonary tuberculosis Bacterial pneumonia Pneumocystis jirovecii pneumonia Pulmonary tuberculosis Duration Acute Subacute Variable Dyspnoea Common Prominent Occasional White cell count Increased Normal Variable Chest X-ray Infiltrate Consolidation Interstitial Variable Bilateral infiltrate Occasional Usual Common Effusion Occasional No Common Nodes Rare No Common C-reactive protein Markedly increased Variable Increased

Presenting problems in HIV infection • 319

Lymphoid interstitial pneumonitis is a slowly progressive disorder causing a diffuse reticulonodular infiltrate. It is caused by a benign polyclonal lymphocytic interstitial infiltrate and is part of the diffuse infiltrative lymphocytosis syndrome (DILS – see p. 321). Patients may have other features of DILS, notably parotidomegaly. KS often spreads to the lungs. Typical chest X-ray appearances are large, irregular nodules, linear reticular patterns and pleural effusions. Bronchoscopy is diagnostic. Nervous system and eye disease The central and peripheral nervous systems are commonly involved in HIV, either as a direct consequence of HIV infection or due to opportunistic diseases. An approach to common presentations is outlined in Figure 12.11. Cognitive impairment HIV-associated neurocognitive disorders HIV is a neurotropic virus and invades the CNS early during infection. Meningo-encephalitis may occur at seroconversion. About 50% of HIV-infected people have abnormal neuropsychiatric testing. The term HIV-associated neurocognitive disorder (HAND) describes a spectrum of disorders: asymptomatic neurocognitive impairment (which is the most common), minor neurocognitive disorder and HIV-associated dementia (also called HIV encephalopathy). The proportion of patients with symptomatic HAND increases with declining CD4 counts. HIV-associated dementia is a subcortical dementia characterised by impairment of executive function, psychomotor retardation and impaired memory. There is no diagnostic test for HIV-associated dementia. CT or magnetic resonance imaging (MRI) shows diffuse cerebral atrophy out of keeping with age. It is important to exclude depression, cryptococcal meningitis and neurosyphilis. ART usually improves HIV-associated dementia but milder forms of HAND often persist. Progressive multifocal leucoencephalopathy Progressive multifocal leucoencephalopathy (PML) is a progressive disease that presents with stroke-like episodes and cognitive commonly presenting with pulmonary infiltrates together with extrapulmonary tuberculosis. The most common sites of concomitant extrapulmonary tuberculosis are the pleura and lymph nodes. Acid-fast bacilli are more often found on wide-needle aspirate of nodes than on sputum (p. 313). Pleural aspirate showing a lymphocytic exudate suggests tuberculosis as a likely cause and pleural biopsy will usually confirm the diagnosis. Tuberculosis in HIV-infected patients responds well to standard short-course therapy (p. 592). Bacterial pneumonia The incidence of bacterial pneumonia is increased about 100-fold by HIV infection. The severity, likelihood of bacteraemia, risk of recurrent pneumonia, and mortality are all increased compared with HIV-uninfected patients. The aetiology is similar to that of community-acquired pneumonia in HIV-uninfected patients with co-morbidity: S. pneumoniae is the most common cause, followed by Haemophilus influenzae, Enterobacteriaceae (e.g. Klebsiella pneumoniae) and Staphylococcus aureus. The prevalence of atypical bacteria in HIV-infected patients with pneumonia is similar to that in the general population. Treatment is with a broadspectrum β-lactam (e.g. ceftriaxone, amoxicillin–clavulanate), with the addition of a macrolide if the pneumonia is severe. Uncommon bacteria causing pneumonia include Pseudomonas aeruginosa, Nocardia (which mimics tuberculosis) and Rhodococcus equi (which can cause pulmonary cavities). Miscellaneous causes of pulmonary infiltrates Pulmonary cryptococcosis may present as a component of disseminated disease or be limited to the lungs. The chest X-ray appearances are variable. Cryptococcomas occur less commonly than in HIV-uninfected people. The most common radiographic pattern seen in HIV infection is patchy consolidation, often with small areas of cavitation resembling tuberculosis. Pleural involvement is rare. The disseminated endemic mycoses (histoplasmosis, coccidioidomycosis and talaromycosis) often cause diffuse pulmonary infiltrates, mimicking miliary tuberculosis. Fig. 12.10 Chest X-ray of pulmonary tuberculosis in advanced HIV infection. Lower-zone infiltrates and hilar or mediastinal nodes in a patient with a CD4 count of < 200 cells/mm3. Fig. 12.11 Presentation and differential diagnosis of HIV-related neurological disorders. (CMV = cytomegalovirus; HAND = HIV-associated neurocognitive disorder; PCNSL = primary CNS lymphoma; PML = progressive multifocal leucoencephalopathy) Neurological presentation Space-occupying lesion Cognitive impairment Meningitis Toxoplasmosis PCNSL Tuberculoma Cryptococcoma Cryptococcal Tuberculous Pneumococcal HIV HAND Depression Neurosyphilis Cryptococcal meningitis PML CMV encephalitis

320 • HIV INFECTION AND AIDS Primary CNS lymphoma Primary CNS lymphomas (PCNSLs) are high-grade B-cell lymphomas associated with EBV infection. Characteristically, imaging demonstrates a single homogeneously enhancing, periventricular lesion with surrounding oedema (Fig. 12.14). If it is considered safe to perform a lumbar puncture, PCR for EBV DNA in the CSF has a high sensitivity and specificity for PCNSL. Brain biopsy is definitive but carries a risk of morbidity and may be non-diagnostic in up to one-third. The prognosis is poor. Tuberculoma Lesions resemble toxoplasmosis on imaging, except that oedema tends to be less marked and single lesions occur more commonly. impairment. Vision is often impaired due to involvement of the occipital cortex. PML is caused by the JC virus. A combination of characteristic appearances on MRI (Fig. 12.12) and detection of JC virus DNA in the cerebrospinal fluid (CSF) by PCR is diagnostic. No specific treatment exists and prognosis remains poor despite ART. CMV encephalitis This presents with behavioural disturbance, cognitive impairment and a reduced level of consciousness. Focal signs may also occur. Detection of CMV DNA in the CSF supports the diagnosis. Response to anti-CMV therapy is usually poor. Space-occupying lesions Space-occupying lesions in AIDS patients typically present over days to weeks. The most common cause is toxoplasmosis. As toxoplasmosis responds rapidly to therapy, a trial of antitoxoplasmosis therapy should be given to all patients presenting with space-occupying lesions while the results of diagnostic tests are being awaited. Cerebral toxoplasmosis Cerebral toxoplasmosis is caused by reactivation of residual Toxoplasma gondii cysts from past infection, which results in the development of space-occupying lesions. The characteristic findings on imaging are multiple space-occupying lesions with ring enhancement on contrast and surrounding oedema (Fig. 12.13). Toxoplasma serology shows evidence of previous exposure (positive immunoglobulin (Ig)G antibodies); a negative serological test effectively rules out toxoplasmosis but a positive test is not specific. The standard therapy for toxoplasmosis is sulfadiazine with pyrimethamine, together with folinic acid, to reduce the risk of bone marrow suppression (see Box 12.11). However, co-trimoxazole has been shown to be as effective and less toxic, and is also more widely available. Response to a trial of therapy is usually diagnostic, with clinical improvement in 1–2 weeks and shrinkage of lesions on imaging in 2–4 weeks. Definitive diagnosis is by brain biopsy but this is seldom necessary. Fig. 12.12 Progressive multifocal leucoencephalopathy. Nonenhancing white-matter lesions without surrounding oedema are seen. Fig. 12.13 Cerebral toxoplasmosis. Multiple ring-enhancing lesions with surrounding oedema are characteristic. Fig. 12.14 Primary CNS lymphoma. A single enhancing periventricular lesion with moderate oedema is typical.

Presenting problems in HIV infection • 321

of the spine is normal but is an important investigation to exclude other causes. Most patients have concomitant HIV-associated dementia. CMV polyradiculitis presents with painful legs, progressive flaccid paraparesis, saddle anaesthesia, absent reflexes and sphincter dysfunction. CSF shows a neutrophil pleocytosis (which is unusual for a viral infection), and the detection of CMV DNA by PCR confirms the diagnosis. Functional recovery is poor despite treatment with ganciclovir or valganciclovir. Psychiatric disease Significant psychiatric morbidity is very common and is a major risk factor for poor adherence. Reactive depression is the most common disorder. Diagnosis is often difficult, as many patients have concomitant HAND. Substance misuse is common in many groups of people at risk of HIV. Some antiretroviral drugs can cause psychiatric adverse effects and these are detailed on page 326. Retinopathy CMV retinitis presents with painless, progressive visual loss in patients with severe immune suppression. On fundoscopy, the vitreous is clear. Haemorrhages and exudates are seen in the retina (p. 306), often with sheathing of vessels (‘frosted branch angiitis’). The disease usually starts unilaterally but progressive bilateral involvement occurs in most untreated patients. Diagnosis is usually clinical, but if there is doubt, demonstrating CMV DNA by PCR of vitreous fluid is diagnostic. Treatment with ganciclovir or valganciclovir stops progression of the disease but lost vision does not recover. Some patients may develop immune recovery uveitis in response to ART, with intraocular inflammation, macular oedema and cataract formation that require prompt treatment with oral and intraocular glucocorticoids to prevent further visual loss. Three other conditions may mimic CMV retinitis: ocular toxoplasmosis, which typically presents with a vitritis and retinitis without retinal haemorrhages; HIV retinopathy, a microangiopathy that causes cotton wool spots, which are not sight-threatening; and varicella zoster virus, which can cause rapidly progressive outer retinal necrosis. Rheumatological disease The immune dysregulation associated with HIV infection may result in autoantibody formation, usually in low titres. Mild arthralgias and a fibromyalgia-like syndrome are common in HIV-infected people. Arthritis HIV can cause a seronegative arthritis, which resembles rheumatoid arthritis. A more benign oligoarthritis may also occur. Reactive arthritis is more severe in HIV infection (p. 1031). Diffuse infiltrative lymphocytosis syndrome Diffuse infiltrative lymphocytosis syndrome (DILS) is a benign disorder involving polyclonal CD8 lymphocytic infiltration of tissues, which has some features in common with Sjögren’s syndrome (p. 1038). It is linked to human leucocyte antigen (HLA)-DRB1. Most patients have a marked CD8 lymphocytosis. DILS usually presents in patients with mild immune suppression. The most common manifestation is bilateral parotid gland enlargement; the glands are often massive, with lymphoepithelial cysts There may be evidence of tuberculosis elsewhere. The CSF may show features consistent with tuberculous meningitis. Response to antituberculosis therapy is slow and paradoxical expansion of lesions despite therapy is not uncommon. Stroke There is a higher incidence of stroke in patients with HIV disease. Atherosclerosis is accelerated by the presence of inflammation due to the immune response to HIV, which is not completely suppressed by ART, and by dyslipidaemia caused by some antiretroviral drugs. HIV vasculopathy, which is thought to be a vasculitis, can also cause a stroke. It is important to exclude tuberculous meningitis and meningovascular syphilis in all patients who present with a stroke. Meningitis Cryptococcal meningitis Cryptococcus neoformans is the most common cause of meningitis in AIDS patients. Patients usually present subacutely with headache, vomiting and decreased level of consciousness. Neck stiffness is present in less than half. CSF pleocytosis is often mild or even absent, and protein and glucose concentrations are variable. It is important to request CSF cryptococcal antigen tests in all HIV-infected patients undergoing lumbar puncture, as this test has a high sensitivity and specificity. Treatment is with amphotericin B (plus flucytosine if available) for 2 weeks, followed by fluconazole (see Box 12.11). Raised intracranial pressure is common and should be treated with repeated therapeutic lumbar punctures, removing sufficient CSF to reduce pressure to less than 20 cmH2O. (Most experts are reluctant to withdraw more than 30 mL at a time.) Tuberculous meningitis The presentation and CSF findings of tuberculous meningitis are similar to those in HIV-uninfected patients (p. 1120), except that concomitant tuberculosis at other sites is more common in HIV infection. Peripheral nerve disease HIV infection causes axonal degeneration, resulting in a sensorimotor peripheral neuropathy in about one-third of AIDS patients. The incidence increases with lower CD4 counts, older age and increased height. Sensory symptoms predominate. Treatment involves foot care, analgesia and analgesic adjuvants. ART has minimal effect on halting or reversing the process. The NRTIs stavudine and didanosine, now largely abandoned due to their toxicity, can cause drug-induced peripheral neuropathy, which is typically more painful and more rapidly progressive than HIV neuropathy. Acute inflammatory demyelinating polyneuropathy is an uncommon manifestation, usually occurring in primary infection. It resembles Guillain–Barré syndrome (p. 1140), except that CSF pleocytosis is more prominent. Mononeuritis may also occur, commonly involving the facial nerve. Myelopathy and radiculopathy The most common cause of myelopathy in HIV infection is cord compression from tuberculous spondylitis. Vacuolar myelopathy is seen in advanced disease and is due to HIV. It typically presents with a slowly progressive paraparesis with no sensory level. MRI

322 • HIV INFECTION AND AIDS is immune-mediated platelet destruction resembling idiopathic thrombocytopenic purpura (p. 971). This responds to glucocorticoids or intravenous immunoglobulin, together with ART. Splenectomy should be avoided if possible because it further increases the risk of infection with encapsulated bacteria. Severe thrombocytopenia with a microangiopathic anaemia also occurs in a thrombotic thrombocytopenic purpura-like illness (p. 979), which has a better prognosis and fewer relapses than the classical disease. Renal disease Acute kidney injury is common, usually due to acute infection or nephrotoxicity of drugs (e.g. tenofovir (p. 412), amphotericin B (p. 126)) HIV-associated nephropathy (HIVAN) is the most important cause of chronic kidney disease (CKD) and is seen most frequently in patients of African descent and those with low CD4 counts. Progression to end-stage disease is more rapid than with most other causes of CKD, and renal size is usually preserved. HIVAN presents with nephrotic syndrome, CKD or a combination of both. ART has some effect in slowing progression of HIVAN. Other important HIV-associated renal diseases include HIV immune complex kidney diseases and thrombotic microangiopathy. With the overall improvement in life expectancy from ART, conditions such as diabetes mellitus, hypertension and vascular disease add to the burden of CKD. Outcomes of renal transplantation are good in patients on ART. Cardiac disease HIV-associated cardiomyopathy resembles idiopathic dilated cardiomyopathy (p. 539) but progresses more rapidly. ART may improve cardiac failure but does not reverse established cardiomyopathy. Pericardial disease due to opportunistic diseases is not uncommon. Globally, the most common cause is tuberculous pericardial effusions. Tuberculous constrictive pericarditis is less common than in HIV-uninfected people. KS and lymphoma may cause pericardial effusions. Septic pericarditis, usually due to S. pneumoniae, is uncommon. HIV is associated with an increased risk of myocardial infarction due to accelerated atherogenesis caused by the inflammatory state, which is not completely suppressed by ART, and by dyslipidaemia caused by some antiretroviral drugs. HIV-related cancers The AIDS-defining cancers are KS (see above), cervical cancer and non-Hodgkin lymphoma (NHL, p. 964). NHL may occur at any CD4 count but is more commonly seen with counts below 200 cells/mm3. Almost all NHLs are B-cell tumours and most are stage 3 or 4. Long-term remission rates similar to those in patients without HIV can be achieved with NHL in AIDS patients using ART and chemotherapy (including the anti-B-cell monoclonal antibody rituximab if it is a B-cell tumour). The incidence of a number of other cancers induced by viruses is also increased in HIV-infected people (Box 12.14). Regular cytological examination of the cervix, and of the anus in people who practise anal sex, should be performed to detect pre-malignant lesions, which are easier to treat. In general, the incidence of cancers that are not induced by viruses is similar to that in the general population. on histology (Fig. 12.15). Sicca symptoms are common but usually mild. Lymphocytic interstitial pneumonitis is the most common manifestation outside the salivary glands. Generalised lymphadenopathy may occur, with nodes larger than those seen with persistent generalised lymphadenopathy of HIV. Hepatitis, mononeuritis, polyarthritis and polymyositis may also occur. The manifestations outside the salivary glands usually respond to systemic glucocorticoids. Parotid gland enlargement may be treated by aspiration of parotid cysts and instillation of a sclerosant for cosmetic reasons, and surgery is best avoided. DILS may regress on ART but response is variable. Haematological abnormalities Disorders of all three major cell lines may occur in HIV. In advanced disease, haematopoiesis is impaired due to the direct effect of HIV and by cytokines. Pancytopenia may occur as a consequence of HIV but it is important to exclude a disorder infiltrating the bone marrow, such as mycobacterial or fungal infections, or lymphoma. Anaemia Normochromic, normocytic anaemia is very common in advanced HIV disease. Opportunistic diseases may cause anaemia of chronic disease (e.g. tuberculosis) or marrow infiltration (e.g. MAC, tuberculosis, lymphoma, fungi). Anaemia is a common adverse effect of zidovudine, which also causes a macrocytosis. Red cell aplasia is rare and may be caused either by parvovirus B19 infection or by lamivudine. Neutropenia Isolated neutropenia is occasionally due to HIV but is nearly always caused by drug toxicity (e.g. zidovudine, co-trimoxazole, ganciclovir). Thrombocytopenia Mild thrombocytopenia is common in HIV-infected people. Transient thrombocytopenia is frequently found in primary infection. The most common disorder causing severe thrombocytopenia Fig. 12.15 CT scan of parotid glands showing multiple cysts (arrows) in a patient with the diffuse infiltrative lymphocytosis syndrome.

Prevention of opportunistic infections • 323

Safer sex HIV-infected individuals should practise safer sex in order to reduce the transmission of HIV. Even if their partners are HIVinfected, condoms should be used, as HIV mutants that have developed antiretroviral drug resistance can be transmitted. Safer sex will also lower the risk of acquiring herpes simplex virus and human herpesvirus 8. Pets Toxoplasma gondii can be acquired from kittens or cat litter, and people living with HIV infection should avoid handling either. Cryptosporidiosis can be transmitted from animals, and patients should be advised to wash their hands after handling animals. Chemoprophylaxis Chemoprophylaxis is the use of antimicrobial agents to prevent infections. Primary prophylaxis is used to prevent opportunistic infections that have not yet occurred. Secondary prophylaxis is used to prevent recurrence of opportunistic infections because many may recur after an initial response to therapy (see Box 12.11). Secondary prophylaxis can be discontinued when ART results in immune reconstitution, with CD4 counts increasing to over 200 cells/mm3, but for CMV and MAC, prophylaxis can be stopped if CD4 counts increase to more than 100 cells/mm3. Co-trimoxazole primary prophylaxis Co-trimoxazole reduces the incidence of a number of opportunistic infections (Box 12.15), resulting in lower hospitalisation and mortality rates. The indications for initiating co-trimoxazole are either clinical evidence of immune suppression (WHO clinical stages 3 or 4) or laboratory evidence of immune suppression (CD4 count < 200 cells/mm3). In low-income countries where malaria and/or severe bacterial infections are highly prevalent, the WHO recommends initiating co-trimoxazole regardless of CD4 counts or clinical stage. The recommended dose of co-trimoxazole is 960 mg daily, but trials have shown that half this dose is as effective and may be associated with less toxicity. Co-trimoxazole prophylaxis can be discontinued when CD4 counts increase to more than 200 cells/mm3 on ART, except in low-income countries where it should be continued life-long. Co-trimoxazole prophylaxis is well tolerated. The most common side-effect is hypersensitivity, causing a maculo-papular rash. If therapy is discontinued, desensitisation or rechallenge under antihistamine cover should be attempted, unless the rash was accompanied by systemic symptoms or mucosal involvement. Prophylactic doses of co-trimoxazole can also cause neutropenia, but this is very uncommon and routine monitoring of blood counts is not necessary. If co-trimoxazole cannot be tolerated, then Prevention of opportunistic infections The best way to prevent opportunistic infections is to improve the CD4 count with ART. However, infections continue to occur in the ART era as CD4 counts take time to improve if ART is initiated in patients with profound immune suppression, immune reconstitution on ART is often suboptimal, and CD4 counts may decline because antiretroviral resistance develops. Preventing exposure The best method for avoiding infection is to prevent exposure to the infectious agent. This is possible only for a few opportunistic infections, however. Furthermore, many opportunistic infections occur after reactivation of latent/dormant infection after prior exposure; examples include herpes simplex virus, zoster (shingles), CMV, toxoplasmosis, cryptococcosis and the endemic mycoses. Safe water and food Cryptosporidiosis, microsporidiosis and cystoisosporiasis may be water-borne. If there is no access to safe water, then water should be boiled before drinking. Food-borne illnesses are also important in HIV infection, notably Salmonella species. Toxoplasma exposure is related to eating raw or undercooked meat. People living with HIV infection need to be informed about food hygiene and the importance of adequately cooked meat. Tuberculosis Preventing exposure to tuberculosis is important when there is an infectious case in the household, in clinics and in hospitals. Adequate ventilation, masks and safe coughing procedures reduce the risk of exposure. Malaria vector control All HIV-infected individuals living in malarious areas should practise vector control, as malaria occurs more frequently and is more severe in HIV-infected people. The most cost-effective way to achieve this is by using insecticide-impregnated bed nets. Other modalities of vector control that are of benefit to the community, such as reducing standing water and spraying with residual insecticides and larvicides, should also be implemented. 12.15 Opportunistic infections reduced by co-trimoxazole • Pneumocystis jirovecii pneumonia • Cerebral toxoplasmosis • Bacterial pneumonia • Bacteraemia • Cystoisosporiasis • Malaria 12.14 Approximate incidence ratio of virus-related cancers compared to the general population Viral cancers Incidence ratio Human herpesvirus 8-related Kaposi’s sarcoma

Epstein–Barr virus-related Non-Hodgkin lymphoma

Hodgkin lymphoma

Human papillomavirus-related Cervical cancer

Vulval cancer

Anal cancer

Penile cancer

Hepatitis B/C virus-related Hepatocellular carcinoma

324 • HIV INFECTION AND AIDS immune. In the UK, the following additional vaccines are also recommended: • hepatitis A: in those at risk • human papillomavirus: in people < 40 years old • measles, mumps and rubella (MMR): in those with negative measles serology • meningococcus: in people < 25 years old, those with asplenia or complement deficiency, during outbreaks • diphtheria/tetanus/acellular pertussis (dTaP)/inactivated poliovirus vaccine (IPV): meeting general indications • chickenpox: if seronegative; those who are seropositive should receive the shingles vaccine. Bacille Calmette–Guérin (BCG) is contraindicated in all HIV-infected people. Antiretroviral therapy ART has transformed HIV from a progressive illness with a fatal outcome into a chronic manageable disease with a near-normal life expectancy. The goals of ART are to: • reduce the viral load to an undetectable level for as long as possible • improve the CD4 count to over 200 cells/mm3 so that severe HIV-related disease is unlikely • improve the quantity and quality of life without unacceptable drug toxicity • reduce HIV transmission. Many of the antiretroviral drugs that were initially used have largely been abandoned because of toxicity or poor efficacy. The drugs that are currently recommended are shown in Box 12.17, and their targets in the HIV life cycle in Figure 12.1. Selecting antiretroviral regimens The standard combination antiretroviral regimens are two NRTIs together with an NNRTI, protease inhibitor (PI) or integrase inhibitor. Dual NRTI combinations are usually emtricitabine or lamivudine (they have the same mechanism of action and so are never combined), together with one of abacavir, tenofovir or zidovudine. It is possible to construct effective regimens without NRTIs if there is intolerance or resistance to the NRTIs. Currently used PIs should always be administered with ritonavir, which dapsone 100 mg daily should be substituted. Dapsone is equally effective at reducing the incidence of P. jirovecii pneumonia, but has little or no effect on reducing the other opportunistic infections prevented by co-trimoxazole. Tuberculosis preventive therapy Trials in patients not on ART showed that preventive therapy, either with isoniazid or combinations of rifamycins with isoniazid, reduces the risk of tuberculosis only in HIV-infected patients with a positive tuberculin skin test. In HIV infection, induration of 5 mm or more on a Mantoux test is regarded as positive. Recent evidence indicates that tuberculin skin tests do not predict benefit in patients starting ART or established on ART in high tuberculosis prevalence settings. There is no CD4 count or clinical threshold for starting or stopping tuberculosis preventive therapy. It is important to rule out active tuberculosis before starting preventive therapy, and symptom screening has been shown to be adequate to achieve this (Box 12.16). The usual duration of isoniazid preventive therapy is 6 months but this does not provide long-term reduction in the risk of tuberculosis. Isoniazid for 36 months has been shown to be much more effective in people with a positive tuberculin skin test. Rifampicin or rifapentine combined with isoniazid for 12 weeks has been shown to be at least as effective as 6–12 months of isoniazid. Mycobacterium avium complex prophylaxis In high-income countries, a macrolide (azithromycin or clarithromycin) is recommended to prevent MAC in patients with a CD4 count below 50 cells/mm3, which can be discontinued once the CD4 count has risen to over 100 cells/mm3 on ART. MAC is uncommon in low- and middle-income countries and primary prophylaxis is thus not warranted. Preventing cryptococcosis Serum cryptococcal antigen test should be done in patients with a CD4 count below 100 cells/mm3. If this is positive, pre-emptive therapy with fluconazole should be commenced. Immunisation There are significant problems associated with vaccination in HIV infection. Firstly, vaccination with live organisms is contraindicated in patients with severe immune suppression, as this may result in disease from the attenuated organisms. Secondly, immune responses to vaccination are impaired in HIV-infected patients. If the CD4 count is below 200 cells/mm3, then immune responses to immunisation are very poor. Therefore it is preferable to wait until the CD4 count has increased to more than 200 cells/mm3 on ART before immunisation is given, and essential if live virus vaccines are used. All patients should be given a conjugate pneumococcal vaccine and annual influenza vaccination. Hepatitis B vaccination should be given to those who are not 12.17 Commonly used antiretroviral drugs Classes Drugs Nucleoside reverse transcriptase inhibitors (NRTIs) Abacavir, emtricitabine, lamivudine, tenofovir, zidovudine* Non-nucleoside reverse transcriptase inhibitors (NNRTIs) Efavirenz*, rilpivirine (only if viral load < 100 000) Protease inhibitors (PIs) Atazanavir, darunavir, lopinavir* Integrase inhibitors Raltegravir, dolutegravir, elvitegravir Chemokine receptor inhibitor Maraviroc *These drugs are no longer recommended as first-line options in high-income countries due to their toxicity. 12.16 Symptom screen for tuberculosis before isoniazid preventive therapy All of the following must be absent: • Active cough • Weight loss • Night sweats • Fever

Antiretroviral therapy • 325

CD4 counts are generally monitored every 6 months together with the viral load, but there is little point in repeating the CD4 count in patients who maintain virological suppression and whose CD4 count is > 350 cells/mm3. The CD4 count increases rapidly in the first month, followed by a more gradual increase. In the first year, the CD4 count typically increases by 100–150 cells/ mm3, and about 80 cells/mm3 per annum thereafter until the reference range is reached, provided the viral load is suppressed. However, CD4 responses are highly variable: in about 15–30% of patients the CD4 count does not increase despite virological suppression, and in a similar proportion of patients the CD4 response is good despite the presence of virological failure. If ART is stopped, the CD4 count rapidly falls to the baseline value before ART was commenced. Antiretroviral resistance Reverse transcription is error-prone, generating a large number of mutations. If the viral load is suppressed on ART, viral replication is suppressed and resistance mutations will not be selected. If ART is taken and there is ongoing replication, due to either resistant mutations or suboptimal adherence, mutations conferring resistance to antiretroviral drugs will be selected. Antiretroviral drugs differ in their ability to select for resistant mutations. Some drugs (e.g. emtricitabine, lamivudine, efavirenz) have a low genetic barrier to resistance, rapidly selecting for a single mutation conferring high-level resistance. PIs and some NRTIs (e.g. zidovudine) select for resistance mutations slowly, and multiple resistant mutations often need to accumulate before the drug’s efficacy is lost. Patients who develop antiretroviral resistance may transmit resistant virus to others and will eventually develop clinical failure. Antiretroviral resistance is assessed by sequencing the relevant viral genes to detect mutations that are known to confer resistance. The patient must be taking ART when the test is performed, as otherwise the wild-type virus will predominate and resistant mutations will not be detected. The resistant proviral DNA is archived in latent CD4 cells and will re-emerge rapidly on re-exposure to the antiretroviral. In regions where resistance testing is affordable, it is recommended at baseline (to detect primary resistance) and at every confirmed virological failure, in order to select the most appropriate antiretrovirals in a new regimen. ART complications Immune reconstitution inflammatory syndrome Immune reconstitution inflammatory syndrome (IRIS) is a common early complication of ART, especially in patients who start ART with CD4 counts below 50 cells/mm3. IRIS presents either with paradoxical deterioration of an existing opportunistic disease (including infections that are responding to appropriate therapy) or with the unmasking of a new infection. The clinical presentation of IRIS events is often characterised by an exaggerated immune response, with pronounced inflammatory features. For example, patients with CMV retinitis developing IRIS on ART develop a uveitis; inflammatory haloes occur around KS lesions. Paradoxical tuberculosis IRIS events are common but it is important to exclude multidrug resistance, which could be responsible for the deterioration. IRIS is associated with a mortality of around 5% but this is higher when it complicates CNS infections. itself is a PI that is toxic in therapeutic doses. Low doses of ritonavir dramatically increase the concentrations and elimination half-lives of other PIs by inhibiting the efflux pump P-glycoprotein and the cytochrome P450 isoenzyme CYP3A. Most guidelines from high-income countries, including the UK, allow clinicians to choose a starting regimen of dual NRTIs combined with an NNRTI, or a PI or an integrase inhibitor, as these three regimens have similar efficacy. Subsequent ART regimen switches for virological failure are guided by the results of resistance testing (see below). For low- and middle-income countries, the WHO recommends a public health approach to using ART with standardised first-line (NNRTI plus dual NRTIs) and second-line (ritonavir-boosted PI plus dual NRTIs) regimens. NNRTIs are preferred by the WHO in first-line regimens, as they are cheaper than PIs and better tolerated. Furthermore, NNRTIs need to be given with two fully active NRTIs because they have a low genetic barrier to resistance (see below), whereas PI-containing regimens are effective even when there are some mutations conferring resistance to the NRTIs. PIs in second-line regimens are therefore preferable in settings where resistance testing is not widely available. The public health approach to using ART can be implemented by nurses and has been successfully applied in resource-poor settings. Criteria for starting ART Guidelines now recommend starting ART in all people with confirmed HIV infection, irrespective of CD4 count or clinical status. Early initiation of ART, compared with the previous strategy of deferring ART until CD4 thresholds or clinical disease occurs, has been shown to reduce morbidity and mortality, and has the additional benefit of reducing the risk of transmission. It is seldom necessary to start ART urgently. Several consultations are required to give patients insight into the need for life-long ART, to stress the importance of adherence and to formulate a personal treatment plan. Disclosure of HIV status, joining support groups and using patient-nominated treatment supporters should be encouraged, as these have been shown to improve adherence. Recognition and management of depression and substance abuse is also important. In patients with major opportunistic infections, ART should generally be started within 2 weeks, with two important exceptions: in cryptococcal meningitis, ART should be deferred for 5 weeks, as earlier initiation increases the risk of death; and in tuberculosis, ART should be deferred until 8 weeks (except if the CD4 count is < 50 cells/mm3), as earlier initiation increases the risk of the immune reconstitution inflammatory syndrome (see below). Monitoring efficacy The most important measure of ART efficacy is the viral load. A baseline viral load should be measured prior to initiating treatment. Viral load measurement should be repeated 4 weeks after starting ART, when there should be at least a 10-fold decrease. The viral load should be suppressed after 6 months. Once the viral load is suppressed, measurement should be repeated 6-monthly. Failure of ART is defined by the viral load becoming detectable after suppression. In most guidelines, a viral load threshold is used to define virological failure, e.g. more than 200 (UK) or more than 1000 (WHO) copies/mL. Adherence support should be enhanced if virological failure is detected, and measurement of the viral load repeated to confirm failure before switching to a new ART regimen.

326 • HIV INFECTION AND AIDS population. Although not yet fully resolved, the current weight of evidence is that fat gain on ART is a return to normal by treating HIV infection. Hypersensitivity rashes These are common but must be differentiated from the other causes described on page 314. The NRTI abacavir typically causes a systemic hypersensitivity reaction, which is limited to people with HLA-B5701, about 50% of whom will develop a hypersensitivity reaction. HLA testing should be done before abacavir is given and the drug should not be prescribed for people who are HLA-B5701-positive, which is rare in people of African descent. Rechallenge must never be attempted after abacavir hypersensitivity, as fatal reactions may occur. Drug rashes are very common with NNRTIs. When the NNRTI rash is mild and not accompanied by systemic involvement, the suspected drug is often continued and antihistamines are administered. The rash usually resolves. If it worsens or if systemic features develop, the NNRTI should be discontinued. Other adverse effects The NNRTI efavirenz causes insomnia, agitation, euphoria or dysphoria in many patients but tolerance to its neuropsychiatric effects develops in a few weeks in most patients. The NRTI zidovudine can cause anaemia and neutropenia, and tenofovir may cause nephrotoxicity and loss of bone mineral density. Some PIs are associated with dyslipidaemias and may increase the risk of myocardial infarction. ART in special situations Pregnancy All pregnant women should have HIV testing at an early stage in pregnancy. The CD4 count falls by about 25% during pregnancy due to haemodilution. The course of HIV disease progression is not altered by pregnancy. In the pre-ART era, the rate of mother-to-child transmission was 15–40%, with rates being influenced by several factors (see Box 12.3). ART has dramatically reduced the risk of mother-to-child transmission of HIV to less than 1%. All pregnant women should start ART at the beginning of the second trimester, unless they have advanced disease, when ART should be started in the first trimester. Caesarean section is associated with a lower risk of motherto-child transmission than vaginal delivery, but the mode of delivery does not affect transmission risk if the viral load is suppressed on ART. HIV is also transmitted by breastfeeding. In high-income countries, exclusive formula feeding is generally recommended. In resource-poor settings, however, formula feeding is associated with a risk of infant morbidity and mortality, which may negate the benefit of not transmitting HIV to the infant. There is minimal risk of transmitting HIV by breastfeeding in women with a suppressed viral load on ART. Furthermore, providing antiretrovirals to infants (usually nevirapine monotherapy) while they are breastfeeding has been shown to reduce the risk of transmission. Breastfeeding is therefore now encouraged in resource-poor settings. Infants should be exclusively breastfed for the first 6 months, as mixed The management of IRIS is to continue ART and to ensure that the opportunistic disease is adequately treated. Symptomatic treatments are helpful. Glucocorticoids are often used for more severe IRIS manifestations but they should not be given to patients with KS, as this can result in rapid progression of KS lesions. Lipodystrophy Long-term use of ART is associated with changes in body fat distribution called lipodystrophy, which can present either with fat accumulation (e.g. visceral fat, ‘buffalo hump’) or with subcutaneous fat loss (‘lipoatrophy’, Fig. 12.16), or with both fat loss and accumulation. The thymidine analogue NRTIs (stavudine and, to a lesser extent, zidovudine) are associated with fat loss. Switching to the non-thymidine NRTIs, abacavir or tenofovir, will result in very gradual improvement of lipoatrophy. Previously, PIs were thought to be the cause of fat accumulation. However, recent studies have shown that all classes of antiretrovirals are associated with fat gain to a similar extent, and visceral adiposity is similar to that seen in the general Fig. 12.16 Fat loss complicating long-term use of the thymidine analogue NRTIs stavudine and zidovudine. 12.18 HIV infection in old age • Epidemiology: the HIV-infected population is ageing due to the life-prolonging effects of ART. • Immunity: age-related decline increases the risk of infections. CD4 counts decline more rapidly as age extends beyond 40 years, resulting in faster disease progression. CD4 responses to ART decrease with increasing age. • Dementia: HIV causes cerebral atrophy and neurocognitive disorders; dementia is therefore more common and more severe than in the HIV-uninfected elderly. • Vascular disease: HIV is associated with an increased risk, exacerbated by some antiretrovirals that increase the risk of vascular disease by causing dyslipidaemia or insulin resistance. • Polypharmacy: treatment of co-morbidities is complex due to the many drug interactions with antiretrovirals.

Further information • 327 Further information Websites with updated clinical guidelines aidsinfo.nih.gov AIDSinfo, a service of the US Department of Health and Human Services (HHS). bhiva.org British HIV Association. who.int/hiv/pub World Health Organisation. feeding (with formula or solids) is associated with a higher risk of transmission. Diagnosis of HIV in infancy requires the detection of HIV RNA by PCR, as maternal antibodies to HIV, which persist for up to 15 months, will give a false-positive result on antibody assays. PCR should ideally be carried out within 6 weeks of birth to facilitate early ART initiation. If the baby is breastfed, the PCR should be repeated 2 weeks after weaning. Prevention of HIV An effective HIV vaccine remains elusive due to the extensive genetic diversity of HIV and the lack of a safe attenuated virus. Measures for the prevention of HIV transmission are shown in Box 12.19. Pre-exposure prophylaxis Pre-exposure prophylaxis (PrEP) with daily tenofovir plus emtricitabine has been shown to reduce the risk of HIV acquisition in people at ongoing high risk (e.g. from sex or injecting drug use) and is well tolerated. Regular HIV testing should be done in people on PrEP. Post-exposure prophylaxis Post-exposure prophylaxis (PEP) is recommended when the risk is deemed to be significant after a careful risk assessment, in both occupational and non-occupational settings. The first dose should be given as soon as possible, preferably within 6–8 hours. There is no point in starting PEP after 72 hours. Tenofovir together with emtricitabine is the most widely used dual NRTI combination, together with either a PI or an integrase inhibitor. PEP should not be given if the exposed person is HIV-infected. HIV antibody testing should be performed at 3 months after exposure. 12.19 Prevention measures for HIV transmission Sexual • Sex education programmes in schools • Easily accessible voluntary counselling and testing centres • Promotion of safer sex practices (delaying sexual debut, condom use, fewer sexual partners) • Effective ART for HIV-infected individuals • Pre-exposure prophylaxis for high-risk groups • Male circumcision • Post-exposure prophylaxis Parenteral • Blood product transmission: donor questionnaire, routine screening of donated blood • Injection drug use: education, needle/syringe exchange, avoidance of ‘shooting galleries’, methadone maintenance programmes Perinatal • Routine ‘opt-out’ antenatal HIV antibody testing • Measures to reduce vertical transmission (see text) Occupational • Education/training: universal precautions, needlestick injury avoidance • Post-exposure prophylaxis

7KLVSDJHLQWHQWLRQDOO\OHIWEODQN

Ch04-3 Clinical Medicine

03-13 Sexually transmitted infections

13 Sexually transmitted infections

Sexually transmitted infections GR Scott Clinical examination in men 330 Clinical examination in women 331 Approach to patients with a suspected STI 332 Presenting problems in men 333 Urethral discharge 333 Genital itch and/or rash 333 Genital ulceration 333 Genital lumps 334 Proctitis in men who have sex with men 334 Presenting problems in women 335 Vaginal discharge 335 Lower abdominal pain 336 Genital ulceration 336 Genital lumps 336 Chronic vulval pain and/or itch 336 Prevention of STI 336 Sexually transmitted bacterial infections 337 Syphilis 337 Gonorrhoea 339 Chlamydial infection 340 Other sexually transmitted bacterial infections 341 Sexually transmitted viral infections 341 Genital herpes simplex 341 Human papillomavirus and anogenital warts 342 Molluscum contagiosum 343 Viral hepatitis 343

330 • SEXUALLY TRANSMITTED INFECTIONS HIV testing It should always be standard practice to offer HIV testing as part of screening for sexually transmitted infection (STI) because the benefits of early diagnosis outweigh other considerations. Extensive pre-test counselling is not required in most instances, but it is important to establish efficient pathways for referral of patients at high risk for whom the clinician wishes specialist support, and for those diagnosed as HIV-positive. Clinical examination in men Insets (Perianal warts) From McMillan A, Scott GR. Sexually transmitted infections: a colour guide. Churchill Livingstone, Elsevier Ltd; 2000. (Coronal papillae, mucopus) From McMillan A, Young H, Ogilvie MM, Scott GR. Clinical practice in sexually transmissible infections. Saunders, Elsevier Inc.; 2002. Observation Rectum (Men who have sex with men practising receptive anal intercourse) Perianal area (Men who have sex with men, and heterosexual men) Urethral meatus Skin of penis (Retract prepuce if present) Genital warts Ulcers Be aware of normal anatomical features such as coronal papillae, or prominent sebaceous or parafrenal glands Pubic area Pthirus pubis (crab louse) Scrotal contents Abnormal masses or tenderness (epididymo-orchitis) • Mouth • Eyes • Joints • Skin: Rash of secondary syphilis Scabies Manifestations of HIV infection (Ch. 12) Skin around groin and scrotum Warts Tinea cruris Discharge Warts

Inguinal glands Significant enlargement

Coronal papillae Proctoscope Proctitis

A urethral swab can be submitted if the patient is unable to pass urine. Investigations for STIs in men who have sex with men • FVU, and pharyngeal and rectal swabs for combined NAAT for gonorrhoea and chlamydia • STS (repeat testing may be necessary in the event of negative test results in the first few weeks following exposure) • Serological tests for hepatitis A/B (with a view to vaccination if seronegative) • HIV test (see note) A urethral swab can be submitted if the patient is unable to pass urine. Investigations for STIs in heterosexual males • First-void urine (FVU) is the specimen of choice for the combined nucleic acid amplification test (NAAT) for gonorrhoea and chlamydia • Alternatively, for gonorrhoea, a urethral swab plated directly on a selective medium such as modified New York City (MNYC), or sent in an appropriate transport medium, can be cultured to allow for assessment of antimicrobial sensitivities • Serological test for syphilis (STS), e.g. enzyme immunoassay (EIA) for antitreponemal immunoglobulin G (IgG) antibody • Human immunodeficiency virus (HIV) test (see note)

Clinical examination in women • 331

Adapted from WHO/UNAIDS, 1997. Those at particular risk from STIs • Sex workers, male and female • Clients of sex workers • Men who have sex with men • Injecting drug users (sex for money or drugs) and their partners • Frequent travellers Management goals in suspected STI • Relief of any symptoms • Screening for treatable STI that may not be causing symptoms • Tracing and treatment of sexual contacts who may also be infected • Advice to reduce risk of infection in the future Investigations for STIs in women • Self-taken vaginal swab, or clinicianobtained cervical or vaginal swab, for combined NAAT for gonorrhoea and chlamydia • Alternatively, for gonorrhoea, cervical and urethral swabs plated directly on a selective medium such as MNYC, or sent in appropriate transport medium, can be cultured to allow for assessment of antimicrobial sensitivities • Wet mount for microscopy or high vaginal swab (HVS) for culture of Trichomonas • STS, e.g. EIA for antitreponemal IgG antibody • HIV test (see note) Inset (Inflammation) From McMillan A, Young H, Ogilvie MM, Scott GR. Clinical practice in sexually transmissible infections. Saunders, Elsevier Inc.; 2002. Clinical examination in women Observation Vagina and cervix Abnormal discharge Warts Ulcers Inflammation In women with lower abdominal pain, bimanual examination for adnexal tenderness (pelvic inflammatory disease) Perineum and perianal skin Warts Ulcers Pubic area Abdomen Abnormal masses or tenderness Inguinal glands Significant enlargement • Mouth • Eyes • Joints • Skin: Rash of secondary syphilis Scabies Manifestations of HIV infection (Ch. 12) Inflammation

Pthirus pubis (crab louse)

Warts Labia majora and minora Ulcers Vulvitis Speculum

332 • SEXUALLY TRANSMITTED INFECTIONS focuses on genital symptoms, with reference to genital ulceration, rash, irritation, pain, swelling and urinary symptoms, especially dysuria. In men, the clinician should ask about urethral discharge, and in women, vaginal discharge, pelvic pain or dyspareunia. Enquiry about general health should include menstrual and obstetric history, cervical cytology, recent medication, especially with antimicrobial or antiviral agents, previous STI and allergy. Immunisation status for hepatitis A and B should be noted, as should information about alcohol intake and recreational drug use. Some MSM use new psychoactive substances (NPS), formerly referred to in the UK as ‘legal highs’, to enhance their sexual experience. Often described as ‘chemsex’, this has been associated with outbreaks of infections including syphilis, LGV and hepatitis C. A detailed sexual history is imperative (Box 13.1), as this informs the clinician of the degree of risk for certain infections, as well as specific sites that should be sampled; for example, rectal samples should be taken from men who have had unprotected anal sex with other men. Sexual partners, whether male or female, and casual or regular, should be recorded. Sexual practices – insertive or receptive vaginal, anal, orogenital or oroanal – should be noted, as should choice of contraception for women, and condom use for both sexes. STI during pregnancy Many STIs can be transmitted from mother to child in pregnancy, either transplacentally or during delivery. Possible outcomes are highlighted in Box 13.2. STI in children The presence of an STI in a child may be indicative of sexual abuse, although vertical transmission may explain some presentations in the first 2 years. In an older child and in adolescents, STI may Sexually transmitted infections (STIs) are a group of contagious conditions whose principal mode of transmission is by intimate sexual activity involving the moist mucous membranes of the penis, vulva, vagina, cervix, anus, rectum, mouth and pharynx, along with their adjacent skin surfaces. A wide range of infections may be sexually transmitted, including syphilis, gonorrhoea, human immunodeficiency virus (HIV), genital herpes, genital warts, chlamydia and trichomoniasis. Bacterial vaginosis and genital candidiasis are not regarded as STIs, although they are common causes of vaginal discharge in sexually active women. Chancroid, lymphogranuloma venereum (LGV) and granuloma inguinale are usually seen in tropical countries. Hepatitis viruses A, B, C and D (p. 871) may be acquired sexually, as well as by other routes. Although primarily transmitted by mosquito bite, cases of male-to-female sexual transmission of Zika virus have been described and the virus is known to persist in semen for several months (p. 247). The World Health Organization (WHO) estimates that 357 million curable STIs (Trichomonas vaginalis, Chlamydia trachomatis, gonorrhoea and syphilis) occur worldwide each year. In the UK in 2014, the most common treatable STIs diagnosed were chlamydia (220 000 cases) and gonorrhoea (nearly 40 000 cases). Genital warts are the second most common complaint seen in genitourinary medicine (GUM) departments. In addition to causing morbidity themselves, STIs may increase the risk of transmitting or acquiring HIV infection (Ch. 12). As coincident infection with more than one STI is seen frequently, GUM clinics routinely offer a full set of investigations at the patient’s first visit (pp. 330–331), regardless of the reason for attendance. In other settings, less comprehensive investigation may be appropriate. The extent of the examination largely reflects the likelihood of HIV infection or syphilis. Most heterosexuals in the UK are at such low risk of these infections that routine extragenital examination is unnecessary. This is not the case in parts of the world where HIV is endemic, or for men who have sex with men (MSM) in the UK. In other words, the extent of the examination is determined by the sexual history (Box 13.1). Approach to patients with a suspected STI Patients concerned about the possible acquisition of an STI are often anxious. Staff must be friendly, sympathetic and reassuring; they should have the ability to put patients at ease, while emphasising that clinic attendance is confidential. The history 13.2 Possible outcomes of STI in pregnancy Organism Mode of transmission Outcome for fetus/neonate Outcome for mother Treponema pallidum Transplacental Ranges from no effect to severe stigmata or miscarriage/stillbirth None directly relating to the pregnancy Neisseria gonorrhoeae Intrapartum Severe conjunctivitis Possibility of ascending infection postpartum Chlamydia trachomatis Intrapartum Conjunctivitis, pneumonia Possibility of ascending infection postpartum Herpes simplex Usually intrapartum, but transplacental infection may occur rarely Ranges from no effect to severe disseminated infection Rarely, primary infection during 2nd/3rd trimesters becomes disseminated, with high maternal mortality Human papillomaviruses Intrapartum Anogenital warts or laryngeal papillomas are very rare Warts may become more florid during pregnancy, but usually regress postpartum 13.1 How to take a sexual history • In your lifetime, have your sexual partners been male, female or both? • Do you have a regular sexual partner at present? • If yes: How long have you been together? When did you last have sex with anyone else? • If no: When did you last have sex? Was this a regular or a casual partner? • Do/did you use a condom?

Presenting problems in men • 333

Management This depends on local epidemiology and the availability of diagnostic resources. Treatment is often presumptive, with prescription of multiple antimicrobials to cover the possibility of gonorrhoea and/or chlamydia. This is likely to include a singledose treatment for gonorrhoea, which is desirable because it eliminates the risk of non-adherence. The recommended agents for treating gonorrhoea vary according to local antimicrobial resistance patterns (p. 340). Appropriate treatment for chlamydia (p. 340) should also be prescribed because concurrent infection is present in up to 50% of men with gonorrhoea. Non-gonococcal, non-chlamydial urethritis is treated as for chlamydia. Patients should be advised to avoid sexual contact until it is confirmed that any infection has resolved and, whenever possible, recent sexual contacts should be traced. The task of contact tracing – also called partner notification – is best performed by trained nurses based in GUM clinics; it is standard practice in the UK to treat current sexual partners of men with gonococcal or non-specific urethritis without waiting for microbiological confirmation. If symptoms clear, a routine test of cure is not necessary, but patients should be re-interviewed to confirm that there was no immediate vomiting or diarrhoea after treatment, that there has been no risk of reinfection, and that traceable partners have sought medical advice. Genital itch and/or rash Patients may present with many combinations of penile/genital symptoms, which may be acute or chronic, and infectious or non-infectious. Box 13.3 provides a guide to diagnosis. Balanitis refers to inflammation of the glans penis, often extending to the under-surface of the prepuce, in which case it is called balanoposthitis. Tight prepuce and poor hygiene may be aggravating factors. Candidiasis is sometimes associated with immune deficiency, diabetes mellitus, and the use of broad-spectrum antimicrobials, glucocorticoids or antimitotic drugs. Local saline bathing is usually helpful, especially when no cause is found. Genital ulceration The most common cause of ulceration is genital herpes. Classically, multiple painful ulcers affect the glans, coronal sulcus or shaft of penis (Fig. 13.2), but solitary lesions occur rarely. Perianal ulcers may be seen in MSM. The diagnosis is made by gently scraping material from lesions and sending this in an appropriate transport medium for culture or detection of HSV DNA by polymerase chain reaction (PCR). Increasingly, laboratories will also test for Treponema pallidum by PCR. In the UK, the possibility of syphilis or any other ulcerating STI is much less likely unless the patient is an MSM and/or has had a sexual partner from a region where tropical STIs are more common. The classic lesion of primary syphilis (chancre) is single, painless and indurated; however, multiple lesions are seen rarely and anal chancres are often painful. Diagnosis is made in GUM clinics by dark-ground microscopy and/or PCR on a swab from a chancre, but in other settings by serological tests for syphilis (p. 338). Other rare infective causes seen in the UK include varicella zoster virus (p. 238) and trauma with secondary infection. Tropical STIs, such as chancroid, be the result of voluntary sexual activity. Specific issues regarding the management of STI and other infections in adolescence are discussed in Box 11.25 (p. 235). Presenting problems in men Urethral discharge In the UK the most important causes of urethral discharge are gonorrhoea and chlamydia. In a significant minority of cases, tests for both of these infections are negative, a scenario often referred to as non-specific urethritis (NSU). Some of these cases may be caused by Trichomonas vaginalis, herpes simplex virus (HSV), mycoplasmas, ureaplasmas or adenoviruses. A small minority seem not to have an infectious aetiology. Gonococcal urethritis usually causes symptoms within 7 days of exposure. The discharge is typically profuse and purulent. Chlamydial urethritis has an incubation period of 1–4 weeks, and tends to result in milder symptoms than gonorrhoea; there is overlap, however, and microbiological confirmation should always be sought. Investigations A presumptive diagnosis of urethritis can be made from a Gram-stained smear of the urethral exudate (Fig. 13.1), which will demonstrate significant numbers of polymorphonuclear leucocytes (≥ 5 per high-power field). A working diagnosis of gonococcal urethritis is made if Gram-negative intracellular diplococci (GNDC) are seen; if no GNDC are seen, a label of NSU is applied. If microscopy is not available, urine samples and/or swabs should be taken and empirical antimicrobials prescribed. A first-void urine (FVU) sample should be submitted for a combined nucleic acid amplification test (NAAT) for gonorrhoea and chlamydia; a urethral swab is an alternative if the patient cannot pass urine. When gonorrhoea is suspected, a urethral swab should be sent for culture and antimicrobial sensitivities of Neisseria gonorrhoeae. Tests for other potential causes of urethritis are not performed routinely. A swab should also be taken from the pharynx because gonococcal infection here is not reliably eradicated by single-dose therapy. In MSM, swabs for gonorrhoea and chlamydia should be taken from the rectum. Fig. 13.1 A Gram-stained urethral smear from a man with gonococcal urethritis. Gram-negative diplococci are seen within polymorphonuclear leucocytes.

334 • SEXUALLY TRANSMITTED INFECTIONS LGV and granuloma inguinale, are described in Box 13.12 (p. 341). Inflammatory causes include Stevens–Johnson syndrome (pp. 1224 and 1254), Behçet’s disease (p. 1043) and fixed drug reactions. In older patients, malignant and pre-malignant conditions, such as squamous cell carcinoma and erythroplasia of Queyrat (intra-epidermal carcinoma), should be considered. Genital lumps The most common cause of genital ‘lumps’ is warts (p. 342). These are classically found in areas of friction during sex, such as the parafrenal skin and prepuce of the penis. Warts may also be seen in the urethral meatus, and less commonly on the shaft or around the base of the penis. Perianal warts are surprisingly common in men who do not have anal sex. The differential diagnosis includes molluscum contagiosum and skin tags. Adolescent boys may confuse normal anatomical features such as coronal papillae (p. 330), parafrenal glands or sebaceous glands (Fordyce spots) with warts. Proctitis in men who have sex with men STIs that may cause proctitis in MSM include gonorrhoea, chlamydia, herpes and syphilis. The substrains of Chlamydia trachomatis that cause LGV (L1–3) have been associated with outbreaks of severe proctitis in Northern Europe, including the UK. Symptoms include mucopurulent anal discharge, rectal bleeding, pain and tenesmus. Fig. 13.2 Penile herpes simplex (HSV-2) infection. 13.3 Differential diagnosis of genital itch and/or rash in men Likely diagnosis Acute or chronic Itch Pain Discharge (non-urethral) Specific characteristics Diagnostic test Treatment Subclinical urethritis Either ± – ± Often intermittent Gram stain and urethral swabs As for urethral discharge Candidiasis Acute ᅚ – White Post-coital Microscopy Antifungal cream, e.g. clotrimazole Anaerobic (erosive) balanitis Acute ± – Yellow Offensive Clinical Saline bathing ± metronidazole Pthirus pubis (‘crab lice’) infection Either ᅚ – – Lice and nits seen attached to pubic hairs Can be by microscopy but usually visual According to local policy – often permethrin Lichen planus (p. 1252) Either ± – – Violaceous papules ± Wickham’s striae Clinical None or mild topical glucocorticoid, e.g. hydrocortisone Lichen sclerosus Chronic ± – – Ivory–white plaques, scarring Clinical or biopsy Strong topical glucocorticoid, e.g. clobetasol Plasma cell balanitis of Zoon Chronic ᅚ – ± Shiny, inflamed circumscribed areas Clinical or biopsy Strong topical glucocorticoid, e.g. clobetasol Dermatoses, e.g. eczema or psoriasis Either ᅚ – – Similar to lesions elsewhere on skin Clinical Mild topical glucocorticoid, e.g. hydrocortisone Genital herpes Acute ± ᅚ – Atypical ulcers are not uncommon Swab for HSV PCR Oral antiviral, e.g. aciclovir Circinate balanitis Either – – – Painless erosions with raised edges; usually as part of sexually acquired reactive arthritis (SARA, p. 1031) Clinical Mild topical glucocorticoid, e.g. hydrocortisone (HSV PCR = herpes simplex virus polymerase chain reaction)

Presenting problems in women • 335

vulvovaginal inflammation. Diagnosis is made by observing motile flagellate protozoa on a wet-mount microscopy slide of vaginal material and/or by culture. If examination reveals the discharge to be cervical in origin, the possibility of chlamydial or gonococcal infection is increased and appropriate cervical or vaginal swabs should be taken (p. 331). In addition, Gram stain of cervical and urethral material may reveal GNDC, allowing presumptive treatment for gonorrhoea to be given. If gonococcal cervicitis is suspected, swabs should also be taken from the pharynx and rectum; infections at these sites are not reliably eradicated by single-dose therapy and a test of cure will therefore be required. GUM clinics in the UK may offer sexually active women presenting with vaginal discharge an STI screen (p. 331). In other settings, such as primary care or gynaecology, testing for chlamydia and gonorrhoea may be considered in young women (< 25 years old), those who have changed partner recently, and those not using a barrier method of contraception, even if a non-STI cause of discharge is suspected clinically. Treatment of infections causing vaginal discharge is shown in Box 13.4. Examination may show mucopus and erythema with contact bleeding (p. 330). In addition to the diagnostic tests listed on page 330, a PCR test for HSV and a request for identification of the LGV substrain should be arranged if chlamydial infection is detected. Treatment is directed at the individual infections. MSM may also present with gastrointestinal symptoms from infection with organisms such as Entamoeba histolytica (p. 286), Shigella spp. (p. 265), Campylobacter spp. (p. 262) and Cryptosporidium spp. (pp. 287 and 317). Presenting problems in women Vaginal discharge The natural vaginal discharge may vary considerably, especially under differing hormonal influences such as puberty, pregnancy or prescribed contraception. A sudden or recent change in discharge, especially if associated with alteration of colour and/ or smell, or vulval itch/irritation, is more likely than a gradual or long-standing change to indicate an infective cause. Local epidemiology is particularly important when assessing possible causes. In the UK, most cases of vaginal discharge are not sexually transmitted, being due to either candidal infection or bacterial vaginosis (BV). Worldwide, the most common treatable STI causing vaginal discharge is trichomoniasis; other possibilities include gonorrhoea and chlamydia. HSV may cause increased discharge, although vulval pain and dysuria are usually the predominant symptoms. Non-infective causes include retained tampons, malignancy and/or fistulae. Speculum examination often allows a relatively accurate diagnosis, with appropriate treatment to follow (Box 13.4). If the discharge is homogeneous and off-white in colour, vaginal pH is greater than 4.5, and Gram stain microscopy reveals scanty or absent lactobacilli with significant numbers of Gram-variable organisms, some of which may be coating vaginal squamous cells (so-called Clue cells, Fig. 13.3), the likely diagnosis is BV. If there is vulval and vaginal erythema, the discharge is curdy in nature, vaginal pH is less than 4.5, and Gram stain microscopy reveals fungal spores and pseudohyphae, the diagnosis is candidiasis. Trichomoniasis tends to cause a profuse yellow or green discharge and is usually associated with significant 13.4 Infections that cause vaginal discharge Cause Clinical features Treatment (in pregnancy seek specialist advice) Candidiasis Vulval and vaginal inflammation Curdy white discharge adherent to walls of vagina Low vaginal pH Clotrimazole1 500 mg pessary once at night and clotrimazole cream twice daily or Econazole1 pessary 150 mg for 3 nights and econazole cream twice daily (topical creams for 7 days) or Fluconazole2 150 mg orally stat Trichomoniasis Vulval and vaginal inflammation Metronidazole3 400 mg twice daily orally for 5–7 days or Frothy yellow/green discharge Metronidazole3 2 g orally as a single dose Bacterial vaginosis No inflammation Metronidazole3 2 g stat or 400 mg twice daily orally for 5–7 days White homogeneous discharge Metronidazole3 vaginal gel 0.75% daily for 5 days High vaginal pH Clindamycin1,4 vaginal cream 2% daily for 7 days Streptococcal/staphylococcal infection Purulent vaginal discharge Choice of antibiotic depends on sensitivity tests 1Clotrimazole, econazole and clindamycin damage latex condoms and diaphragms. 2Avoid in pregnancy and breastfeeding. 3Avoid alcoholic drinks until 48 hours after finishing treatment. Avoid high-dose regimens in pregnancy or breastfeeding. 4Clostridium difficile colitis has been reported with the use of clindamycin cream. Fig. 13.3 Gram stain of a Clue cell from a patient with bacterial vaginosis. The margin of this vaginal epithelial cell is obscured by a coating of anaerobic organisms. From McMillan A, Young H, Ogilvie MM, Scott GR. Clinical practice in sexually transmissible infections. Saunders, Elsevier Inc.; 2002.

336 • SEXUALLY TRANSMITTED INFECTIONS Genital lumps The most common cause of genital ‘lumps’ is warts. These are classically found in areas of friction during sex, such as the fourchette and perineum. Perianal warts are surprisingly common in women who do not have anal sex. The differential diagnosis includes molluscum contagiosum, skin tags, and normal papillae or sebaceous glands. Chronic vulval pain and/or itch Women may present with a range of chronic symptoms that may be intermittent or continuous (Box 13.5). Recurrent candidiasis may lead to hypersensitivity to candidal antigens, with itch and erythema becoming more prominent than increased discharge. Effective treatment may require regular oral antifungals, e.g. fluconazole 150 g once a week, plus a combined antifungal/glucocorticoid cream. Prevention of STI Case-finding Early diagnosis and treatment facilitated by active case-finding will help to reduce the spread of infection by limiting the period of infectivity; tracing and treating sexual partners will also reduce the risk of reinfection. Unfortunately, the majority of individuals with an STI are asymptomatic and therefore unlikely to seek medical attention. Improving access to diagnosis in primary care or non-medical settings, especially through opportunistic testing, may help. However, the impact of medical intervention through improved access alone is likely to be small. Changing behaviour The prevalence of STIs is driven largely by sexual behaviour. Primary prevention encompasses efforts to delay the onset of sexual activity and limit the number of sexual partners thereafter. Encouraging the use of barrier methods of contraception will also help to reduce the risk of transmitting or acquiring STIs. This Lower abdominal pain Pelvic inflammatory disease (PID, infection or inflammation of the Fallopian tubes and surrounding structures) is part of the extensive differential diagnosis of lower abdominal pain in women, especially those who are sexually active. The possibility of PID is increased if, in addition to acute/subacute pain, there is dyspareunia, abnormal vaginal discharge and/or bleeding. There may also be systemic features, such as fever and malaise. On examination, lower abdominal pain is usually bilateral, and vaginal examination reveals adnexal tenderness with or without cervical excitation. Unfortunately, a definitive diagnosis can only be made by laparoscopy. A pregnancy test should be performed (as well as the diagnostic tests on p. 331) because the differential diagnosis includes ectopic pregnancy. Broad-spectrum antibiotics, including those active against gonorrhoea and chlamydia, such as ofloxacin and metronidazole, should be prescribed if PID is suspected, along with appropriate analgesia. Delaying treatment increases the likelihood of adverse sequelae, such as abscess formation, and tubal scarring that may lead to ectopic pregnancy or infertility. Hospital admission may be indicated for severe symptoms. Genital ulceration The most common cause of ulceration is genital herpes. Classically, multiple painful ulcers affect the introitus, labia and perineum, but solitary lesions occur rarely. Inguinal lymphadenopathy and systemic features, such as fever and malaise, are more common than in men. Diagnosis is made by gently scraping material from lesions and sending this in an appropriate transport medium for culture or detection of HSV DNA by PCR. Increasingly, laboratories will also test such samples for Treponema pallidum by PCR. In the UK, the possibility of any other ulcerating STI is unlikely unless the patient has had a sexual partner from a region where tropical STIs are more common (see Box 13.12). Inflammatory causes include lichen sclerosus, Stevens–Johnson syndrome (pp. 1224 and 1254), Behçet’s disease (p. 1043) and fixed drug reactions. In older patients, malignant and premalignant conditions, such as squamous cell carcinoma, should be considered. 13.5 Chronic vulval pain and/or itch Likely diagnosis Itch Pain Specific characteristics Diagnostic test Treatment Candidiasis ᅚ ± Usually cyclical Microscopy (culture for yeasts other than Candida albicans in recurrent/refractory disease) Oral antifungal, e.g. fluconazole 150 mg Lichen planus ± – Violaceous papules ± Wickham’s striae Clinical No treatment, or mild topical glucocorticoid, e.g. hydrocortisone Lichen sclerosus ± – Ivory–white plaques, scarring ± labial resorption Clinical or biopsy Strong topical glucocorticoid, e.g. clobetasol Vestibulitis – ᅚ Dyspareunia common, pain on touching erythematous area Clinical Refer to specialist vulva clinic Vulvodynia – ᅚ Pain usually neuropathic in nature Clinical Refer to specialist vulva clinic Dermatoses, e.g. eczema or psoriasis ᅚ – Similar to lesions elsewhere on skin Clinical Mild topical glucocorticoid, e.g. hydrocortisone Genital herpes ± ᅚ Atypical ulcers are not uncommon Swab for HSV PCR Oral antiviral, e.g. aciclovir (HSV PCR = herpes simplex virus polymerase chain reaction)

Sexually transmitted bacterial infections • 337

Chancres may develop on the vaginal wall and on the cervix. Extragenital chancres are found in about 10% of patients, affecting sites such as the finger, lip, tongue, tonsil, nipple, anus or rectum. Anal chancres often resemble fissures and may be painful. Secondary syphilis This occurs 6–8 weeks after the development of the chancre, when treponemes disseminate to produce a multisystem disease. Constitutional features, such as mild fever, malaise and headache, are common. Over 75% of patients present with a rash on the trunk and limbs that may later involve the palms and soles; this is initially macular but evolves to maculopapular or papular forms, which are generalised, symmetrical and non-irritable. Scales may form on the papules later. Lesions are red, changing to a ‘gun-metal’ grey as they resolve. Without treatment, the rash may last for up to 12 weeks. Condylomata lata (papules coalescing to plaques) may develop in warm, moist sites such as the vulva or perianal area. Generalised non-tender lymphadenopathy is present in over 50% of patients. Mucosal lesions, known as mucous patches, may affect the genitalia, mouth, pharynx or larynx and are essentially modified papules, which become eroded. Rarely, confluence produces characteristic ‘snail track ulcers’ in the mouth. Other features, such as meningitis, cranial nerve palsies, anterior or posterior uveitis, hepatitis, gastritis, glomerulonephritis or periostitis, are sometimes seen. Neurological involvement may be more common in HIV-positive patients. The differential diagnosis of secondary syphilis can be extensive, but in the context of a suspected STI, primary HIV infection is the most important alternative condition to consider (Ch. 12). Non-STI conditions that mimic the rash include psoriasis, pityriasis rosea, scabies, allergic drug reaction, erythema multiforme and pityriasis (tinea) versicolor. The clinical manifestations of secondary syphilis will resolve without treatment but relapse may occur, usually within the first year of infection. Thereafter, the disease enters the phase of latency. Latent syphilis This phase is characterised by the presence of positive syphilis serology or the diagnostic cerebrospinal fluid (CSF) abnormalities of neurosyphilis in an untreated patient with no evidence of clinical disease. It is divided into early latency (within 2 years of infection), when syphilis may be transmitted sexually, and late latency, when the patient is no longer sexually infectious. is especially important in the setting of ‘sexual concurrency’, where sexual relationships overlap. Unfortunately, there is contradictory evidence as to which (if any) interventions can reduce sexual activity. Knowledge alone does not translate into behaviour change, and broader issues, such as poor parental role modelling, low self-esteem, peer group pressure in the context of the increased sexualisation of our societies, gender power imbalance and homophobia, all need to be addressed. Throughout the world there is a critical need to enable women to protect themselves from undisciplined and coercive male sexual activity. Economic collapse and the turmoil of war regularly lead to situations where women are raped or must turn to prostitution to feed themselves and their children, and an inability to negotiate safe sex increases their risk of acquiring STI, including HIV. Sexually transmitted bacterial infections Syphilis Syphilis is caused by infection, through abrasions in the skin or mucous membranes, with the spirochaete Treponema pallidum. In adults the infection is usually sexually acquired; however, transmission by kissing, blood transfusion and percutaneous injury has been reported. Transplacental infection of the fetus can occur. The natural history of untreated syphilis is variable. Infection may remain latent throughout, or clinical features may develop at any time. The classification of syphilis is shown in Box 13.6. All infected patients should be treated. Penicillin remains the drug of choice for all stages of infection. Acquired syphilis Early syphilis Primary syphilis The incubation period is usually between 14 and 28 days, with a range of 9–90 days. The primary lesion or chancre (Fig. 13.4) develops at the site of infection, usually in the genital area. A dull red macule develops, becomes papular and then erodes to form an indurated ulcer (chancre). The draining inguinal lymph nodes may become moderately enlarged, mobile, discrete and rubbery. The chancre and the lymph nodes are both painless and non-tender, unless there is concurrent or secondary infection. Without treatment, the chancre will resolve within 2–6 weeks to leave a thin atrophic scar. 13.6 Classification of syphilis Stage Acquired Congenital Early Primary Secondary Latent Clinical and latent Late Latent Benign tertiary Cardiovascular Neurosyphilis Clinical and latent Fig. 13.4 Primary syphilis. A painless ulcer (chancre) is shown in the coronal sulcus of the penis. This is usually associated with inguinal lymphadenopathy. Courtesy of Dr P. Hay, St George’s Hospital, London.

338 • SEXUALLY TRANSMITTED INFECTIONS • birth of a baby who develops signs of early congenital syphilis during the first few weeks of life (Box 13.7) • birth of a baby with latent infection who either remains well or develops congenital syphilis/stigmata later in life (see Box 13.7). Investigations in adult cases Treponema pallidum may be identified in serum collected from chancres, or from moist or eroded lesions in secondary syphilis using a dark-field microscope, a direct fluorescent antibody test or PCR. The serological tests for syphilis (STS) are listed in Box 13.8. These are antibody tests that almost always remain positive, even after successful treatment. Prolonged untreated infection results in higher titres that may not decline at all. Interpretation of results requires knowledge of any treatment, which may include antibiotics given coincidentally, e.g. for skin or respiratory tract infections. Many centres use treponemal enzyme immunoassays (EIAs) for IgG and IgM antibodies to screen for syphilis. EIA for antitreponemal IgM becomes positive at approximately 2 weeks, while non-treponemal tests become positive about 4 weeks after primary syphilis. All positive results in asymptomatic patients must be confirmed by repeat tests. Biological false-positive reactions occur occasionally; these are most commonly seen with Venereal Diseases Research Laboratory (VDRL) or rapid plasma reagin (RPR) tests (when treponemal tests will be negative). Acute false-positive reactions may be associated with infections, such as infectious mononucleosis, chickenpox and malaria, and may also occur in pregnancy. Chronic falsepositive reactions may be associated with autoimmune diseases. False-negative results for non-treponemal tests may be found in secondary syphilis because extremely high antibody levels can Transmission of syphilis from a pregnant woman to her fetus, and rarely by blood transfusion, is possible for several years following infection. Late syphilis Late latent syphilis This may persist for many years or for life. Without treatment, over 60% of patients might be expected to suffer little or no ill health. Coincidental prescription of antibiotics for other illnesses, such as respiratory tract or skin infections, may treat latent syphilis serendipitously and make the interpretation of serological test results difficult (see below). Benign tertiary syphilis This may develop between 3 and 10 years after infection but is now rarely seen in the UK. Skin, mucous membranes, bone, muscle or viscera can be involved. The characteristic feature is a chronic granulomatous lesion called a gumma, which may be single or multiple. Healing with scar formation may impair the function of the structure affected. Skin lesions may take the form of nodules or ulcers, while subcutaneous lesions may ulcerate with a gummy discharge. Healing occurs slowly, with the formation of characteristic tissue-paper scars. Mucosal lesions may occur in the mouth, pharynx, larynx or nasal septum, appearing as punched-out ulcers. Of particular importance is gummatous involvement of the tongue, healing of which may lead to leucoplakia with the attendant risk of malignant change. Gummas of the tibia, skull, clavicle and sternum have been described, as has involvement of the brain, spinal cord, liver, testis and, rarely, other organs. Resolution of active disease should follow treatment, though some tissue damage may be permanent. Paroxysmal cold haemoglobinuria (p. 950) may be seen. Cardiovascular syphilis This may present many years after initial infection. Aortitis, which may involve the aortic valve and/or the coronary ostia, is the key feature. Clinical features include aortic incompetence, angina and aortic aneurysm (p. 505). The condition typically affects the ascending aorta and sometimes the aortic arch; aneurysm of the descending aorta is rare. Treatment with penicillin will not correct anatomical damage and surgical intervention may be required. Neurosyphilis This may also take years to develop. Asymptomatic infection is associated with CSF abnormalities in the absence of clinical signs. Meningovascular disease, tabes dorsalis and general paralysis of the insane constitute the symptomatic forms (p. 1125). Neurosyphilis and cardiovascular syphilis may coexist and are sometimes referred to as quaternary syphilis. Congenital syphilis Congenital syphilis is rare where antenatal serological screening is practised. Antisyphilitic treatment in pregnancy treats the fetus, if infected, as well as the mother. Treponemal infection may give rise to a variety of outcomes after 4 months of gestation, when the fetus becomes immunocompetent: • miscarriage or stillbirth, prematurely or at term • birth of a syphilitic baby (a very sick baby with hepatosplenomegaly, bullous rash and perhaps pneumonia) 13.7 Clinical features of congenital syphilis Early congenital syphilis (neonatal period) • Maculopapular rash • Condylomata lata • Mucous patches • Fissures around mouth, nose and anus • Rhinitis with nasal discharge (snuffles) • Hepatosplenomegaly • Osteochondritis/periostitis • Generalised lymphadenopathy • Choroiditis • Meningitis • Anaemia/thrombocytopenia Late congenital syphilis • Benign tertiary syphilis • Periostitis • Paroxysmal cold haemoglobinuria • Neurosyphilis • 8th nerve deafness • Interstitial keratitis • Clutton’s joints (painless effusion into knee joints) Stigmata • Hutchinson’s incisors (anterior–posterior thickening with notch on narrowed cutting edge) • Mulberry molars (imperfectly formed cusps/deficient dental enamel) • High arched palate • Maxillary hypoplasia • Saddle nose (following snuffles) • Rhagades (radiating scars around mouth, nose and anus following rash) • Salt and pepper scars on retina (from choroiditis) • Corneal scars (from interstitial keratitis) • Sabre tibia (from periostitis) • Bossing of frontal and parietal bones (healed periosteal nodes)

Sexually transmitted bacterial infections • 339

Pregnancy Penicillin is the treatment of choice in pregnancy. Erythromycin stearate can be given if there is penicillin hypersensitivity, but it crosses the placenta poorly; the newborn baby must therefore be treated with a course of penicillin and consideration given to retreating the mother. Some specialists recommend penicillin desensitisation for pregnant mothers so that penicillin can be given during temporary tolerance. A 10-day course of ceftriaxone is a further alternative. Babies should be treated in hospital with the help of a paediatrician. Treatment reactions • Anaphylaxis. Penicillin is a common cause; on-site facilities should be available for management (p. 75). • Jarisch–Herxheimer reaction. This is an acute febrile reaction that follows treatment and is characterised by headache, malaise and myalgia; it resolves within 24 hours. It is common in early syphilis and rare in late syphilis. Fetal distress or premature labour can occur in pregnancy. The reaction may also cause worsening of neurological (cerebral artery occlusion) or ophthalmic (uveitis, optic neuritis) disease, myocardial ischaemia (inflammation of the coronary ostia) and laryngeal stenosis (swelling of a gumma). Prednisolone 40–60 mg daily for 3 days is recommended to prevent the reaction in patients with these forms of the disease; antisyphilitic treatment can be started 24 hours after introducing glucocorticoids. In high-risk situations it is wise to initiate therapy in hospital. • Procaine reaction. Fear of impending death occurs immediately after the accidental intravenous injection of procaine penicillin and may be associated with hallucinations or fits. Symptoms are short-lived, but verbal assurance and sometimes physical restraint are needed. The reaction can be prevented by aspiration before intramuscular injection to ensure the needle is not in a blood vessel. Gonorrhoea Gonorrhoea is caused by infection with Neisseria gonorrhoeae and may involve columnar epithelium in the lower genital tract, rectum, pharynx and eyes. Transmission is usually the result of vaginal, anal or oral sex. Gonococcal conjunctivitis may be caused by accidental infection from contaminated fingers. Untreated mothers may infect babies during delivery, resulting in ophthalmia neonatorum (Fig. 13.5). Infection of children beyond the neonatal period usually indicates sexual abuse. Clinical features The incubation period is usually 2–10 days. In men the anterior urethra is commonly infected, causing urethral discharge and dysuria, but symptoms are absent in about 10% of cases. Examination will usually show a mucopurulent or purulent urethral discharge. Rectal infection in MSM is usually asymptomatic but may present with anal discomfort, discharge or rectal bleeding. Proctoscopy may reveal either no abnormality, or clinical evidence of proctitis (p. 334) such as inflamed rectal mucosa and mucopus. In women, the urethra, paraurethral glands/ducts, Bartholin’s glands/ducts or endocervical canal may be infected. The rectum may also be involved either due to contamination from a urogenital site or as a result of anal sex. Occasionally, the rectum is the prevent the formation of the antibody–antigen lattice necessary for the visualisation of the flocculation reaction (the prozone phenomenon). In benign tertiary and cardiovascular syphilis, examination of CSF should be considered because asymptomatic neurological disease may coexist. The CSF should also be examined in patients with clinical signs of neurosyphilis (p. 1125) and in both early and late congenital syphilis. Positive STS may be found in patients who are being investigated for neurological disease, especially dementia. In many instances, the serology reflects previous infection unrelated to the presenting complaint, especially when titres are low. Examination of CSF is occasionally necessary. Chest X-ray, electrocardiogram (ECG) and echocardiogram are useful in the investigation of cardiovascular syphilis. Biopsy may be required to diagnose gumma. Endemic treponematoses, such as yaws, endemic (nonvenereal) syphilis (bejel) and pinta (pp. 253 and 254), are caused by treponemes that are morphologically indistinguishable from T. pallidum and cannot be differentiated by serological tests. A VDRL or RPR test may help to elucidate the correct diagnosis because adults with late yaws usually have low titres. Investigations in suspected congenital syphilis Passively transferred maternal antibodies from an adequately treated mother may give rise to positive serological tests in her baby. In this situation, non-treponemal tests should become negative within 3–6 months of birth. A positive EIA test for antitreponemal IgM suggests early congenital syphilis. A diagnosis of congenital syphilis mandates investigation of the mother, her partner and any siblings. Management Penicillin is the drug of choice. Currently, a single dose of 2.4 megaunits of intramuscular benzathine benzylpenicillin is recommended for early syphilis (< 2 years’ duration), with three doses at weekly intervals being recommended in late syphilis. A 14-day course of procaine penicillin is recommended for the treatment of neurosyphilis, supplemented by a 3-day course of prednisolone (see below). Doxycycline is indicated for patients allergic to penicillin, except in pregnancy (see below). Azithromycin is less favoured due to the potential for resistance. All patients must be followed up to ensure cure, and partner notification is of particular importance. Resolution of clinical signs in early syphilis with declining titres for non-treponemal tests, usually to undetectable levels within 6 months for primary syphilis and 12–18 months for secondary syphilis, is an indicator of successful treatment. Specific treponemal antibody tests may remain positive for life. In patients who have had syphilis for many years there may be little serological response following treatment. 13.8 Serological tests for syphilis Non-treponemal (non-specific) tests • Venereal Diseases Research Laboratory (VDRL) test • Rapid plasma reagin (RPR) test Treponemal (specific) antibody tests • Treponemal antigen-based enzyme immunoassay (EIA) for IgG and IgM • Treponema pallidum haemagglutination assay (TPHA) • T. pallidum particle agglutination assay (TPPA) • Fluorescent treponemal antibody-absorbed (FTA-ABS) test

340 • SEXUALLY TRANSMITTED INFECTIONS be seen as soon as possible. Delay in treatment may lead to complications (Box 13.10). Chlamydial infection Chlamydial infection in men Chlamydia is transmitted and presents in a similar way to gonorrhoea; however, urethral symptoms are usually milder and may be absent in over 50% of cases. Conjunctivitis is also milder than in gonorrhoea; pharyngitis does not occur. The incubation period varies from 1 week to a few months. Without treatment, symptoms may resolve but the patient remains infectious for several months. Complications, such as epididymo-orchitis and sexually acquired reactive arthritis (SARA, p. 1031), are rare. Sexually transmitted pathogens, such as chlamydia or gonococci, are usually responsible for epididymo-orchitis in men aged less than 35 years, whereas bacteria such as Gram-negative enteric organisms are more commonly implicated in older men. Treatments for chlamydia are listed in Box 13.11. NSU is treated identically. The partner(s) of men with chlamydia should be treated, even if laboratory tests for chlamydia are negative. Investigation is not mandatory but serves a useful epidemiological purpose; moreover, positive results encourage further attempts at contact-tracing. Chlamydial infection in women The cervix and urethra are commonly involved. Infection is asymptomatic in about 80% of patients but may cause intermenstrual and/or post-coital bleeding, dysuria or vaginal discharge. Lower abdominal pain and dyspareunia are features of PID. Examination may reveal mucopurulent cervicitis, contact only site infected. About 80% of women who have gonorrhoea are asymptomatic. There may be vaginal discharge or dysuria but these symptoms are often due to additional infections, such as chlamydia (see below), trichomoniasis or candidiasis, making full investigation essential (p. 331). Lower abdominal pain, dyspareunia and intermenstrual bleeding may be indicative of PID. Clinical examination may show no abnormality, or pus may be expressed from urethra, paraurethral ducts or Bartholin’s ducts. The cervix may be inflamed, with mucopurulent discharge and contact bleeding. Pharyngeal gonorrhoea is the result of receptive orogenital sex and is usually symptomless. Gonococcal conjunctivitis is an uncommon complication, presenting with purulent discharge from the eye(s), severe inflammation of the conjunctivae and oedema of the eyelids, pain and photophobia. Gonococcal ophthalmia neonatorum presents similarly with purulent conjunctivitis and oedema of the eyelids. Conjunctivitis must be treated urgently to prevent corneal damage. Disseminated gonococcal infection (DGI) is seen rarely, and typically affects women with asymptomatic genital infection. Symptoms include arthritis of one or more joints, pustular skin lesions, tenosynovitis and fever. Gonococcal endocarditis has been described. Investigations Gram-negative diplococci may be seen on microscopy of smears from infected sites (see Fig. 13.1). Pharyngeal smears are difficult to analyse due to the presence of other diplococci, so the diagnosis must be confirmed by culture or NAAT. Management of adults Emerging resistance is making it increasingly difficult to cure gonorrhoea with a single oral dose of antimicrobials, and recommended treatment in the UK has changed to intramuscular ceftriaxone 500 mg given with an oral dose of azithromycin 1 g, in the hope that combination therapy will slow down the development of cephalosporin resistance. The alternatives listed in Box 13.9 are less likely to be effective. Longer courses of antibiotics are required for complicated infection. The partner(s) of patients with gonorrhoea should Fig. 13.5 Gonococcal ophthalmia neonatorum. From McMillan A, Scott GR. Sexually transmitted infections: a colour guide. Churchill Livingstone, Elsevier Ltd; 2000. 13.10 Complications of delayed therapy in gonorrhoea • Acute prostatitis • Epididymo-orchitis • Bartholin’s gland abscess • Pelvic inflammatory disease (may lead to infertility or ectopic pregnancy) • Disseminated gonococcal infection 1Contraindicated in pregnancy and breastfeeding. 2If prevalence of quinolone resistance for Neisseria gonorrhoeae is < 5%. 3May be available only in specialist clinics. 13.9 Treatment of uncomplicated anogenital gonorrhoea Uncomplicated infection • Ceftriaxone 500 mg IM plus azithromycin 1 g orally or • Cefixime 400 mg stat or • Ciprofloxacin 500 mg orally stat1,2 or • Ofloxacin 400 mg orally stat1,2 Pregnancy and breastfeeding • Ceftriaxone 500 mg plus azithromycin 1 g IM stat or • Spectinomycin 2 g IM stat3 Pharyngeal gonorrhoea • Ceftriaxone 500 mg IM plus azithromycin 1 g stat or • Ciprofloxacin 500 mg1,2 orally stat or • Ofloxacin 400 mg1,2 orally stat

Sexually transmitted viral infections • 341

bleeding from the cervix, evidence of PID or no obvious clinical signs. Treatment options are listed in Box 13.11. The patient’s male partner(s) should be investigated and treated. Many infections clear spontaneously but others persist. PID, with the risk of tubal damage and subsequent infertility or ectopic pregnancy, is a rare but important long-term complication. Other complications include perihepatitis, chronic pelvic pain, conjunctivitis and SARA (p. 1031). Perinatal transmission may lead to ophthalmia neonatorum and/or pneumonia in the neonate. Other sexually transmitted bacterial infections Chancroid, granuloma inguinale and LGV as causes of genital ulcers in the tropics are described in Box 13.12. LGV is also a cause of proctitis in MSM (p. 334). 13.11 Treatment of chlamydial infection Standard regimens • Azithromycin 1 g orally as a single dose1 or • Doxycycline 100 mg twice daily orally for 7 days2 Alternative regimens • Erythromycin 500 mg four times daily orally for 7 days or 500 mg twice daily for 2 weeks or • Ofloxacin 200 mg twice daily orally for 7 days2 1Safety in pregnancy and breastfeeding has not been fully established. 2Contraindicated in pregnancy and breastfeeding. 13.12 Salient features of lymphogranuloma venereum, chancroid and granuloma inguinale (Donovanosis) Infection and distribution Organism Incubation period Genital lesion Lymph nodes Diagnosis Management Lymphogranuloma venereum (LGV) E/W Africa, India, SE Asia, S America, Caribbean Chlamydia trachomatis types L1, 2, 3 3–30 days Small, transient, painless ulcer, vesicle, papule; often unnoticed Tender, usually unilateral, matted, suppurative bubo; inguinal/femoral nodes involved1 Serological tests for L1–3 serotypes; swab from ulcer or bubo pus for Chlamydia Doxycycline2 twice daily orally for 21 days or Erythromycin 500 mg four times daily orally Chancroid Africa, Asia, Central and S America Haemophilus ducreyi (short Gram-negative bacillus) 3–10 days Single or multiple painful ulcers with ragged undermined edges As above but unilocular, suppurative bubo; inguinal nodes involved in ~50% Microscopy and culture of scrapings from ulcer or pus from bubo Azithromycin3 1 g orally once or Ceftriaxone 250 mg IM once or Ciprofloxacin2 500 mg twice daily orally for 3 days Granuloma inguinale Australia, India, Caribbean, S Africa, S America, Papua New Guinea Klebsiella granulomatis (Donovan bodies) 3–40 days Ulcers or hypertrophic granulomatous lesions; usually painless4 Initial swelling of inguinal nodes, then spread of infection to form abscess or ulceration through adjacent skin Microscopy of cellular material for intracellular bipolar-staining Donovan bodies Azithromycin3 1 g weekly orally or 500 mg daily orally or Doxycycline2 100 mg twice daily orally or Ceftriaxone 1 g IM daily N.B. Partners of patients with LGV, chancroid and granuloma inguinale should be investigated and treated, even if asymptomatic. 1The genito-ano-rectal syndrome is a late manifestation of LGV. 2Doxycycline and ciprofloxacin are contraindicated in pregnancy and breastfeeding. 3The safety of azithromycin in pregnancy and breastfeeding has not been fully assessed. 4Mother-to-baby transmission of granuloma inguinale may rarely occur. Sexually transmitted viral infections Genital herpes simplex Infection with herpes simplex virus type 1 (HSV-1) or type 2 (HSV-2) produces a wide spectrum of clinical problems (p. 247), and may facilitate HIV transmission. Infection is usually acquired sexually (vaginal, anal, orogenital or oroanal), but perinatal transmission to the neonate may also occur. Primary infection at the site of HSV entry, which may be symptomatic or asymptomatic, establishes latency in local sensory ganglia. Recurrences, either symptomatic or asymptomatic viral shedding, are a consequence of HSV reactivation. The first symptomatic episode is usually the most severe. Although HSV-1 is classically associated with orolabial herpes and HSV-2 with anogenital herpes, HSV-1 now accounts for more than 50% of anogenital infections in the UK. Clinical features The first symptomatic episode presents with irritable vesicles that soon rupture to form small, tender ulcers on the external genitalia (Fig. 13.6 and see Fig. 13.2). Lesions at other sites (e.g. urethra, vagina, cervix, perianal area, anus or rectum) may cause dysuria, urethral or vaginal discharge, or anal, perianal or rectal pain. Constitutional symptoms, such as fever, headache and malaise, are common. Inguinal lymph nodes become enlarged and tender, and there may be nerve root pain in the 2nd and 3rd sacral dermatomes. Extragenital lesions may develop at other sites, such as the buttock, finger or eye, due to auto-inoculation. Oropharyngeal infection may result from orogenital sex. Complications, such

342 • SEXUALLY TRANSMITTED INFECTIONS Analgesia may be required and saline bathing can be soothing. Treatment may be continued for longer than 5 days if new lesions develop. Occasionally, intravenous therapy may be indicated if oral therapy is poorly tolerated or aseptic meningitis occurs. Catheterisation via the suprapubic route is advisable for urinary retention due to autonomic neuropathy because the transurethral route may introduce HSV into the bladder. Recurrent genital herpes Symptomatic recurrences are usually mild and may require no specific treatment other than saline bathing. For more severe episodes, patient-initiated treatment at onset, with one of the following 5-day oral regimens, should reduce the duration of the recurrence: • aciclovir 200 mg five times daily • famciclovir 125–250 mg twice daily • valaciclovir 500 mg twice daily. In a few patients, treatment started at the onset of prodromal symptoms may abort recurrence. Suppressive therapy may be required for patients with frequent recurrences, especially if these are experienced at intervals of less than 4 weeks. Treatment should be given for a minimum of 1 year before stopping to assess recurrence rate. About 20% of patients will experience reduced attack rates thereafter, but for those whose recurrences remain unchanged, resumption of suppressive therapy is justified. Aciclovir 400 mg twice daily is most commonly prescribed. Management in pregnancy If her partner is known to be infected with HSV, a pregnant woman with no previous anogenital herpes should be advised to protect herself during sexual intercourse because the risk of disseminated infection is increased in pregnancy. Consistent condom use during pregnancy may reduce transmission of HSV. Genital herpes acquired during the first or second trimester of pregnancy is treated with aciclovir as clinically indicated. Although aciclovir is not licensed for use in pregnancy in the UK, there is considerable clinical evidence to support its safety. Third-trimester acquisition of infection has been associated with life-threatening haematogenous dissemination and should be treated with aciclovir. Vaginal delivery should be routine in women who are symptomless in late pregnancy. Caesarean section is sometimes considered if there is a recurrence at the beginning of labour, although the risk of neonatal herpes through vaginal transmission is very low. Caesarean section is often recommended if primary infection occurs after 34 weeks because the risk of viral shedding is very high in labour. Human papillomavirus and anogenital warts Human papillomavirus (HPV) DNA typing has demonstrated over 90 genotypes (p. 1238), of which HPV-6, HPV-11, HPV-16 and HPV-18 most commonly infect the genital tract through sexual transmission. It is important to differentiate between the benign genotypes (HPV-6 and 11) that cause anogenital warts, and genotypes such as 16 and 18 that are associated with dysplastic conditions and cancers of the genital tract but are not a cause of benign warts. All genotypes usually result in subclinical infection of the genital tract rather than clinically obvious lesions affecting penis, vulva, vagina, cervix, perineum or anus. as urinary retention due to autonomic neuropathy, and aseptic meningitis, are occasionally seen. First episodes usually heal within 2–4 weeks without treatment; recurrences are usually milder and of shorter duration than the initial attack. They occur more often in HSV-2 infection and their frequency tends to decrease with time. Prodromal symptoms, such as irritation or burning at the subsequent site of recurrence, or neuralgic pain affecting buttocks, legs or hips are commonly seen. The first symptomatic episode may be a recurrence of a previously undiagnosed primary infection. Recurrent episodes of asymptomatic viral shedding are important in the transmission of HSV. Diagnosis Swabs are taken from vesicular fluid or ulcers for detection of DNA by PCR, or tissue culture and typing as either HSV-1 or 2. Electron microscopy of such material will give only a presumptive diagnosis, as herpes group viruses appear similar. Type-specific antibody tests are available but are not sufficiently accurate for general use. Management First episode The following 5-day oral regimens should be started within 5 days of the beginning of the episode, or while lesions are still forming: • aciclovir 400 mg three times daily • valaciclovir 500 mg twice daily. Famciclovir 250 mg three times daily or aciclovir 200 mg five times daily is an alternative. Fig. 13.6 Herpetic ulceration of the vulva. From McMillan A, Scott GR. Sexually transmitted infections: a colour guide. Churchill Livingstone, Elsevier Ltd; 2000.

Sexually transmitted viral infections • 343

• Surgical removal may be used to excise refractory warts, especially pedunculated perianal lesions, under local or general anaesthesia. Molluscum contagiosum Infection by molluscum contagiosum virus, both sexual and non-sexual, produces flesh-coloured, umbilicated, hemispherical papules usually up to 5 mm in diameter after an incubation period of 3–12 weeks (Fig. 13.7). Larger lesions may be seen in HIV infection (p. 306). Lesions are often multiple and, once established in an individual, may spread by auto-inoculation. They are found on the genitalia, lower abdomen and upper thighs when sexually acquired. Facial lesions are highly suggestive of underlying HIV infection. Diagnosis is made clinically or very rarely by electron microscopy. Typically, lesions persist for several months before spontaneous resolution occurs. Treatment regimens are therefore cosmetic; they include cryotherapy, hyfrecation, topical applications of 0.15% podophyllotoxin cream (contraindicated in pregnancy) or expression of the central core. Clinical features Anogenital warts caused by HPV may be single or multiple, exophytic, papular or flat. Perianal warts (p. 330), while being more common in MSM, are also found in heterosexual men and in women. Rarely, a giant condyloma (Buschke–Löwenstein tumour) develops, with local tissue destruction. Atypical warts should be biopsied. In pregnancy, warts may dramatically increase in size and number, making treatment difficult. Rarely, they are large enough to obstruct labour and, in this case, delivery by caesarean section will be required. Uncommonly, perinatal transmission of HPV leads to anogenital warts, or possibly laryngeal papillomas, in the neonate. Management The use of condoms can help prevent the transmission of HPV to non-infected partners, but HPV may affect parts of the genital area not protected by condoms. Vaccination against HPV infection has been introduced and is in routine use in many countries. There are three types of vaccine: • A bivalent vaccine offers protection against HPV types 16 and 18, which account for approximately 75% of cervical cancers in the UK. • A quadrivalent vaccine offers additional protection against HPV types 6 and 11, which account for over 90% of genital warts. • A nonovalent vaccine protects against five additional high-risk types (31, 33, 45, 52 and 58). All vaccines have been shown to be highly effective in the prevention of cervical intra-epithelial neoplasia in young women, and the quadrivalent and nonovalent vaccines have also been demonstrated to be highly effective in protecting against HPVassociated genital warts. It is currently recommended that HPV vaccination should be administered prior to the onset of sexual activity, typically at age 11–13, in a course of three injections. In the UK, only girls are offered vaccination, but it is possible that vaccination will be extended to MSM in whom HPV transmission is associated with an increased risk of anal cancer. As no vaccine protects against all oncogenic types of HPV, cervical screening programmes will still be necessary. A variety of treatments are available for established disease, including the following: • Podophyllotoxin, 0.5% solution or 0.15% cream (contraindicated in pregnancy), applied twice daily for 3 days, followed by 4 days’ rest, for up to 4 weeks, is suitable for home treatment of external warts. • Imiquimod cream (contraindicated in pregnancy), applied 3 times weekly (and washed off after 6–10 hours) for up to 16 weeks, is also suitable for home treatment of external warts. • Catephen (an extract of the green tea plant, Camellia sinensis) is applied by the patient three times daily for up to 16 weeks. • Cryotherapy using liquid nitrogen to freeze warty tissue is suitable for external and internal warts but often requires repeated clinic visits. • Hyfrecation – electrofulguration that causes superficial charring – is suitable for external and internal warts. Hyfrecation results in smoke plume, which contains HPV DNA and has the potential to cause respiratory infection in the operator/patient. Masks should be worn during the procedure and adequate extraction of fumes should be provided. Fig. 13.7 Molluscum contagiosum of the shaft of the penis. From McMillan A, Scott GR. Sexually transmitted infections: a colour guide. Churchill Livingstone, Elsevier Ltd; 2000. Viral hepatitis The hepatitis viruses A–D (p. 871) may be sexually transmitted: • Hepatitis A (HAV). Insertive oroanal sex, insertive digital sex, insertive anal sex and multiple sexual partners have been linked with HAV transmission in MSM. HAV transmission in heterosexual men and women is also possible through oroanal sex. • Hepatitis B (HBV). Insertive oroanal sex, anal sex and multiple sexual partners are linked with HBV infection in MSM. Heterosexual transmission of HBV is well documented and commercial sex workers are at particular risk. Hepatitis D (HDV) may also be sexually transmitted. • Hepatitis C (HCV). Sexual transmission of HCV is well documented in MSM but less so in heterosexuals. Sexual transmission is less efficient than for HBV.

344 • SEXUALLY TRANSMITTED INFECTIONS Further information Books and journal articles Pattman R, Sankar N, Elawad B, et al. (eds). Oxford handbook of genitourinary medicine, HIV, and sexual health. Oxford: Oxford University Press; 2010. Rogstad KE (ed.). ABC of sexually transmitted infections, 6th edn. Oxford: Wiley–Blackwell; 2011. Website bashh.org/guidelines British Association for Sexual Health and HIV; updates on treatment of all STIs. The sexual partner(s) of patients with HAV and HBV should be seen as soon as possible and offered immunisation where appropriate. Patients with HAV should abstain from all forms of unprotected sex until non-infectious. Those with HBV should likewise abstain from unprotected sex until they are non-infectious or until their partners have been vaccinated successfully. No active or passive immunisation is available for protection against HCV but the consistent use of condoms is likely to protect susceptible partners. Active immunisation against HAV and HBV should be offered to susceptible people at risk of infection. Many STI clinics offer HAV immunisation to MSM along with routine HBV immunisation; a combined HAV and HBV vaccine is available.

Ch04-3 Clinical Medicine

04-14 Clinical biochemistry and metabolic medicine

14 Clinical biochemistry and metabolic medicine

Clinical biochemistry and metabolic medicine A Mather L Burnett DR Sullivan P Stewart Clinical examination in biochemical and metabolic disorders 346 Biochemical investigations 348 Water and electrolyte homeostasis 349 Sodium homeostasis 349 Functional anatomy and physiology 349 Presenting problems in sodium and water balance 352 Hypovolaemia 352 Hypervolaemia 353 Water homeostasis 355 Functional anatomy and physiology 355 Presenting problems in regulation of osmolality 356 Hyponatraemia 357 Hypernatraemia 358 Potassium homeostasis 360 Functional anatomy and physiology 360 Presenting problems in potassium homeostasis 361 Hypokalaemia 361 Hyperkalaemia 362 Acid–base homeostasis 363 Functional anatomy and physiology 363 Presenting problems in acid–base balance 364 Metabolic acidosis 364 Metabolic alkalosis 366 Respiratory acidosis 367 Respiratory alkalosis 367 Mixed acid–base disorders 367 Calcium homeostasis 367 Magnesium homeostasis 367 Functional anatomy and physiology 367 Presenting problems in magnesium homeostasis 367 Hypomagnesaemia 368 Hypermagnesaemia 368 Phosphate homeostasis 368 Functional anatomy and physiology 368 Presenting problems in phosphate homeostasis 368 Hypophosphataemia 368 Hyperphosphataemia 369 Disorders of amino acid metabolism 369 Disorders of carbohydrate metabolism 370 Disorders of complex lipid metabolism 370 Lipids and lipoprotein metabolism 370 Functional anatomy and physiology 371 Lipids and cardiovascular disease 373 Investigations 373 Presenting problems in lipid metabolism 373 Hypercholesterolaemia 373 Hypertriglyceridaemia 374 Mixed hyperlipidaemia 375 Rare dyslipidaemias 375 Principles of management 375 The porphyrias 378

346 • CLINICAL BIOCHEMISTRY AND METABOLIC MEDICINE Clinical examination in biochemical and metabolic disorders Many biochemical and metabolic disorders are clinically silent or present with non-specific manifestations, and are first detected by laboratory testing. Several abnormalities can be picked up by history and physical examination, however, as summarised below. Insets: (ankle oedema) From Huang H-W, Wong L-S, Lee C-H. Sarcoidosis with bilateral leg lymphedema as the initial presentation: a review of the literature. Dermatologica Sinica 2016; 34:29–32; (raised jugular venous pressure) Newby D, Grubb N. Cardiology: an illustrated colour text. Edinburgh: Churchill Livingstone, Elsevier Ltd; 2005; (cherry-red spots) Vieira de Rezende Pinto WB, Sgobbi de Souza PV, Pedroso JL, et al. Variable phenotype and severity of sialidosis expressed in two siblings presenting with ataxia and macular cherry-red spots. J Clin Neurosci 2013; 20:1327–1328; (photosensitive rash) Ferri FF. Ferri’s Color atlas and text of clinical medicine. Philadelphia: Saunders, Elsevier Inc.; 2009; courtesy of the Institute of Dermatology, London. Hyperlipidaemia Xanthelasma Corneal arcus Gangliosidosis Cherry-red spot fundus Porphyria Photosensitive rash Hyperlipidaemia Tendon xanthoma Eruptive xanthoma Observation • General appearance • Skin turgor • Oedema • Rash • Eyes Hypervolaemia Raised jugular venous pressure Ankle oedema Hypovolaemia Low blood pressure Rapid pulse Acute hypernatraemia Extra heart sounds Dizziness Delirium Weakness Acute hyponatraemia Cerebral oedema Vomiting Somnolence Seizures Coma Glycogen storage disease Hepatomegaly Abdominal pain Extra heart sounds Atheroma Lung crepitations B C N O P A K L I M J D E F G H H G K N O P D C B A J J L M F I E

Clinical examination in biochemical and metabolic disorders • 347

Assessment of volume status and electrolyte disturbances Check blood pressure, pulse and jugular venous pressure Check for dry mouth Check for sacral and ankle oedema Examine chest for pleural effusion Examine abdomen for hepatomegaly and ascites Check bloods Review results Check ECG Hypokalaemia Hyperkalaemia Check skin turgor Check for signs of hyperlipidaemia Check skin and tendons for xanthomas Check eyes for arcus and xanthelasma Peaked T wave U wave ST depression

348 • CLINICAL BIOCHEMISTRY AND METABOLIC MEDICINE high-speed transport systems (such as pneumatic tubes) and identified with machine-readable labels (such as bar codes). Laboratory instruments have been miniaturised and integrated with robot transport systems to enable multiple rapid analyses of a single sample. Statistical process control techniques are used to assure the quality of analytical results, and increasingly to monitor other aspects of the laboratory, such as the time taken to complete the analysis (‘turn-around time’). • Point-of-care testing (POCT) brings selected laboratory analytical systems into clinical areas, to the patient’s bedside or even connected to an individual patient. These systems allow the clinician to receive results almost instantaneously for immediate treatment of the patient, although often with lesser precision or at greater cost than using a central laboratory. • The diversity of analyses has widened considerably with the introduction of many techniques borrowed from the chemical or other industries (Box 14.1). Good medical practice involves the appropriate ordering of laboratory investigations and correct interpretation of test results (Box 14.2). The key principles, including the concepts of sensitivity and specificity, are described on page 4. Reference intervals for laboratory results are provided in Chapter 35. Many laboratory investigations can be subject to variability arising from whether the sample is being taken in the fed or fasted state; the timing of sample collection, in relation to diurnal variation of analytes; dosage intervals for therapeutic drug monitoring; sample type, such as serum plasma; use of anticoagulants, such as EDTA, which can interfere with some assays; or artefacts, such as There is a worldwide trend towards increased use of laboratorybased diagnostic investigations, and biochemical investigations in particular. In the health-care systems of developed countries, it has been estimated that 60–70% of all critical decisions taken in regard to patients, and over 90% of data stored in electronic medical records systems, involve a laboratory service or result. This chapter covers a diverse group of disorders affecting adults that are not considered elsewhere in this book, whose primary manifestation is in abnormalities of biochemistry laboratory results, or whose underlying pathophysiology involves disturbance in specific biochemical pathways. Biochemical investigations There are three broad reasons why a clinician may request a biochemical laboratory investigation: • to screen an asymptomatic subject for the presence of disease • to assist in diagnosis of a patient’s presenting complaint • to monitor changes in test results, as a marker of disease progression or response to treatment. Contemporary medical practice has become increasingly reliant on laboratory investigation and, in particular, on biochemical investigation. This has been associated with extraordinary improvements in the analytical capacity and speed of laboratory instrumentation and the following operational trends: • Large central biochemistry laboratories feature extensive use of automation and information technology. Specimens are transported from clinical areas to the laboratory using 14.1 Range of analytical modalities used in the clinical biochemistry laboratory Analytical modality Analyte Typical applications Ion-selective electrodes Blood gases, electrolytes (Na, K, Cl) Point-of-care testing (POCT) High-throughput analysers Colorimetric chemical reaction or coupled enzymatic reaction Simple mass or concentration measurement (creatinine, phosphate) Simple enzyme activity High-throughput analysers Ligand assay (usually immunoassay) Specific proteins Hormones Drugs Increasingly available for POCT or high-throughput analysers Chromatography: gas chromatography (GC), highperformance liquid chromatography (HPLC), thin-layer chromatography (TLC) Organic compounds Therapeutic drug monitoring (TDM) Mass spectroscopy (MS) Drug screening (drugs of misuse) Vitamins Biochemical metabolites Spectrophotometry, turbidimetry, nephelometry, fluorimetry Haemoglobin derivatives Specific proteins Immunoglobulins Xanthochromia Lipoproteins Paraproteins Electrophoresis Proteins Some enzymes Paraproteins Isoenzyme analysis Atomic absorption (AA) Inductively coupled plasma/mass spectroscopy (ICP-MS) Trace elements and metals Quantitation of heavy metals Molecular diagnostics Nucleic acid quantification and/or sequence Inherited and somatic cell mutations (Ch. 3) Genetic polymorphisms (Ch. 3) Variations in rates of drug metabolism (Ch. 2) Microbial diagnosis (Ch. 6)

Sodium homeostasis • 349

pump (Na,K-activated adenosine triphosphatase (ATPase)), which is present in all cell membranes. Maintenance of these gradients is essential for many cell processes, including the excitability of conducting tissues such as nerve and muscle. The difference in protein content between the plasma and the interstitial fluid compartment is maintained by the impermeability of the capillary wall to protein. This protein concentration gradient (the colloid osmotic, or oncotic, pressure of the plasma) contributes to the balance of forces across the capillary wall that favour fluid retention within the plasma compartment. The concentration of sodium in the ECF plays a pivotal role in determining plasma osmolality and thereby controlling intracellular volume through changes in water balance between the intracellular and extracellular space. In contrast, plasma volume is largely controlled by total body sodium, which determines volume change. Therefore, disturbances in water homeostasis typically present with biochemical abnormalities such as hyponatraemia or hypernatraemia, whereas disturbances in sodium homeostasis present with hypervolaemia or hypovolaemia as the result of expansion or contraction of ECF volume, respectively. Sodium homeostasis Most of the body’s sodium is located in the ECF, where it is by far the most abundant cation. Accordingly, total body sodium is the principal determinant of ECF volume. Sodium intake varies widely between individuals, ranging between 50 and 250 mmol/24 hrs. The kidneys can compensate for these wide variations in sodium intake by increasing excretion of sodium when there is sodium overload, and retaining sodium in the presence of sodium depletion, to maintain normal ECF volume and plasma volume. Functional anatomy and physiology The functional unit for renal excretion is the nephron (Fig. 14.2). Blood undergoes ultrafiltration in the glomerulus, generating a Fig. 14.1 Normal distribution of body water and electrolytes. Schematic representation of volume (L = litres) and composition (dominant ionic species only shown) of the intracellular fluid (ICF) and extracellular fluid (ECF) in a 70 kg male. The main difference in composition between the plasma and interstitial fluid (ISF) is the presence of appreciable concentrations of protein in the plasma but not the ISF. The Na/K differential is maintained by the Na,K-adenosine triphosphatase (ATPase) pump. Intracellular fluid Interstitial fluid Plasma Protein Extracellular fluid Cl− HCO3− HPO4 2 − Proteinn − 2K + 3Na + Na+ K+ (12 L) (3 L) (25 L) The term urea and electrolytes (U&Es) refers to urea, electrolyes and creatinine. In some countries this is abbreviated to EUC (electrolytes/urea/creatinine). 14.2 How to interpret urea and electrolytes results Sodium • Largely reflects changes in sodium and water balance • See ‘Hypernatraemia’ and ‘Hyponatraemia’ (pp. 358 and 357) Potassium • May reflect K shifts in and out of cells • Low levels usually mean excessive losses (gastrointestinal or renal) • High levels usually mean renal dysfunction • See ‘Hypokalaemia’ and ‘Hyperkalaemia’ (pp. 361 and 362) Chloride • Generally changes in parallel with plasma Na • Low in metabolic alkalosis • High in some forms of metabolic acidosis Bicarbonate • Abnormal in acid–base disorders • See Box 14.18 (p. 365) Urea • Increased with a fall in glomerular filtration rate (GFR), reduced renal perfusion or urine flow rate, and in high protein intake or catabolic states • See page 386 Creatinine • Increased with a fall in GFR, in individuals with high muscle mass, and with some drugs • See Fig. 15.2 (p. 387) taking a venous sample proximal to the site of an intravenous infusion. It is therefore important for clinical and laboratory staff to communicate effectively and for clinicians to follow local recommendations concerning collection and transport of samples in the appropriate container and with appropriate labelling. Water and electrolyte homeostasis Total body water (TBW) is approximately 60% of body weight in an adult male, although the proportion is somewhat more for infants and less for women. In a 70 kg man TBW is therefore about 40 L. Approximately 25 L is located inside cells (the intracellular fluid or ICF), while the remaining 15 L is in the extracellular fluid (ECF) compartment (Fig. 14.1). Most of the ECF (approximately 12 L) is interstitial fluid, which is within the tissues but outside cells, whereas the remainder (about 3 L) is in the plasma compartment. The ion composition between the main body fluid compartments intracellularly and extracellularly is illustrated in Figure 14.1. The dominant positively charged ion (cation) within cells is potassium, whereas phosphates and negatively charged proteins constitute the major intracellular negatively charged ions (anions). In the ECF the dominant cation is sodium, while chloride and, to a lesser extent, bicarbonate are the most important ECF anions. An important difference between the intravascular (plasma) and interstitial compartments of the ECF is that only plasma contains significant concentrations of protein. The major force maintaining the difference in cation concentrations between the ICF and ECF is the sodium–potassium

350 • CLINICAL BIOCHEMISTRY AND METABOLIC MEDICINE Fig. 14.2 The nephron. Letters A–D refer to tubular segments shown in more detail in Figure 14.3. (aa = afferent arteriole; ea = efferent arteriole; md = macula densa) Cortex Medulla A B Thin descending limb Loop of Henle Thin ascending limb Medullary collecting duct Pars recta Proximal (convoluted) tubule Glomerulus C Early distal (convoluted) tubule Late distal tubule Cortical collecting duct D Thick ascending limb aa ea md fluid that is free from cells and protein and which resembles plasma in its electrolyte composition. This is delivered into the renal tubules, where reabsorption of water and various electrolytes occurs. (More detail on the structure and function of the glomerulus is given in Ch. 15.) The glomerular filtration rate (GFR) is approximately 125 mL/min (equivalent to 180 L/24 hrs) in a normal adult. Over 99% of the filtered fluid is reabsorbed into the blood in the peritubular capillaries during its passage through successive segments of the nephron, largely as a result of tubular reabsorption of sodium. The processes mediating sodium reabsorption, and the factors that regulate it, are key to understanding clinical disturbances and pharmacological interventions of sodium and fluid balance. The nephron can be divided into at least four different functional segments in terms of sodium reabsorption (Fig. 14.3). Proximal renal tubule About 65% of the filtered sodium load is reabsorbed in the proximal renal tubule. The cellular mechanisms are complex but some of the key features are shown in Figure 14.3A. Filtered sodium in the luminal fluid enters the proximal tubular cell through transporters in the apical membrane that couple sodium transport to the entry of glucose, amino acid, phosphate and other organic molecules. Entry of sodium into the tubular cells at this site is also linked to secretion of H+ ions, through the sodium–hydrogen exchanger (NHE-3). Intracellular H+ ions are generated within tubular cells from the breakdown of carbonic acid, which is produced from carbon dioxide and water under the influence of carbonic anhydrase. Large numbers of Na,K-ATPase pumps are present on the basolateral membrane of tubular cells, which transport sodium from the cells into the blood. In addition, a large component of the transepithelial flux of sodium, water and other dissolved solutes occurs through gaps between the cells (the ‘shunt’ pathway). Overall, fluid and electrolyte reabsorption is almost isotonic in this segment, as water reabsorption is matched very closely to sodium fluxes, such that the osmolality of fluid passing into the loop of Henle is very similar to that of plasma. A component of this water flow also passes through the cells, via aquaporin-1 (AQP-1) water channels, which are not sensitive to hormonal regulation. Loop of Henle The thick ascending limb of the loop of Henle (Fig. 14.3B) reabsorbs a further 25% of the filtered sodium but is impermeable to water, resulting in dilution of the luminal fluid. The primary driving force is the Na,K-ATPase on the basolateral cell membrane, but in this segment sodium enters the cell from the lumen through a specific carrier molecule, the Na,K,2Cl co-transporter (‘triple co-transporter’, or NKCC2), which allows electroneutral entry of these ions into the renal tubular cell by balancing transport of anions (Na+/K+) with cations (Cl−). Some of the potassium accumulated inside the cell recirculates across the apical membrane back into the lumen through a specific potassium channel (ROMK), providing a continuing supply of potassium to match the high concentrations of sodium and chloride in the lumen. A small positive transepithelial potential difference exists in the lumen of this segment relative to the interstitium, and this serves to drive cations such as sodium, potassium, calcium and magnesium between the cells, forming a reabsorptive shunt pathway. Early distal renal tubule About 6% of filtered sodium is reabsorbed in the early distal tubule (also called distal convoluted tubule) (Fig. 14.3C), again driven by the activity of the basolateral Na,K-ATPase. In this segment, entry of sodium into the cell from the luminal fluid occurs through a sodium–chloride co-transport carrier (NCCT). This segment is also impermeable to water, resulting in further dilution of the luminal fluid. There is no significant transepithelial flux of potassium in this segment, but calcium is reabsorbed through the mechanism shown in Figure 14.3C: a basolateral sodium–calcium exchanger leads to low intracellular concentrations of calcium, promoting calcium entry from the luminal fluid through a calcium channel. Late distal renal tubule and collecting ducts The late distal tubule and cortical collecting duct are anatomically and functionally continuous (Fig. 14.3D). Here, sodium entry from the luminal fluid occurs through the epithelial sodium channel (ENaC), generating a substantial lumen-negative transepithelial potential difference. This sodium flux into the tubular cells is balanced by secretion of potassium and hydrogen ions into the lumen and by reabsorption of chloride ions. Potassium is accumulated in the cell by the basolateral Na,K-ATPase, and passes into the luminal fluid down its electrochemical gradient, through an apical potassium channel (ROMK). Chloride ions pass largely between cells. Hydrogen ion secretion is mediated by an H+-ATPase located on the luminal membrane of the intercalated cells, which constitute approximately one-third of the epithelial cells in this segment of the nephron. The distal tubule and collecting duct have a variable permeability to water, depending on circulating levels of vasopressin (antidiuretic hormone, ADH).

Sodium homeostasis • 351

sinus) and the afferent arterioles within the kidney. A further afferent signal is generated within the kidney itself: the enzyme renin is released from specialised smooth muscle cells in the walls of the afferent and efferent arterioles, at the point where they make contact with the early distal tubule (at the macula densa; see Fig. 14.2) to form the juxtaglomerular apparatus. Renin release is stimulated by: • reduced perfusion pressure in the afferent arteriole • increased sympathetic nerve activity • decreased sodium chloride concentration in the distal tubular fluid. Renin acts on the peptide substrate, angiotensinogen (which is produced by the liver), to produce angiotensin I, which is cleaved by angiotensin-converting enzyme (ACE), largely in the pulmonary capillary bed, to produce angiotensin II (see Fig. 18.18, p. 666). Angiotensin II has multiple actions: it stimulates proximal tubular sodium reabsorption and release of aldosterone from the zona glomerulosa of the adrenal cortex, and causes vasoconstriction of small arterioles. Aldosterone amplifies sodium All ion transport processes in this segment are stimulated by the steroid hormone aldosterone, which can increase sodium reabsorption in this segment to a maximum of 2–3% of the filtered sodium load. Less than 1% of sodium reabsorption occurs in the medullary collecting duct, where it is inhibited by atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP). Regulation of sodium transport The amount of sodium excreted by the kidney is dependent on the filtered load of sodium (which is largely determined by GFR) and the control of tubular sodium reabsorption. A number of interrelated mechanisms serve to maintain whole-body sodium balance, and hence ECF volume, by matching urinary sodium excretion to sodium intake (Fig. 14.4), and controlling those two processes. Important sensing mechanisms include volume receptors in the cardiac atria and the intrathoracic veins, as well as pressure receptors located in the central arterial tree (aortic arch and carotid Fig. 14.3 Principal transport mechanisms in segments of the nephron. The apical membrane of tubular cells is the side facing the lumen and the basolateral membrane is the side facing the blood. Black circles indicate active transport pumps linked to ATP hydrolysis and white symbols indicate ion channels and transporter molecules. Details of the proportion of sodium reabsorbed, influence of regulatory factors, water permeability and sites of action for different classes of diuretics are shown. The SGLT2 inhibitors are primarily used for the treatment of diabetes but have diuretic properties by blocking SGLT2 in the proximal tubule. At the same site, acetazolamide inhibits carbonic anhydrase (CA), which, by reducing production of hydrogen ions by proximal tubular cells, inhibits sodium–hydrogen exchange through the NHE-3 transporter. Loop diuretics block the NKCC2 transporter in the loop of Henle, whereas thiazide diuretics block the NCCT channel in the early distal tubule. Amiloride and spironolactone block the ENaC channel in the late distal tubule and collecting ducts. See text for further details and abbreviations. Na+ Gluc SGLT2 NHE-3 Na+ ‘Shunt’ 3Na+ 2K+ CO2+H2O HCO3– H+ CA A Proximal Transporter Na+, K+, Ca2+, Mg2+ Na+ 3Na+ 2K+ B Loop of Henle Na+ 3Na+ 2K+ C Early distal Na+ ENaC 3Na+ 2K+ D Late distal 2Cl− NKCC2 K+ K+ Cl− Ca2+ Ca2+ 3Na+ H+ HCO3 – Cl− Cl− Principal cell Intercalated cell Lumen Blood Urine Na reabsorption (%) hormonal control Water permeability Diuretics Highly permeable SGLT2 inhibitors Acetazolamide (25%) Impermeable Loop diuretics (6%) Impermeable Thiazide diuretics (2–3%) Aldosterone Permeability increased by vasopressin Amiloride Spironolactone

(65%) Angiotensin II Sympathetic nerves Peritubular forces K+ ROMK ROMK NCCT

352 • CLINICAL BIOCHEMISTRY AND METABOLIC MEDICINE of sodium-containing fluids or acute blood loss, as summarised in Box 14.4. Pathogenesis Loss of sodium-containing fluid triggers the changes in renal sodium handling and activation of the renin–angiotensin system that were described on page 349. Loss of whole blood, as in acute haemorrhage, is another cause of hypovolaemia, and elicits the same mechanisms for the conservation of sodium and water as loss of sodium-containing fluid. Clinical features Hypovolaemia is primarily a clinical diagnosis, based on characteristic symptoms such as thirst, dizziness and weakness along with characteristic clinical signs (see Box 14.3) in the context of a relevant precipitating illness. Investigations Serum sodium concentrations are usually normal in hypovolaemia. The GFR is usually maintained unless the hypovolaemia is very severe or prolonged, but urinary flow rate is reduced as a consequence of activation of sodium- and water-retaining mechanisms in the nephron. Serum creatinine, which reflects GFR, is usually normal, but serum urea concentration is typically elevated due to a low urine flow rate, which is accompanied retention by its action on the cortical collecting duct. The net effect of activation of the renin–angiotensin system is to raise blood pressure and cause sodium and water retention, thereby correcting hypovolaemia. Changes in GFR alter peritubular hydrostatic pressure and oncotic pressure in opposite directions, resulting in a change in sodium reabsorption. In particular, with hypovolaemia, and a reduction in hydrostatic pressure and an increase in oncotic pressure, there is an increase in sodium reabsorption. The sympathetic nervous system also acts to increase sodium retention, both through haemodynamic mechanisms (afferent arteriolar vasoconstriction and GFR reduction) and by direct stimulation of proximal tubular sodium reabsorption. In contrast, other humoral mediators, such as the natriuretic peptides, which inhibit sodium reabsorption, contribute to natriuresis during periods of sodium and volume excess. Increases in sodium intake cause hypervolaemia, which increases renal perfusion and GFR and suppresses renin production through increased delivery of sodium into the macula densa. This sets in motion a train of events opposite to those that occur in hypovolaemia, to cause an increase in sodium excretion. Presenting problems in sodium and water balance When the balance of sodium intake and excretion is disturbed, any tendency for plasma sodium concentration to change is usually corrected by the osmotic mechanisms controlling water balance (p. 349). As a result, disorders in sodium balance present chiefly as alterations in the ECF volume, resulting in hypovolaemia or hypervolaemia, rather than as an alteration in plasma sodium concentration. Clinical manifestations of altered ECF volume are illustrated in Box 14.3. Hypovolaemia Hypovolaemia is defined as a reduction in circulating blood volume. The most common causes are loss or sequestration Fig. 14.4 Mechanisms involved in the regulation of sodium transport. (ANP = atrial natriuretic peptide; BNP = brain natriuretic peptide; ECF = extracellular fluid; GFR = glomerular filtration rate; RAA = renin–angiotensin–aldosterone system; SNS = sympathetic nervous system. Պ indicates an effect to stimulate Na reabsorption and hence reduce Na excretion, while Ջ indicates an effect to inhibit Na reabsorption and hence increase Na excretion) • Volume receptors Cardiac atria Intrathoracic veins • Pressure receptors Aortic arch/carotids Afferent arteriole • Tubular fluid [NaCl] Macula densa • Neurohumoral RAA SNS/catecholamines ANP BNP Prostaglandins • Haemodynamic GFR Peritubular forces ECF Na content and volume Afferent Efferent Sensors Effectors 14.3 Clinical features of hypovolaemia and hypervolaemia Hypovolaemia Hypervolaemia Symptoms Thirst Dizziness on standing Weakness Ankle swelling Abdominal swelling Breathlessness Signs Postural hypotension Tachycardia Dry mouth Reduced skin turgor Reduced urine output Weight loss Delirium, stupor Peripheral oedema Raised JVP Pulmonary crepitations Pleural effusion Ascites Weight gain Hypertension (sometimes) (JVP = jugular venous pressure) 14.4 Causes of hypovolaemia Mechanism Examples Inadequate sodium intake Environmental deprivation, inadequate therapeutic replacement Gastrointestinal sodium loss Vomiting, diarrhoea, nasogastric suction, external fistula Skin sodium loss Excessive sweating, burns Renal sodium loss Diuretic therapy, mineralocorticoid deficiency, tubulointerstitial disease Internal sequestration* Bowel obstruction, peritonitis, pancreatitis, crush injury Reduced blood volume Acute blood loss *A cause of circulatory volume depletion, although total body sodium and water may be normal or increased.

Sodium homeostasis • 353

You would expect that solutions containing plasma proteins (colloids) would be better retained within the vascular space and to be more effective at correcting hypovolaemia than protein-free fluids (crystalloids). However, recent clinical studies have not shown any advantage of giving albumin-containing infusions in the treatment of acute hypovolaemia. Furthermore, synthetic colloids such as dextrans have been shown to be associated with an increased risk of acute kidney injury and mortality in the critically ill. Therefore, crystalloids are the fluid of choice for resuscitation in acute hypovolaemia. More studies, however, are required to clarify the most appropriate crystalloid in this situation, given that normal saline can cause a mild metabolic acidosis, perhaps related to excessive chloride loading, whereas ‘balanced solutions’, such as Hartmann’s, may cause a mild hyponatraemia, as its composition is slightly hypotonic. Hypervolaemia Hypervolaemia is the result of sodium and water excess and is rare in patients with normal cardiac and renal function, since by increased tubular reabsorption of urea. Similarly, serum uric acid may also rise, reflecting increased reabsorption in the proximal renal tubule. The urine osmolality increases due to increased reabsorption of sodium and water, while the urine sodium concentration falls and sodium excretion may fall to less than 0.1% of the filtered sodium load. Management Management of sodium and water depletion has two main components: • treat the cause where possible, to stop ongoing salt and water losses • replace the salt and water deficits, and provide ongoing maintenance requirements, usually by intravenous fluid replacement when depletion is severe. Intravenous fluid therapy Intravenous fluid therapy can be used to maintain water, sodium and potassium intake when the patient is fasting, such as during an acute illness or post-operatively. If any deficits or continuing pathological losses are identified, additional fluid and electrolytes will be required. In prolonged periods of fasting (more than a few days), attention also needs to be given to providing sufficient caloric and nutritional intake to prevent excessive catabolism of body energy stores (p. 704). The daily maintenance requirements for water and electrolytes in a typical adult are shown in Box 14.5 and the composition of some widely available intravenous fluids are given in Box 14.6. The choice of fluid and the rate of administration depend on the clinical circumstances, as assessed at the bedside and from laboratory data, as described in Box 14.7. The choice of intravenous fluid therapy in the treatment of significant hypovolaemia relates to the concepts in Figure 14.1. If fluid containing neither sodium nor protein is given, it will distribute in the body fluid compartments in proportion to the normal distribution of total body water. For example, administration of 1 L of 5% dextrose contributes little (approximately 3/40 of the infused volume) towards expansion of the plasma volume, which makes this fluid unsuitable for restoring the circulation and perfusion of vital organs. Intravenous infusion of an isotonic (normal) saline solution, on the other hand, is more effective at expanding the ECF, although only a small proportion (about 3/15) of the infused volume actually contributes to plasma volume. 14.5 Basic daily water and electrolyte requirements Requirement per kg Typical 70 kg adult Water 35–45 mL/kg 2.45–3.15 L/24 hrs Sodium 1.5–2 mmol/kg 105–140 mmol/24 hrs Potassium 1.0–1.5 mmol/kg 70–105 mmol/24 hrs 14.6 Composition of some isotonic intravenous fluids Fluid D-glucose Calories Na+ (mmol/L) Cl− (mmol/L) Other (mmol/L) 5% dextrose 50 g

Normal (0.9%) saline

Hartmann’s solution

K+ 5 Ca2+ 2 Lactate− 29 14.7 How to assess fluid and electrolyte balance in hospitalised patients Step 1: assess clinical volume status • Examine patient for signs of hypovolaemia or hypervolaemia (see Box 14.3) • Check daily weight change Step 2: review fluid balance chart • Check total volumes IN and OUT on previous day (IN–OUT is positive by ~400 mL in normal balance, reflecting insensible fluid losses of ~800 mL and metabolic water generation of ~400 mL) • Check cumulative change in daily fluid balance over previous 3–5 days • Correlate chart figures with weight change and clinical volume status to estimate net fluid balance Step 3: assess ongoing pathological process • Check losses from gastrointestinal tract and surgical drains • Estimate increased insensible losses (e.g. in fever) and internal sequestration (‘third space’) Step 4: check plasma U&Es (see Box 14.2) • Check plasma Na as marker of relative water balance • Check plasma K as a guide to extracellular K balance • Check HCO3 − as a clue to acid–base disorder • Check urea and creatinine to monitor renal function Step 5: prescribe appropriate intravenous fluid replacement therapy • Replace basic water and electrolytes each day (see Box 14.5) • Allow for anticipated oral intake and pathological fluid loss • Adjust amounts of water (if IV, usually given as isotonic 5% dextrose), sodium and potassium according to plasma electrolyte results

354 • CLINICAL BIOCHEMISTRY AND METABOLIC MEDICINE importance. In Conn’s syndrome (p. 674), the pathophysiology also differs, in that increased secretion of aldosterone directly stimulates sodium reabsorption. Clinical features Peripheral oedema is the most common physical sign of hypervolaemia since the excess fluid leaks out of the capillaries to expand the interstitial compartment of the ECF. This is particularly the case in nephrotic syndrome and chronic liver disease, in which hypoalbuminaemia is a prominent feature. The main exception is primary hyperaldosteronism (Conn’s syndrome), which presents with hypertension and often hypokalaemia, but in which peripheral oedema is not commonly seen. Investigations Although hypervolaemia is accompanied by an excess of total body sodium, serum sodium concentrations are normal due to the accompanying water retention. Serum concentrations of potassium are normal except in Conn’s syndrome, where there is hypokalaemia due to the increased aldosterone production (p. 674). Creatinine, GFR and urea are usually normal, unless the underlying cause of hypervolaemia is renal failure. General investigations may reveal evidence of cardiac, renal or liver disease. Management The management of hypervolaemia involves a number of components: • specific treatment directed at the underlying cause, such as ACE inhibitors in heart failure and glucocorticoids in minimal change nephropathy • restriction of dietary sodium (to 50–80 mmol/24 hrs) to match the diminished excretory capacity • treatment with diuretics. Diuretic therapy Diuretics play a pivotal role in the treatment of hypervolaemia due to salt and water retention and in hypertension (p. 513). They act by inhibiting sodium reabsorption at various locations along the nephron (see Fig. 14.3). Their potency and adverse effects relate to their mechanism and site of action. Carbonic anhydrase inhibitors Acetazolamide is a carbonic anhydrase inhibitor that inhibits intracellular production of H+ ions in the proximal tubule, reducing the fraction of sodium reabsorption that is exchanged for H+ by the apical membrane sodium–hydrogen exchanger. It is a weak diuretic but is seldom used clinically for this purpose, since only a small fraction of proximal sodium reabsorption uses this mechanism, and much of the sodium that is not reabsorbed in the proximal tubule can be reabsorbed by downstream segments of the nephron. Sodium-dependent glucose transporter inhibitors Inhibitors of the sodium-dependent glucose transporter 2 (SGLT2), such as dapagliflozin and canagliflozin, simultaneously block glucose and sodium reabsorption in the proximal tubule. They have mild diuretic properties but are principally used to lower blood glucose in the treatment of diabetes (p. 745). Loop diuretics Loop diuretics, such as furosemide, inhibit sodium reabsorption in the thick ascending limb of the loop of Henle, by blocking the action of the apical membrane NKCC2 co-transporter. Because this segment reabsorbs a large fraction the kidney has a large capacity to increase renal excretion of sodium and water via the homeostatic mechanisms described on page 349. Pathogenesis The most common systemic disorders responsible for hypervolaemia are outlined in Box 14.8. In cardiac failure, cirrhosis and nephrotic syndrome, sodium retention occurs in response to circulatory insufficiency caused by the primary disorder, as illustrated in Figure 14.5. The pathophysiology is different in renal failure, when the primary cause of volume expansion is the profound reduction in GFR impairing sodium and water excretion, while secondary tubular mechanisms are of lesser 14.8 Causes of sodium and water excess Mechanism Examples Impaired renal function Primary renal disease Primary hyperaldosteronism* Conn’s syndrome Secondary hyperaldosteronism (see Fig. 14.5) Congestive cardiac failure Cirrhotic liver disease Nephrotic syndrome Protein-losing enteropathy Malnutrition Idiopathic/cyclical oedema Renal artery stenosis* *Conditions in this box other than primary hyperaldosteronism and renal artery stenosis are typically associated with generalised oedema. Fig. 14.5 Secondary mechanisms causing sodium excess and oedema in cardiac failure, cirrhosis and nephrotic syndrome. Primary renal retention of Na and water may also contribute to oedema formation when glomerular filtration rate is significantly reduced (see Box 14.8 and p. 395). Cirrhosis Nephrotic syndrome Heart failure Peripheral vasodilatation/ splanchnic pooling Reduced albumin synthesis Heavy proteinuria ↓Cardiac output ↓ Plasma albumin ↓ Arterial filling • ↑ Renin–angiotensin–aldosterone • ↑ Renal sympathetic drive • Altered renal haemodynamics ↑Venous pressure Na+ + H2O retention ↑Capillary hydrostatic pressure ↓ Capillary oncotic pressure Oedema

Water homeostasis • 355

An important feature of the most commonly used diuretic drugs (furosemide, thiazides and amiloride) is that they act on their target molecules from the luminal side of the tubular epithelium. Since they are highly protein-bound in the plasma, very little reaches the urinary fluid by glomerular filtration, but there are active transport mechanisms for secreting organic acids and bases, including these drugs, across the proximal tubular wall into the lumen, resulting in adequate drug concentrations being delivered to later tubular segments. This secretory process may be impaired by certain other drugs, and also by accumulated organic anions as occurs in chronic kidney disease and chronic liver failure, leading to resistance to diuretics. Diuretic resistance is encountered under a variety of circumstances, including impaired renal function, activation of sodium-retaining mechanisms, impaired oral bioavailability (such as in patients with gastrointestinal disease) and decreased renal blood flow. In these circumstances, short-term intravenous therapy with a loop-acting agent such as furosemide may be useful. Combinations of diuretics administered orally may also increase potency. Either a loop or a thiazide drug can be combined with a potassium-sparing drug, and all three classes can be used together for short periods, with carefully supervised clinical and laboratory monitoring. Water homeostasis Daily water intake can vary from about 500 mL to several litres a day. About 800 mL of water is lost daily through the stool, sweat and the respiratory tract (insensible losses) and about 400 mL is generated daily through oxidative metabolism (metabolic water). The kidneys are chiefly responsible for adjusting water excretion to balance intake, endogenous production and losses so as to maintain total body water content and serum osmolality within the reference range of 280–296 mOsmol/kg. Functional anatomy and physiology While regulation of total ECF volume is largely achieved through renal control of sodium excretion, mechanisms exist to allow for the excretion of urine that is hypertonic or hypotonic in relation to plasma to maintain constant plasma osmolality. These functions are largely achieved by the loop of Henle and the collecting ducts (see Fig. 14.2). The countercurrent configuration of flow in adjacent limbs of the loop (Fig. 14.6) involves osmotic movement of water from the descending limbs and reabsorption of of the filtered sodium, these drugs are potent diuretics, and are commonly used in diseases associated with significant oedema. Loop diuretics cause excretion not only of sodium (and with it water) but also of potassium. This occurs largely as a result of delivery of increased amounts of sodium to the late distal tubule and cortical collecting ducts, where sodium reabsorption is associated with excretion of potassium, and is amplified if circulating aldosterone levels are high. Thiazide diuretics Thiazide diuretics inhibit sodium reabsorption in the early distal tubule, by blocking the NCCT co-transporter in the apical membrane. Since this segment reabsorbs a much smaller fraction of the filtered sodium, these are less potent than loop diuretics, but are widely used in the treatment of hypertension and less severe oedema. Like loop diuretics, thiazides increase excretion of potassium through delivery of increased amounts of sodium to the late distal tubule and collecting duct. They are the diuretics that are most likely to be complicated by the development of hyponatraemia, as outlined on page 357. Potassium-sparing diuretics Potassium-sparing diuretics act on the late distal renal tubule and cortical collecting duct segment to inhibit sodium reabsorption. Since sodium reabsorption and potassium secretion are linked at this site, the reduced sodium reabsorption is accompanied by reduced potassium secretion. The apical sodium channel (see Fig. 14.3) is blocked by amiloride and triamterene, while spironolactone and eplerenone also act at this site by blocking binding of aldosterone to the mineralocorticoid receptor. Osmotic diuretics These act independently of a specific transport mechanism. As they are freely filtered at the glomerulus but not reabsorbed by any part of the tubular system, they retain fluid osmotically within the tubular lumen and limit the extent of sodium reabsorption in multiple segments. Mannitol is the most commonly used osmotic diuretic. It is given by intravenous infusion to achieve short-term diuresis in conditions such as cerebral oedema. Clinical use of diuretics The following principles should be observed when using diuretics: • Use the minimum effective dose. • Use for as short a period of time as necessary. • Monitor regularly for adverse effects. The choice of diuretic is determined by the potency required, the presence of coexistent conditions, and the side-effect profile. Adverse effects encountered with the most frequently used classes of diuretic (loop drugs and thiazide drugs) are summarised in Box 14.9. Volume depletion and electrolyte disorders are the most common, as predicted from their mechanism of action. The metabolic side-effects listed are rarely of clinical significance and may reflect effects on K+ channels that influence insulin secretion (p. 723). Since most drugs from these classes are sulphonamides, there is a relatively high incidence of hypersensitivity reactions, and occasional idiosyncratic side-effects in a variety of organ systems. The side-effect profile of the potassium-sparing diuretics differs in a number of important respects from that of other diuretics. The disturbances in potassium, magnesium and acid–base balance are in the opposite direction, so that normal or increased levels of potassium and magnesium are found in the blood, and there is a tendency to metabolic acidosis, especially when renal function is impaired. 14.9 Adverse effects of loop-acting and thiazide diuretics Renal side-effects • Hypovolaemia • Hyponatraemia • Hypokalaemia • Metabolic alkalosis • Hyperuricaemia • Hypomagnesaemia • Hypercalciuria (loop) • Hypocalciuria (thiazide) Metabolic side-effects • Glucose intolerance/ hyperglycaemia • Hyperlipidaemia Miscellaneous side-effects • Hypersensitivity reactions • Erectile dysfunction • Acute pancreatitis/cholecystitis (thiazides)

356 • CLINICAL BIOCHEMISTRY AND METABOLIC MEDICINE osmolality approaching that in the medullary tip (up to 1200 mOsmol/kg). Parallel to these changes in vasopressin release are changes in water-seeking behaviour triggered by the sensation of thirst, which also becomes activated as plasma osmolality rises. In summary, for adequate dilution of the urine there must be: • adequate solute delivery to the loop of Henle and early distal tubule • normal function of the loop of Henle and early distal tubule • absence of vasopressin in the circulation. If any of these processes is faulty, water retention and hyponatraemia may result. Conversely, to achieve concentration of the urine there must be: • adequate solute delivery to the loop of Henle • normal function of the loop of Henle • vasopressin release into the circulation • vasopressin action on the collecting ducts. Failure of any of these steps may result in inappropriate water loss and hypernatraemia. Presenting problems in regulation of osmolality Changes in plasma osmolality are largely determined by changes in serum sodium concentration and its associated anions. Changes in sodium concentration usually occur because of disturbances in water balance either because there is a relative excess of body water compared to total body sodium (hyponatraemia) or solute from neighbouring ascending limbs, to set up a gradient of osmolality from isotonic (like plasma) in the renal cortex to hypertonic (around 1200 mOsmol/kg) in the inner part of the medulla. At the same time, the fluid emerging from the thick ascending limb is hypotonic compared to plasma because it has been diluted by the reabsorption of sodium, but not water, from the thick ascending limb and is further diluted in the early distal tubule. As this dilute fluid passes from the cortex through the collecting duct system to the renal pelvis, it traverses the medullary interstitial gradient of osmolality set up by the operation of the loop of Henle, and water is able to be reabsorbed. Further changes in the urine osmolality on passage through the collecting ducts depend on the circulating level of vasopressin, which is released by the posterior pituitary gland under conditions of increased plasma osmolality or hypovolaemia (p. 688). • When water intake is high and plasma osmolality is normal or low–normal (Fig. 14.6B), vasopressin levels are suppressed and the collecting ducts remain impermeable to water. The luminal fluid osmolality remains low, resulting in the excretion of a dilute urine (minimum osmolality approximately 50 mOsmol/kg in a healthy young person). • When water intake is restricted and plasma osmolality is high (Fig. 14.6A), or in the presence of plasma volume depletion, vasopressin levels rise. This causes water permeability of the collecting ducts to increase through binding of vasopressin to the V2 receptor, which enhances collecting duct water permeability through the insertion of AQP-2 channels into the luminal cell membrane. This results in osmotic reabsorption of water along the entire length of the collecting duct, with maximum urine Fig. 14.6 Mechanisms of renal water handling. (1) Filtrate from the proximal tubule is isosmotic to plasma and cortical interstitial fluid. (2) Water moves down its osmotic gradient, concentrating the filtrate but not diluting the interstitium, as the vasa recta carries away the water. (3) The filtrate is at its highest concentration at the bend of the loop and therefore the surrounding medulla is also concentrated. (4) NaCl is pumped out of the filtrate in the thick ascending limb and early distal tubule, increasing the interstitial fluid osmolality. (5) The filtrate has a concentration of 100 mOsmol/kg as it leaves the early distal tubule. A In the face of water deficit, vasopressin causes water permeability of the collecting ducts, resulting in osmotic reabsorption of water. B In the situation of water overload, vasopressin secretion is suppressed and urine remains dilute. A Loop of Henle Passive diffusion of H2O Active transport of NaCl Portions of tubule impermeable to H2O Permeability to H2O increased by vasopressin Vasa recta From proximal tubule Blood flow Blood flow

H2O NaCl NaCl NaCl H2O H2O H2O H2O H2O H2O

Distal tubule Distal tubule

Water deficit B Water overload Cortex Medulla Collecting tubule

Water homeostasis • 357

euvolaemic, with no evidence of cardiac, renal or hepatic disease potentially associated with hyponatraemia. Other non-osmotic stimuli that cause release of vasopressin (pain, stress, nausea) should also be excluded. Supportive laboratory findings are shown in Box 14.11. Hyponatraemia with hypervolaemia In this situation, excess water retention is associated with sodium retention and volume expansion, as in heart failure, liver disease or kidney disease. Clinical features Hyponatraemia is often asymptomatic but can also be associated with profound disturbances of cerebral function, manifesting as anorexia, nausea, vomiting, delirium, lethargy, seizures and coma. The likelihood of symptoms occurring is related to the speed at which hyponatraemia develops rather than the severity of hyponatraemia. This is because water rapidly flows into cerebral cells when plasma osmolality falls acutely, causing them to become swollen and ischaemic. However, when hyponatraemia develops gradually, cerebral neurons have time to respond by reducing intracellular osmolality, through excreting potassium and reducing synthesis of intracellular organic osmolytes (Fig. 14.7). The osmotic gradient favouring water movement into the cells is thus reduced and symptoms are avoided. This process takes about 24–48 hours and hyponatraemia is therefore classified as acute (< 48 hours) and chronic (> 48 hours). Hyponatraemia can also be defined as mild (130–135 mmol/L), moderate (125–129 mmol/L) or severe (< 124 mmol/L), based on biochemical findings or on the degree of severity of symptoms (Box 14.12). Investigations An algorithm for the clinical assessment of patients with hyponatraemia is shown in Figure 14.8. Artefactual causes of hyponatraemia should be considered in all cases. These include severe hyperlipidaemia or hyperproteinaemia, when the aqueous fraction of the serum specimen is reduced because of the volume occupied by the macromolecules (although this artefact is dependent on the assay technology). Transient hyponatraemia a relative lack of body water compared to total body sodium (hypernatraemia). Abnormalities of water balance can result from disturbances in urinary concentration or dilution. If extracellular osmolality falls abruptly, water flows rapidly across cell membranes, causing cell swelling, whereas cell shrinkage occurs when osmolality rises. Cerebral function is particularly sensitive to such volume changes, particularly brain swelling during hypo-osmolality, which can lead to an increase in intracerebral pressure and reduced cerebral perfusion. Hyponatraemia Hyponatraemia is defined as a serum Na < 135 mmol/L. It is a common electrolyte abnormality with many potential underlying causes, as summarised in Box 14.10. Pathophysiology In all cases, hyponatraemia is caused by greater retention of water relative to sodium. The causes are best categorised according to associated changes in the ECF volume (Box 14.10). Hyponatraemia with hypovolaemia In this situation there is depletion of sodium and water but the sodium deficit exceeds the water deficit, causing hypovolaemia and hyponatraemia (see Box 14.3). The cause of sodium loss is usually apparent and common examples are shown in Box 14.10. Hyponatraemia with euvolaemia In this situation there are no major disturbances of body sodium content and the patient is clinically euvolaemic. Excess body water may be the result of abnormally high intake, either orally (primary polydipsia) or as a result of medically infused fluids (as intravenous dextrose solutions, or by absorption of sodium-free bladder irrigation fluid after prostatectomy). Water retention also occurs in the syndrome of inappropriate secretion of antidiuretic hormone, or vasopressin (SIADH). In this condition, an endogenous source of vasopressin (either cerebral or tumour-derived) promotes water retention by the kidney in the absence of an appropriate physiological stimulus (Box 14.11). The clinical diagnosis requires the patient to be 14.10 Causes of hyponatraemia Volume status Examples Hypovolaemic Renal sodium losses: Diuretic therapy (especially thiazides) Adrenocortical failure Gastrointestinal sodium losses: Vomiting Diarrhoea Skin sodium losses: Burns Euvolaemic Primary polydipsia Excessive electrolyte-free water infusion SIADH Hypothyroidism Hypervolaemic Congestive cardiac failure Cirrhosis Nephrotic syndrome Chronic kidney disease (during free water intake) (SIADH = syndrome of inappropriate antidiuretic hormone (vasopressin) secretion; see Box 14.11). 14.11 Causes and diagnosis of syndrome of inappropriate antidiuretic hormone secretion Causes • Tumours • Central nervous system disorders: stroke, trauma, infection, psychosis, porphyria • Pulmonary disorders: pneumonia, tuberculosis, obstructive lung disease • Drugs: anticonvulsants, psychotropics, antidepressants, cytotoxics, oral hypoglycaemic agents, opiates • Idiopathic Diagnosis • Low plasma sodium concentration (typically < 130 mmol/L) • Low plasma osmolality (< 275 mOsmol/kg) • Urine osmolality not minimally low (typically > 100 mOsmol/kg) • Urine sodium concentration not minimally low (> 30 mmol/L) • Low–normal plasma urea, creatinine, uric acid • Clinical euvolaemia • Absence of adrenal, thyroid, pituitary or renal insufficiency • No recent use of diuretics • Exclusion of other causes of hyponatraemia (see Box 14.10) • Appropriate clinical context (above)

358 • CLINICAL BIOCHEMISTRY AND METABOLIC MEDICINE Fig. 14.7 Hyponatraemia and the brain. Numbers represent osmolality (osmo) in mOsmol/kg. Acute hyponatraemia Slowly developing hyponatraemia Normal cerebral cell Plasma osmo

Osmo

Osmo

Osmo

H2O H2O Loss of cellular osmolytes Osmo

Cerebral swelling → cerebral oedema Osmo

Plasma osmo

No change in cerebral cell size Plasma osmo falls abruptly 290→220 Plasma osmo falls gradually 290→220 14.12 Symptoms and severity of hyponatraemia Severity Serum sodium Symptoms Mild 130–135 mmol/L None Moderate 125–129 mmol/L Nausea Delirium Headache Severe < 124 mmol/L Vomiting Somnolence Seizures Coma Cardiorespiratory arrest may also occur due to osmotic shifts of water out of cells during hyperosmolar states caused by acute hyperglycaemia or by mannitol infusion, but in these cases plasma osmolality is normal. When these conditions have been excluded, serum and urine electrolytes and osmolality (Fig. 14.8) are usually the only tests required to clarify the underlying cause. Hypovolaemic hyponatraemia is characterised by a low urinary sodium concentration (< 30 mmol/L) when there are extrarenal causes of sodium loss and high urinary sodium concentration (> 30 mmol/L) in patients with excessive renal sodium loss. Measurement of vasopressin is not generally helpful in distinguishing between different categories of hyponatraemia. This is because concentrations of vasopressin are raised both in hypovolaemic states and in most chronic hypervolaemic states, as the impaired circulation in those disorders activates vasopressin release through non-osmotic mechanisms. Indeed, patients with these disorders may have higher circulating vasopressin (ADH) levels than patients with SIADH. The only disorders listed in Box 14.10 in which vasopressin is suppressed are primary polydipsia and iatrogenic water intoxication, where the hypo-osmolar state inhibits vasopressin release from the pituitary. Management The treatment of hyponatraemia is critically dependent on its rate of development, severity, presence of symptoms and underlying cause. If hyponatraemia has developed rapidly (< 48 hours) and there are signs of cerebral oedema, such as obtundation or convulsions, sodium levels should be restored rapidly to normal by infusion of hypertonic (3%) sodium chloride. A common approach is to give an initial bolus of 150 mL over 20 minutes, which may be repeated once or twice over the initial hours of observation, depending on the neurological response and rise in plasma sodium. Rapid correction of hyponatraemia that has developed more slowly (> 48 hours) can be hazardous, since brain cells adapt to slowly developing hypo-osmolality by reducing the intracellular osmolality, thus maintaining normal cell volume (see Fig. 14.7). Under these conditions, an abrupt increase in extracellular osmolality can lead to water shifting out of neurons, abruptly reducing their volume and causing them to detach from their myelin sheaths. The resulting ‘myelinolysis’ can produce permanent structural and functional damage to mid-brain structures, and is generally fatal. The rate of correction of the plasma Na concentration in chronic asymptomatic hyponatraemia should not exceed 10 mmol/L/24 hrs, and an even slower rate is generally safer. The underlying cause should also be treated. For hypovolaemic patients, this involves controlling the source of sodium loss, and administering intravenous saline if clinically warranted. Patients with euvolaemic hyponatraemia generally respond to fluid restriction in the range of 600–1000 mL/24 hrs, accompanied where possible by withdrawal of the precipitating stimulus (such as drugs causing SIADH). In patients with persistent hyponatraemia due to prolonged SIADH, oral urea therapy (30–45 g/day) can be used, which provides a solute load to promote water excretion. Oral vasopressin receptor antagonists such as tolvaptan may also be used to block the vasopressin-mediated component of water retention in a range of hyponatraemic conditions, but concerns exist with regard to the risk of overly rapid correction of hyponatraemia with these agents. Hypervolaemic patients with hyponatraemia need treatment of the underlying condition, accompanied by cautious use of diuretics in conjunction with strict fluid restriction. Potassium-sparing diuretics may be particularly useful in this context when there is significant secondary hyperaldosteronism. Hypernatraemia Hypernatraemia is defined as existing when the serum Na is

145 mmol/L. The causes are summarised in Box 14.13, grouped according to any associated disturbance in total body sodium content. Pathophysiology Hypernatraemia occurs due to inadequate concentration of the urine in the face of restricted water intake. This can arise because

Water homeostasis • 359

of failure to generate an adequate medullary concentration gradient in the kidney due to low GFR or loop diuretic therapy, but more commonly is caused by failure of the vasopressin system. This can occur because of pituitary damage (cranial diabetes insipidus, p. 687) or because the collecting duct cells are unable to respond to circulating vasopressin concentrations in the face of restricted water intake (nephrogenic diabetes insipidus). Whatever the underlying cause, sustained or severe hypernatraemia generally reflects an impaired thirst mechanism or responsiveness to thirst. Clinical features Patients with hypernatraemia generally have reduced cerebral function, either as a primary problem or as a consequence of the hypernatraemia itself, which results in dehydration of neurons and brain shrinkage. In the presence of an intact thirst mechanism and preserved capacity to obtain and ingest water, Fig. 14.8 Algorithm for the diagnosis of hyponatraemia. (ECF = extracellular fluid; SIADH = syndrome of inappropriate antidiuretic hormone (vasopressin) secretion) Low serum sodium (<135mmol/L) Check urine osmolality Excessive water intake Measure urine sodium Normal Abnormal <100mOsmol/kg

100mOsmol/kg Low intravascular volume Evidence of kidney disease? < 30mmol/L 30mmol/L Vomiting Diarrhoea Pancreatitis Cirrhosis Heart failure Nephrotic syndrome Check for evidence of hypovolaemia Signs of volume depletion? Signs of fluid overload? Signs of hypovolaemia Normal ECF volume Diuretics Adrenal insufficiency SIADH Hypothyroidism Check urea, glucose, lipids, immunoglobins Hypotonic hyponatraemia (osmolality <275mOsmol/kg) Primary polydipsia Beer potomania Low solute intake Consider non-hypotonic hyponatraemia Yes No Hyponatraemia may be secondary to kidney disease Investigate and treat underlying disorder 14.13 Causes of hypernatraemia Volume status Examples Hypovolaemic Renal sodium losses: Diuretic therapy (especially osmotic diuretic, or loop diuretic during water restriction) Glycosuria (hyperglycaemic hyperosmolar state, p. 738) Gastrointestinal sodium losses: Colonic diarrhoea Skin sodium losses: Excessive sweating Euvolaemic Diabetes insipidus (central or nephrogenic) (p. 687) Hypervolaemic Enteral or parenteral feeding Intravenous or oral salt administration Chronic kidney disease (during water restriction)

360 • CLINICAL BIOCHEMISTRY AND METABOLIC MEDICINE the urine occurs in the late distal tubule and cortical collecting duct to ensure that the amount removed from the blood is proportional to the ingested load. The mechanism for potassium secretion in the distal parts of the nephron is shown in Figure 14.3D. Movement of potassium from blood to lumen is dependent on active uptake across the basal cell membrane by the Na,K-ATPase, followed by diffusion of potassium through the ROMK channel into the tubular fluid. The electrochemical gradient for potassium movement into the lumen is contributed to both by the high intracellular potassium concentration and by the negative luminal potential difference relative to the blood. A number of factors influence the rate of potassium secretion. Luminal influences include the rate of sodium delivery and fluid flow through the late distal tubule and cortical collecting ducts. This is a major factor responsible for the increased potassium loss that accompanies diuretic treatment. Agents interfering with the generation of the negative luminal potential also impair potassium secretion, and this is the basis of reduced potassium secretion associated with potassium-sparing diuretics such as amiloride. Factors acting on the blood side of this tubular segment include plasma potassium and pH, such that hyperkalaemia and alkalosis both enhance potassium secretion directly. However, the most important factor in the acute and chronic adjustment of potassium secretion to match metabolic potassium load is aldosterone. As shown in Figure 14.9, a negative feedback relationship exists between the plasma potassium concentration and aldosterone. In addition to its regulation by the renin–angiotensin system (see Fig. 18.18, p. 666), aldosterone is released from the adrenal cortex in direct response to an elevated plasma potassium. Aldosterone then acts on the kidney to enhance potassium secretion, hydrogen secretion and sodium reabsorption, in the late distal tubule and cortical collecting ducts. The resulting increased excretion of potassium maintains plasma potassium within a narrow range (3.6–5.0 mmol/L). Factors that reduce angiotensin II levels may indirectly affect potassium balance by blunting the rise in aldosterone that would otherwise be provoked by hyperkalaemia. This accounts for the increased risk of hyperkalaemia during therapy with ACE inhibitors and related drugs. Fig. 14.9 Feedback control of plasma potassium concentration. Kidney ↑K+ excretion Adrenal cortex (Zona glomerulosa) ↑Plasma [K+] ↓Plasma [K+] ↑K+ intake Negative feedback ↑Aldosterone hypernatraemia may not progress very far. If adequate water is not obtained, dizziness, delirium, weakness and, ultimately, coma and death can result. Management Treatment of hypernatraemia depends on both the rate of development and the underlying cause. If there is reason to think that the condition has developed rapidly, neuronal shrinkage may be acute and relatively rapid correction may be attempted. This can be achieved by infusing an appropriate volume of intravenous fluid (isotonic 5% dextrose or hypotonic 0.45% saline) at an initial rate of 50–70 mL/hr. In older, institutionalised patients, however, it is more likely that the disorder has developed slowly, and extreme caution should be exercised in lowering plasma sodium to avoid the risk of cerebral oedema. Where possible, the underlying cause should also be addressed (Box 14.13). Elderly patients are predisposed, in different circumstances, to both hyponatraemia and hypernatraemia, and a high index of suspicion of these electrolyte disturbances is appropriate in elderly patients with recent alterations in behaviour (Box 14.14). Potassium homeostasis Potassium is the major intracellular cation (see Fig. 14.1), and the steep concentration gradient for potassium across the cell membrane of excitable cells plays an important part in generating the resting membrane potential and allowing the propagation of the action potential that is crucial to normal functioning of nerve, muscle and cardiac tissues. Control of body potassium balance is described below. Functional anatomy and physiology The kidneys normally excrete some 90% of the daily intake of potassium, typically 80–100 mmol/24 hrs. Potassium is freely filtered at the glomerulus; around 65% is reabsorbed in the proximal tubule and a further 25% in the thick ascending limb of the loop of Henle. Little potassium is transported in the early distal tubule but a significant secretory flux of potassium into 14.14 Hyponatraemia and hypernatraemia in old age • Decline in GFR: older patients are predisposed to both hyponatraemia and hypernatraemia, mainly because, as glomerular filtration rate declines with age, the capacity of the kidney to dilute or concentrate the urine is impaired. • Hyponatraemia: occurs when free water intake continues in the presence of a low dietary salt intake and/or diuretic drugs (particularly thiazides). • Vasopressin release: water retention is aggravated by any condition that stimulates vasopressin release, especially heart failure. Moreover, the vasopressin response to non-osmotic stimuli may be brisker in older subjects. Appropriate water restriction may be a key part of management. • Hypernatraemia: occurs when water intake is inadequate, due to physical restrictions preventing access to drinks and/or blunted thirst. Both are frequently present in patients with advanced dementia or following a severe stroke. • Dietary salt: hypernatraemia is aggravated if dietary supplements or medications with a high sodium content (especially effervescent preparations) are administered. Appropriate prescription of fluids is a key part of management.

Potassium homeostasis • 361

Pathophysiology Hypokalaemia is generally indicative of abnormal potassium loss from the body, through either the kidney or the gastrointestinal tract. Renal causes of hypokalaemia can be divided into those with and those without hypertension. Hypokalaemia in the presence of hypertension may be due to increased aldosterone secretion in Conn’s syndrome (p. 674) or a genetic defect affecting sodium channels in the distal nephron (Liddle’s syndrome). Excessive intake of liquorice or treatment with carbenoxolone may result in a similar clinical picture, due to inhibition of the renal 11βHSD2 enzyme, which inactivates cortisol in peripheral tissues. If blood pressure is normal or low, hypokalaemia can be classified according to the associated change in acid–base balance. Inherited defects in tubular transport should be suspected when hypokalaemia occurs in association with alkalosis, provided that diuretic use has been excluded. One such disease is Bartter’s syndrome, in which sodium reabsorption in the thick ascending limb of Henle is defective, usually due to a loss-of-function mutation of the NKCC2 transporter. The clinical and biochemical features are similar to those in chronic treatment with furosemide. In Gitelman’s syndrome there is a loss-of-function mutation affecting the NCCT transporter in the early distal tubule. The clinical and biochemical features are similar to chronic thiazide treatment. Note that while both Bartter’s and Gitelman’s syndromes are characterised by hypokalaemia and hypomagnesaemia, urinary calcium excretion is increased in Bartter’s syndrome but decreased in Gitelman’s syndrome, analogous to the effects of the loop and thiazide diuretics, respectively, on calcium transport (see Box 14.9). If hypokalaemia occurs in the presence of a normal blood pressure and metabolic acidosis, renal tubular acidosis (proximal or ‘classical’ distal) should be suspected (p. 364). When hypokalaemia is due to potassium wasting through the gastrointestinal tract, the cause is usually obvious clinically. In some cases, when there is occult induction of vomiting, the hypokalaemia is characteristically associated with metabolic alkalosis, due to loss of gastric acid. If, however, potassium loss has occurred through the surreptitious use of aperients, the hypokalaemia is generally associated with metabolic acidosis. In both cases, urinary potassium excretion is low unless there is significant extracellular volume depletion, which can raise urinary potassium levels by stimulating aldosterone production. Hypokalaemia can also be caused by redistribution of potassium into cells as the result of insulin, β-adrenoceptor agonists and alkalosis, or as the result of K+ flux into muscle in hypokalaemic periodic paralysis, which is associated with mutations in several genes that regulate transmembrane ion flow into muscle cells. Finally, reduced dietary intake of potassium can contribute to hypokalaemia but is seldom the only cause, except in extreme cases. Clinical features Patients with mild hypokalaemia (plasma K+ 3.0–3.3 mmol/L) are generally asymptomatic, but more profound reductions in plasma potassium often lead to muscular weakness and associated tiredness. Ventricular ectopic beats or more serious arrhythmias may occur and the arrhythmogenic effects of digoxin may be potentiated. Typical electrocardiogram (ECG) changes occur, affecting the T wave in particular (p. 347). Functional bowel obstruction may occur due to paralytic ileus. Long-standing hypokalaemia may cause renal tubular damage (hypokalaemic nephropathy) and can interfere with the tubular response to vasopressin (acquired nephrogenic diabetes insipidus), resulting in polyuria and polydipsia. Presenting problems in potassium homeostasis Changes in the distribution of potassium between the ICF and ECF compartments can alter plasma potassium concentration, without any overall change in total body potassium content. Potassium is driven into the cells by extracellular alkalosis and by a number of hormones, including insulin, catecholamines (through the β2-receptor) and aldosterone. Any of these factors can produce hypokalaemia, whereas extracellular acidosis, lack of insulin, and insufficiency or blockade of catecholamines or aldosterone can cause hyperkalaemia due to efflux of potassium from the intracellular compartment. Hypokalaemia Hypokalaemia is a common electrolyte disturbance and is defined as existing when serum K+ falls below 3.5 mmol/L. The main causes of hypokalaemia are shown in Box 14.15. } } } } } } Cause Other features and comment Reduced intake Urine K+ > 20–30 mmol/24 hrs Dietary deficiency Potassium-free intravenous fluids Redistribution into cells Alkalosis Insulin Catecholamines β-adrenergic agonists Hypokalaemic periodic paralysis Caused by flux of K+ into cells Increased urinary excretion Urine K+ > 20–30 mmol/24 hrs Activation of mineralocorticoid receptor: Conn’s syndrome Cushing’s syndrome Glucocorticoid excess Carbenoxelone/liquorice Associated with hypertension and alkalosis Genetic disorders: Liddle’s syndrome Bartter’s syndrome Gitelman’s syndrome Renal tubular acidosis Type 1 (distal) Type 2 (proximal) Associated with hypertension and alkalosis Associated with hypertension, alkalosis and hypomagnesaemia Inherited and acquired forms; associated with high serum chloride. Type 2 associated with glycosuria, aminoaciduria and phosphaturia Acetazolamide Associated with acidosis Diuresis: Loop diuretics Thiazides Recovery from acute tubular necrosis Recovery from renal obstruction Increased sodium delivery to distal tubule Increased gastrointestinal loss Urine K+ < 20–30 mmol/L Upper gastrointestinal tract: Vomiting Nasogastric aspiration Loss of gastric acid Associated with metabolic alkalosis Lower gastrointestinal tract: Diarrhoea Laxative abuse Villous adenoma Bowel obstruction/fistula Ureterosigmoidostomy Associated with metabolic acidosis 14.15 Causes of hypokalaemia

362 • CLINICAL BIOCHEMISTRY AND METABOLIC MEDICINE Investigations Measurement of plasma electrolytes, bicarbonate, urine potassium and sometimes of plasma calcium and magnesium is usually sufficient to establish the diagnosis. If the diagnosis remains unclear, plasma renin should be measured. Levels are low in patients with primary hyperaldosteronism (p. 674) and other forms of mineralocorticoid excess, but raised in other causes of hypokalaemia. When there is no obvious clinical clue to which pathway is involved, measurement of urinary potassium may be helpful; if the kidney is the route of potassium loss, the urine potassium is high (> 30 mmol/24 hrs), whereas if potassium is being lost through the gastrointestinal tract, the kidney retains potassium, resulting in a lower urinary potassium (generally < 20 mmol/24 hrs). It should be noted, however, that if gastrointestinal fluid loss is also associated with hypovolaemia, activation of the renin–angiotensin–aldosterone system may occur, causing increased loss of potassium in the urine. The cause of hypokalaemia may remain unclear despite the above investigations when urinary potassium measurements are inconclusive and the history is incomplete or unreliable. Many such cases are associated with metabolic alkalosis, and in this setting the measurement of urine chloride concentration can be helpful. A low urine chloride (< 30 mmol/L) is characteristic of vomiting (spontaneous or self-induced, in which chloride is lost in HCl in the vomit), while a urine chloride > 40 mmol/L suggests diuretic therapy (acute phase) or a tubular disorder such as Bartter’s or Gitelman’s syndrome. Differentiation between occult diuretic use and primary tubular disorders can be achieved by performing a screen of urine for diuretic drugs. Management Treatment of hypokalaemia involves first determining the cause and correcting this where possible. If the problem is mainly one of redistribution of potassium into cells, reversal of the process responsible may be sufficient to restore plasma potassium without providing supplements. In most cases, however, some form of potassium replacement will be required. This can generally be achieved with slow-release potassium chloride tablets, but in more acute circumstances intravenous potassium chloride may be necessary. The rate of administration depends on the severity of hypokalaemia and the presence of cardiac or neuromuscular complications, but should generally not exceed 10 mmol of potassium per hour. In patients with severe, life-threatening hypokalaemia, the concentration of potassium in the infused fluid may be increased to 40 mmol/L if a peripheral vein is used, but higher concentrations must be infused into a large ‘central’ vein with continuous cardiac monitoring. In the less common situation where hypokalaemia occurs in the presence of systemic acidosis, alkaline salts of potassium, such as potassium bicarbonate, can be given by mouth. If magnesium depletion is also present, replacement of magnesium may also be required, since low cell magnesium can promote tubular potassium secretion, causing ongoing urinary losses. In some circumstances, potassium-sparing diuretics, such as amiloride, can assist in the correction of hypokalaemia, hypomagnesaemia and metabolic alkalosis, especially when renal loss of potassium is the underlying cause. Hyperkalaemia Hyperkalaemia is a common electrolyte disorder, which is defined as existing when serum K+ is > 5 mmol/L. The causes of hyperkalaemia are summarised in Box 14.16. Pathophysiology It is important to remember that hyperkalaemia can be artefactual due to haemolysis of blood specimens during collection or in vitro, or due to release of potassium from platelets in patients with thrombocytosis. True hyperkalaemia, however, can occur either because of redistribution of potassium between the ICF and ECF, or because potassium intake exceeds excretion. Redistribution Cause Other features and comment Artefactual Haemolysis during venepuncture Haemolysis in vitro Thrombocytosis/leucocytosis Release of intracellular K+ during sample collection, transit or clotting Increased intake Dietary potassium Potassium-containing intravenous fluids Redistribution from cells Acidosis Insulin deficiency Severe hyperglycaemia β-adrenergic blockers (β-blockers) Hyperkalaemic periodic paralysis Rhabdomyolysis Severe haemolysis Tumour lysis syndrome Caused by flux of intracellular K+ into plasma Reduced urinary excretion Reduced glomerular filtration: Acute kidney injury Chronic kidney disease Plasma creatinine typically

500 μmol/L (5.67 mg/dL) Reduced mineralocorticoid receptor activation: Addison’s disease Congenital adrenal hyperplasia Isolated aldosterone deficiency Angiotensin-converting enzyme (ACE) inhibitors Angiotensin-receptor blockers (ARBs) ACE inhibitors and ARBs reduce aldosterone levels Calcineurin inhibitors Spironolactone Eplerenone All block the mineralocorticoid receptor Heparin Heparin inhibits aldosterone production Inhibitors of renin production: Non-steroidal antiinflammatory drugs (NSAIDs) β-blockers Tubulointerstitial disease: Interstitial nephritis Diabetic nephropathy Obstructive uropathy Other: Amiloride Blocks K+ exchange in distal tubule Gordon’s syndrome Direct effect on K+ transport in renal tubule } } } } 14.16 Causes of hyperkalaemia

Acid–base homeostasis • 363

serum potassium constitutes severe hyperkalaemia and requires urgent treatment. Patients who have potassium concentrations < 6.5 mmol/L in the absence of neuromuscular symptoms or ECG changes can be treated with a reduction of potassium intake and correction of predisposing factors. However, in acute and/ or severe hyperkalaemia (plasma potassium > 6.5–7.0 mmol/L), more urgent measures must be taken (Box 14.17). The first step should be infusion of 10 mL 10% calcium gluconate to stabilise conductive tissue membranes (calcium has the opposite effect to potassium on conduction of an action potential). Measures to shift potassium from the ECF to the ICF should also be applied, as they generally have a rapid effect and may avert arrhythmias. Ultimately, a means of removing potassium from the body is generally necessary. When renal function is reasonably preserved, loop diuretics (accompanied by intravenous saline if hypovolaemia is present) may be effective. In renal failure, dialysis may be required. Oral ion exchange resins, such as sodium polystyrene sulfonate (SPS), have traditionally been used to bind and excrete gastrointestinal potassium. There are concerns, however, with regard to SPS’s lack of proven efficacy and safety, with a number of reports of intestinal necrosis associated with its use. Alternative cation exchanges have been developed and are currently being trialled, with the aim of providing more effective and safer alternatives for the treatment of hyperkalaemia. Acid–base homeostasis The pH of arterial plasma is normally 7.40, corresponding to an H+ concentration of 40 nmol/L, and under normal circumstances H+ concentrations do not vary outside the range of 37–45 nmol/L (pH 7.43–7.35). Abnormalities of acid–base balance can occur in a wide range of diseases. Increases in H+ concentration cause acidosis with a decrease in pH, whereas decreases in H+ concentration cause alkalosis with a rise in pH. Functional anatomy and physiology A variety of physiological mechanisms maintain pH of the ECF within narrow limits. The first is the action of blood and tissue buffers, of which the most important involves reaction of H+ ions with bicarbonate to form carbonic acid, which, under the of potassium from the ICF to the ECF may take place in the presence of systemic acidosis, or when the circulating levels of insulin, catecholamines and aldosterone are reduced, or when the effects of these hormones are blocked (p. 361). High dietary potassium intake may contribute to hyperkalaemia, but is seldom the only explanation unless renal excretion mechanisms are impaired. The mechanism of hyperkalaemia in acute kidney injury and chronic kidney disease is impaired excretion of potassium into the urine as the result of a reduced GFR. In addition, acute kidney injury can be associated with severe hyperkalaemia when there is an increased potassium load, such as in rhabdomyolysis or in sepsis, particularly when acidosis is present. In chronic kidney disease, adaptation to moderately elevated plasma potassium levels commonly occurs. However, acute rises in potassium triggered by excessive dietary intake, hypovolaemia or drugs (see below) may occur and destabilise the situation. Hyperkalaemia can also develop when tubular potassium secretory processes are impaired, even if the GFR is normal. This can arise in association with low levels of aldosterone, as is found in Addison’s disease, hyporeninaemic hypoaldosteronism or inherited disorders such as congenital isolated hypoaldosteronism, in which there is a defect in aldosterone biosynthesis, and pseudohypoaldosteronism type 2 (Gordon’s syndrome), caused by mutations in the WNK2 and WNK4 genes, which causes decreased potassium secretion in the renal tubules. Drug-induced causes include ACE inhibitors, angiotensinreceptor blockers (ARBs), non-steroidal anti-inflammatory drugs (NSAIDs) and β-adrenoceptor antagonists (β-blockers). In another group of conditions, tubular potassium secretion is impaired as the result of aldosterone resistance. This can occur in a variety of diseases in which there is inflammation of the tubulointerstitium, such as systemic lupus erythematosus; following renal transplantation; during treatment with potassiumsparing diuretics; and in a number of inherited disorders of tubular transport. In aldosterone deficiency or aldosterone resistance, hyperkalaemia may be associated with acid retention, giving rise to the pattern of hyperkalaemic distal (‘type 4’) renal tubular acidosis (p. 364). Clinical features Mild to moderate hyperkalaemia (< 6.5 mmol/L) is usually asymptomatic. More severe hyperkalaemia can present with progressive muscular weakness, but sometimes there are no symptoms until cardiac arrest occurs. The typical ECG changes are shown on page 347. Peaking of the T wave is an early ECG sign, but widening of the QRS complex presages a dangerous cardiac arrhythmia. However, these characteristic ECG findings are not always present, even in severe hyperkalaemia. Investigations Measurement of electrolytes, creatinine and bicarbonate, when combined with clinical assessment, usually provides the explanation for hyperkalaemia. In aldosterone deficiency, plasma sodium concentration is characteristically low, although this can occur with many causes of hyperkalaemia. Addison’s disease should be excluded unless there is an obvious alternative diagnosis, as described on page 671. Management Treatment of hyperkalaemia depends on its severity and the rate of development, but opinions vary as to what level of 14.17 Treatment of severe hyperkalaemia Objective Therapy Stabilise cell membrane potential1 IV calcium gluconate (10 mL of 10% solution) Shift K+ into cells Inhaled β2-adrenoceptor agonist IV glucose (50 mL of 50% solution) and insulin (5 IU Actrapid) IV sodium bicarbonate2 Remove K+ from body IV furosemide and normal saline3 Ion-exchange resin (e.g. Resonium) orally or rectally Dialysis 1If severe hyperkalaemia (K+ typically > 6.5 mmol/L). 2If acidosis present. 3If adequate residual renal function.

364 • CLINICAL BIOCHEMISTRY AND METABOLIC MEDICINE are generated in the tubular cell from the hydration of CO2 to form carbonic acid, which dissociates into an H+ ion secreted luminally, and a bicarbonate ion that passes across the basolateral membrane into the blood. The secreted H+ ions contribute to the reabsorption of any residual bicarbonate present in the luminal fluid, by generating intracellular OH− that reacts with CO2 to form HCO3 −, which exits across the basolateral membrane. However, H+ secretion also contributes net acid for removal from the body, bound to a variety of urinary buffers, of which phosphate and ammonia are the most important. Urinary buffers are required to prevent a reduction in urinary pH, which would create an unfavourable gradient that would prevent further H+ secretion. Filtered phosphate (HPO4 2−) combines with H+ in the distal tubular lumen to form dihydrogen phosphate (H2PO4 −), which is excreted in the urine with sodium. Ammonia (NH3) is generated within tubular cells by deamination of the amino acid glutamine by the enzyme glutaminase. The NH3 then reacts with secreted H+ in the tubular lumen to form ammonium (NH4 +), which becomes trapped in the luminal fluid and is excreted with chloride ions. These two mechanisms remove approximately 1 mmol/kg of hydrogen ions from the body per day, which equates to the non-volatile acid load arising from the metabolism of dietary protein. The slightly alkaline plasma pH of 7.4 (H+ 40 nmol/L) that is maintained during health can be accounted for by the kidney’s ability to generate an acidic urine (typically pH 5–6 (H+ 1000–10 000 nmol/L), in which the net daily excess of metabolic acid produced by the body can be excreted. Presenting problems in acid–base balance Patients with disturbances of acid–base balance may present clinically either with the effects of tissue malfunction due to disturbed pH (such as altered cardiac and central nervous system function), or with secondary changes in respiration that occur as a response to the underlying metabolic change (such as Kussmaul respiration during metabolic acidosis). The clinical picture is often dominated by the underlying cause rather than the acid–base abnormality itself. Frequently, acid–base disturbances only become evident when the venous plasma bicarbonate concentration is measured and found to be abnormal, or when blood gas analysis shows abnormalities in pH, PCO2 or bicarbonate. The most common patterns of abnormality in blood gas parameters are shown in Box 14.18. Note that the terms acidosis and alkalosis strictly refer to the underlying direction of the acid–base change, while acidaemia and alkalaemia more correctly refer to the net change present in the blood. Interpretation of arterial blood gases is also described on page 555. In metabolic disturbances, respiratory compensation is almost immediate, so that the predicted compensatory change in PCO2 is achieved soon after the onset of the metabolic disturbance. In respiratory disorders, on the other hand, a small initial change in bicarbonate occurs as a result of chemical buffering of CO2, largely within red blood cells, but over days and weeks the kidney achieves further compensatory changes in bicarbonate concentration as a result of long-term adjustments in acid secretory capacity. When the clinically obtained acid–base parameters do not accord with the predicted compensation shown, a mixed acid–base disturbance should be suspected (p. 367). Metabolic acidosis Metabolic acidosis occurs when an acid other than carbonic acid (due to CO2 retention) accumulates in the body, resulting in a influence of the enzyme carbonic anhydrase (CA), dissociates to form CO2 and water: CO H O H CO H HCO CA

↔ + + − ⇋ This buffer system is important because bicarbonate is present at a relatively high concentration in ECF (21–29 mmol/L), and two of its key components are under physiological control: CO2 by the lungs, and bicarbonate by the kidneys. These relationships are illustrated in Figure 14.10 (a form of the Henderson–Hasselbalch equation). Respiratory compensation for acid–base disturbances can occur quickly. In response to acid accumulation, pH changes in the brainstem stimulate ventilatory drive, reduce PCO2 and increase pH (p. 555). Conversely, systemic alkalosis leads to inhibition of ventilation, causing a rise in PCO2 and reduction in pH, although it should be noted that this mechanism has limited capacity to change pH because hypoxia provides an alternative stimulus to drive ventilation. The kidneys provide a third line of defence against disturbances of arterial pH. When acid accumulates due to chronic respiratory or metabolic (non-renal) causes, the kidneys have the long-term capacity to enhance urinary excretion of acid, effectively increasing the plasma bicarbonate. Renal control of acid–base balance Regulation of acid–base balance occurs at several sites in the kidney. The proximal tubule reabsorbs about 85% of the filtered bicarbonate ions, through the mechanism for H+ secretion illustrated in Figure 14.3A. This is dependent on the enzyme carbonic anhydrase, both in the cytoplasm of the proximal tubular cells and on the luminal surface of the brush border membranes. The system has a high capacity and is required to rescue filtered bicarbonate, but does not lead to significant acidification of the luminal fluid. Distal nephron segments also have an important role in acid excretion. Hydrogen ions are secreted into the lumen by an H+-ATPase in the intercalated cells of the cortical collecting duct and the outer medullary collecting duct cells. The H+ ions Fig. 14.10 Relationship between pH, PCO2 (in mmHg) and plasma bicarbonate concentration (in mmol/L). Note that changes in HCO3 − concentration are also part of the renal correction for sustained metabolic acid–base disturbances as long as the kidney itself is not the cause of the primary disturbance. pH = 6.1 + log [HCO3 − ] 0.03 × PCO2 1° changes in metabolic disturbances 2° changes after renal compensation 2° changes after respiratory compensation 1° changes in respiratory disturbances

Acid–base homeostasis • 365

due to mutations in the genes that regulate acid or bicarbonate transport in the renal tubules (see Fig. 14.3). Acidosis with an increased anion gap is most commonly seen in ketoacidosis, renal failure and lactic acidosis, where there is endogenous production of anions distinct from Cl− and HCO3 −. Ketoacidosis is caused by insulin deficiency and is exacerbated by catecholamine and stress hormone excess, which combine to cause lipolysis and the formation of acidic ketones (acetoacetate, 3-hydroxybutyrate and acetone). The most common cause of ketoacidosis is diabetic ketoacidosis (DKA); its aetiology and management are discussed on page 735. Starvation ketoacidosis occurs when there is reduced food intake in situations of high glucose demand, such as in neonates, and in pregnant or breastfeeding women. In alcoholic ketoacidosis, there is usually a background of chronic malnutrition and a recent alcohol binge. Two subtypes of lactic acidosis have been defined: • type 1, due to tissue hypoxia and peripheral generation of lactate, as in patients with circulatory failure and shock • type 2, due to impaired metabolism of lactate, as in liver disease or by a number of drugs and toxins, including metformin, which inhibit lactate metabolism (p. 746). Metabolic acidosis with an increased anion gap may also be a consequence of exogenous acid loads from poisoning with aspirin, methanol or ethylene glycol. 14.18 Principal patterns of acid–base disturbance Disturbance Blood H+ Primary change Compensatory response Predicted compensation Metabolic acidosis

401 HCO3 − < 24 mmol/L PCO2 < 5.33 kPa2 PCO2 fall in kPa = 0.16 × HCO3 − fall in mmol/L Metabolic alkalosis < 401 HCO3 − > 24 mmol/L PCO2 > 5.33 kPa2,3 PCO2 rise in kPa = 0.08 × HCO3 − rise in mmol/L Respiratory acidosis 401 PCO2 > 5.33 kPa2 HCO3 − > 24 mmol/L Acute: HCO3 − rise in mmol/L = 0.75 × PCO2 rise in kPa Chronic: HCO3 − rise in mmol/L = 2.62 × PCO2 rise in kPa Respiratory alkalosis < 401 PCO2 < 5.33 kPa2 HCO3 − < 24 mmol/L Acute: HCO3 − fall in mmol/L = 1.50 × PCO2 fall in kPa Chronic: HCO3 − fall in mmol/L = 3.75 × PCO2 fall in kPa 1H+ of 40 nmol/L = pH of 7.40. 2PCO2 of 5.33 kPa = 40 mmHg. 3PCO2 does not rise above 7.33 kPa (55 mmHg) because hypoxia then intervenes to drive respiration. fall in the plasma bicarbonate. The causes of metabolic acidosis are summarised in Box 14.19, subdivided into two categories, depending on whether the anion gap is normal or raised. Pathophysiology Metabolic acidosis with a normal anion gap occurs when there is a primary loss of bicarbonate from the ECF, or when there is poisoning with or therapeutic infusion of a mineral acid such as hydrochloric acid or ammonium chloride. Renal tubular acidosis (RTA) is an important cause of metabolic acidosis with a normal anion gap. It can be caused by a defect in one of three processes: • impaired bicarbonate reabsorption in the proximal tubule (proximal RTA) • impaired acid secretion in the late distal tubule or cortical collecting duct intercalated cells (classical distal RTA) • impaired sodium reabsorption in the late distal tubule or cortical collecting duct, which is associated with reduced secretion of both potassium and H+ ions (hyperkalaemic distal RTA). Various subtypes of RTA are recognised and the most common causes are shown in Box 14.20. The inherited forms of RTA are 14.20 Causes of renal tubular acidosis Proximal renal tubular acidosis (type II RTA) • Inherited: Fanconi’s syndrome Cystinosis Wilson’s disease • Paraproteinaemia: Myeloma • Amyloidosis • Hyperparathyroidism • Heavy metal toxicity: Lead, cadmium and mercury poisoning • Drugs: Carbonic anhydrase inhibitors Ifosfamide Classical distal renal tubular acidosis (type I RTA) • Inherited • Autoimmune diseases: Systemic lupus erythematosus Sjögren’s syndrome • Hyperglobulinaemia • Toxins and drugs: Toluene Lithium Amphotericin Hyperkalaemic distal renal tubular acidosis (type IV RTA) • Hypoaldosteronism (primary or secondary) • Obstructive nephropathy • Renal transplant rejection • Drugs: Amiloride Spironolactone 14.19 Causes of metabolic acidosis Disorder Mechanism Normal anion gap Ingestion or infusion of inorganic acid Therapeutic infusion of or poisoning with NH4Cl, HCl Gastrointestinal HCO3 − loss Loss of HCO3 − in diarrhoea, small bowel fistula, urinary diversion procedure Renal tubular acidosis (RTA) Urinary loss of HCO3 − in proximal RTA; impaired tubular acid secretion in distal RTA Increased anion gap Endogenous acid load Diabetic ketoacidosis Accumulation of ketones1 with hyperglycaemia (p. 735) Starvation ketosis Alcoholic ketoacidosis Accumulation of ketones without hyperglycaemia (p. 725) Lactic acidosis Shock, liver disease, drugs Kidney disease Accumulation of organic acids Exogenous acid load Aspirin poisoning Accumulation of salicylate2 Methanol poisoning Accumulation of formate Ethylene glycol poisoning Accumulation of glycolate, oxalate 1Ketones include acid anions acetoacetate and β-hydroxybutyrate (p. 725). 2Salicylate poisoning is also associated with respiratory alkalosis due to direct ventilatory stimulation. }

366 • CLINICAL BIOCHEMISTRY AND METABOLIC MEDICINE needed. In alcoholism and starvation ketosis, intravenous glucose is indicated. By stimulating endogenous insulin secretion, this will reverse hepatic ketone production. Malnourished patients may also require thiamin, potassium, magnesium and phosphate supplements (p. 706). Use of intravenous bicarbonate in metabolic acidosis is controversial. Because rapid correction of acidosis can induce hypokalaemia or a fall in plasma ionised calcium, the use of bicarbonate infusions is best reserved for situations where the underlying disorder cannot be readily corrected and acidosis is severe (H+ > 100 nmol/L, pH < 7.00) or associated with evidence of tissue dysfunction. The acidosis in RTA can sometimes be controlled by treating the underlying cause (see Box 14.20), but usually supplements of sodium and potassium bicarbonate are also necessary in types I and II RTA to achieve a target plasma bicarbonate level of > 18 mmol/L and normokalaemia. In type IV RTA, loop diuretics, thiazides or fludrocortisone (as appropriate to the underlying diagnosis) may be effective in correcting the acidosis and the hyperkalaemia. Metabolic alkalosis Metabolic alkalosis is characterised by an increase in the plasma bicarbonate concentration and the plasma pH (see Box 14.18). There is a compensatory rise in PCO2 due to hypoventilation but this is limited by the need to avoid hypoxia. Classical causes include primary hyperaldosteronism (Conn’s syndrome, p. 674), Cushing’s syndrome (p. 666) and glucocorticoid therapy (p. 670). Occasionally, overuse of antacid salts for treatment of dyspepsia produces a similar pattern. Pathophysiology Metabolic alkalosis is best classified according to the accompanying changes in ECF volume. Hypovolaemic metabolic alkalosis is the most common pattern. This can be caused by sustained vomiting, in which acid-rich fluid is lost directly from the body, or by treatment with loop diuretics or thiazides. In the case of sustained vomiting, loss of gastric acid is the immediate cause of the alkalosis, but several factors act to sustain or amplify this in the context of volume depletion (Fig. 14.11). Loss of sodium and fluid leads to hypovolaemia and secondary hyperaldosteronism, triggering proximal sodium bicarbonate reabsorption and additional acid secretion by the distal tubule. Hypokalaemia occurs due to potassium loss in the vomitus and by the kidney as the result of secondary hyperaldosteronism, and itself is a stimulus to acid secretion. Additionally, the compensatory rise in PCO2 further enhances tubular acid secretion. The net result is sustained metabolic alkalosis with an inappropriately acid urine, which cannot be corrected until the deficit in circulating volume has been replaced. Normovolaemic (or hypervolaemic) metabolic alkalosis occurs when bicarbonate retention and volume expansion occur simultaneously. Clinical features Clinically, apart from manifestations of the underlying cause, there may be few symptoms or signs related to alkalosis itself. When the rise in systemic pH is abrupt, however, plasma ionised calcium falls and signs of increased neuromuscular irritability, such as tetany, may develop (p. 663). Investigations The diagnosis can be confirmed by measurement of electrolytes and arterial blood gases. Clinical features Normal anion gap metabolic acidosis is usually due either to bicarbonate loss in diarrhoea, where the clinical diagnosis is generally obvious, or to RTA. Although some forms of RTA are inherited, it may also be an acquired disorder, and in these circumstances the discovery of metabolic acidosis may serve as an early clue to the underlying diagnosis. The presentation of increased anion gap acidosis is usually dominated by clinical features of the underlying disease, such as uncontrolled diabetes mellitus, kidney failure or shock, or may be suggested by the clinical history of starvation, alcoholism or associated symptoms, such as visual complaints in methanol poisoning (p. 147). Investigations The different types of metabolic acidosis can be distinguished by blood gas measurements, along with measurements of creatinine, electrolytes and bicarbonate. Under normal circumstances, the anion gap, defined as the numerical difference between the main measured cations (Na+ + K+) and the anions (Cl− + HCO3 −) is about 5–11 mmol/L. This gap is normally made up of anions, such as phosphate and sulphate, as well as albumin. RTA should be suspected when there is a hyperchloraemic acidosis with a normal anion gap in the absence of gastrointestinal disturbance. The diagnosis can be confirmed by finding an inappropriately high urine pH (> 5.5) in the presence of systemic acidosis. Sometimes, distal RTA may be incomplete, such that the plasma bicarbonate concentration may be normal under resting conditions. In this case, an acid challenge test can be performed by administration of an acid load in the form of ammonium chloride to reduce plasma bicarbonate. The diagnosis of incomplete distal RTA can be confirmed if the urine pH fails to fall below 5.3 in the presence of a low bicarbonate. The different subtypes of RTA can be differentiated by various biochemical features. Patients with proximal and distal RTA often present with features of profound hypokalaemia, while type IV RTA is associated with hyperkalaemia. Proximal RTA is frequently associated with urinary wasting of amino acids, phosphate and glucose (Fanconi’s syndrome), as well as bicarbonate and potassium. Patients with this disorder can lower the urine pH when the acidosis is severe and plasma bicarbonate levels have fallen below 16 mmol/L, since distal H+ secretion mechanisms are intact. In the classical form of distal RTA, however, acid accumulation is relentless and progressive, resulting in mobilisation of calcium from bone and osteomalacia with hypercalciuria, renal stone formation and nephrocalcinosis. Potassium is also lost in classical distal RTA, while it is retained in hyperkalaemic distal RTA. Investigations in patients with raised anion gap metabolic acidosis show features of the underlying cause, such as reduced GFR in renal failure and raised urine or blood ketones in ketoacidosis. In DKA, blood glucose is raised, while in starvation and alcoholic acidosis blood glucose is not elevated and may be low. Measurement of plasma lactate is helpful in the diagnosis of lactic acidosis when values are increased over the normal maximal level of 2 mmol/L. Management The first step in management of metabolic acidosis is to identify and correct the underlying cause when possible (see Box 14.19). This may involve controlling diarrhoea, treating diabetes mellitus, correcting shock, stopping drugs that might cause the condition, or using dialysis to remove toxins. Since metabolic acidosis is frequently associated with sodium and water depletion, resuscitation with intravenous fluids is often

Magnesium homeostasis • 367

in plasma pH. If the condition is sustained, renal compensation occurs, such that tubular acid secretion is reduced and the plasma bicarbonate falls. Respiratory alkalosis is usually of short duration, occurring in anxiety states or as the result of over-vigorous assisted ventilation. It can be prolonged in the context of pregnancy, pulmonary embolism, chronic liver disease, and ingestion of certain drugs such as salicylates that directly stimulate the respiratory centre in the brainstem. Clinical features are those of the underlying cause but agitation associated with perioral and digital tingling may also occur, as alkalosis promotes the binding of calcium to albumin, resulting in a reduction in ionised calcium concentrations. In severe cases, Trousseau’s sign and Chvostek’s sign may be positive, and tetany or seizures may develop (p. 663). Management involves correction of identifiable causes, reduction of anxiety, and a period of rebreathing into a closed bag to allow CO2 levels to rise. Mixed acid–base disorders It is not uncommon for more than one disturbance of acid–base metabolism to be present at the same time in the same patient: for example, a respiratory acidosis due to narcotic overdose with metabolic alkalosis due to vomiting. In these situations, the arterial pH will represent the net effect of all primary and compensatory changes. Indeed, the pH may be normal, but the presence of underlying acid–base disturbances can be gauged from concomitant abnormalities in the PCO2 and bicarbonate concentration. In assessing these disorders, all clinical influences on the patient’s acid–base status should be identified, and reference should be made to the table of predicted compensation given in Box 14.18. If the compensatory change is discrepant from the rules of thumb provided, more than one disturbance of acid–base metabolism may be suspected. Calcium homeostasis Disorders of calcium homeostasis are discussed in Chapter 18 and bone disease is discussed in Chapter 24. Magnesium homeostasis Magnesium is mainly an intracellular cation. It is important to the function of many enzymes, including the Na,K-ATPase, and can regulate both potassium and calcium channels. Its overall effect is to stabilise excitable cell membranes. Functional anatomy and physiology Renal handling of magnesium involves filtration of free plasma magnesium at the glomerulus (about 70% of the total), with extensive reabsorption (50–70%) in the loop of Henle and other parts of the proximal and distal renal tubule. Magnesium reabsorption is also enhanced by parathyroid hormone (PTH). Presenting problems in magnesium homeostasis Disturbances in magnesium homeostasis usually occur because of increased loss of magnesium through the gut or kidney or Management Metabolic alkalosis with hypovolaemia can be corrected by intravenous infusions of 0.9% saline with potassium supplements. This reverses the secondary hyperaldosteronism and allows the kidney to excrete the excess alkali in the urine. In metabolic alkalosis with normal or increased volume, treatment should focus on management of the underlying endocrine cause (Ch. 18). Respiratory acidosis Respiratory acidosis occurs when there is accumulation of CO2 due to type II respiratory failure (p. 565). This results in a rise in the PCO2, with a compensatory increase in plasma bicarbonate concentration, particularly when the disorder is of long duration and the kidney has fully developed its capacity for increased acid excretion. This acid–base disturbance can arise from lesions anywhere along the neuromuscular pathways from the brain to the respiratory muscles that result in impaired ventilation. It can also arise during intrinsic lung disease if there is significant mismatching of ventilation and perfusion. Clinical features are primarily those of the underlying cause of the respiratory disorder, such as paralysis, chest wall injury or chronic obstructive lung disease, but the CO2 accumulation may itself lead to drowsiness that further depresses respiratory drive. Management involves correction of causative factors where possible, but ultimately ventilatory support may be necessary. Respiratory alkalosis Respiratory alkalosis develops when there is a period of sustained hyperventilation, resulting in a reduction of PCO2 and increase Fig. 14.11 Generation and maintenance of metabolic alkalosis during prolonged vomiting. Loss of H+Cl− generates metabolic alkalosis, which is maintained by renal changes. Vomiting Na+Cl− Metabolic alkalosis Gastric loss of H+Cl− K+Cl− Hypovolaemia ↑ Proximal Na+HCO3− reabsorption ↑ Renin – angiotensin – aldosterone Hypokalaemia ↑ Distal H+ secretion ↑ Renal NH3 synthesis ↑ H+ excretion

368 • CLINICAL BIOCHEMISTRY AND METABOLIC MEDICINE Management The underlying cause should be identified and treated where possible. When symptoms are present, the treatment of choice is intravenous magnesium chloride at a rate not exceeding 0.5 mmol/kg in the first 24 hours. If intravenous access is not feasible, magnesium sulphate can be given intramuscularly. Oral magnesium salts have limited effectiveness due to poor absorption and may cause diarrhoea. If hypomagnesaemia is caused by diuretic treatment, adjunctive use of a potassium-sparing agent can also help by reducing magnesium loss into the urine. Hypermagnesaemia This is a much less common abnormality than hypomagnesaemia. Predisposing conditions include acute kidney injury, chronic kidney disease and adrenocortical insufficiency. The condition is generally precipitated in patients at risk from an increased intake of magnesium, or from the use of magnesium-containing medications, such as antacids, laxatives and enemas. Clinical features include bradycardia, hypotension, reduced consciousness and respiratory depression. Management involves ceasing all magnesium-containing drugs and reducing dietary magnesium intake, improving renal function if possible, and promoting urinary magnesium excretion using a loop diuretic with intravenous hydration, if residual renal function allows. Calcium gluconate may be given intravenously to ameliorate cardiac effects. Dialysis may be necessary in patients with poor renal function. Phosphate homeostasis Inorganic phosphate (mainly present as HPO4 2−) is intimately involved in cell energy metabolism, intracellular signalling and bone and mineral homeostasis (Ch. 24). The normal plasma concentration is 0.8–1.4 mmol/L (2.48–4.34 mg/dL). Functional anatomy and physiology Phosphate is freely filtered at the glomerulus and approximately 65% is reabsorbed by the proximal tubule, through an apical sodium–phosphate co-transport carrier. A further 10–20% is reabsorbed in the distal tubules, leaving a fractional excretion of some 10% to pass into the urine, usually as H2PO4 −. Proximal reabsorption is decreased by PTH, fibroblast growth factor 23 (FGF23), volume expansion, osmotic diuretics and glucose infusion. Presenting problems in phosphate homeostasis The following section deals primarily with conditions that cause acute disturbances in serum phosphate concentrations. Chronic disorders that are accompanied by phosphate depletion, such as osteomalacia and hypophosphataemic rickets, are discussed in Chapter 24. Acute kidney injury and chronic kidney disease, which are associated with hyperphosphataemia, are discussed below and also in Chapter 15. Hypophosphataemia Hypophosphataemia is defined as existing when serum phosphate values fall below 0.8 mmol/L (2.48 mg/dL). The causes are shown in Box 14.22, subdivided into the underlying pathogenic mechanisms. inability to excrete magnesium normally in patients with renal impairment. Hypomagnesaemia Hypomagnesaemia is defined as existing when plasma magnesium concentrations are below the reference range of 0.75–1.0 mmol/L (1.5–2.0 mEq/L). Pathophysiology Hypomagnesaemia usually is a reflection of magnesium depletion (Box 14.21), which can be caused by excessive magnesium loss from the gastrointestinal tract (notably in chronic diarrhoea) or the kidney (during prolonged use of loop diuretics). Excessive alcohol ingestion can cause magnesium depletion through both gut and renal losses. Some inherited tubular transport disorders, such as Gitelman’s and Bartter’s syndromes, can also result in urinary magnesium wasting (p. 361). Magnesium depletion has important effects on calcium homeostasis because magnesium is required for the normal secretion of PTH in response to a fall in serum calcium, and because hypomagnesaemia causes end-organ resistance to PTH. Clinical features Mild degrees of hypomagnesaemia may be asymptomatic but more severe hypomagnesaemia may be associated with symptoms of hypocalcaemia, such as tetany, cardiac arrhythmias (notably torsades de pointes, p. 476), central nervous excitation and seizures, vasoconstriction and hypertension. Hypomagnesaemia and magnesium depletion are also associated (through uncertain mechanisms) with hyponatraemia and hypokalaemia, which may contribute to some of the clinical manifestations. 14.21 Causes of hypomagnesaemia Mechanism Examples Inadequate intake Starvation Malnutrition Alcoholism Parenteral alimentation Excessive losses Gastrointestinal Prolonged vomiting/nasogastric aspiration Chronic diarrhoea/laxative abuse Malabsorption Small bowel bypass surgery Fistulae Urinary Diuretic therapy Alcohol Tubulotoxic drugs: Gentamicin Cisplatin Volume expansion Diabetic ketoacidosis Post-obstructive diuresis Recovery from acute tubular necrosis Inherited tubular transport defect: Bartter’s syndrome Gitelman’s syndrome Primary renal magnesium wasting Miscellaneous Acute pancreatitis Foscarnet therapy Proton pump inhibitor therapy Hungry bone syndrome Diabetes mellitus

Disorders of amino acid metabolism • 369

primary hyperparathyroidism and hypophosphataemic rickets are described in more detail on pages 664 and 1053. Hyperphosphataemia Hyperphosphataemia is most commonly caused by acute kidney injury or chronic kidney disease (pp. 413 and 419). Pathophysiology In acute kidney injury and chronic kidney disease, the primary cause is reduced phosphate excretion as the result of a low GFR. In contrast, the hyperphosphataemia in hypoparathyroidism and pseudohypoparathyroidism is due to increased tubular phosphate reabsorption. Redistribution of phosphate from cells into the plasma can also be a contributing factor in the tumour lysis syndromes and other catabolic states. Phosphate accumulation can be aggravated in any of these conditions if the patient takes phosphate-containing preparations or inappropriate vitamin D therapy. Clinical features The clinical features relate to hypocalcaemia and metastatic calcification, particularly in chronic kidney disease with tertiary hyperparathyroidism (when a high calcium–phosphate product occurs). Management Hyperphosphataemia in patients with kidney disease should be treated with dietary phosphate restriction and the use of oral phosphate binders (p. 418). Hyperphosphataemia in hypoparathyroidism and pseudohypoparathyroidism does not usually require treatment. Hyperphosphataemia associated with tumour lysis syndromes and catabolic states can be treated with intravenous normal saline, which is given to promote phosphate excretion. Disorders of amino acid metabolism Congenital disorders of amino acid metabolism usually present in the neonatal period and may involve life-long treatment regimens. However, some disorders, particularly those involved in amino acid transport, may not present until later in life. Phenylketonuria Phenylketonuria (PKU) is inherited as an autosomal recessive disorder caused by loss-of-function mutations in the PAH gene, which encodes phenylalanine hydroxylase, an enzyme required for degradation of phenylalanine. As a result, phenylalanine accumulates at high levels in the neonate’s blood, causing intellectual disability. The diagnosis of PKU is almost always made by routine neonatal screening (p. 56). Treatment involves life-long adherence to a low-phenylalanine diet. Early and adequate dietary treatment prevents major intellectual disability, although there may still be a slight reduction in IQ. Homocystinuria Homocystinuria is an autosomal recessive disorder caused by loss-of-function mutations in the CBS gene, which encodes cystathionine β-synthase. The enzyme deficiency causes accumulation of homocysteine and methionine in the blood. Many cases of homocystinuria are diagnosed through newborn screening programmes. Pathophysiology Phosphate may redistribute into cells during periods of increased energy utilisation (such as refeeding after a period of starvation) and during systemic alkalosis. However, severe hypophosphataemia usually represents an overall body deficit due to either inadequate intake or absorption through the gut, or excessive renal losses, most notably in primary hyperparathyroidism (p. 663) or as the result of acute plasma volume expansion, osmotic diuresis and diuretics acting on the proximal renal tubule. Less common causes include inherited defects of proximal sodium–phosphate co-transport and tumour-induced osteomalacia due to ectopic production of the hormone FGF23 (p. 1053). Clinical features The clinical features of phosphate depletion are wide-ranging, reflecting the involvement of phosphate in many aspects of metabolism. Defects appear in the blood (impaired function and survival of all cell lineages), skeletal muscle (weakness, respiratory failure), cardiac muscle (congestive cardiac failure), smooth muscle (ileus), central nervous system (decreased consciousness, seizures and coma) and bone (osteomalacia in severe prolonged hypophosphataemia, p. 1053). Investigations Measurement of creatinine, electrolytes, phosphate, albumin, calcium and alkaline phosphatase should be performed. In selected cases, measurement of PTH and 25(OH)D may be helpful to exclude osteomalacia or hypophosphataemic rickets. The combination of hypophosphataemia and hypercalcaemia suggests primary hyperparathyroidism, which should be further investigated by measurements of PTH, as described on page 663. The presence of hypocalcaemia suggests hypophosphataemic rickets, which should be further investigated as described on page 1053. Management Management of hypophosphataemia due to decreased dietary intake or excessive losses involves administering oral phosphate supplements and high-protein/high-dairy dietary supplements that are rich in naturally occurring phosphate. Intravenous treatment with sodium or potassium phosphate salts can be used in critical situations, but there is a risk of precipitating hypocalcaemia and metastatic calcification. Management of 14.22 Causes of hypophosphataemia Mechanism Examples Redistribution into cells Refeeding after starvation Respiratory alkalosis Treatment for diabetic ketoacidosis Inadequate intake or absorption Malnutrition Malabsorption Chronic diarrhoea Phosphate binders Antacids Vitamin D deficiency or resistance Increased renal excretion Hyperparathyroidism Extracellular fluid volume expansion with diuresis Osmotic diuretics Fanconi’s syndrome Familial hypophosphataemic rickets Tumour-induced hypophosphataemic rickets

370 • CLINICAL BIOCHEMISTRY AND METABOLIC MEDICINE after the physician who first described the condition (Box 14.23). Most forms of GSD are inherited in an autosomal recessive manner. The diagnosis of GSD is made on the basis of the symptoms, physical examination and results of biochemical tests. Occasionally, a muscle or liver biopsy is required to confirm the enzyme defect. Different types of GSD present at different ages, and some may require life-long modifications of diet and lifestyle. Disorders of complex lipid metabolism Complex lipids are key components of the cell membrane that are normally catabolised in organelles called lysosomes. The lysosomal storage diseases are a heterogeneous group of disorders caused by loss-of-function mutations in various lysosomal enzymes (Box 14.24), resulting in an inability to break down complex glycolipids or other intracellular macromolecules. These disorders have diverse clinical manifestations, typically including intellectual disability. Some can be treated with enzyme replacement therapy, while others (such as Tay–Sachs disease) can be prevented through community participation in genetic carrier screening programmes. Lipids and lipoprotein metabolism The three main biological classes of lipid are: • cholesterol, which is composed of hydrocarbon rings • triglycerides (TGs), which are esters composed of glycerol linked to three long-chain fatty acids • phospholipids, which are composed of a hydrophobic ‘tail’ consisting of two long-chain fatty acids linked through glycerol to a hydrophilic head containing a phosphate group. Phospholipids are present in cell membranes and are important signalling molecules. Despite their poor water solubility, lipids need to be absorbed from the gastrointestinal tract and transported throughout the body. This is achieved by incorporating lipids within lipoproteins. Plasma cholesterol and TGs are clinically important because they are major treatable risk factors for cardiovascular disease, while severe hypertriglyceridaemia also predisposes to acute pancreatitis. Clinical manifestations are wide-ranging and involve the eyes (ectopia lentis – displacement of the lens), central nervous system (intellectual disability, delayed developmental milestones, seizures, psychiatric disturbances), skeleton (resembling Marfan’s syndrome, and also with generalised osteoporosis), vascular system (thrombotic lesions of arteries and veins) and skin (hypopigmentation). Treatment is dietary, involving a methionine-restricted, cystinesupplemented diet, as well as large doses of pyridoxine. Disorders of carbohydrate metabolism The most common disorder of carbohydrate metabolism is diabetes mellitus, which is discussed in Chapter 20. There are also some rare inherited defects, discussed below. Galactosaemia Galactosaemia is caused by loss-of-function mutations in the GALT gene, which encodes galactose-1-phosphate uridyl transferase. It is usually inherited in an autosomal recessive manner. The neonate is unable to metabolise galactose, one of the hexose sugars contained in lactose. Vomiting or diarrhoea usually begins within a few days of ingestion of milk, and the neonate may become jaundiced. Failure to thrive is the most common clinical presentation. The classic form of the disease results in hepatomegaly, cataracts and intellectual disability. Fulminant infection with Escherichia coli is a frequent complication. Treatment involves life-long avoidance of galactose- and lactosecontaining foods. The widespread inclusion of galactosaemia in newborn screening programmes has resulted in the identification of a number of milder (‘Duarte’) variants. Glycogen storage diseases Glycogen storage diseases (GSDs, or glycogenoses) result from inherited defects in one of the many enzymes responsible for the formation or breakdown of glycogen, a complex carbohydrate that can be broken down quickly to release glucose during exercise or between meals. There are several major types of GSD, which are classified by a number, by the name of the defective enzyme, or eponymously 14.23 Glycogen storage diseases Type Eponym Enzyme deficiency Clinical features and complications I Von Gierke Glucose-6-phosphatase Childhood presentation, hypoglycaemia, hepatomegaly II Pompe α-glucosidase (acid maltase) Classical presentation in infancy, muscle weakness (may be severe) III Cori Glycogen debrancher enzyme Childhood presentation, hepatomegaly, mild hypoglycaemia IV Andersen Brancher enzyme Presentation in infancy, severe muscle weakness (may affect heart), cirrhosis V McArdle Muscle glycogen phosphorylase Exercise-induced fatigue and myalgia VI Hers Liver phosphorylase Mild hepatomegaly VII Tarui Muscle phosphofructokinase Exercise-induced fatigue and myalgia IX1 Liver phosphorylase kinase Mild hepatomegaly

Hepatic glycogen synthase Fasting hypoglycaemia, post-prandial hyperglycaemia X2 Muscle phosphoglycerate mutase Exercise-induced myoglobinuria 1Note that type VIII has been merged into type IX and no longer exists as a separate entity. 2Recent progress in molecular genetics has recognised a number of additional, rarer types of glycogen storage disease. These are not shown in this table, which stops at type X.

Lipids and lipoprotein metabolism • 371

Lysosomal storage disease Enzyme deficiency Clinical features Human enzyme replacement therapy Fabry’s disease α-galactosidase A Variable age of onset Neurological (pain in extremities) Dermatological (hypohidrosis, angiokeratomas) Cerebrovascular (renal, cardiac, central nervous system) Available for clinical use Gaucher’s disease (various types) Glucocerebrosidase Splenic and liver enlargement, with variable severity of disease Some types also have neurological involvement Available for clinical use in some types Mucopolysaccharidosis Hurler’s syndrome Hunter’s syndrome Sanfilippo’s syndrome Morquio’s syndrome + several other types Several enzymes involved in breakdown of glycosaminoglycans Vary with syndrome: can cause intellectual disability, skeletal and joint abnormalities, abnormal facies, obstructive respiratory diseases and recurrent respiratory infections Available for clinical use in some types; clinical trials under way for other types Niemann–Pick disease Acid sphingomyelinase Most common presentation is as a progressive neurological disorder, accompanied by organomegaly Some variants do not have neurological symptoms Clinical trials planned for some types GM2-gangliosidosis Tay–Sachs disease Hexosaminidase A Severe progressive neurological disorder Cherry-red spot in macula Organomegaly in Sandhoff’s disease Hexosaminidase activator deficiency Hexosaminidase activator Sandhoff’s disease Hexosaminidase A and B } Functional anatomy and physiology Lipids are transported and metabolised by apolipoproteins, which combine with lipids to form spherical or disc-shaped lipoproteins, consisting of a hydrophobic core and a less hydrophobic coat (Fig. 14.12). The structure of some apolipoproteins also enables them to act as enzyme co-factors or cell receptor ligands. Variations in lipid and apolipoprotein composition result in distinct classes of lipoprotein that perform specific metabolic functions. Processing of dietary lipid The intestinal absorption of dietary lipid is described on page 768 (see also Fig. 14.13). Enterocytes lining the gut extract monoglyceride and free fatty acids from micelles and re-esterify them into TGs, which are combined with a truncated form of apolipoprotein B (Apo B48) as it is synthesised. Intestinal cholesterol derived from dietary and biliary sources is also absorbed through a specific intestinal membrane transporter termed NPC1L1. This produces chylomicrons containing TG and cholesterol ester that are secreted basolaterally into lymphatic lacteals and carried to the circulation through the thoracic duct. On entering the blood stream, nascent chylomicrons are modified by further addition of apolipoproteins. Chylomicron TGs are hydrolysed by lipoprotein lipase located on the endothelium of tissue capillary beds. This releases fatty acids that are used locally for energy production or stored as TG in muscle or fat. The residual ‘remnant’ chylomicron particle is avidly cleared by low-density lipoprotein receptors (LDLRs) in the liver, which recognise Apo E on the remnant lipoproteins. Complete absorption of dietary lipids takes about 6–10 hours, so chylomicrons are usually undetectable in the plasma after a 12-hour fast. The main dietary determinants of plasma cholesterol concentrations are the intake of saturated and trans-unsaturated fatty acids, which reduce LDLR levels (see below), whereas dietary cholesterol has surprisingly little effect on fasting cholesterol levels. Plant sterols and drugs that inhibit cholesterol absorption are effective because they also reduce the re-utilisation of biliary cholesterol. The dietary determinants of plasma TG concentrations are complex since excessive intake of carbohydrate, fat or alcohol may all contribute to increased plasma TG by different mechanisms. Endogenous lipid synthesis In the fasting state, the liver is the major source of plasma lipids (Fig. 14.13). The liver may acquire lipids by uptake, synthesis or conversion from other macronutrients. These lipids are transported to other tissues by secretion of very low-density lipoproteins (VLDLs), which are rich in TG but differ from chylomicrons in that they are less massive and contain full-length Apo B100. Following secretion into the circulation, VLDLs undergo metabolic processing similar to that of chylomicrons. Hydrolysis of VLDL TG releases fatty acids to tissues and converts VLDLs into ‘remnant’ particles, referred to as intermediate-density lipoproteins (IDLs). Most IDLs are rapidly cleared by LDLRs in the liver but some are Fig. 14.12 Structure of lipoproteins. Apolipoprotein Free cholesterol Phospholipid Triglyceride Cholesteryl ester 14.24 Lysosomal storage diseases

372 • CLINICAL BIOCHEMISTRY AND METABOLIC MEDICINE of the half-life of LDLR through PCSK9, and modulation of cholesterol esterification. Cholesterol transport Peripheral tissues are further guarded against excessive cholesterol accumulation by high-density lipoproteins (HDLs; Fig. 14.13). Lipid-poor Apo A1 (derived from the liver, intestine and th e outer layer of chylomicrons and VLDL) accepts cellular cholesterol and phospholipid from a specific membrane transporter known as the ATP-binding cassette A1 (ABCA1). This produces small HDLs that are able to accept more free cholesterol from cholesterolrich regions of the cell membrane known as ‘rafts’ via another membrane transporter (ABCG1). The cholesterol that has been accepted by these small HDLs is esterified by lecithin cholesterol acyl transferase (LCAT), thus maintaining an uptake gradient and Fig. 14.13 Absorption, transport and storage of lipids. Pathways of lipid transport are shown; in addition, cholesterol ester transfer protein exchanges triglyceride and cholesterol ester between very low-density lipoprotein/chylomicrons and high-/low-density lipoprotein, and free fatty acids released from peripheral lipolysis can be taken up in the liver. (ABCA1/ABCG1 = adenosine triphosphate-binding cassette A1/G1; Apo = apolipoprotein; BA = bile acids; C = cholesterol; CE = cholesterol ester; FFA = free fatty acids; HDL = mature high-density lipoprotein; HL = hepatic lipase; HMGCoAR = hydroxy-methylglutaryl-co-enzyme A reductase; IDL = intermediate-density lipoprotein; iHDL = immature high-density lipoprotein; LCAT = lecithin cholesterol acyl transferase; LDL = low-density lipoprotein; LDLR = low-density lipoprotein receptor (Apo B100 receptor); LPL = lipoprotein lipase; PCSK9 = proprotein convertase subtilisin kexin 9; SRB1 = scavenger receptor B1; TG = triglyceride; VLDL = very low-density lipoprotein) Synthesis Oxidation FFA TG Bile acids (BA) Apo B100 Cholesterol HMGCoAR Synthesis Liver LDLR LDLR HL SRB1 FFA LPL LPL LDLR LDLR degraded ABCA1 ABCG1 Lipid rafts Cholesterol Oxidation Peripheral tissues TG LCAT HDL iHDL Lipid-poor Apo A1 C CE TG CE PCSK9 LDLR degraded LDLR degraded CE TG TG TG CE iHDL IDL TG CE Chylomicron remnant iHDL iHDL TG TG TG CE Chylomicron VLDL LDL Dietary TG, C and CE Biliary BA and C excretion BA reabsorption Post-prandial Endogenous TG supply Endogenous cholesterol supply Reverse cholesterol transport Biliary excretion/enterohepatic circulation Lymph TG TG TG CE Chylomicron Small intestine iHDL PCSK9 PCSK9 processed by hepatic lipase, which converts the particle to an LDL by removing TG and most materials other than Apo B100, and free and esterified cholesterol. The catabolism of TG-rich chylomicrons and VLDL by lipoprotein lipase is modulated by Apos C2 and C3 on the surface of these particles. The LDL particles act as a source of cholesterol for cells and tissues (Fig. 14.13). LDL cholesterol is internalised by receptor-mediated endocytosis through the LDLR. Delivery of cholesterol via this pathway down-regulates expression of LDLR and reduces the synthesis and activity of the rate-limiting enzyme for cholesterol synthesis, hydroxy-methyl-glutaryl-co-enzyme A (HMGCoA) reductase. Another important regulator of LDLR levels is the sterol-sensitive protease proprotein convertase subtilisin kexin 9 (PCSK9), which degrades the LDLR. Intracellular free cholesterol concentrations are maintained within a narrow range by the inhibitory effects of LDL on expression of LRLR, fine-tuning

Lipids and lipoprotein metabolism • 373

than LDL-C, particularly when TG levels are increased. The use of non-fasting samples is increasing because non-fasting TG is a more sensitive marker of the risk of cardiovascular disease. Nevertheless, a 12-hour fast is required for formal diagnosis of the presence of hypertriglyceridaemia or use of the Friedewald equation. Consideration must be given to confounding factors, such as recent illness, after which cholesterol, LDL and HDL levels temporarily decrease in proportion to severity. Results that will affect major decisions, such as initiation of drug therapy, should be confirmed with a repeat measurement. Elevated levels of TG are common in obesity, diabetes and insulin resistance (Chs 19 and 20), and are frequently associated with low HDL and increased ‘small, dense’ LDL. Under these circumstances, LDL-C may under-estimate risk. This is one situation in which measurement of non-HDLC or Apo B may provide more accurate risk assessment. Presenting problems in lipid metabolism Hyperlipidaemia can occur in association with various diseases and drugs, as summarised in Box 14.25. Overt or subclinical hypothyroidism (p. 639) may cause hypercholesterolaemia, and so measurement of thyroid function is warranted in most cases, even in the absence of typical symptoms and signs. Once secondary causes are excluded, primary lipid abnormalities may be diagnosed. Primary lipid abnormalities can be classified according to the predominant lipid problem: hypercholesterolaemia, hypertriglyceridaemia or mixed hyperlipidaemia (Box 14.26). Although single-gene disorders are encountered in all three categories, most cases are due to multiple-gene (polygenic) loci interacting with environmental factors. Clinical consequences of dyslipidaemia vary somewhat between these causes (pp. 346–347). Hypercholesterolaemia Hypercholesterolaemia is a polygenic disorder that is the most common cause of a mild to moderate increase in remodelling the particle into a mature spherical HDL. These HDLs release their cholesterol to the liver and other cholesterol-requiring tissues via the scavenger receptor B1 (SRB1). The cholesterol ester transfer protein (CETP) in plasma allows transfer of cholesterol from HDLs or LDLs to VLDLs or chylomicrons in exchange for TG. When TG is elevated, the action of CETP may reduce HDL cholesterol and remodel LDLs into ‘small, dense’ LDL particles that may be more atherogenic in the blood-vessel wall. Animal species that lack CETP are resistant to atherosclerosis. Lipids and cardiovascular disease Plasma lipoprotein levels are major modifiable risk factors for cardiovascular disease. Increased levels of atherogenic lipoproteins (especially LDL, but also IDL, and possibly chylomicron remnants) contribute to the development of atherosclerosis (p. 484). A sub-population of LDL particles bears an additional protein known as apolipoprotein (a), which shares homology with plasminogen. The combination of LDL and apolipoprotein (a) is known as lipoprotein (a) (Lp(a)). It transports oxidised phospholipid and is regarded as atherogenic because its plasma concentration is an independent risk factor for cardiovascular disease. Following chemical modifications such as oxidation, Apo B-containing lipoproteins are no longer cleared by normal mechanisms. They trigger a self-perpetuating inflammatory response, during which they are taken up by macrophages to form foam cells, a hallmark of atherosclerotic lesions. These processes also have an adverse effect on endothelial function. Conversely, HDL removes cholesterol from the tissues to the liver, where it is metabolised and excreted in bile. HDL may also counteract some components of the inflammatory response, such as the expression of vascular adhesion molecules by the endothelium. Consequently, low HDL cholesterol levels, which are often associated with TG elevation, are also associated with atherosclerosis. Investigations Lipid measurements are usually performed for the following reasons: • screening for primary or secondary prevention of cardiovascular disease • investigation of patients with clinical features of lipid disorders (p. 347) and their relatives • monitoring of response to diet, weight control and medication. Abnormalities of lipid metabolism most commonly come to light following these tests. Non-fasting measurements of total cholesterol (TC) and HDL cholesterol (HDL-C) allow estimation of non-HDL cholesterol (non-HDLC, calculated as TC − HDL-C), but a 12-hour fasting sample is required to standardise TG measurement and allow calculation of LDL cholesterol (LDL-C) according to the Friedewald formula: LDL-C TC HDL-C TG/ mmol/L

− −( . ) 2 2 or LDL-C TC HDL-C TG/ mg/dL

− −( )

The formula becomes unreliable when TG levels exceed 4 mmol/L (350 mg/dL). Measurements of non-HDLC or Apo B100 may assess risk of cardiovascular disease more accurately 14.25 Causes of secondary hyperlipidaemia Secondary hypercholesterolaemia Moderately common • Drugs: Diuretics Ciclosporin Glucocorticoids Androgens Antiretroviral agents • Hypothyroidism • Pregnancy • Cholestatic liver disease Less common • Nephrotic syndrome • Anorexia nervosa • Porphyria • Hyperparathyroidism Secondary hypertriglyceridaemia Common • Type 2 diabetes mellitus • Chronic renal disease • Abdominal obesity • Excess alcohol • Hepatocellular disease • Drugs: β-blockers Retinoids Glucocorticoids Antiretroviral agents

374 • CLINICAL BIOCHEMISTRY AND METABOLIC MEDICINE consanguineous marriage. Homozygosity results in more extensive xanthomas and precocious cardiovascular disease, often in childhood. Hyperalphalipoproteinaemia refers to increased levels of HDL-C. In the absence of an increase in LDL-C, this condition rarely causes cardiovascular disease, but exceptions can occur so it should not be regarded as universally benign. Familial combined hyperlipidaemia, and dysbetalipoproteinaemia, may present with the pattern of predominant hypercholesterolaemia (see ‘Mixed hyperlipidaemia’ below). Hypertriglyceridaemia Hypertriglyceridaemia also usually involves polygenic factors (see Box 14.26). Other common causes include excess alcohol intake, medications (such as β-blockers and retinoids), type 2 diabetes, impaired glucose tolerance, central obesity or other manifestations of insulin resistance (p. 728) and impaired absorption of bile acids. It is often accompanied by post-prandial hyperlipidaemia and reduced HDL-C, both of which may contribute to cardiovascular risk. Excessive intake of alcohol or dietary fat, or other exacerbating factors, may precipitate a massive increase in TG levels, which, if they exceed 10 mmol/L (880 mg/dL), may pose a risk of acute pancreatitis. Monogenic forms of hypertriglyceridaemia also occur due to loss-of-function mutations in the genes encoding lipoprotein lipase, Apo C2 or ANGPTL4, which coordinate the lipolytic breakdown of TG-rich lipoproteins. These cause recessively inherited forms of severe hypertriglyceridaemia that is not readily amenable to drug treatment. They can present in childhood and may be associated with episodes of acute abdominal pain and pancreatitis. In common with other causes of severe hypertriglyceridaemia, hepatomegaly, lipaemia retinalis and eruptive xanthomas may occur (p. 346). Familial hypertriglyceridaemia may also be inherited in a dominant manner due to mutations in the APOA5 gene, which encodes Apo A5 – a co-factor that is essential for lipoprotein lipase activity. These disorders may also be associated with increased risk of cardiovascular disease. Familial combined hyperlipidaemia, and dysbetalipoproteinaemia, may present with the pattern of predominant hypertriglyceridaemia (see ‘Mixed hyperlipidaemia’, below). LDL-C (Box 14.26). Physical signs, such as corneal arcus and xanthelasma, may be found in this as well as other forms of lipid disturbance (p. 346). The risk of cardiovascular disease is proportional to the degree of LDL-C (or Apo B) elevation, but is modified by other major risk factors, including low HDL-C and high Lp(a). Familial hypercholesterolaemia (FH) is a more severe disorder with a prevalence of at least 0.4% in most populations. It is usually caused by loss-of-function mutations affecting the LDLR gene, which results in an autosomal dominant pattern of inheritance. A similar syndrome can arise with loss-of-function mutations in the ligand-binding domain of Apo B100 or gain-of-function mutations in PCSK9, which promote LDLR degradation. Causative mutations can be detected in one of these three genes by genetic testing in about 70% of patients with FH. Most patients with these types of FH have LDL-C levels that are approximately twice as high as in normal subjects of the same age and gender. Affected patients suffer from severe hypercholesterolaemia and premature cardiovascular disease. FH may be accompanied by xanthomas of the Achilles or extensor digitorum tendons (p. 346), which are strongly suggestive of FH. The onset of corneal arcus before age 40 is also suggestive of this condition. Identification of an index case of FH (the first case of FH in a family) should trigger genetic and biochemical screening of other family members, which is a cost-effective method for case detection. Affected individuals should be managed from childhood (Box 14.27). Homozygous FH may occur sporadically, especially in populations in which there is a ‘founder’ gene effect or 14.26 Classification of hyperlipidaemia Disease Elevated lipid results Elevated lipoprotein CHD risk Pancreatitis risk Predominant hypercholesterolaemia Polygenic (majority) TC ± TG LDL ± VLDL + – Familial hypercholesterolaemia (LDLR defect, defective Apo B100, increased function of PCSK9) TC ± TG LDL ± VLDL +++ – Hyperalphalipoproteinaemia TC ± TG HDL – – Predominant hypertriglyceridaemia Polygenic (majority) TG VLDL ± LDL Variable + Lipoprotein lipase deficiency TG Ԡ TC Chylo ? +++ Familial hypertriglyceridaemia TG > TC VLDL ± Chylo ? ++ Mixed hyperlipidaemia Polygenic (majority) TC + TG VLDL + LDL Variable + Familial combined hyperlipidaemia* TC and/or TG LDL and/or VLDL ++ + Dysbetalipoproteinaemia* TC and/or TG IDL +++ +

Lipids and lipoprotein metabolism • 375

Fish eye disease, Apo A1 Milano and lecithin cholesterol acyl transferase (LCAT) deficiency demonstrate that very low HDL-C levels do not necessarily cause cardiovascular disease, but Apo A1 deficiency, and possibly Tangier disease, demonstrate that low HDL-C can be atherogenic under some circumstances. Autosomal recessive FH and PCSK9 gain-of-function mutations reveal the importance of proteins that chaperone the LDLR. Sitosterolaemia and cerebrotendinous xanthomatosis demonstrate that sterols other than cholesterol can cause xanthomas and cardiovascular disease, while PCSK9 loss-of-function mutations, abetalipoproteinaemia and hypobetalipoproteinaemia suggest that low levels of Apo B-containing lipoproteins reduce the risk of cardiovascular disease. The only adverse health outcomes associated with extremely low plasma lipid levels in the latter two conditions are attributable to fat-soluble vitamin deficiency, or impaired transport of lipid from intestine or liver. Principles of management Lipid-lowering therapies have a key role in the secondary and primary prevention of cardiovascular diseases (p. 487). Assessment of absolute risk of cardiovascular disease, treatment of all modifiable risk factors and optimisation of lifestyle, especially diet and exercise, are central to management in all cases. Patients with the greatest absolute risk of cardiovascular disease derive the greatest absolute benefit from treatment. Public health organisations recommend thresholds for the introduction of lipid-lowering therapy based on the identification of patients in very high-risk categories, or those calculated to be at high absolute risk according to algorithms or tables such as the Joint British Societies Coronary Risk Prediction Chart (see Fig. 16.77, p. 511). These tables, which are based on large epidemiological studies, should be recalibrated for the local population, if possible. In general, patients who have cardiovascular disease, diabetes mellitus, chronic renal impairment, familial hypercholesterolaemia or an absolute risk of cardiovascular disease of more than 20% in the ensuing 10 years are arbitrarily regarded as having sufficient risk to justify drug treatment. Age is such an overwhelming determinant of absolute cardiovascular risk that some recent recommendations consider ‘lifetime’ risk. This diminishes the pressure to treat very elderly patients and supports earlier intervention in non-elderly patients. Public health organisations also recommend target levels for patients receiving drug treatment. High-risk patients should aim for HDL-C > 1 mmol/L (38 mg/dL) and fasting TG < 2 mmol/L (approximately 180 mg/dL), while target levels for LDL-C have been reduced to 1.8 mmol/L (76 mg/dL) or less. In general, total cholesterol should be < 5 mmol/L (190 mg/dL) during treatment, and < 4 mmol/L (approximately 150 mg/dL) in high-risk patients and in secondary prevention of cardiovascular disease. Recent trials have demonstrated continuous benefit of LDL-C reduction to a level of 1.4 mmol/L (54 mg/dL), so further reduction in treatment targets may be anticipated. Non-pharmacological management Patients with lipid abnormalities should receive medical advice and, if necessary, dietary counselling to: • reduce intake of saturated and trans-unsaturated fat to less than 7–10% of total energy • reduce intake of cholesterol to < 250 mg/day • replace sources of saturated fat and cholesterol with alternative foods, such as lean meat, low-fat dairy Mixed hyperlipidaemia It is difficult to define quantitatively the distinction between predominant hyperlipidaemias and mixed hyperlipidaemia. The term ‘mixed’ usually implies the presence of hypertriglyceridaemia, as well as an increase in LDL-C or IDL. Treatment of massive hypertriglyceridaemia may improve TG faster than cholesterol, thus temporarily mimicking mixed hyperlipidaemia. Primary mixed hyperlipidaemia is usually polygenic and, like predominant hypertriglyceridaemia, often occurs in association with type 2 diabetes, impaired glucose tolerance, central obesity or other manifestations of insulin resistance (p. 728). Both components of mixed hyperlipidaemia may contribute to the risk of cardiovascular disease. Familial combined hyperlipidaemia is a term used to identify an inherited tendency towards the over-production of atherogenic Apo B-containing lipoproteins. It results in elevation of cholesterol, TG or both in different family members at different times. It is associated with an increased risk of cardiovascular disease but it does not produce any pathognomonic physical signs. In practice, this relatively common condition is substantially modified by factors such as age and weight. It may not be a monogenic condition, but rather one end of a heterogeneous spectrum that overlaps insulin resistance. Dysbetalipoproteinaemia (also referred to as type 3 hyperlipidaemia, broad-beta dyslipoproteinaemia or remnant hyperlipidaemia) involves accumulation of roughly equimolar levels of cholesterol and TG. It is caused by homozygous inheritance of the Apo E2 allele, which is the isoform least avidly recognised by the LDLR. In conjunction with other exacerbating factors, such as obesity or diabetes, it leads to accumulation of atherogenic IDL and chylomicron remnants. Premature cardiovascular disease is common, as is peripheral vascular disease. It may also result in the formation of palmar xanthomas, tuberous xanthomas or tendon xanthomas. Rare dyslipidaemias Several rare disturbances of lipid metabolism have been described (Box 14.28). They provide important insights into lipid metabolism and its impact on risk of cardiovascular disease. 14.28 Miscellaneous and rare forms of hyperlipidaemia Condition Lipoprotein pattern CVD risk Tangier disease Very low HDL, low TC + Apo A1 deficiency Very low HDL ++ Apo A1 Milano Very low HDL – Fish eye disease Very low HDL, high TG – LCAT deficiency Very low HDL, high TG ? Autosomal recessive FH Very high LDL ++ Sitosterolaemia High plant sterols including sitosterol + Cerebrotendinous xanthomatosis Bile acid defect (cholestanol accumulation) +

376 • CLINICAL BIOCHEMISTRY AND METABOLIC MEDICINE of LDL and its precursor, IDL, resulting in a secondary reduction in LDL synthesis. Statins reduce LDL-C by up to 60%, reduce TG by up to 40% and increase HDL-C by up to 10%. They also reduce the concentration of intermediate metabolites such as isoprenes, which may lead to other effects such as suppression of the inflammatory response. There is clear evidence of protection against total and coronary mortality, stroke and cardiovascular events across the spectrum of cardiovascular disease risk. Statins are generally well tolerated and serious side-effects are rare (well below 2%). Liver function test abnormalities and muscle problems, such as myalgia, asymptomatic increase in creatine kinase (CK), myositis and, infrequently, rhabdomyolysis, are the most common. Side-effects are more likely in patients who are elderly, debilitated or receiving other drugs that interfere with statin degradation, which usually involves cytochrome P450 3A4 or glucuronidation. Ezetimibe Ezetimibe inhibits activity of the intestinal mucosal transporter NPC1L1, which is responsible for absorption of dietary and biliary cholesterol. The resulting depletion of hepatic cholesterol up-regulates hepatic LDLR production. This mechanism of action is synergistic with the effect of statins. Monotherapy in a 10 mg/day dose reduces LDL-C by 15–20%. Slightly greater (17–25%) incremental LDL-C reduction occurs when ezetimibe is added to statins. Ezetimibe is well tolerated, and evidence of a beneficial effect on cardiovascular disease endpoints is now available. Plant sterol-supplemented foods, which also reduce cholesterol absorption, lower LDL-C by 7–15%. Bile acid-sequestering resins Drugs in this class include colestyramine, colestipol and colesevelam. These prevent the reabsorption of bile acids, thereby increasing de novo bile acid synthesis from hepatic cholesterol. As with ezetimibe, the resultant depletion of hepatic cholesterol up-regulates LDL receptor activity and reduces LDL-C in a manner that is synergistic with the action of statins. Resins reduce LDL-C and modestly increase HDL-C, but may increase TG. They are safe but may interfere with bioavailability of other drugs. Colesevelam has fewer gastrointestinal effects than older products, polyunsaturated spreads and low-glycaemicindex carbohydrates • reduce energy-dense foods such as fats and soft drinks, while increasing activity and exercise to maintain or lose weight • increase consumption of cardioprotective and nutrientdense foods, such as vegetables, unrefined carbohydrates, fish, pulses, nuts, legumes, and fruit • adjust alcohol consumption, reducing intake if excessive or if associated with hypertension, hypertriglyceridaemia or central obesity • achieve additional benefits with preferential intake of foods containing lipid-lowering nutrients such as n-3 fatty acids, dietary fibre and plant sterols. The response to diet is usually apparent within 3–4 weeks but dietary adjustment may need to be introduced gradually. Although hyperlipidaemia in general, and hypertriglyceridaemia in particular, can be very responsive to these measures, LDL-C reductions are often only modest in routine clinical practice. Explanation, encouragement and persistence are often required to assist patient adherence. Even minor weight loss can substantially reduce cardiovascular risk, especially in centrally obese patients (p. 700). All other modifiable cardiovascular risk factors should be assessed and treated. If possible, intercurrent drug treatments that adversely affect the lipid profile should be replaced. Pharmacological management The main diagnostic categories provide a useful framework for management and the selection of first-line pharmacological treatment (Fig. 14.14). Hypercholesterolaemia Hypercholesterolaemia can be treated with one or more of the cholesterol-lowering drugs as described below. Statins These reduce cholesterol synthesis by inhibiting the HMGCoA reductase enzyme. The reduction in cholesterol synthesis up-regulates production of the LDLR, which increases clearance Fig. 14.14 Flow chart for the drug treatment of hyperlipidaemia. Interrupt treatment if creatine kinase is more than 5–10 times the upper limit of normal, or if elevated with muscle symptoms, or if alanine aminotransferase is more than 2–3 times the upper limit. To convert triglyceride (TG) in mmol/L to mg/dL, multiply by 88. To convert low-density lipoprotein (LDL)-C in mmol/L to mg/dL, multiply by 38. Predominant hypercholesterolaemia Mixed hyperlipidaemia Predominant hypertriglyceridaemia First-line treatment with statin Ezetimibe if intolerant Monitor lipids, Monitor for side-effects Titrate dose Statin ± ezetimibe ± resin ± nicotinate if resistant Combination treatment if TG and LDL > 4 mmol/L Statin + fish oil Fibrate + ezetimibe Statin + nicotinate Statin + fibrate Monitor for side-effects* First-line treatment with fibrate Fish oil if intolerant Monitor lipids, Monitor for side-effects* Titrate fish oil Fibrate ± fish oil ± nicotinate if resistant

Lipids and lipoprotein metabolism • 377

Highly polyunsaturated long-chain n-3 fatty acids These include eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), which comprise approximately 30% of the fatty acids in fish oil. EPA and DHA are potent inhibitors of VLDL TG formation. Intakes of more than 2 g n-3 fatty acid (equivalent to 6 g of most forms of fish oil) per day lower TG in a dose-dependent fashion. Up to 50% reduction in TG may be achieved with 15 g fish oil per day. Changes in HDL-C are variable but fish oils do not routinely reduce LDL-C. Fish oil fatty acids have also been shown to inhibit platelet aggregation and improve cardiac arrhythmia in animal models. Dietary and pharmacological trials suggested that n-3 fatty acids may reduce mortality from coronary heart disease, but the benefit of fish oil supplements has been less conclusive in recent trials. Fish oils appear to be safe and well tolerated but dietary fish consumption is the preferred source. Patients with predominant hypertriglyceridaemia who do not respond to lifestyle intervention can be treated with fibrates or fish oil, depending on individual response and tolerance. If target levels are not achieved, the fibrates, fish oil and possibly nicotinic acid can be combined. Massive hypertriglyceridaemia may require more aggressive limitation of dietary fat intake (< 10–20% energy as fat). Any degree of insulin deficiency should be corrected because insulin is required for optimal activity of lipoprotein lipase. The initial target for patients with massive hypertriglyceridaemia is TG < 10 mmol/L (880 mg/dL), to reduce the risk of acute pancreatitis. Mixed hyperlipidaemia Mixed hyperlipidaemia can be difficult to treat. First-line therapy with statins alone is unlikely to achieve target levels once fasting TGs exceed approximately 4 mmol/L (350 mg/dL). Fibrates preparations that are less well tolerated. The depletion of bile acids is sensed via the farnesyl X receptor and the response may also improve glucose metabolism. PCSK9 inhibitors Monoclonal antibodies have been developed that neutralise PCSK9, an enzyme that degrades the LDLR. This causes levels of LDLR to increase, which markedly reduces LDL-C. The PCSK9 inhibitors currently available are evolocumab and alirocumab, which are administered by subcutaneous injection every 2–4 weeks. These drugs are well tolerated and highly effective. Reductions in LDL-C of about 50–60% have been observed in patients who have not responded adequately to standard lipid-lowering therapy and this has been accompanied by a reduction in the risk of cardiovascular events of about 15%. The PCSK9 inhibitors do not deplete intracellular concentrations and, because of that, do not trigger compensatory mechanisms that blunt the effect of other cholesterol-lowering medications. Nicotinic acid Pharmacological doses reduce peripheral fatty acid release, with the result that VLDL and LDL decline while HDL-C increases. Recent randomised clinical trials have been disappointing regarding effects on atherosclerosis and cardiovascular events. The same may be said of novel agents that inhibit cholesterol ester transfer protein. Neither of these HDL-C-raising drugs is indicated in current lipid management. Combination therapy In many patients, treatment of predominant hypercholesterolaemia can be achieved by diet plus the use of a statin in sufficient doses to achieve target LDL-C levels. Patients who do not reach LDL targets on the highest tolerated statin dose, or who are intolerant of statins, may receive ezetimibe, plant sterols, or resins. Ezetimibe and resins are safe and effective in combination with a statin because the mechanisms of action of individual therapies complement each other while blunting each other’s compensatory mechanisms. Hypertriglyceridaemia Predominant hypertriglyceridaemia can be treated with one of the TG-lowering drugs described below (see Fig. 14.14). Fibrates These stimulate peroxisome proliferator-activated receptor (PPAR) alpha, which controls the expression of gene products that mediate the metabolism of TG and HDL. As a result, synthesis of fatty acids, TG and VLDL is reduced, while that of lipoprotein lipase, which catabolises TG, is enhanced. In addition, production of Apo A1 and ABC A1 is up-regulated, leading to increased reverse cholesterol transport via HDL. Consequently, fibrates reduce TG by up to 50% and increase HDL-C by up to 20%, but LDL-C changes are variable. Fewer large-scale trials have been conducted with fibrates than with statins. The results are less conclusive, but reduced rates of cardiovascular disease have been reported with fibrate therapy in the subgroup of patients with low HDL-C levels and elevated TG (TG > 2.3 mmol/L (200 mg/dL)). Fibrates are usually well tolerated but share a similar side-effect profile to statins. In addition, they may increase the risk of cholelithiasis and prolong the action of anticoagulants. Accumulating evidence suggests that they may also have a protective effect against diabetic microvascular complications. 14.29 Management of hyperlipidaemia in old age • Prevalence of atherosclerotic cardiovascular disease: greatest in old age. • Associated cardiovascular risk: lipid levels become less predictive, as do other risk factors apart from age itself. • Benefit of statin therapy: maintained up to the age of 80 years but evidence is lacking beyond this. • Life expectancy and statin therapy: lives saved by intervention are associated with shorter life expectancy than in younger patients, and so the impact of statins on quality-adjusted life years is smaller in old age. 14.30 Dyslipidaemia in pregnancy • Lipid metabolism: lipid and lipoprotein levels increase during pregnancy. This includes an increase in low-density lipoprotein cholesterol, which resolves post-partum. Remnant dyslipidaemia and hypertriglyceridaemia may be exacerbated during pregnancy. • Treatment: dyslipidaemia is rarely thought to warrant urgent treatment so pharmacological therapy is usually contraindicated when conception or pregnancy is anticipated. Teratogenicity has been reported with systemically absorbed agents, and non-absorbed agents may interfere with nutrient bioavailability. • Monitoring: while still uncommon among women of child-bearing age, cardiovascular disease is increasing in prevalence. Preconception cardiovascular review should be considered for women at high risk to optimise medications for pregnancy and to ensure that the patient will be able to withstand the demands of pregnancy and labour.

378 • CLINICAL BIOCHEMISTRY AND METABOLIC MEDICINE combination with fibrates, or other drugs that may interfere with their clearance. If myalgia or weakness occurs in association with CK elevation over 5–10 times the upper limit of normal, or if sustained alanine aminotransferase (ALT) elevation more than 2–3 times the upper limit of normal occurs that is not accounted for by fatty liver (p. 882), treatment should be discontinued and alternative therapy sought. The principles of the management of dyslipidaemia can be applied broadly, but the objectives of treatment in the elderly (Box 14.29) and the safety of pharmacological therapy in pregnancy (Box 14.30) warrant special consideration. The porphyrias This group of disorders is caused by inherited abnormalities in the haem biosynthetic pathway (Fig. 14.15). Most of the described forms are due to partial enzyme deficiencies with a dominant mode of inheritance. They are commonly classified as hepatic or erythropoietic, depending on whether the major site of excess porphyrin production is in the liver or red cell. The porphyrias have a penetrance in the order of 25%, emphasising the importance of environmental factors in disease expression. In porphyria cutanea tarda (PCT), which is the most are first-line therapy for dysbetalipoproteinaemia, but they may not control the cholesterol component in other forms of mixed hyperlipidaemia. Combination therapy is often required. Effective combinations include: • statin plus fenofibrate (recognising that the risk of myopathy is increased with gemfibrozil, but fenofibrate is relatively safe in this regard) • statin plus fish oil when TG is not too high • fibrate plus ezetimibe when cholesterol is not too high. Monitoring of therapy The effects of lipid-lowering therapy should be assessed after 6 weeks (12 weeks for fibrates). At this point, it is prudent to review side-effects, lipid response (see target levels above), CK and liver function tests. During longer-term follow-up, adherence to treatment, diet and exercise should be assessed, with monitoring of weight, blood pressure and lipid levels. The presence of cardiovascular symptoms or signs should be noted and absolute cardiovascular risk assessed periodically. Effective statin therapy may be associated with a paradoxical and as yet unexplained increase in coronary calcium score. It is not necessary to perform routine checks of CK and liver function unless symptoms occur, or if statins are used in Fig. 14.15 Haem biosynthetic pathway and enzyme defects responsible for the porphyrias. (ALA = δ-aminolaevulinic acid; CoA = co-enzyme A; N = neurovisceral; P = photosensitive; PBG = porphobilinogen) δ-aminolaevulinic acid (ALA) Porphobilinogen (PBG) Hydroxymethylbilane Uroporphyrinogen III Coproporphyrinogen III Protoporphyrinogen IX Protoporphyrin IX (proto IX) Haem ALA dehydratase Coproporphyrin I (Copro I) Uroporphyrin I (Uro I) Isocoproporphyrin (Isocopro) Coproporphyrin III (Copro III) Plumboporphyria PBG deaminase Acute intermittent porphyria Uroporphyrinogen synthetase Congenital erythropoietic porphyria Uroporphyrinogen decarboxylase Porphyria cutanea tarda Coproporphyrinogen oxidase Hereditary coproporphyria Protoporphyrinogen oxidase Variegate porphyria Ferrochelatase Erythropoietic protoporphyria +Fe2+ N N P P N + P P N + P Pathway Metabolites Enzyme Deficiency disease Symptomatology Glycine + succinyl CoA

The porphyrias • 379

difficult to obtain suitable specimens for analysis. All the genes of the haem biosynthetic pathway have now been characterised. This has made it possible to identify affected individuals in families by genetic testing, a significant advance considering that penetrance of porphyria is low. Metabolite excretory patterns are always grossly abnormal during an acute attack or with cutaneous manifestations of porphyria, and are diagnostic of the particular porphyria. A normal metabolite profile under these circumstances effectively excludes porphyria. Metabolites usually remain abnormal for long periods after an acute attack, and in some individuals never return to normal. The diagnosis is not so straightforward in patients who are in remission, or in asymptomatic individuals with a positive family history. Neurological porphyria rarely manifests before puberty, nor can it be readily diagnosed after the menopause as porphyrin excretion may be normal. Genetic testing for disease-specific mutations can clarify the situation. Management For patients predisposed to neurovisceral attacks, general management includes avoidance of any agents known to precipitate acute porphyria. Specific management includes intravenous glucose, as provision of 5000 kilojoules per day can, in some cases, terminate acute attacks through a reduction in δ-aminolaevulinic acid (ALA) synthetase activity, leading to reduced ALA and porphyrin synthesis. More recently, administration of haem (in various forms such as haematin or haem arginate) has been shown to reduce metabolite excretory rates, relieve pain and accelerate recovery. Cyclical acute attacks in women sometimes respond to suppression of the menstrual cycle using gonadotrophin-releasing hormone analogues. In rare cases with frequent prolonged attacks or attacks intractable to treatment, liver transplantation has been effective. There are few specific or effective measures to treat the photosensitive manifestations. The primary goal is to avoid sun exposure and skin trauma. Barrier sun creams containing zinc or titanium oxide are the most effective products. New colourless creams containing nanoparticle formulations have improved patient acceptance. Beta-carotene is used in some patients with erythropoietic porphyria with some efficacy. Afamelanotide, a synthetic analogue of alpha-melanocyte stimulating hormone (αMSH), has also been shown to provide protection in erythropoietic protoporphyria, and is now undergoing approval in many countries. In porphyria cutanea tarda, a course of venesections to remove iron can result in long-lasting clinical and biochemical remission, common cause of porphyria, environmental triggers include alcohol, iron accumulation, exogenous oestrogens and exposure to various chemicals. Many cases are associated with hepatitis C infection and this should always be screened for on presentation. Clinical features The clinical features of porphyria fall into two broad categories: photosensitivity and acute neurovisceral syndrome. The enzyme defects responsible for the diseases are shown in Figure 14.15. Photosensitive skin manifestations, attributable to excess production and accumulation of porphyrins in the skin, cause pain, erythema, bullae, skin erosions, hirsutism and hyperpigmentation, and occur predominantly on areas of the skin that are exposed to sunlight (p. 1220). The skin also becomes sensitised to damage from minimal trauma. The other pattern of presentation is with an acute neurological syndrome. This almost always presents with acute abdominal pain together with features of autonomic dysfunction, such as tachycardia, hypertension and constipation. Neuropsychiatric manifestations, hyponatraemia due to inappropriate ADH release (p. 357), and an acute neuropathy may also occur (p. 1138). The neuropathy is predominantly motor and may, in severe cases, progress to respiratory failure. There is no proven explanation for the episodic nature of the attacks in porphyria, which can relapse and remit or follow a prolonged and unremitting course. Sometimes, specific triggers can be identified, such as alcohol, fasting, or drugs such as anticonvulsants, sulphonamides, oestrogen and progesterone. The oral contraceptive pill is a common precipitating factor. In a significant number, no precipitant can be identified. Investigations The diagnosis of porphyria and classification into the various forms have traditionally relied on measurements of porphyrins and porphyrin precursors found in blood, urine and faeces (Box 14.31). The diagnosis is straightforward when the metabolites are significantly elevated, but this is not always the case in asymptomatic individuals who may have normal porphyrin studies. More recently, measurement of the enzymes that are deficient in the various porphyrias has provided further diagnostic information. An example is measurement of porphobilinogen deaminase activity in red blood cells to diagnose acute intermittent porphyria. There is often considerable overlap between enzyme activities in affected and normal subjects, however. Furthermore, some of the enzymes occur in the mitochondria, for which it is more 14.31 Diagnostic biochemical findings in the porphyrias1 Elevated porphyrins and precursors Condition Blood Urine Faeces ALA dehydratase deficiency (plumboporphyria) Proto IX2 ALA, Copro III2 Acute intermittent porphyria (AIP) ALA, PBG Congenital erythropoietic porphyria (CEP) Uro I Uro I Copro I Porphyria cutanea tarda (PCT) Uro I Isocopro Hereditary coproporphyria (HCP) ALA, PBG, Copro III Copro III Variegate porphyria (VP) ALA, PBG, Copro III Proto IX Erythropoietic protoporphyria (EPP) Proto IX Proto IX 1Refer to Figure 14.15 for metabolic pathways. 2The paradoxical rise in coproporphyrin III (Copro III) and protoporphyrin (Proto) in this very rare condition is poorly understood. (ALA = δ-aminolaevulinic acid; Isocopro = isocoproporphyrin; PBG = porphobilinogen; Uro = uroporphyrin)

380 • CLINICAL BIOCHEMISTRY AND METABOLIC MEDICINE especially if exposure to identified precipitants, such as alcohol or oestrogens, is reduced. Alternatively, a prolonged course of low-dose chloroquine therapy is effective. Further information Journal articles Spasovski G, Vanholder R, Allolio B, et al. Clinical practice guideline on diagnosis and treatment of hyponatraemia. Eur J Endocrinol 2014; 170:G1–G47. Walsh S, Unwin R. Renal tubular disorders. Clin Med 2012; 12(5):476–479. Websites emedicine.medscape.com The Nephrology link on this site contains a useful compendium of articles. lipidsonline.org Summarises management strategies for dyslipidaemia. ncbi.nlm.nih.gov The link to OMIM (Online Mendelian Inheritance in Man) provides updated information on the genetic basis of metabolic disorders. porphyria-europe.com and drugs-porphyria.org Excellent resources on drug safety in porphyria.

Ch04-3 Clinical Medicine

05-15 Nephrology and urology

15 Nephrology and urology

Nephrology and urology B Conway PJ Phelan GD Stewart Clinical examination of the kidney and urinary tract 382 Functional anatomy and physiology 384 Investigation of renal and urinary tract disease 386 Glomerular filtration rate 386 Urine investigations 387 Blood tests 388 Imaging 389 Renal biopsy 391 Presenting problems in renal and urinary tract disease 391 Oliguria/anuria 391 Haematuria 391 Proteinuria 392 Oedema 395 Hypertension 396 Loin pain 396 Dysuria 396 Frequency 396 Polyuria 396 Nocturia 397 Urinary incontinence 397 Glomerular diseases 397 Glomerulonephritis 397 Tubulo-interstitial diseases 401 Genetic renal diseases 403 Inherited glomerular diseases 403 Inherited tubulo-interstitial diseases 404 Isolated defects of tubular function 405 Cystic diseases of the kidney 405 Renal vascular diseases 406 Renal artery stenosis 406 Acute renal infarction 408 Diseases of small intrarenal vessels 408 Renal involvement in systemic conditions 409 Acute kidney injury 411 Chronic kidney disease 415 Renal replacement therapy 420 Conservative treatment 421 Haemodialysis 421 Haemofiltration 423 Haemodiafiltration 423 Peritoneal dialysis 424 Renal transplantation 424 Renal disease in pregnancy 426 Renal disease in adolescence 426 Drugs and the kidney 426 Drug-induced renal disease 426 Prescribing in renal disease 426 Infections of the urinary tract 426 Urolithiasis 431 Diseases of the collecting system and ureters 433 Congenital abnormalities 433 Retroperitoneal fibrosis 434 Tumours of the kidney and urinary tract 434 Urinary incontinence 436 Prostate disease 437 Testicular tumours 439 Erectile dysfunction 440

382 • NEPHROLOGY AND UROLOGY Clinical examination of the kidney and urinary tract Blood pressure Often elevated Jugular venous pressure Elevated in fluid overload Hypertensive changes ‘Brown line’ pigmentation of nails Splinter haemorrhages Lungs Crepitations in fluid overload Observation • Tiredness • Respiratory rate and depth increased in metabolic acidosis • Pallor* Abdomen Renal mass Local tenderness Renal or other arterial bruits in renal vascular disease Rectal examination — prostate Heart Extra heart sounds in fluid overload Pericardial friction rub* Features of advanced chronic kidney disease (see also Fig. 15.22) Phimosis Skin Yellow complexion Bruising* Excoriation of pruritus* Reduced skin turgor in fluid depletion Fundoscopy

Hands

10 Sacral oedema 11 Ankle oedema 12 Peripheral neuropathy*

Genitalia Scrotal swellings Urinalysis for blood and protein Urine microscopy See Fig. 15.3

Many diseases of the kidney and urinary tract are clinically silent, at least in the early stages. Accordingly, it is common for these conditions to be detected first by routine blood tests or on dipstick testing of the urine. Several important abnormalities can also be picked up on physical examination, however, and these are summarised below.

Clinical examination of the kidney and urinary tract • 383

Clinical examination techniques to evaluate urological and renal abnormalities. Inset (Dipstick): From Pitkin J, Peattie AB, Magowan BA. Obstetrics and gynaecology: An Iilustrated colour text. Edinburgh: Churchill Livingstone, Elsevier Ltd; 2003. Blood pressure measurements

Blood tests for abnormal creatinine and electrolytes Urinalysis for protein, blood, nitrites and leucocytes

Abdominal examination for palpable kidneys Right kidney Left kidney Percussing for tenderness in renal angle Digital rectal examination for prostate enlargement Checking sacrum and ankles for pitting oedema Male lower urinary tract demonstrating the relationship of the bladder, urethra, vas deferens and testes. Bladder Pubic bones Corpus spongiosum Corpus cavernosum Urethra Glans penis Prepuce Scrotum Testis Epididymis Vas deferens Prostate gland Ejaculatory duct Anus Seminal vesicle Rectum Ureter

384 • NEPHROLOGY AND UROLOGY proximal tubule termed Bowman’s capsule, which is composed of epithelial cells. The glomerular capillary endothelial cells contain pores (fenestrae), through which circulating molecules can pass to reach the underlying glomerular basement membrane (GBM), which is formed by fusion of the basement membranes of tubular epithelial and vascular endothelial cells (Fig. 15.1C and D). Glomerular epithelial cells (podocytes) have multiple long foot processes that interdigitate with those of the adjacent epithelial cells, thereby maintaining a selective barrier to filtration (Fig. 15.1E). Mesangial cells lie in the central region of the glomerulus. They have contractile properties similar to those of vascular smooth muscle cells and play a role in regulating glomerular filtration rate. Under normal circumstances, the glomerulus is impermeable to proteins the size of albumin (67 kDa) or larger, while proteins of 20 kDa or smaller are filtered freely. The ability of molecules between 20 and 67 kDa to pass through the GBM is variable and depends on the size (smaller molecules are filtered more easily) and charge (positively charged molecules are filtered more easily). Very little lipid is filtered by the glomerulus. Filtration pressure at the glomerulus is normally maintained at a constant level, in the face of wide variations in systemic blood pressure and cardiac output, by alterations in muscle tone within the afferent and efferent arterioles and mesangial cells. This is known as autoregulation. Reduced renal perfusion pressure increases local production of prostaglandins that mediate vasodilatation of the afferent arteriole, thereby increasing the intraglomerular pressure (Fig. 15.1D). In addition, renin is released by specialised smooth muscle cells in the juxtaglomerular apparatus in response to reduced perfusion pressure, stimulation of sympathetic nerves or low sodium concentration of fluid in the distal convoluted tubule at the macula densa. Renin cleaves angiotensinogen to release angiotensin I, which is further cleaved by angiotensin-converting enzyme (ACE) to produce angiotensin II. This restores glomerular perfusion pressure in the short term by causing vasoconstriction of the efferent arterioles within the kidney to raise intraglomerular pressure selectively (Fig. 15.1D), and by inducing systemic vasoconstriction to increase blood pressure and thus renal perfusion pressure. In the longer term, angiotensin II increases plasma volume by stimulating aldosterone release, which enhances sodium reabsorption by the renal tubules (see Fig. 18.18, p. 666). Consumption of non-steroidal anti-inflammatory preparations and renin–angiotensin system inhibitors in the context of volume depletion may impair the ability of the kidney to maintain glomerular filtration and exacerbate pre-renal failure (see Fig. 15.19, p. 413). Renal tubules, loop of Henle and collecting ducts The proximal renal tubule, loop of Henle, distal renal tubule and collecting ducts are responsible for reabsorption of water, electrolytes and other solutes, as well as regulating acid–base balance, as described in detail on page 350 and in Figure 14.3. They also play a key role in regulating calcium homeostasis by converting 25-hydroxyvitamin D to the active metabolite 1,25-dihydroxyvitamin D (p. 1049). Failure of this process contributes to the pathogenesis of hypocalcaemia and bone disease that occurs in chronic kidney disease (CKD, p. 415). Fibroblast-like cells that lie in the interstitium of the renal cortex are responsible for production of erythropoietin, which in turn is required for production of red blood cells. Erythropoietin synthesis is regulated by oxygen tension; anaemia and hypoxia increase production, whereas polycythaemia and hyperoxia inhibit it. This chapter describes the disorders of the kidneys and urinary tract that are commonly encountered in routine practice, as well as giving an overview of the highly specialised field of renal replacement therapy. Disorders of renal tubular function, which may cause alterations in electrolyte and acid–base balance, are described in Chapter 14. Functional anatomy and physiology The kidneys The kidneys play a central role in excretion of many metabolic breakdown products, including ammonia and urea from protein, creatinine from muscle, uric acid from nucleic acids, drugs and toxins. They achieve this by making large volumes of an ultrafiltrate of plasma (120 mL/min, 170 L/24 hrs) at the glomerulus, and selectively reabsorbing components of this ultrafiltrate at points along the nephron. The rates of filtration and reabsorption are controlled by many hormonal and haemodynamic signals to regulate fluid and electrolyte balance (p. 349), blood pressure (p. 447), and acid–base (p. 363) and calcium–phosphate homeostasis (pp. 367 and 368). In addition, the kidneys activate vitamin D and control the synthesis of red blood cells by producing erythropoietin. Strategies to replace each of these important functions are required when managing patients with kidney failure. Each kidney is approximately 11–14 cm in length in healthy adults; they are located retroperitoneally on either side of the aorta and inferior vena cava between the 12th thoracic and 3rd lumbar vertebrae (Fig. 15.1A). The right kidney is usually a few centimetres lower because the liver lies above it. Both kidneys rise and descend several centimetres with respiration. The kidneys have a rich blood supply and receive approximately 20–25% of cardiac output through the renal arteries, which arise from the abdominal aorta. The renal arteries undergo various subdivisions within the kidney, eventually forming interlobular arteries that run through the renal cortex. These eventually give rise to afferent glomerular arterioles that supply the glomeruli. The efferent arteriole, leading from the glomerulus, supplies the distal nephron and medulla in a ‘portal’ circulation (Fig. 15.1B). This highly unusual arrangement of two serial capillary beds reflects the role of the afferent and efferent arterioles in autoregulation of glomerular filtration. The nephron Each kidney contains approximately 1 million individual functional units, called nephrons. Each nephron consists of a glomerulus, which is responsible for ultrafiltration of blood, a proximal renal tubule, a loop of Henle, a distal renal tubule and a collecting duct, which together are responsible for selective reabsorption of water and electrolytes that have been filtered at the glomerulus (see Fig. 14.2, p. 350, and Fig. 15.1B). Under normal circumstances, more than 99% of the 170 L of glomerular filtrate that is produced each day is reabsorbed in the tubules. The remainder passes through the collecting ducts of multiple nephrons and drains into the renal pelvis and ureters. The glomerulus The glomerulus comprises a tightly packed loop of capillaries supplied by an afferent arteriole and drained by an efferent arteriole. It is surrounded by a cup-shaped extension of the

Functional anatomy and physiology • 385

Fig. 15.1 Functional anatomy of the kidney. A Anatomical relationships of the kidney. B A single nephron. For the functions of different segments, see Figures 14.2 and 14.3 (pp. 350 and 351). C Histology of a normal glomerulus. D Schematic cross-section of a glomerulus, showing five capillary loops, to illustrate structure and show cell types. E Electron micrograph of the filtration barrier. (GBM = glomerular basement membrane) (C) Courtesy of Dr J.G. Simpson, Aberdeen Royal Infirmary. Distal convoluted tubule Endothelial cell Angiotensin II vasoconstricts Prostaglandins vasodilate Pelvis Cortex Calyx Medulla Vena cava Ureter Bladder Afferent arteriole Glomerulus Efferent arteriole Proximal convoluted tubule Collecting duct Thickwalled segment Loop of Henle Thin-walled segment Ureter Renal artery Renal vein Epithelial cell (podocyte) Urinary space Bowman's capsule Parietal epithelium Capillary loops Efferent arteriole Afferent arteriole Mesangial cell Mesangial matrix Juxtaglomerular apparatus Aorta Endothelial cell Epithelial cell (podocyte) Foot process GBM Macula densa Renal artery A B C D E

386 • NEPHROLOGY AND UROLOGY Investigation of renal and urinary tract disease Glomerular filtration rate The glomerular filtration rate (GFR) is the sum of the ultrafiltration rates from plasma into the Bowman’s space in each nephron and is a measure of renal excretory function. It is proportionate to body size and the reference value is usually expressed after correction for body surface area as 120 ± 25 mL/min/1.73 m2. The GFR may be measured directly by injecting and measuring the clearance of compounds such as inulin or radiolabelled ethylenediamine-tetra-acetic acid (EDTA), which are completely filtered at the glomerulus and are not secreted or reabsorbed by the renal tubules (Box 15.1). This is not performed routinely, however, and is usually reserved for special circumstances, such as the assessment of renal function in potential live kidney donors. Instead, GFR is usually assessed indirectly in clinical 15.1 How to estimate glomerular filtration rate (GFR) Measuring GFR • Direct measurement using labelled ethylenediamine-tetra-acetic acid (EDTA) or inulin • Creatinine clearance (CrCl): Minor tubular secretion of creatinine causes CrCl to exaggerate GFR when renal function is poor; can be affected by drugs (e.g. trimethoprim, cimetidine) Needs 24-hr urine collection (inconvenient and often unreliable) CrCl mL/min urine creatinine concentration mol/L volume ( ) ( )

× μ ( ) ( ) ( ) mL plasma creatinine concentration mol/L time min μ × Estimating GFR with equations • The Modification of Diet in Renal Disease (MDRD) study equation (see www.renal.org/eGFR): Requires knowledge of age and sex only; it can therefore be reported automatically by laboratories For limitations, see Box 15.2 eGFR * creatinine in mol/L/ age in yrs

× × − −

88 4 1 154

( . ) ( ) . μ . ( . ) ( . )

0 742 1 21 × × if female if black • The Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation: More accurately estimates the actual GFR than the MDRD eGFR in those with relatively preserved renal function eGFR min SCr

max SCr

/ / 12 9 Age

× × × × −

1 018

( , ) ( , ) . . . κ κ α ( ) . ( ) if female if black ×1 159 Where SCr = serum creatinine in μmol/L κ = 61.9 if female and 79.6 if male α = − 0.329 if female and − 0.411 if male min = whichever is the minimum of serum creatinine/κ or 1 max = whichever is the maximum of serum creatinine/κ or 1 • No equations perform well in unusual circumstances, such as extremes of body (and muscle) mass or in acutely unwell patients (see Box 15.2) *A correction factor of 175 is used for isotope dilution mass spectrometry traceable creatinine measurements. To convert creatinine in mg/dL to μmol/L, multiply by 88.4. Failure of erythropoietin production plays an important role in the pathogenesis of anaemia in CKD. The ureters and bladder The ureters drain urine from the renal pelvis (Fig. 15.1A) and deliver it to the bladder, a muscular organ that lies anteriorly in the lower part of the pelvis, just behind the pubic bone. The function of the bladder is to store and then release urine during micturition. The bladder is richly innervated. Sympathetic nerves arising from T10–L2 relay in the pelvic ganglia to cause relaxation of the detrusor muscle and contraction of the bladder neck (both via α-adrenoceptors), thereby preventing release of urine from the bladder. The distal sphincter mechanism is innervated by somatic motor fibres from sacral segments S2–4, which reach the sphincter either by the pelvic plexus or via the pudendal nerves. Afferent sensory impulses pass to the cerebral cortex, from where reflex-increased sphincter tone and suppression of detrusor contraction inhibit micturition until it is appropriate. Conversely, parasympathetic nerves arising from S2–4 stimulate detrusor contraction, promoting micturition. The micturition cycle has a storage (filling) phase and a voiding (micturition) phase. During the filling phase, the high compliance of the detrusor muscle allows the bladder to fill steadily without a rise in intravesical pressure. As bladder volume increases, stretch receptors in its wall cause reflex bladder relaxation and increased sphincter tone. The act of micturition is initiated first by voluntary and then by reflex relaxation of the pelvic floor and distal sphincter mechanism, followed by reflex detrusor contraction. These actions are coordinated by the pontine micturition centre. Intravesical pressure remains greater than urethral pressure until the bladder is empty. The prostate gland The prostate gland is situated at the base of the bladder, surrounding the proximal urethra (p. 383). Exocrine glands within the prostate produce fluid, which comprises about 20% of the volume of ejaculated seminal fluid and is rich in zinc and proteolytic enzymes. The remainder of the ejaculate is formed in the seminal vesicles and bulbo-urethral glands, with spermatozoa arising from the testes. Smooth muscle fibres within the prostate, which are under sympathetic control, play a role in controlling urine flow through the bulbar urethra, and also contract at orgasm to move seminal fluid through ejaculatory ducts into the bulbar urethra (emission). Contraction of the bulbocavernosus muscle (via a spinal muscle reflex) then ejaculates the semen out of the urethra. The penis Blood flow into the corpus cavernosum of the penis is controlled by sympathetic nerves from the thoracolumbar plexus, which maintain smooth muscle contraction (p. 383). In response to afferent input from the glans penis and from higher centres, pelvic splanchnic parasympathetic nerves actively relax the cavernosal smooth muscle via neurotransmitters such as nitric oxide, acetylcholine, vasoactive intestinal polypeptide (VIP) and prostacyclin, with consequent dilatation of the lacunar space. At the same time, draining venules are compressed, trapping blood in the lacunar space with consequent elevation of pressure and erection (tumescence) of the penis.

Investigation of renal and urinary tract disease • 387

practice by measuring serum levels of endogenously produced compounds that are excreted by the kidney. The most widely used is serum creatinine, which is produced by muscle at a constant rate, is almost completely filtered at the glomerulus, and is not reabsorbed. Although creatinine is secreted to a small degree by the proximal tubule, this is only usually significant in terms of GFR estimation in severe renal impairment, where it accounts for a larger proportion of the creatinine excreted. Accordingly, provided muscle mass remains constant, changes in serum creatinine concentrations closely reflect changes in GFR. The relationship between serum creatinine and GFR is not linear, however, and a modest elevation in serum creatinine above the normal range may therefore reflect a substantial decline in GFR (Fig. 15.2). For this reason, several methods have been developed to estimate GFR from serum creatinine measurements (see Box 15.1) but the most widely used is the Modification of Diet in Renal Disease (MDRD) equation. Routine reporting by laboratories of estimated GFR (eGFR) has increased recognition of moderate kidney damage and encouraged early deployment Fig. 15.2 Serum creatinine and the glomerular filtration rate (GFR). A The relationship between serum creatinine and estimated GFR (eGFR) is non-linear; small increases above the normal range (e.g. 80–100 μmol/L; green lines) can therefore indicate a substantial decline in renal function (e.g. 105–80 mL/min/1.73 m2; conversely, in the high range, large changes in creatinine (e.g. 400–600 μmol/L; blue lines) can occur with only small declines in renal function (e.g. 20–15 mL/ min/1.73m2). B Creatinine is dependent on muscle mass; the same creatinine value may therefore reflect very different levels of renal function depending on the age and sex of the individual. To convert creatinine in mg/dL to μmol/L, multiply by 88.4.

GFR (mL/min/1.73 m2) GFR (mL/min/1.73 m2)

A

Serum creatinine (μmol/L) Serum creatinine (μmol/L)

25-year-old male 80-year-old female B 15.2 Limitations of estimated glomerular filtration rate (eGFR) • It is only an estimate, with wide confidence intervals (90% of patients will have eGFR within 30% of their measured GFR, and 98% within 50%) • It is based on serum creatinine, and so may over-estimate actual GFR in patients with low muscle mass (e.g. those with cachexia, amputees) and under-estimate actual GFR in individuals taking creatine supplements (creatinine is a metabolite of creatine) or trimethoprim (inhibits secretion of creatinine) • Creatinine level must be stable over days; eGFR is not valid in assessing acute kidney injury • It tends to under-estimate normal or near-normal function, so slightly low values should not be over-interpreted • In the elderly, who constitute the majority of those with low eGFR, there is controversy about categorising people as having chronic kidney disease (Box 15.3) on the basis of eGFR alone, particularly at stage 3A, since there is little evidence of adverse outcomes when eGFR is > 45 mL/min/1.73 m2 unless there is also proteinuria • eGFR is not valid in under-18s or during pregnancy • Ethnicity is not taken into account in routine laboratory reporting; the laboratory eGFR value should therefore be multiplied by 1.21 for black people • Few patients will understand eGFR in terms of mL/min/1.73 m2; it may therefore be helpful to assume that a GFR of 100 mL/ min/1.73 m2 is approximately normal and to discuss eGFR values in terms of a percentage of normal, e.g. 25 mL/min/1.73 m2 = 25% of normal kidney function of protective therapies; however, some limitations remain (Boxes 15.2 and 15.3). In particular, the MDRD formula is based on the serum creatinine value and so is heavily influenced by muscle mass; eGFR may therefore be misleading in individuals whose muscle bulk is outside the normal range for their sex and age. Measurement of other endogenous metabolites, such as cystatin C, may provide a more accurate estimate of GFR in this setting; this test, however, is not yet widely available in routine clinical practice. Direct measurement of creatinine clearance by collecting a 24-hour urine sample and relating serum creatinine levels to urinary creatinine excretion (see Box 15.1) is now less commonly performed due to the difficulty in obtaining accurate 24-hour urine collections. It may still have a role in assessing renal function in patients at extremes of muscle mass, where the creatinine-based equations perform poorly. Urine investigations Screening for the presence of blood (p. 391), protein (p. 392), glucose, ketones, nitrates and leucocytes, and assessment of urinary pH and osmolality can be achieved by dipstick testing. The presence of leucocytes and nitrites in urine is indicative of renal tract infection. Urine pH can provide diagnostic information in the assessment of renal tubular acidosis (p. 365). Urine microscopy (Fig. 15.3) may detect dysmorphic erythrocytes, which suggest the presence of nephritis or red cell casts, indicative of glomerular disease. White cell casts are strongly suggestive of pyelonephritis. Microscopy may also detect the presence of bacteria in those with urinary infection and crystals in patients with renal stone disease. It should be noted that calcium oxalate and urate crystals can sometimes be found in normal urine that has been left to stand, due to crystal formation ex vivo.

388 • NEPHROLOGY AND UROLOGY Fig. 15.3 Urine microscopy. A Erythrocytes due to bleeding from lower in the urinary tract (×400). B Dysmorphic erythrocytes due to glomerular inflammation (×400). C Hyaline casts in normal urine. D Erythrocytes and a red cell cast in glomerulonephritis (×100). Panels A–C are phase contrast images; D is a bright field image. (A, B) Courtesy of Dr G.M. Iadorola and Dr F. Quarello, B. Bosco Hospital, Turin (from www.sin-italia .org/imago/sediment/sed.htm). A B C D 15.3 Stages of chronic kidney disease (CKD) Stage1 Definition2 Description Prevalence4 Clinical presentation5

Kidney damage3 with normal or high GFR (> 90) Normal function 3.5% Asymptomatic

Kidney damage and GFR 60–89 Mild CKD 3.9% Asymptomatic 3A GFR 45–59 Mild to moderate CKD 7.6% (3A and 3B combined) Usually asymptomatic 3B GFR 30–44 Moderate to severe CKD Anaemia in some patients at 3B Most are non-progressive or progress very slowly

GFR 15–29 Severe CKD 0.4% First symptoms often at GFR < 20 Electrolyte problems likely as GFR falls

GFR < 15 or on dialysis Kidney failure 0.1% Significant symptoms and complications usually present Dialysis initiation varies but usually at GFR < 10 1Stages of CKD 1–5 were originally defined by the US National Kidney Foundation Kidney Disease Quality Outcomes Initiative 2002. In the 2013 Kidney Disease Outcomes Quality Initiative (K/DOQI) CKD guideline update, the suffices A1, A2 and A3 are recommended, indicating the presence of albuminuria of < 30, 30–300 and > 300 mg/ 24 hrs respectively, in view of the prognostic importance of albuminuria. 2Two GFR values 3 months apart are required to assign a stage. All GFR values are in mL/ min/1.73 m2. 3Kidney damage means pathological abnormalities or markers of damage, including abnormalities in urine tests or imaging studies. 4From Hill NR, Fatoba ST, Oke JL et al. Global prevalence of chronic kidney disease – a systematic review and meta-analysis. PLoS One 2016; 11:e0158765. 5For further information, see page 415. Urine collection over a 24-hour period may be performed to measure excretion of solutes, such as calcium, oxalate and urate, in patients with recurrent renal stone disease (p. 431). Proteinuria can also be measured on 24-hour collections but is usually now quantified by protein/creatinine ratio on spot urine samples. Other dynamic tests of tubular function, including concentrating ability (p. 688), ability to excrete a water load (p. 357) and ability to excrete acid (p. 415), and calculation of fractional calcium, phosphate or sodium excretion, are valuable in some circumstances but are usually performed in very specific contexts. The fractional excretion of these ions can be calculated by the general formula: 100 × (urine concentration of analyte × serum creatinine) / (serum concentration of analyte × urinary creatinine). Calculation of fractional excretion of sodium (FENa) can help in the setting of acute kidney injury (AKI) to differentiate volume depletion, when the tubules are avidly conserving sodium (FENa typically < 1.0%), from acute tubular necrosis, when the tubules are damaged and are less able to conserve sodium (FENa typically

1.0%). In clinical practice this is seldom required. Blood tests Haematology A normochromic normocytic anaemia is common in CKD and is due in part to deficiency of erythropoietin and bone marrow suppression secondary to toxins retained in CKD. Other causes of anaemia include iron deficiency from urinary tract bleeding, and haemolytic anaemia secondary to disorders such as haemolytic uraemic syndrome (HUS) and thrombotic thrombocytopenic purpura (TTP). Other abnormalities may be observed that reflect underlying disease processes, such as neutrophilia and raised erythrocyte sedimentation rate (ESR) in vasculitis or sepsis, and lymphopenia and raised ESR in systemic lupus erythematosus (SLE). Fragmented red cells on blood film and low platelets may be observed in thrombotic microangiopathies such as HUS/TTP and malignant hypertension. Pancytopenia may occur in SLE or bone marrow suppression due to myeloma. Biochemistry Abnormalities of routine biochemistry are common in renal disease. Serum levels of creatinine may be raised, reflecting reduced GFR (see above), as may serum potassium. Serum levels of urea are often increased in kidney disease but this analyte has limited value as a measure of GFR since levels increase with protein intake, following gastrointestinal haemorrhage and in catabolic states. Conversely, urea levels may be reduced in patients with chronic liver disease or anorexia and in malnourished patients, independently of changes in renal function. In the absence of the other causes mentioned above, an elevated urea:creatinine

Investigation of renal and urinary tract disease • 389

renal ultrasound is operator-dependent and the results are often less clear in obese patients. Computed tomography Computed tomography urography (CTU) is used to evaluate cysts and mass lesions in the kidney or filling defects within the collecting systems. It usually entails an initial scan without contrast medium, and subsequent scans following injection of contrast to obtain a nephrogram image and images during the excretory phases. CTU has largely replaced the previous gold-standard investigation of intravenous urography (IVU) for investigation of the upper urinary tract, having the advantage of providing complete staging information and details of surrounding organs. Contrast enhancement is particularly useful for characterising mass lesions within the kidney and differentiating benign from malignant lesions (see Fig. 15.32A, p. 435). CT without contrast gives clear definition of retroperitoneal anatomy regardless of obesity and is superior to ultrasound in this respect. Non-contrast CT of kidneys, ureters and bladder (CTKUB) is the method of choice for demonstrating stones within the kidney or ureter (see Fig. 15.29, p. 432). For investigation of patients with renal trauma, a triple-phase CT scan with a delayed phase, to assess the integrity of the collecting system, is performed. Drawbacks of contrast-enhanced CT scans include the fact that relatively large doses of contrast medium are required, which can cause renal dysfunction, and that the radiation dose is significant (Box 15.4). Magnetic resonance imaging Magnetic resonance imaging (MRI) offers excellent resolution and gives good distinction between different tissue types (see Fig. 15.15, p. 406). It is very useful for local staging of prostate, bladder and penile cancers. Magnetic resonance angiography (MRA) provides an alternative to CT for imaging renal vessels but involves administration of gadolinium-based contrast media, which may carry risks for patients with impaired renal function (Box 15.4). Whilst MRA gives good images of the main renal vessels, stenosis of small branch arteries may be missed. Renal arteriography Renal arteriography involves taking X-rays following an injection of contrast medium directly into the renal artery. The main indication is to investigate renal artery stenosis (p. 406) or haemorrhage following renal trauma. Renal angiography can often be combined with therapeutic balloon dilatation or stenting of the renal artery. It can be used to occlude bleeding vessels and arteriovenous fistulae by the insertion of thin platinum wires (coils). These curl up within the vessel and promote thrombosis, thereby securing haemostasis. ratio is indicative of volume depletion and pre-renal failure. Serum calcium tends to be reduced and phosphate increased in CKD, in association with high parathyroid hormone (PTH) levels caused by reduced production of 1,25-dihydroxyvitamin D (1,25(OH)2D) by the kidney (secondary hyperparathyroidism). In some patients, this may be accompanied by raised serum alkaline phosphatase levels, which are indicative of renal osteodystrophy. Serum bicarbonate may be low in renal failure and in renal tubular acidosis. Serum albumin may be low in liver disease, as a negative acute phase response or due to malnutrition/malabsorption, but if it is a new finding it should prompt urinalysis to exclude nephrotic syndrome. Other biochemical abnormalities may be observed that reflect underlying disease processes, such as raised glucose and HbA1c levels in diabetes mellitus (p. 726) and raised levels of C-reactive protein (CRP) in sepsis and vasculitis. Immunology Antinuclear antibodies, antibodies to extractable nuclear antigens and anti-double-stranded DNA antibodies may be detected in patients with renal disease secondary to SLE (p. 1034). Antineutrophil cytoplasmic antibodies (ANCAs) may be detected in patients with glomerulonephritis secondary to systemic vasculitis (p. 1040), as may antibodies to GBM in patients with Goodpasture’s syndrome (p. 401), and low levels of complement may be observed in a number of kidney diseases (see Box 15.17, p. 401). Imaging Ultrasound Renal ultrasound is a valuable non-invasive technique that may be performed to assess renal size and to investigate patients who are suspected of having obstruction of the urinary tract (Fig. 15.4), renal tumours, cysts or stones. Ultrasound can also be used to provide images of the prostate gland and bladder, and to estimate the completeness of emptying in patients with suspected bladder outflow obstruction. In addition, it can reveal other abdominal, pelvic and retroperitoneal pathology. Ultrasonography may show increased signal in the renal cortex with loss of distinction between cortex and medulla, which is characteristic of CKD. Doppler imaging can be used to study blood flow in extrarenal and larger intrarenal vessels, and to assess the resistivity index (peak systolic velocity − end-diastolic velocity/peak systolic velocity in the intrarenal arteries), which may be elevated (> 0.7) in various diseases, including acute tubular necrosis and rejection of a renal transplant. However, Fig. 15.4 Renal ultrasound. A Normal kidney. The normal cortex is less echo-dense (blacker) than the adjacent liver. (RC = renal cortex; RS = renal sinus – calyx, renal pelvis, blood vessels, sinus fat) B Typical simple renal cyst: round, echo-free content, no septa, posterior acoustic enhancement. (C = calyx; P = thinned parenchyma; RP = renal pelvis; U = ureter) C The renal pelvis and calyces are dilated due to obstruction. The thinness of the parenchyma indicates chronic obstruction. D A typical renal stone with posterior shadowing. (AS = posterior acoustic shadow) E A T1b renal tumour. (K = kidney; L = liver; T = tumour) (A–E) Courtesy of Dr Tobias Klatte, Addenbrooke’s Hospital, Cambridge. RC P C C C RP AS T K K L U RS Normal kidney A Simple renal cyst B Hydronephrosis C Renal stone D Renal tumour T1b E

390 • NEPHROLOGY AND UROLOGY Formal measurements of GFR can be made by radionuclide studies following the injection of diethylenetriamine penta-acetic acid (99mTc-DPTA). Static radionuclide studies are performed with dimercaptosuccinic acid labelled with technetium (99mTc-DMSA), which is taken up by proximal tubular cells. Following intravenous injection, images of the renal cortex are obtained that show the shape, size and relative function of each kidney (Fig. 15.6). This is a sensitive method for demonstrating cortical scarring in reflux nephropathy and a way of assessing the individual function of each kidney. Radionuclide bone scanning following the injection of methylene diphosphonate (99mTc-MDP) is indicated to assess the presence and extent of bone metastases in men with advanced prostate cancer (p. 438). Pyelography Pyelography involves direct injection of contrast medium into the collecting system from above (antegrade) or below (retrograde). It offers the best views of the collecting system and upper tract, and is often used to identify the cause of urinary tract obstruction (p. 391). Antegrade pyelography requires the insertion of a fine needle into the pelvicalyceal system under ultrasound or radiographic control. In addition to visualising the cause of obstruction, percutaneous nephrostomy drainage can be established and often stents can be passed through any obstruction. Retrograde pyelography can be performed by inserting a ureteric catheter into the ureteric orifice at cystoscopy (Fig. 15.5) and again a stent can be inserted to bypass any obstruction. Radionuclide studies These are functional studies requiring the injection of gamma ray-emitting radiopharmaceuticals that are taken up and excreted by the kidney, a process that can be monitored by an external gamma camera. Dynamic radionuclide studies are performed with mercaptoacetyltriglycine labelled with technetium (99mTc-MAG3), which is filtered by the glomerulus and excreted into the urine. Imaging following 99mTc-MAG3 injection can provide valuable information about the perfusion of each kidney but is not a reliable method for identifying renal artery stenosis. In patients with significant obstruction of the outflow tract, 99mTc-MAG3 persists in the renal pelvis and a loop diuretic fails to accelerate its disappearance. This can be useful in determining the functional significance of an equivocally obstructed collecting system without undertaking pyelography. Fig. 15.5 Retrograde pyelography. The best views of the normal collecting system are shown by pyelography. A catheter has been passed into the left renal pelvis at cystoscopy. The anemone-like calyces are sharp-edged and normal. Courtesy of Dr A.P. Bayliss and Dr P. Thorpe, Aberdeen Royal Infirmary. 15.4 Renal complications of radiological investigations Contrast nephrotoxicity • Acute deterioration in renal function commencing < 48 hrs after administration of IV radiographic contrast media Risk factors • Pre-existing renal impairment • Use of high-osmolality, ionic contrast media and repetitive dosing in short time periods • Diabetes mellitus • Myeloma Prevention • Provide hydration with free oral fluids plus IV isotonic saline 500 mL, then 250 mL/hr during procedure • Avoid nephrotoxic drugs; withhold non-steroidal anti-inflammatory drugs (NSAIDs). Omit metformin for 48 hrs after the procedure, in case renal impairment occurs • N-acetylcysteine may provide some protection but data are conflicting • If the risks are high, consider alternative methods of imaging Cholesterol atheroembolism • Typically follows days to weeks after intra-arterial investigations or interventions (p. 409) Nephrogenic sclerosing fibrosis after MRI contrast agents • Chronic progressive sclerosis of skin, deeper tissues and other organs, associated with gadolinium-based contrast agents • Only reported in patients with renal impairment, typically on dialysis or with GFR < 15 mL/min/1.73 m2, but caution is advised in patients with GFR < 30 mL/min/1.73 m2 Fig. 15.6 DMSA radionuclide scan. A posterior view is shown of a normal left kidney and a small right kidney (with evidence of cortical scarring at upper and lower poles) that contributes only 39% of total renal function. L LEFT = 61% RIGHT = 39% POSTERIOR R

Presenting problems in renal and urinary tract disease • 391

with marked glycosuria. Urine volumes are variable in AKI due to intrinsic renal disease, but a rapid decline in urine volume may be observed. Anuria should prompt a differential including complete urinary obstruction, severe vascular compromise or rapidly progressive glomerulonephritis (Box 15.6). Obstruction of the renal tract can produce oliguria and anuria, but to do so, obstruction must be complete and occur distal to the bladder neck, be bilateral, or be unilateral on the side of a single functioning kidney. Unilateral ureteric obstruction may not lead to any noticeable reduction in urine output. The presence of pain that is exacerbated by a fluid load suggests an acute obstruction of the renal tract, and its characteristics may be of value in reaching a diagnosis. Obstruction at the bladder neck is associated with lower midline abdominal discomfort, whereas ureteric obstruction typically presents as loin pain radiating to the groin and at the level of the renal pelvis may present as flank pain. Chronic obstruction rarely produces pain but may give rise to a dull ache. Urethral strictures should be considered as a possible cause, especially in patients with a history of instrumentation of the renal tract. The presence of bladder enlargement in a middle-aged or elderly man suggests benign or malignant enlargement of the prostate gland as a potential cause of oliguria or anuria (pp. 437 and 438). It is important to note that many cases of acute urinary retention are observed after general anaesthesia, particularly in patients with pre-existing prostatic enlargement. Partial obstruction can be associated with a normal or even high urine volume due to chronic tubular injury, which causes loss of tubular concentrating ability. Management of oliguria and anuria should be directed at the underlying cause and is outlined later in the chapter (p. 413). Haematuria Healthy individuals may have occasional red blood cells in the urine (up to 12 500 cells/mL), but the presence of visible (macroscopic) haematuria or non-visible haematuria (microscopic, only detectable on dipstick testing) is indicative of significant bleeding from somewhere in the urinary tract (Fig. 15.7). Once infection, menstruation and causes of a positive urinary dipstick in the absence of red cells (haemoglobinuria/myoglobinuria) have 15.5 Renal biopsy Indications • Acute kidney injury and chronic kidney disease of uncertain aetiology • Nephrotic syndrome or glomerular proteinuria (protein:creatinine ratio > 100 mg/mol) in adults • Nephrotic syndrome in children that has atypical features or is not responding to treatment • Nephritic syndrome • Renal transplant dysfunction • Rarely performed for isolated haematuria or isolated low-grade proteinuria in the absence of impaired renal function or evidence of a multisystem disorder Contraindications • Disordered coagulation or thrombocytopenia. Aspirin and other antiplatelet agents increase bleeding risk • Uncontrolled hypertension • Kidneys < 60% predicted size • Solitary kidney* (except transplants) Complications • Pain, usually mild • Bleeding into urine, usually minor but may produce clot colic and obstruction • Bleeding around the kidney, occasionally massive and requiring angiography with intervention, or surgery • Arteriovenous fistula, rarely significant clinically *Relative contraindication. Renal biopsy Renal biopsy is used to establish the diagnosis and severity of renal disease in order to judge the prognosis and need for treatment (Box 15.5). The procedure is performed transcutaneously under local anaesthetic with ultrasound or contrast radiography guidance to ensure accurate needle placement into a renal pole. Light microscopy, electron microscopy and immunohistological assessment of the specimen may all be required. Presenting problems in renal and urinary tract disease Oliguria/anuria Oliguria is defined as being present when less than 400 mL of urine is passed per day, whereas anuria is deemed to exist when less than 100 mL of urine is passed per day. The volume of urine produced represents a balance between the amount of fluid that is filtered at the glomerulus and that reabsorbed by the renal tubules. When GFR is low, urine volumes may still be normal if tubular reabsorption is also reduced; hence urine volume alone is a poor indicator of the severity of kidney disease. Oliguria and anuria may be caused by a reduction in urine production, as in pre-renal AKI, when GFR is reduced and tubular homeostatic mechanisms increase reabsorption to conserve salt and water. A high solute load or associated tubular dysfunction may, however, produce normal or high urine volumes in such cases until the pre-renal insult becomes severe and GFR is markedly reduced, such as occurs in diabetic ketoacidosis 15.6 Causes of anuria (< 100 mL urine output per day) Condition Examples Urinary obstruction (complete) Urinary retention due to prostatic enlargement, urethral stenosis, bladder tumour Bilateral ureteric obstruction due to retroperitoneal fibrosis, cancer, radiation injury Bilateral renal stones (usually staghorn calculi) Massive crystalluria obstruction of tubules (rare) Lack of renal perfusion (bilateral) Aortic dissection involving renal arteries Severe acute tubular necrosis Severe functional hypoperfusion (cardiorenal, hepatorenal) Rapidly progressive glomerulonephritis Anti-glomerular basement membrane disease, severe antineutrophil cytoplasmic antibody (ANCA) vasculitis (100% glomerular crescents on biopsy)

392 • NEPHROLOGY AND UROLOGY Dipstick test positive Urine microscopy Suggested cause Haematuria White blood cells Abnormal epithelial cells Infection Tumour Red cell casts Dysmorphic erythrocytes (phase contrast microscopy) Glomerular bleeding* Haemoglobinuria No red cells Intravascular haemolysis Myoglobinuria (brown urine) No red cells Rhabdomyolysis } 15.7 Interpretation of non-visible haematuria Glomerular bleeding implies that the GBM is ruptured. It can occur physiologically following very strenuous exertion but usually indicates intrinsic renal disease and is an important feature of the nephritic syndrome. glomerular cause is not suspected (see below), it may be appropriate to manage them by periodic observation in primary care, although occasionally these individuals develop significant overt renal disease during follow-up. Glomerular bleeding occurs when inflammatory, destructive or degenerative processes disrupt the GBM, permitting passage of red blood cells into the urine. A characteristic feature of glomerular bleeding is an ‘active urinary sediment’ (the presence of dysmorphic red blood cells or red cell casts on microscopy); this is not always present, however. Patients with visible and non-visible haematuria should also be assessed for hypertension, proteinuria, reduced/declining renal function, family history of renal disease or features of systemic disease (Fig. 15.8). The presence of any of these features raises the possibility of intrinsic renal pathology and warrants referral to nephrology for further investigation, including consideration of renal biopsy. Nephritic syndrome The nephritic syndrome is characterised by the presence of haematuria in association with hypertension, oliguria, fluid retention and reduced/declining renal function. Many patients with glomerulonephritis, particularly those with milder disease, do not exhibit all of these features; their combined presence, however, is typical of a rapidly progressive glomerulonephritis and warrants urgent investigation. In many cases, investigation will include a renal biopsy to confirm diagnosis and guide management, but less invasive investigations may also be useful (Box 15.8). Patients with nephritic syndrome may also exhibit varying degrees of proteinuria, including nephrotic-range proteinuria; the prominence of haematuria on dipstick should, however, alert the physician to the possibility of a glomerulonephritis. Indeed, it is important to recognise that the characteristic features of nephritic syndrome and nephrotic syndrome do not always present in isolation, but should be considered to be the extreme phenotypes at either end of a spectrum of presentations (Fig. 15.9). Proteinuria While very small amounts of high-molecular-weight proteins and moderate amounts of low-molecular-weight proteins pass been excluded (Box 15.7), both visible and persistent non-visible haematuria require investigation, as they may be caused by malignancy or indicate glomerulonephritis. Visible haematuria is most likely to be caused by tumour, which can affect any part of the urogenital tract (Fig. 15.7), and patients with visible haematuria must therefore be referred to urology for imaging (ultrasound or CT scan) and cystoscopy (Fig. 15.8). Other common causes of visible haematuria are urine infection and stones. Visible haematuria may also be encountered in patients with IgA nephropathy, typically following an upper respiratory tract infection. Non-visible haematuria may also indicate an underlying tumour, and all patients over 40 years old with persistent (detected on at least 2 of 3 consecutive dipstick tests) non-visible haematuria should therefore undergo imaging and cystoscopy. In younger patients, an underlying tumour is much less likely, and if a Fig. 15.7 Causes of haematuria. Polyarteritis nodosa Vascular malformation Renal infarction Coagulation disorders Cysts Renal tumour Glomerulonephritis Small-vessel vasculitis Systemic lupus erythematosus Other glomerular diseases Interstitial nephritis Pyelonephritis Calculus Calculus Cystitis Bladder tumour Benign prostatic enlargement Prostate cancer Trauma Urethritis Trauma Trauma Ureteric tumour 15.8 Investigation of nephritic syndrome Cause Investigations Rapidly progressive glomerulonephritis (RPGN) Post-infectious glomerulonephritis ASOT, C3, C4 Anti-GBM disease Anti-GBM antibody Small-vessel vasculitis p-ANCA, c-ANCA Lupus nephritis ANA, dsDNA, C3, C4 Mild glomerulonephritic presentation IgA nephropathy Serum IgA (polyclonal rise in 50% of patients) Mesangioproliferative glomerulonephritis C3, C4, hepatitis B,C + HIV serology, ANA, dsDNA, immunoglobulins, PPE Alport’s syndrome Genetic screening, hearing test *Not a glomerulonephritis but may present in a similar manner with haematuria, variable proteinuria, hypertension and slowly declining renal function. (ANA = antinuclear antibody; ANCA = antineutrophil cytoplasmic antibody; ASOT = anti-streptolysin O titre; C3, C4 = complement proteins 3, 4; dsDNA = double-stranded DNA; GBM = glomerular basement membrane; HIV = human immunodeficiency virus; IgA = immunoglobulin A; PPE = plasma protein electrophoresis)

Presenting problems in renal and urinary tract disease • 393

disease (see Box 15.20, p. 405). The presence of larger amounts of protein is usually indicative of significant renal disease. Proteinuria is usually asymptomatic and is often picked up by urinalysis, although large amounts of protein may make the urine frothy. Transient proteinuria can occur after vigorous exercise, during fever, in heart failure and in people with urinary through the healthy GBM, these proteins normally are completely reabsorbed by receptors on tubular cells. Hence, in healthy individuals, less than 150 mg of protein is excreted in the urine each day, much of which is derived from tubular cells. This includes Tamm–Horsfall protein (uromodulin), encoded by the UMOD gene that has recently been linked to tubulo-interstitial Fig. 15.8 Investigation of haematuria. *Symptomatic: lower urinary tract voiding symptoms such as hesitancy, frequency, urgency and dysuria. (ACR = albumin:creatinine ratio; BP = blood pressure; CT = computed tomography; eGFR = estimated glomerular filtration rate; NVH = non-visible haematuria; UTI = urinary tract infection) Persistent non-visible haematuria 2 of 3 positive dipsticks Exclude menstruation/UTI Refer to nephrology Consider renal biopsy Refer to urology Ultrasound/CT renal tracts Cystoscopy Observation Annual: urinalysis, BP, ACR, eGFR *Symptomatic NVH Assess: BP, eGFR, ACR Abnormal OR Normal <40 years

40 years Family history of renal disease Evidence of systemic disease Visible haematuria Exclude menstruation/UTI Check BP, eGFR Fig. 15.9 Nephritic and nephrotic syndrome. At one extreme, specific injury to podocytes causes proteinuria and nephrotic syndrome. The histology to the left shows diabetic nephropathy. At the other end of the spectrum, inflammation leads to cell damage and proliferation, breaks form in the glomerular basement membrane (GBM) and blood leaks into urine. In its extreme form, with acute sodium retention and hypertension, such disease is labelled nephritic syndrome. The histology to the right shows a glomerulus with many extra nuclei from proliferating intrinsic cells, and influx of inflammatory cells leading to crescent formation (arrows) in response to severe post-infectious glomerulonephritis. (FSGS = focal and segmental glomerulosclerosis; IgA = immunoglobulin A; MCGN = mesangiocapillary glomerulonephritis; SLE = systemic lupus erythematosus) Nephrotic Mechanism • Injury to podocytes • Changed architecture

Scarring

Deposition of matrix or other elements Clinical features • Overt proteinuria: usually > 3.5 g/24 hrs (urine may be frothy) • Hypoalbuminaemia (> 30 g/L) • Oedema and generalised fluid retention • Possible intravascular volume depletion with hypotension, or intravascular expansion with hypertension Nephritic Mechanism • Inflammation • Reactive cell proliferation • Breaks in GBM • Crescent formation Clinical features • Haematuria (red or brown urine) • Oedema and generalised fluid retention • Hypertension • Oliguria • Reduced renal function Haematuria Proteinuria SLE IgA nephropathy Minimal change nephropathy Diabetic nephropathy MCGN Anti-GBM disease FSGS Membranous nephropathy Amyloid Smallvessel vasculitis Post-streptococcal glomerulonephritis

394 • NEPHROLOGY AND UROLOGY 15.9 Quantifying proteinuria in random urine samples ACR1 PCR2 Typical dipstick results3 Significance < 3.5 (female) < 2.5 (male) < 25 – Normal 3.5–30 25–50 – Moderately elevated albuminuria 30–70 50–100

300 350 +++ to ++++ Nephrotic range: almost always glomerular disease, equivalent to > 3.5 g/24 hrs 1Urinary albumin (mg/L)/urine creatinine (mmol/L). 2Urine protein (mg/L)/urine creatinine (mmol/L). (If urine creatinine is measured in mg/dL, reference values for PCR and ACR can be derived by dividing by 11.31.) 3Dipstick results are affected by urine concentration and are occasionally weakly positive on normal samples. tract infection. Patients should be assessed for the presence of these conditions and urine testing repeated once the potential trigger has been treated or resolved. Testing for proteinuria is best done on an early morning sample, as some individuals exhibit orthostatic proteinuria. In these patients, typically less than 1 g/24 hrs of protein is excreted only in association with an upright posture, the first morning sample being negative. Orthostatic proteinuria is regarded as a benign disorder that does not require treatment. Moderately elevated albuminuria (microalbuminuria) In healthy individuals, there is virtually no urinary excretion of large-molecular-weight serum proteins, such as albumin, in contrast to modest urinary excretion of tubule-derived proteins. The presence of even moderate amounts of albuminuria (previously referred to as microalbuminuria) is therefore abnormal, and may indicate early glomerular pathology, at a time when the standard dipstick test remains negative (Box 15.9). Screening for moderately elevated albuminuria should be performed regularly in patients with diabetes, as persistently elevated levels warrant therapy with inhibitors of the renin–angiotensin–aldosterone system, even in normotensive individuals, to reduce the rate of loss of renal function (see Box 20.39, p. 758). Persistent moderately increased albuminuria has also been associated with cardiovascular mortality in patients with and without diabetes, but an explanation for this association has not yet been established. Overt (dipstick-positive) proteinuria Urinary dipstick testing is a valuable screening tool for the detection of proteinuria; it is only semi-quantitative, however, as it is highly dependent on the concentration of the urine. Typically, standard dipsticks test positive for protein once the urinary protein exceeds approximately 0.5 g/24 hrs; however, trace to 1+ on dipstick may be observed in very concentrated urine from individuals with no evidence of renal pathology. Hence all patients with persistent proteinuria on dipstick should have the amount of protein quantified to guide further investigations (Fig. 15.10). When more than 1 g of protein per day is being excreted, glomerular disease is likely and this is an indication for renal biopsy. Since quantification by 24-hour urine collection is often inaccurate, the protein:creatinine ratio (PCR) in a spot sample of urine is preferred. This makes an allowance for the variable degree of urinary dilution and can be used to extrapolate to 24-hour values (Box 15.9). Changes in PCR also give valuable information about the progression of renal disease and response to therapy in CKD. It is possible to measure albumin:creatinine ratio (ACR), but this requires a more expensive immunoassay and is usually reserved for situations when high sensitivity is required, such as detection of the early stages of diabetic nephropathy (p. 757). It is sometimes helpful to identify the type of protein in the urine. Large amounts of low-molecular-weight proteins, such as β2-microglobulin (molecular weight 12 kDa), in the urine suggest renal tubular damage and are referred to as tubular proteinuria. This rarely exceeds 1.5–2 g/24 hrs (maximum PCR 150–200 mg/ mmol; see Box 15.9 for conversion of mg/mmol to mg/dL). Free immunoglobulin light chains (molecular weight 25 kDa) are filtered freely at the glomerulus but are poorly identified by Fig. 15.10 Investigation of proteinuria. (ACR = albumin:creatinine ratio; PCR = protein:creatinine ratio.) Substantial Total 24-hr protein > 1 g PCR > 100 mg/mmol ACR > 70 mg/mmol Yes Quantify Repeated proteinuria on dipstick Features of significant renal disease? Hypertension Abnormal renal function Family history of renal disease Signs of systemic disease No Consider renal biopsy Observation Urinalysis, blood pressure, creatinine every 6 – 12 mths Re-assess if anything changes Moderate or low-grade Total 24-hr protein < 1 g PCR < 100 mg/mmol ACR < 70 mg/mmol

Presenting problems in renal and urinary tract disease • 395

scarring or deposition of exogenous material such as amyloid into the glomerulus. Investigation of nephrotic syndrome usually involves renal biopsy, although non-invasive tests may also be helpful in suggesting the underlying cause (Box 15.10). In children, minimal change disease is by far the most common cause of nephrotic syndrome and therefore renal biopsy is not usually required unless the patient fails to respond to high-dose glucocorticoid therapy. Similarly, most patients with diabetes presenting with nephrotic syndrome will have diabetic nephropathy, and so renal biopsy is usually not performed unless the course of the disease is atypical (rapidly increasing proteinuria or rapid decline in renal function; p. 757). Management of nephrotic syndrome should be directed at the underlying cause. In addition, nephrotic syndrome is associated with a number of complications (Box 15.11), which may require supportive management unless the nephrosis is expected to resolve rapidly, such as in glucocorticoid-responsive minimal change disease. Oedema Oedema is caused by an excessive accumulation of fluid within the interstitial space. Clinically, this can be detected by persistence of an indentation in tissue following pressure on the affected area (pitting oedema). Pitting oedema tends to accumulate in the ankles during the day and improves overnight as the interstitial fluid is reabsorbed. Non-pitting oedema is typical of lymphatic obstruction and may also occur as the result of excessive matrix deposition in tissues: for example, in hypothyroidism (p. 639) or systemic sclerosis (p. 1037). Clinical assessment Dependent areas, such as the ankles and lower legs, are typically affected first but oedema can be restricted to the sacrum in bed-bound patients. With increasing severity, oedema spreads to affect the upper parts of the legs, the genitalia and abdomen. Ascites is common and often an earlier feature in children or young adults, and in liver disease. Pleural effusions are common but frank pulmonary oedema is rare. Facial oedema on waking is common. Features of intravascular volume depletion (tachycardia, postural hypotension) may occur when oedema is due to decreased 15.10 Investigation of nephrotic syndrome Cause Typical age group Investigations Fulminant presentation Minimal change disease Children, young adults, occasionally seen in older patients None specific Primary focal segmental glomerulosclerosis Young adults None specific Subacute presentation Membranous nephropathy Middle-aged to older patients Hepatitis B, C + HIV serology, ANA, dsDNA Amyloid Older patients Immunoglobulins, PPE, Bence Jones protein, serum free light chains Gradual progression Diabetic nephropathy Any age, but rarely < 10 years from diagnosis of type 1 diabetes Glucose, glycosylated haemoglobin (ANA = antinuclear antibody; dsDNA = double-stranded DNA; HIV = human immunodeficiency virus; PPE = plasma protein electrophoresis) dipstick tests. Hence, electrophoresis of the urine and specific immunodetection methods are required to detect immunoglobulin light chains, known as ‘Bence Jones protein’. This may occur in AL amyloidosis (p. 81) and in B-cell dyscrasias but is particularly important as a marker for myeloma (p. 966). Nephrotic syndrome Nephrotic syndrome is characterised by very heavy proteinuria (> 3.5 g/24 hrs), hypoalbuminaemia and oedema (see below). Blood volume may be normal, reduced or increased. Renal sodium retention is an early and universal feature; the mechanisms of this are shown in Figure 14.5 (p. 354). The diseases that cause nephrotic syndrome all affect the glomerulus (see Fig. 15.9), either directly, by damaging podocytes, or indirectly, by causing 15.11 Consequences of the nephrotic syndrome and their management Feature Mechanism Consequence Management Hypoalbuminaemia Urinary protein losses exceed synthetic capacity of liver Reduced oncotic pressure Oedema Treatment of underlying cause Avid sodium retention Secondary hyperaldosteronism Additional poorly characterised intrarenal mechanisms Oedema Diuretics and a low-sodium diet* Hypercholesterolaemia Non-specific increase in lipoprotein synthesis by liver in response to low oncotic pressure High rate of atherosclerosis Statins, ezetimibe Hypercoagulability Relative loss of inhibitors of coagulation (antithrombin III, protein C and S) and increase in liver synthesis of procoagulant factors Venous thromboembolism Consideration of prophylaxis in chronic or severe nephrotic syndrome Infection Hypogammaglobulinaemia due to urinary loss of immunoglobulins Pneumococcal and meningococcal infection Consideration of vaccination *Severe nephrotic syndrome may need very large doses of combinations of diuretics acting on different parts of the nephron (e.g. loop diuretic plus thiazide plus amiloride). In occasional patients with hypovolaemia, intravenous salt-poor albumin infusions may help to establish a diuresis, although efficacy is controversial. Over-diuresis risks secondary impairment of renal function through hypovolaemia.

396 • NEPHROLOGY AND UROLOGY at risk of developing CKD and current recommendations are that hypertensive patients should have renal function checked annually. Control of hypertension is very important in patients with renal impairment because of its close relationship with further decline of renal function (p. 420) and because of the exaggerated cardiovascular risk associated with CKD. Pathophysiology and management are discussed on pages 509 and 510. Loin pain Loin pain is often caused by musculoskeletal disease but can be a manifestation of renal tract disease; in the latter case, it may arise from renal stones, ureteric stones, renal tumours, acute pyelonephritis and urinary tract obstruction. Acute loin pain radiating anteriorly and often to the groin is termed renal colic. When combined with haematuria, this is typical of ureteric obstruction due to calculi (p. 431). Precipitation of loin pain by a large fluid intake (Dietl’s crisis) suggests upper urinary tract obstruction caused by a congenital abnormality of the pelvi-ureteric junction (p. 433). Dysuria Dysuria refers to painful urination, often described as burning, scalding or stinging, and commonly accompanied by suprapubic pain. It is often associated with frequency of micturition and a feeling of incomplete emptying of the bladder. By far the most common cause is urinary tract infection, as described on page 426. Other diagnoses that need to be considered in patients with dysuria include sexually transmitted infections (p. 329) and bladder stones (p. 431). Frequency Frequency describes daytime micturition more often than a patient would expect. It may be a consequence of polyuria, when urine volume is normal or high, but is also found in patients with dysuria and prostatic diseases, when the urine volume is normal. Polyuria Polyuria is defined as a urine volume in excess of 3 L/24 hrs. Various underlying conditions, both renal and extrarenal, may be responsible, as outlined in Box 15.13. Investigation of polyuria includes measurement of urea, creatinine and electrolytes, glucose, calcium and albumin. A 24-hour urine collection may be helpful to confirm the severity of polyuria. The presence of nocturnal polyuria suggests a oncotic pressure or increased capillary permeability. If oedema is localised – for example, to one ankle but not the other – then venous thrombosis, inflammation or lymphatic disease should be suspected. Investigations Oedema may be due to a number of causes (Box 15.12), which are usually apparent from the history and examination of the cardiovascular system and abdomen. Blood should be taken for measurement of urea and electrolytes, liver function and serum albumin, and the urine tested for protein. Further imaging of the liver, heart or kidneys may be indicated, based on history and clinical examination. Where ascites or pleural effusions occur in isolation, aspiration of fluid with measurement of protein and glucose, and microscopy for cells, will usually help to clarify the diagnosis in differentiating a transudate (typical of oedema) from an exudate (more suggestive of local pathology, p. 564). Management Mild oedema usually responds to elevation of the legs, compression stockings, or a thiazide or a low dose of a loop diuretic, such as furosemide or bumetanide. In nephrotic syndrome, renal failure and severe cardiac failure, very large doses of diuretics, sometimes in combination, may be required to achieve a negative sodium and fluid balance. Restriction of sodium intake and fluid intake may be required. Diuretics are not helpful in the treatment of oedema caused by venous or lymphatic obstruction or by increased capillary permeability. Specific causes of oedema, such as venous thrombosis, should be treated. Hypertension Hypertension is a very common feature of renal disease. Additionally, the presence of hypertension identifies a population 15.13 Causes of polyuria • Excess fluid intake • Osmotic diuresis: hyperglycaemia, hypercalcaemia • Cranial diabetes insipidus • Nephrogenic diabetes insipidus: Rare inherited mutations in vasopressin receptor or aquaporin 2 genes Lithium Diuretics Interstitial nephritis Hypokalaemia Hypercalcaemia 15.12 Causes of oedema Increased total extracellular fluid • Congestive heart failure • Renal failure • Liver disease High local venous pressure • Deep venous thrombosis or venous insufficiency • Pregnancy • Pelvic tumour Low plasma oncotic pressure/serum albumin • Nephrotic syndrome • Liver failure • Malnutrition/malabsorption Increased capillary permeability • Leakage of proteins into the interstitium, reducing the osmotic pressure gradient that draws fluid into the lymphatics and blood • Infection/inflammation • Severe sepsis • Calcium channel blockers Lymphatic obstruction • Infection: filariasis, lymphogranuloma venereum (pp. 290 and 341) • Malignancy • Radiation injury • Congenital abnormality

Glomerular diseases • 397

Most types of glomerulonephritis are immunologically mediated and several respond to immunosuppressive drugs. Deposition of antibody occurs in many types of glomerulonephritis and testing for circulating or glomerular deposition of antibodies may aid diagnosis (see Fig. 15.11 and Boxes 15.8 and 15.10). In small-vessel vasculitis, no glomerular antibody deposition is observed (pauci-immune), but the antibodies may be indirectly pathogenic by activating neutrophils to promote endothelial injury (Fig. 15.11). Glomerulonephritis is generally classified in terms of the histopathological appearances, as summarised in Box 15.15 and Figure 15.12. Many non-specialists find the terminology used in describing glomerulonephritis to be confusing; some definitions are provided in Box 15.16. It is important to stress that the histological appearance rarely confirms a specific renal disease but rather suggests a limited range of diagnoses, which may be confirmed by further investigation. Conversely, some diseases, such as lupus, are associated with more than one histological pattern of injury. The most common histological subtypes may be categorised according to their typical clinical presentation, as discussed below. Genetic disorders associated with glomerular disease are described later (p. 403). pathological cause. Investigation and management of suspected diabetes insipidus are described on page 688. Nocturia Nocturia is defined as waking up at night to void urine. It may be a consequence of polyuria but may also result from increased fluid intake or diuretic use in the late evening (including caffeine). Nocturia also occurs in CKD, and in prostatic enlargement when it is associated with poor stream, hesitancy, incomplete bladder emptying, terminal dribbling and urinary frequency due to partial urethral obstruction (p. 437). Nocturia may also occur due to sleep disturbance without any functional abnormalities of the urinary tract. Urinary incontinence Urinary incontinence is defined as any involuntary leakage of urine. It may occur in patients with a normal urinary tract, as the result of dementia or poor mobility, or transiently during an acute illness or hospitalisation, especially in older people (see Box 15.54, p. 436). The pathophysiology, investigation and management of urinary incontinence are discussed in detail later in the chapter (p. 436). Glomerular diseases Glomerular diseases account for a significant proportion of acute and chronic kidney disease. Most patients with glomerular disease do not present acutely and are asymptomatic until abnormalities are detected on routine screening of blood or urine samples. There are many causes of glomerular damage, including immunological injury, inherited diseases such as Alport’s syndrome (p. 403), metabolic diseases such as diabetes mellitus (p. 757), and deposition of abnormal proteins such as amyloid in the glomeruli (p. 81). The glomerular cell types that may be the target of injury are shown in Figure 15.11. Proteinuria is the hallmark of glomerular disease; however, the response of the glomerulus to injury and hence the predominant clinical features vary according to the nature of the insult, ranging from fulminant nephrotic syndrome to rapidly progressive glomerulonephritis (see Fig. 15.9). Several prognostic indicators are common to all causes of glomerulonephritis (Box 15.14) and may be helpful in assessing the need for immunosuppressive therapy. Glomerulonephritis While glomerulonephritis literally means ‘inflammation of glomeruli’, the term is often used more broadly to describe all types of glomerular disease, even though some of these (e.g. minimal change nephropathy) are not associated with inflammation. Fig. 15.11 Glomerulonephritis associated with antibody production. Antibodies and antigen–antibody (immune) complexes may target or be deposited in specific components of the glomerulus, resulting in different patterns of histological injury and clinical presentation. Testing for antibody deposition in the glomerulus by immunofluorescence (IF) on renal biopsy tissue or for antibodies in the serum may aid diagnosis. Diagnostic tests are shown in italics. (ANA = antinuclear antibody; ANCA = antineutrophil cytoplasmic antibody; dsDNA = double-stranded DNA; GBM = glomerular basement membrane; IgA = immunoglobulin A; SLE = systemic lupus erythematosus) Endothelium (indirectly) Small-vessel vasculitis ANCA (serum) GBM Goodpasture's disease Anti-GBM antibody (serum + IF on biopsy; see Fig.15.12H) Podocyte Membranous nephropathy Anti-phosphilipase A2 receptor 1 (serum + IF on biopsy; experimental at present; see Fig.15.12F) Planted antigens SLE – ANA, anti-dsDNA (serum) Post-infectious glomerulonephritis Circulating immune complexes Cryoglobulinaemia (Cryoglobulins in serum) Serum sickness Endocarditis Mesangium IgA nephropathy (polyclonal rise in serum IgA in 50% patients; IF on biopsy; see Fig.15.12G) 15.14 Poor prognostic indicators in glomerular disease • Male sex • Hypertension • Persistent and severe proteinuria • Elevated creatinine at time of presentation • Rapid rate of decline in renal function • Tubulo-interstitial fibrosis observed on renal biopsy

398 • NEPHROLOGY AND UROLOGY discussed elsewhere, including diabetic nephropathy (p. 757) and amyloid (p. 81). Minimal change nephropathy Minimal change disease occurs at all ages but accounts for most cases of nephrotic syndrome (see Box 15.15) in children and about one-quarter of adult cases. It is caused by reversible dysfunction of podocytes. On light microscopy, the glomeruli appear normal (Fig. 15.12A), but fusion of podocyte foot processes is observed on electron microscopy. The presentation is with nephrotic syndrome, which typically is severe; it remits Diseases typically presenting with nephrotic syndrome In these diseases, the injury is focused on the podocyte and there is little histological evidence of inflammation or cell proliferation in the glomerulus (non-proliferative, Fig. 15.12). Minimal change and primary focal segmental glomerulosclerosis (FSGS) typically present with fulminant nephrotic syndrome, whereas in membranous nephropathy and secondary FSGS, the nephrosis tends to be more indolent in nature. Other causes of nephrotic syndrome due to systemic disease are 15.15 Glomerulonephritis categorised by clinical presentation and histological classification Histology Immune deposits Pathogenesis Associations Comments Nephrotic presentation Minimal change Normal, except on electron microscopy, where fusion of podocyte foot processes is observed (non-specific finding) None Unknown; probable circulating factor promoting podocyte injury Some cases are genetic (p. 403) Atopy Drugs, most commonly NSAIDs Haematological malignancies Acute and often severe nephrotic syndrome Good response to glucocorticoids Dominant cause of idiopathic nephrotic syndrome in childhood Focal segmental glomerulosclerosis (FSGS) Segmental scars in some glomeruli No acute inflammation Podocyte foot process fusion seen in primary FSGS Non-specific trapping in focal scars Unknown; circulating factors may increase glomerular permeability Injury to podocytes may be common feature Some cases are genetic (p. 403) APOL1 variant in people of West African descent Causes of secondary FSGS include: Healing of previous local glomerular injury HIV infection Heroin misuse Morbid obesity Chronic hypertension Primary FSGS presents as idiopathic nephrotic syndrome but is less responsive to treatment than minimal change; may progress to renal impairment, and can recur after transplantation Secondary FSGS presents with variable proteinuria and outcome Membranous nephropathy Thickening of GBM Progressing to increased matrix deposition and glomerulosclerosis Granular subepithelial IgG Antibodies to a podocyte surface antigen (commonly phospholipase A2 receptor 1), with complementdependent podocyte injury HLA-DQA1 (for idiopathic) Drugs: Penicillamine, NSAIDs, heavy metals Hepatitis B virus Malignancy Lupus1 Common cause of adult idiopathic nephrotic syndrome One-third progress, one-third spontaneously remit and one-third remain stable; may respond to glucocorticoids and immunosuppressants Mild glomerulonephritic presentation IgA nephropathy Increased mesangial matrix and cells Focal segmental nephritis in acute disease Mesangial IgA (and C3) Unknown Mucosal infections (e.g. helminths) may be involved Usually idiopathic, flares triggered by upper respiratory infection Liver disease Coeliac disease Common disease with range of presentations, usually including haematuria and hypertension Henoch–Schönlein purpura is an acute IgA variant common in children Mesangiocapillary glomerulonephritis Immunoglobulin type Immunoglobulins Deposition of circulating immune complexes or ‘planted’ antigens Infections, autoimmunity or monoclonal gammopathies Most common pattern found in association with subacute bacterial infection, but also with cryoglobulinaemia ± hepatitis C virus, and others Complement type Complement components Complement abnormalities, inherited or acquired Dense deposit disease is associated with abnormal activation of alternative complement pathway Complement gene mutations C3 nephritic factor and partial lipodystrophy In dense deposit disease, intramembranous deposits No proven treatments Continued

Glomerular diseases • 399

15.15 Glomerulonephritis categorised by clinical presentation and histological classification – continued Histology Immune deposits Pathogenesis Associations Comments Rapidly progressive glomerulonephritis presentation Focal necrotising glomerulonephritis Segmental inflammation and/or necrosis in some glomeruli ± crescent formation Variable according to cause but typically negative (or ‘pauciimmune’) Small-vessel vasculitis, often ANCA-mediated Primary or secondary small-vessel vasculitis Often occurs in systemic disease Responds to treatment with glucocorticoids and immunosuppressants Diffuse proliferative glomerulonephritis 2 Infection-related diffuse proliferative glomerulonephritis 3 Diffuse proliferation of endothelial and mesangial cells Infiltration by neutrophils and macrophages ± crescent formation Subendothelial and subepithelial Immune complex-mediated (e.g. to streptococcal infection with presumed cross-reactive epitopes) Post-streptococcal Concurrent infection with staphylococci, endocarditis Presents with severe sodium and fluid retention, hypertension, haematuria, oliguria Usually resolves spontaneously Anti-glomerular basement membrane disease Usually crescentic nephritis Linear IgG along GBM Autoantibodies to α3 chain of type IV collagen in GBM HLA-DR15 (previously known as DR2) Associated with lung haemorrhage but renal or lung disease may occur alone Treat with glucocorticoids, cyclophosphamide and plasma exchange 1Systemic lupus erythematosus can cause almost any histological injury pattern, most commonly membranous nephropathy or diffuse proliferative glomerulonephritis. 2In addition to the association with infection and anti-GBM disease, a diffuse proliferative glomerulonephritis picture may also be seen with lupus and occasionally IgA nephropathy. 3Infection may also present with mesangioproliferative glomerulonephritis and membranous nephropathy (HIV). (ANA = antinuclear antibody; ANCA = antineutrophil cytoplasmic antibody; APOL1 = apolipoprotein L1; GBM = glomerular basement membrane; HLA = human leucocyte antigen; IgA = immunoglobulin A; NSAIDs = non-steroidal anti-inflammatory drugs) Fig. 15.12 Histopathology of glomerular disease. ( A – E Light microscopy) A A normal glomerulus. Note the open capillary loops and thinness of their walls. B Focal segmental glomerulosclerosis (GS). The portion of the glomerulus arrowed shows loss of capillary loops and cells, which are replaced by matrix. C Focal necrotising glomerulonephritis (GN). A portion of the glomerulus (N = focal necrotising lesion) is replaced by bright pink material with some ‘nuclear dust’. Neutrophils may be seen elsewhere in the glomerulus. There is surrounding interstitial inflammation (I). This is most commonly associated with small-vessel vasculitis and may progress to crescentic nephritis (see E ). D Membranous glomerulonephritis. The capillary loops (C) are thickened (compare with the normal glomerulus) and there is expansion of the mesangial regions by matrix deposition (M). However, there is no gross cellular proliferation or excess of inflammatory cells. E Crescentic glomerulonephritis. The lower part of Bowman’s space is occupied by a semicircular formation (‘crescent’, Cr) of large pale cells, compressing the glomerular tuft. This is seen in aggressive inflammatory glomerulonephritis. Antibody deposition in the glomerulus. ( F – H Direct immunofluorescence) F Granular deposits of IgG along the basement membrane in a subepithelial pattern, typical of membranous GN. G Immunoglobulin A (IgA) deposits in the mesangium, as seen in IgA nephropathy. H Ribbon-like linear deposits of anti-GBM antibodies along the glomerular basement membrane in Goodpasture’s disease. The glomerular structure is well preserved in all of these examples. (A, C, D, E) Courtesy of Dr J.G. Simpson, Aberdeen Royal Infirmary. (F, G, H) Courtesy of Dr R. Herriot. A B C D E F G H Normal glomerulus Focal segmental GS Membranous GN Focal necrotising GN Crescentic GN Membranous GN IgA nephropathy Anti-GBM disease C N I Cr M

400 • NEPHROLOGY AND UROLOGY rarely exhibit full-blown nephrotic syndrome. Management of secondary FSGS is focused on treating the underlying cause and reducing proteinuria by inhibiting the renin–angiotensin system (p. 417). Membranous nephropathy Membranous nephropathy is the most common cause of nephrotic syndrome in Caucasian adults. It is caused by antibodies (usually autoantibodies) directed at antigen(s) expressed on the surface of podocytes, including the M-type phospholipase A2 receptor 1. While most cases are idiopathic, a proportion are associated with other causes, such as heavy metal poisoning, drugs, infections, lupus and tumours (see Box 15.15 and Fig. 15.12D and F). Approximately one-third of patients with idiopathic membranous nephropathy undergo spontaneous remission, one-third remain in a nephrotic state, and one-third develop progressive CKD. High doses of glucocorticoids and cyclophosphamide may improve both the nephrotic syndrome and the long-term prognosis. However, because of the toxicity of these regimens, many nephrologists reserve such treatment for those with severe nephrotic syndrome or deteriorating renal function. Treatment of secondary membranous nephropathy is directed at the underlying cause. Diseases typically presenting with mild nephritic syndrome Patients with mild glomerulonephritis typically present with nonvisible haematuria and modest proteinuria, and their renal disease tends to follow a slowly progressive course. IgA nephropathy and mesangiocapillary glomerulonephritis (MCGN) typically fall in this category. Their presentation is highly variable, however; IgA nephropathy occasionally presents with rapidly progressive glomerulonephritis while MCGN may present with nephrotic syndrome. Other diseases that present with haematuria, modest proteinuria and slow progression include Alport’s syndrome (p. 403). IgA nephropathy This is one of the most common types of glomerulonephritis and can present in many ways. Haematuria is the earliest sign and non-visible haematuria is almost universal, while hypertension is also very common. These are often detected during routine screening: for example, at occupational medical examinations. Proteinuria can also occur but is usually a later feature. In many cases, there is slowly progressive loss of renal function leading to end-stage renal disease (ESRD). A particular hallmark of IgA nephropathy in young adults is the occurrence of acute self-limiting exacerbations, often with visible haematuria, in association with minor respiratory infections. This may be so acute as to resemble acute post-infectious glomerulonephritis, with fluid retention, hypertension and oliguria with dark or red urine. Characteristically, the latency from clinical infection to nephritis is short: a few days or less. Asymptomatic presentations dominate in older adults, with non-visible haematuria, hypertension and reduction in GFR. Occasionally, IgA nephropathy progresses rapidly in association with crescent formation on biopsy. Management is largely directed towards the control of blood pressure, with renin–angiotensin system inhibitors preferable in those with proteinuria. There is some evidence for additional benefit from several months of high-dose glucocorticoid treatment in those at high-risk of progressive disease (see Box 15.14), but no strong evidence for other immunosuppressive agents. A role for other therapies, such as fish oil, remains uncertain. with high-dose glucocorticoid therapy (1 mg/kg prednisolone for 6 weeks), though the response to therapy is often less satisfactory in older patients. Some patients who respond incompletely (glucocorticoid-resistant) or relapse frequently need maintenance glucocorticoids (glucocorticoid dependence), cytotoxic therapy or other agents. Glucocorticoid resistance in children warrants a biopsy to exclude an alternative diagnosis, but if minimal change is confirmed, a genetic cause should be considered (p. 403). Minimal change disease typically does not progress to CKD but can present with problems related to the nephrotic syndrome (see Box 15.11) and complications of treatment. Focal segmental glomerulosclerosis Primary focal segmental glomerulosclerosis (FSGS) (Fig. 15.12B) can occur in all age groups but is particularly common in people of West African descent, who, compared with other ethnicities, have a much higher carriage rate of an apolipoprotein L1 (APOL1) gene variant that is associated with increased risk of FSGS. Histological analysis shows sclerosis initially limited to segments of the glomeruli, which may also show positive staining for deposits of C3 and IgM on immunofluorescence. Since FSGS is a focal process, abnormal glomeruli may not be seen on renal biopsy if only a few are sampled, leading to an initial diagnosis of minimal change nephropathy. In most cases the underlying cause is unknown (primary FSGS) and these patients typically present with abrupt onset of severe nephrotic syndrome. Primary FSGS may respond to high-dose glucocorticoid therapy (0.5–2.0 mg/ kg/day) but the response is rarely as rapid or complete as for minimal change disease. Immunosuppressive drugs, such as ciclosporin, cyclophosphamide and mycophenolate mofetil, have also been used but their efficacy is uncertain. Progression to CKD is common in patients who do not respond to glucocorticoids and the disease frequently recurs after renal transplantation. FSGS may also be secondary to other diseases such as human immunodeficiency virus (HIV) renal disease (particularly in African Americans), morbid obesity or chronic hypertension. In addition, it may reflect scarring from previous focal glomerular injury resulting from HUS, cholesterol embolism or vasculitis. Patients with secondary FSGS typically present with more modest proteinuria than those with primary disease and 15.16 Terminology used in glomerulonephritis Light microscopy • Focal: affecting some but not all glomeruli • Diffuse: affecting > 50% of glomeruli • Segmental: affecting a portion of a glomerulus • Global: affecting all of the glomerulus • Necrotising: severe injury leading to an area of necrosis, usually associated with vasculitis • Crescentic: a crescent-shaped area of inflammatory cells responding to severe glomerular injury Electron microscopy • Subendothelial immune deposits: found between the endothelial cell and the GBM – often found in nephritic presentations • Intramembranous immune deposits: found within the GBM – found in the dense deposit variant of mesangiocapillary glomerulonephritis • Subepithelial immune deposits: found between the epithelial cell and the GBM – often found in nephrotic presentations, including membranous presentation of lupus (GBM = glomerular basement membrane)

Tubulo-interstitial diseases • 401

Anti-glomerular basement membrane disease Anti-GBM disease is a rare autoimmune disease in which antibodies develop against the α3 chain of type 4 collagen GBM. Expression of the α3 chain is largely restricted to the basement membranes of glomeruli and lungs, and hence the disease may present with rapidly progressive glomerulonephritis, lung haemorrhage, or disease of both organs, when it is known as Goodpasture’s disease. Goodpasture’s disease is more common in younger patients, while elderly patients often present with renal-limited disease. Patients with anti-GBM disease should be treated with plasma exchange combined with glucocorticoids and immunosuppressants, but early diagnosis is essential, as renal function is rarely recoverable in those requiring dialysis at presentation. The combination of glomerulonephritis and pulmonary haemorrhage (Goodpasture’s syndrome) may also be observed with small-vessel vasculitis (particularly granulomatosis with polyangiitis, previously known as Wegener’s granulomatosis) and lupus. Infection-related glomerulonephritis RPGN may occur either during or following an infection. In both cases, circulating immune complexes are present and activation of the complement system promotes consumption of complement factors, resulting in low serum C3 and C4 concentration, as observed in many causes of glomerulonephritis (Box 15.17). Post-infectious glomerulonephritis is observed most commonly in children and young adults, and typically presents 10 days after a streptococcal throat infection or longer after a skin infection. The clinical presentation ranges from mild abnormalities on urinalysis to RPGN with severe AKI. The anti-streptolysin (ASO) test is positive in up to 95% of patients with streptococcal throat infections. Treatment is supportive, with control of blood pressure and fluid overload with salt restriction, diuretics and dialysis if required. Antibiotic therapy is rarely needed, as the renal disease occurs after the infection has subsided. The medium-term prognosis for children and most adults is good, with recovery of renal function typical even in those requiring dialysis therapy. Some patients may develop CKD 20–30 years after the original presentation, however. An immune complex-mediated disease may also be observed during an infection, typically a staphylococcal infection such as endocarditis, skin infection or pneumonia, but also with subacute endocarditis due to Streptococcus viridans. This occurs more commonly in older adults and the presentation tends not to be as fulminant as with post-streptococcal disease. In addition to supportive measures, antibiotic therapy is required, as infection is usually concurrent with renal disease. Tubulo-interstitial diseases These diseases primarily affect the renal tubules and interstitial components of the renal parenchyma. They are characterised Henoch–Schönlein purpura This condition most commonly occurs in children but can also be observed in adults. It is a systemic vasculitis that often arises in response to an infectious trigger. It presents with a tetrad of features: • a characteristic petechial rash typically affecting buttocks and lower legs • abdominal pain due to vasculitis involving the gastrointestinal tract • arthralgia • renal disease characterised by visible or non-visible haematuria, with or without proteinuria. Renal biopsy shows mesangial IgA deposition and appearances that are indistinguishable from acute IgA nephropathy (Fig. 15.12G). Treatment is supportive in nature; in most patients, the prognosis is good, with spontaneous resolution, though relapses are common. Some patients, particularly adults and those with severe or persistent proteinuria, progress to develop ESRD. Mesangiocapillary glomerulonephritis Mesangiocapillary glomerulonephritis (MCGN), also known as membranoproliferative glomerulonephritis, is a pattern of injury seen on renal biopsy that is characterised by an increase in mesangial cellularity with thickening of glomerular capillary walls. The typical presentation is with proteinuria and haematuria. Several underlying causes have been identified, as summarised in Box 15.15. It can be classified into two main subtypes. The first is characterised by deposition of immunoglobulins within the glomeruli. This subtype is associated with chronic infections, autoimmune diseases and monoclonal gammopathy. The second is characterised by deposition of complement in the glomeruli and is associated with inherited or acquired abnormalities in the complement pathway. This category comprises ‘dense deposit disease’, which is typified by electron-dense deposits within the GBM, and C3 glomerulonephritis that shows deposits similar to immunoglobulin-type MCGN. Treatment of MCGN associated with immunoglobulin deposits consists of the identification and treatment of the underlying disease, if possible, and the use of immunosuppressive drugs such as mycophenolate mofetil or cyclophosphamide. There are few specific treatments for MCGN associated with complement dysregulation, although eculizumab, the anti-C5 inhibitor that prevents formation of the membrane attack complex, has shown promise. Diseases typically presenting with rapidly progressive glomerulonephritis Rapidly progressive glomerulonephritis (RPGN) is characterised by rapid loss of renal function over days to weeks, usually in association with hypertension and oedema. Non-visible haematuria is almost always present with variable amounts of proteinuria, while characteristic red cell casts and dysmorphic red cells may be observed on urine microscopy (see Fig. 15.3). Renal biopsy typically shows crescentic lesions (see Fig. 15.12E), often associated with necrotising lesions within the glomerulus (Fig. 15.12C), particularly in small-vessel vasculitides. This pattern of presentation is typical of post-infectious glomerulonephritis, anti-GBM disease and small-vessel vasculitides (p. 1040). It can also be observed in SLE (p. 1034) and occasionally in IgA and other nephropathies (see Fig. 15.9). 15.17 Causes of glomerulonephritis associated with low serum complement • Post-infectious glomerulonephritis • Subacute bacterial infection, especially endocarditis • Systemic lupus erythematosus • Cryoglobulinaemia • Mesangiocapillary glomerulonephritis, usually complement type

402 • NEPHROLOGY AND UROLOGY signs of a generalised drug hypersensitivity reaction with fever, rash and eosinophilia. Proteinuria is generally modest (PCR < 100 mg/mmol) and tubular in type (see Box 15.25, p. 412). The urine may contain white blood cells and white cell casts but is sterile on culture. Eosinophils are present in up to 70% of patients but this is a non-specific finding. AIN should always be considered in patients with non-oliguric AKI. There may be a rapid deterioration of renal function in some cases of drug-induced AIN, causing the condition to be mistaken for RPGN. Investigations Renal biopsy is usually required to confirm the diagnosis (Fig. 15.13D). This typically shows evidence of intense inflammation, with infiltration of the tubules and interstitium by polymorphonuclear leucocytes and lymphocytes. Eosinophils may also be observed, especially in drug-induced AIN. Often granulomas may be evident, especially in drug-induced AIN or sarcoidosis (p. 608). The degree of chronic inflammation in a biopsy is a useful predictor of long-term renal function. Eosinophiluria may be present but is not a good discriminator for AIN. Management Some patients with drug-induced AIN recover following withdrawal of the drug alone, but high-dose glucocorticoids (prednisolone 1 mg/kg/day) may accelerate recovery and prevent long-term scarring. Other specific causes (see Box 15.18) should be treated, if possible. Chronic interstitial nephritis Chronic interstitial nephritis (CIN) is characterised by renal dysfunction with fibrosis and infiltration of the renal parenchyma by lymphocytes, plasma cells and macrophages, in association with tubular damage. by tubular dysfunction with electrolyte abnormalities, moderate levels of proteinuria and varying degrees of renal impairment. Often the urinary output may be relatively preserved for any given GFR, and indeed there may be polyuria and nocturia. Acute interstitial nephritis Acute interstitial nephritis (AIN) is an immune-mediated disorder, characterised by acute inflammation affecting the tubulointerstitium of the kidney. It is commonly drug-induced, with proton pump inhibitors (PPIs) fast becoming the most common cause, but can be caused by other toxins, and can complicate a variety of systemic diseases and infections (Box 15.18). Clinical features The clinical presentation is typically with renal impairment but, in some patients with drug-induced AIN, there may be 15.18 Causes of acute interstitial nephritis Allergic Many drugs but particularly: • Penicillins • Non-steroidal antiinflammatory drugs (NSAIDs) • Proton pump inhibitors • Mesalazine (delayed) Immune • Autoimmune nephritis ± uveitis • Transplant rejection Infections • Acute bacterial pyelonephritis • Leptospirosis • Tuberculosis • Hantavirus Toxic • Myeloma light chains • Mushrooms (Cortinarius) Fig. 15.13 Tubular histopathology. A Normal tubular histology. The tubules are back to back. Brush borders can be seen on the luminal borders of cells in the proximal tubule. B Acute tubular necrosis. There are scattered breaks (B) in tubular basement membranes, swelling and vacuolation of tubular cells, and, in places, apoptosis and necrosis of tubular cells with shedding of cells into the lumen. During the regenerative phase, there is increased tubular mitotic activity. The interstitium (I) is oedematous and infiltrated by inflammatory cells. The glomeruli (not shown) are relatively normal, although there may be endothelial cell swelling and fibrin deposition. C Acute bacterial pyelonephritis. A widespread inflammatory infiltrate that includes many neutrophils is seen. Granulocyte casts (G) are forming within some dilated tubules (T). Other tubules are scarcely visible because of the extent of the inflammation and damage. D Acute (allergic) interstitial nephritis. In this patient who received a non-steroidal anti-inflammatory drug (NSAID), an extensive mononuclear cell infiltrate (no neutrophils) involving tubules (T) is seen. This inflammation does not involve the glomeruli (not shown). Sometimes eosinophils are prominent. Transplant rejection looks similar to this. A B C D T G T I B Normal tubular histology Acute tubular necrosis Acute pyelonephritis Acute interstitial nephritis

Genetic renal diseases • 403

Clinical features Most patients with CIN present in adult life with CKD, hypertension and small kidneys. Urinalysis abnormalities are non-specific. A minority present with salt-losing nephropathy, characterised by hypotension, polyuria and features of sodium and water depletion. People with CIN have an impairment of urine-concentrating ability and sodium conservation, which puts them at risk of AKI due to salt and water depletion during an acute illness. Renal tubular acidosis (p. 365) may complicate CIN but is seen most often in myeloma, sarcoidosis, cystinosis, amyloidosis and Sjögren’s syndrome. Management Management is supportive in nature, with correction of acidosis and hyperkalaemia; replacement of fluid and electrolytes, as required; and renal replacement therapy if irreversible renal damage has occurred. Papillary necrosis The renal papillae lie within a hypertonic environment in the renal medulla, at the end of the vasa recta. They are susceptible to ischaemic damage because of this and can undergo necrosis when their vascular supply is impaired as the result of diabetes mellitus, sickle-cell disease or long-term ingestion of NSAIDs. The condition may occasionally occur in other diseases. There is an association with pyelonephritis but it is difficult to determine whether this is a cause of papillary necrosis or a complication. The clinical presentation is variable. Some patients are asymptomatic and clinically silent, whereas others present with renal colic and renal impairment as necrosed papillae slough off and cause ureteric obstruction. Urinalysis may be normal but more frequently haematuria and sterile pyuria are present. Significant proteinuria is unusual, unless there is renal failure. The imaging method of choice to make the diagnosis is CTU or intravenous pyelography. Management is based on relieving obstruction, where present, and withdrawal of the offending drugs. Genetic renal diseases The advent of modern genetic techniques such as next-generation sequencing has allowed us to understand the breadth of inherited renal diseases on a much deeper level than before. Inherited glomerular diseases AIport’s syndrome A number of uncommon diseases may involve the glomerulus in childhood but the most important one affecting adults is Alport’s syndrome. Most cases arise from a mutation or deletion of the COL4A5 gene on the X chromosome, which encodes type IV collagen, resulting in inheritance as an X-linked recessive disorder (p. 48). Mutations in COL4A3 or COL4A4 genes are less common and cause autosomal recessive disease. The accumulation of abnormal collagen results in a progressive degeneration of the GBM (Fig. 15.14). Affected patients progress from haematuria to ESRD in their late teens or twenties. Female carriers of COL4A5 mutations usually have haematuria but less commonly develop significant renal disease. Some other basement membranes containing the same collagen isoforms are similarly involved, notably in the cochlea, so that Alport’s syndrome is associated with sensorineural deafness and ocular abnormalities. Pathophysiology This disease may follow on from AIN that does not resolve, or may be associated with ingestion of various toxins and drugs, or with metabolic and chronic inflammatory diseases, as summarised in Box 15.19. In many patients, CIN presents at a late stage and no underlying cause can be identified. Genetic causes may underlie many of these cases (p. 404). Toxins that have been associated with CIN include those contained within the plant Aristolochia clematitis (birthwort). These are probably responsible for the severe nephrotoxicity that can be associated with treatment with herbal medicines in Asia and for Balkan nephropathy, which affects isolated rural communities in Bosnia, Bulgaria, Croatia, Romania and Serbia, possibly through contaminated flour. The nephropathy is commonly linked with tumours of the collecting system and is probably due to the mutagenic effects of the plant toxin on the urothelial epithelium. Ingestion of mushrooms within the Cortinarius genus can cause a devastating and irreversible renal tubular toxicity. It is encountered occasionally in Scandinavia and Scotland. 15.19 Causes of chronic interstitial nephritis Acute interstitial nephritis • Any of the causes of acute interstitial nephritis, if persistent (see Box 15.18) Glomerulonephritis • Varying degrees of interstitial inflammation occur in association with most types of inflammatory glomerulonephritis Immune/inflammatory • Sarcoidosis • Sjögren’s syndrome • Chronic transplant rejection • Systemic lupus erythematosus, primary autoimmune Toxic • Aristolochia in herbal medicines • Lead • Balkan nephropathy • Mushrooms (Cortinarius) Drugs • All drugs causing acute interstitial nephritis • Tenofovir • Lithium toxicity • Analgesic nephropathy • Ciclosporin, tacrolimus Infection • Consequence of severe pyelonephritis Congenital/developmental • Vesico-ureteric reflux: associated but causation not clear • Renal dysplasias: often associated with reflux • Inherited: now well recognised but mechanisms unclear • Other: Wilson’s disease, sickle-cell nephropathy, medullary sponge kidney (nephrocalcinosis) Metabolic and systemic diseases • Calcium phosphate crystallisation after excessive phosphate administration (e.g. phosphate enemas in patients with chronic kidney disease) • Hypokalaemia • Hyperoxaluria

404 • NEPHROLOGY AND UROLOGY all code for podocyte proteins, including nephrin (‘Finnish-type’ nephropathy) and podocin, which both cause early congenital nephrotic syndrome. Autosomal dominant mutations in various genes may cause FSGS as part of systemic syndromes; the genes include INF2 (Charcot–Marie–Tooth disease), LMX1B (nail–patella syndrome) and WT1 (abnormal genitalia, Wilms’ tumour, mental retardation). Inheriting variants in the APOL1 gene, which is observed predominantly in people of West African ancestry, leads to a greatly increased risk of kidney disease including FSGS (p. 400). Inherited tubulo-interstitial diseases It has become evident in recent years that a significant number of cases of CKD with low or absent proteinuria have genetic causes, which may be inherited in an autosomal dominant or recessive pattern (Box 15.20). The histological pattern of injury is identical to other forms of CIN (p. 402). This is a heterogeneous group of inherited disorders. Small cysts are sometimes evident, explaining the previous name of medullary cystic kidney disease, but tubulo-interstitial nephritis is the predominant pattern of injury. Many of these conditions, especially those formerly known as nephronophthisis, are associated with retinal dystrophies and brain or other abnormalities, and some may be associated with hyperuricaemia or gout (UMOD or HNF1-beta mutations). Modern genetics have brought clarity to a disease spectrum comprising many different conditions with inexact previous names. Angiotensin-converting enzyme (ACE) inhibitors may slow but not prevent loss of kidney function. Patients with Alport’s syndrome are good candidates for renal replacement therapy (RRT), as they are young and usually otherwise healthy. They can develop an immune response to the normal collagen antigens present in the GBM of the donor kidney and, in a small minority, anti-GBM disease develops and destroys the allograft. Thin glomerular basement membrane disease In thin glomerular basement membrane disease there is glomerular bleeding, which is usually non-visible, without associated hypertension, proteinuria or a reduction in GFR. The glomeruli appear normal by light microscopy but, on electron microscopy, the GBM is abnormally thin. The condition may be familial and some patients are carriers of Alport mutations. This does not appear to account for all cases, and in many patients the cause is unclear. Monitoring of these patients is advisable, as proteinuria may develop in some and there appears to be an increased rate of progressive CKD in the long term. Hereditary nephrotic syndrome Many genes have been discovered that cause early-onset nephrotic syndrome, often with an FSGS pattern of injury. Inheritance may be autosomal dominant or recessive, the former conditions having a less severe and later-onset phenotype and often exhibiting incomplete penetrance. The involved genes almost Fig. 15.14 Alport’s syndrome. A Diagrammatic structure of the normal glomerular basement membrane (GBM). B The normal GBM (electron micrograph) contains mostly the tissue-specific (α3, α4 and α5) chains of type IV collagen. C In Alport’s syndrome, this network is disrupted and replaced by α1 and α2 chains. Although the GBM appears structurally normal in early life, in time thinning appears, progressing to thickening, splitting and degeneration. (B, C) Courtesy of Dr J. Collar, St Mary’s Hospital, London. Urinary space Foot process of podocyte Endothelial cell Glomerular capillary GBM A B C 15.20 Hereditary tubulo-interstitial kidney diseases Inheritance Gene(s) Other name(s) Clinical features Autosomal dominant UMOD MCKD type 2 Juvenile hyperuricaemic nephropathy Gout MUC1 MCKD type 1 Progressive CKD without other manifestations HNF1-beta Juvenile hyperuricaemic nephropathy Cystic kidneys, solitary kidney; gout; MODY; abnormal LFTs; pancreatic atrophy; hypomagnesaemia REN (codes for renin) Juvenile hyperuricaemic nephropathy Gout; hyperkalaemia; salt-losing nephropathy Autosomal recessive NPHP genes (17 discovered so far) Nephronophthisis Part of many syndromes (Bardet–Biedl) Common cause of paediatric ESRD Occurs earlier than AD interstitial nephritis Extrarenal manifestation common (learning difficulty, eye/limb problems) (AD = autosomal dominant; CKD = chronic kidney disease; ESRD = end-stage renal disease; LFTs = liver function tests; MCKD = medullary cystic kidney disease; MODY = maturity-onset diabetes of the young)

Genetic renal diseases • 405

Clinical features Common clinical features are shown in Box 15.21. Affected people are usually asymptomatic until later life but hypertension usually occurs from the age of 20 onwards. One or both kidneys may be palpable and the surface may feel nodular. About 30% of patients with PKD also have hepatic cysts (see Fig. 22.39, p. 893) but disturbance of liver function is rare. Sometimes (almost always in women) this causes massive and symptomatic hepatomegaly, usually concurrent with renal enlargement but occasionally with only minor renal involvement. Berry aneurysms of cerebral vessels are an associated feature in about 5% of patients with PKD. This feature appears to be largely restricted to certain families (and presumably specific mutations). Mitral and aortic regurgitation is frequent but rarely severe, and colonic diverticula and abdominal wall hernias may occur. Investigations The diagnosis is usually based on family history, clinical findings and ultrasound examination. Ultrasound demonstrates cysts in approximately 95% of affected patients over the age of 20 and is the screening method of choice, but may not detect small developing cysts in younger subjects. Cysts may also be identified by other imaging modalities, such as MRI (Fig. 15.15). Simple renal cysts may occur in normal individuals but are uncommon below the age of 30. The following criteria exist for an ultrasound diagnosis of PKD in patients with a family history but unknown genotype: • 15–39 years of age: at least three unilateral or bilateral kidney cysts • 40–59 years of age: at least two cysts in each kidney • 60 years or older: at least four cysts in each kidney. It is now possible to make a molecular diagnosis by mutation screening of PDK1 or PDK2 but this is seldom used in routine clinical practice because the PKD1 gene is so large and has many possible mutations. Next-generation sequencing allows faster and simpler genetic screening for PKD1 and PKD2. This is likely to be used in cases with an uncertain diagnosis (young patients, few cysts, lack of family history), for workup of living kidney donors, or for screening for mutations associated with a worse prognosis (see below). Screening for intracranial aneurysms is not generally indicated but can be done by MR angiography in families with a history of subarachnoid haemorrhage. The yield of screening is low, however, and the risk:benefit ratio of intervention in asymptomatic aneurysms in this disease is not clear. Management Blood pressure control is important because cardiovascular morbidity and mortality are so common in renal disease, but evidence is lacking that controlling blood pressure to generally recommended CKD targets (e.g. <130/80 mmHg) influences renal outcomes. There are data suggesting that targeting a very low blood pressure (<110/75 mmHg) with ACE inhibitors or angiotensin II Isolated defects of tubular function An increasing number of disorders have been identified that are caused by specific defects in transporter molecules expressed in renal tubular cells. Only the most common are mentioned here. Renal glycosuria is a benign autosomal recessive defect of tubular reabsorption of glucose, caused by mutations of the sodium/glucose co-transporter SGLT2. Glucose appears in the urine in the presence of a normal blood glucose concentration. It is notable that SGLT2 inhibitors have been developed as a treatment for diabetes mellitus and evidence suggests they may improve renal and cardiovascular outcomes. Cystinuria is a rare condition, in which reabsorption of filtered cystine, ornithine, arginine and lysine is defective. It is caused by mutations in the SLC3A1 amino acid transporter gene. The high concentration of cystine in urine leads to cystine stone formation (p. 431). Other uncommon tubular disorders include hereditary hypophosphataemic rickets (p. 1052), in which reabsorption of filtered phosphate is reduced; nephrogenic diabetes insipidus (p. 687), in which the tubules are resistant to the effects of vasopressin (antidiuretic hormone, ADH); and Bartter’s and Gitelman’s syndromes, in which there is sodium-wasting and hypokalaemia (p. 361). The term ‘Fanconi’s syndrome’ is used to describe generalised proximal tubular dysfunction. The condition typically presents with low blood phosphate and uric acid concentrations, glycosuria, aminoaciduria and proximal renal tubular acidosis. In addition to the causes of interstitial nephritis described above, some congenital metabolic disorders are associated with Fanconi’s syndrome, notably Wilson’s disease, cystinosis and hereditary fructose intolerance. Renal tubular acidosis describes the common end-point of a variety of diseases affecting distal (classical or type 1) or proximal (type 2) renal tubular function. These syndromes are described on page 365. Cystic diseases of the kidney It is common to encounter patients with a single renal cyst or even multiple cysts as an incidental finding, especially in those aged 50 years and over. Usually, these cysts are of no clinical consequence and are asymptomatic, but occasionally they can cause pain or haematuria. In addition, several specific diseases are recognised as being caused by the formation of multiple renal cysts. These are discussed in more detail below. Adult polycystic kidney disease Adult polycystic kidney disease (PKD) is a common condition, with a prevalence of approximately 1:1000, and is inherited as an autosomal dominant trait. Small cysts lined by tubular epithelium develop from infancy or childhood and enlarge slowly and irregularly. The surrounding normal kidney tissue is compressed and progressively damaged. Mutations in the PKD1 gene account for 85% of cases and those in PKD2 for about 15% (coding for polycystin 1 and 2, respectively). ESRD occurs in approximately 50% of patients with PKD1 mutations, with a mean age of onset of 52 years, but in a minority of patients with PKD2 mutations, with a mean age of onset of 69 years. It has been estimated that between 5% and 10% of patients on RRT have PKD. 15.21 Adult polycystic kidney disease: common clinical features • Vague discomfort in loin or abdomen due to increasing mass of renal tissue • Acute loin pain or renal colic due to haemorrhage into a cyst • Hypertension • Haematuria (with little or no proteinuria) • Urinary tract or cyst infections • Renal failure

406 • NEPHROLOGY AND UROLOGY causes cysts but also may cause a tubulo-interstitial pattern of injury or congenital absence of a kidney. It also causes a form of MODY (p. 733). Autosomal recessive PKD is caused by mutations in the PKHD1 gene, encoding fibrocystin. It is less common than autosomal dominant PKD (about 1:20 000 live births). Patients often present in infancy or young childhood with renal cysts and congenital hepatic fibrosis. Some uncommon autosomal dominantly inherited conditions are associated with multiple renal cysts and tumours in adult life. In tuberous sclerosis (p. 1264), replacement of renal tissue by multiple angiomyolipomas may occasionally cause renal failure in adults. Patients may also develop renal cysts and have a higher risk of renal cell carcinoma. Other organs affected include the skin (adenoma sebaceum on the face) and brain (causing seizures and mental retardation). The von Hippel–Lindau syndrome (p. 1132) is associated with multiple renal cysts, renal adenomas and renal adenocarcinoma. Other involved organs include the central nervous system (haemangioblastomas), pancreas (serous cystadenomas) and adrenals (phaeochromocytoma). A number of other rarer inherited cystic diseases are recognised that have some similarities to PKD but distinct genetic causes. Multicystic dysplastic kidneys are often unilateral and are a developmental abnormality found in children. Most of these seem to involute during growth, leaving a solitary kidney in adults. Acquired cystic kidney disease can develop in patients with a very long history of renal failure, so it is not an inherited cystic disease. It is associated with increased erythropoietin production and sometimes with the development of renal cell carcinoma. Renal vascular diseases Diseases that affect renal blood vessels may cause renal ischaemia, leading to acute or chronic kidney disease or secondary hypertension. The rising prevalence of atherosclerosis and diabetes mellitus in ageing populations has made renovascular disease an important cause of ESRD. Renal artery stenosis A stenosis of more than 50% may be observed on imaging of the renal arteries in up to 20% of older patients with advanced kidney disease; however, a haemodynamically significant effect will be present in only a relatively small proportion. Renal artery stenosis is the most common cause of secondary hypertension, with an estimated prevalence of about 2% in unselected patients, but this may increase to 4% in older patients who have evidence of atherosclerotic disease elsewhere. Most cases of renal artery stenosis are caused by atherosclerosis but fibromuscular dysplasia involving the vessel wall may be responsible in younger patients. Rare causes include vasculitis, thromboembolism and aneurysms of the renal artery. Pathophysiology Renal artery stenosis results in a reduction in renal perfusion pressure, which activates the renin–angiotensin system, leading to increased circulating levels of angiotensin II. This results in hypertension by provoking vasoconstriction and increasing aldosterone production by the adrenal, causing sodium retention by the renal tubules (p. 351). Significant reduction of renal blood flow occurs when there is more than 70% narrowing of the artery, and this is commonly associated with distal, post-stenotic Fig. 15.15 MRI images of the kidneys. A Normal kidneys. B Polycystic kidneys; although the kidney enlargement is extreme, this patient had only slightly reduced GFR. A B receptor blocker (ARBs) leads to slower increases in kidney volume, but no improvements in eGFR decline were observed and these targets are often not tolerated. This tight blood pressure target did lead to a greater decline in left ventricular mass index, which may have implications for improved cardiovascular risk later in life. The vasopressin V2 receptor antagonist tolvaptan may retard kidney volume increase and slow the rate of GFR decline. It has now been licensed in many countries for patients at high risk of progression. Risk factors for progression include large kidneys (more specifically height-adjusted kidney volume), truncating PKD1 mutations, and family history of early progression, as well as male sex, hypertension, proteinuria and development of early symptomatic cysts. Patients with PKD are usually good candidates for dialysis and transplantation. Sometimes kidneys are so large that one or both have to be removed to make space for a renal transplant. Otherwise, they are usually left in situ unless they are a source of pain or infection. Other cystic diseases Renal cysts and diabetes syndrome is caused by HNF1-beta mutations (see above); it has a varying renal phenotype that often

Renal vascular diseases • 407

although this is insufficiently sensitive or specific to be of value in diagnosis of renovascular disease in hypertensive patients. Management The first-line management in patients with renal artery stenosis is medical therapy with antihypertensive drugs, supplemented, where appropriate, by statins and low-dose aspirin in those with atherosclerotic disease. Interventions to correct the vessel narrowing should be considered in: • young patients (age below 40) suspected of having renal artery stenosis • those whose blood pressure cannot easily be controlled with antihypertensive agents • those who have a history of ‘flash’ pulmonary oedema • those with accelerated phase (malignant) hypertension • those whose renal function is deteriorating. The most commonly used technique is angioplasty. The best results are obtained in non-atheromatous fibromuscular dysplasia, where correction of the stenosis has a high chance of success in improving blood pressure and protecting renal function. Beyond the indications above, angioplasty and stenting is now rarely dilatation. Atherosclerotic lesions are typically ostial and are associated with more widespread atherosclerosis within the aorta and other vessels, particularly the iliac vessels. There is often concurrent small-vessel disease in affected kidneys, due to subclinical atheroemboli. As the stenosis becomes more severe, global renal ischaemia leads to shrinkage of the affected kidney and may cause renal failure if bilateral, or if unilateral in the presence of a single kidney (ischaemic nephropathy). In younger patients, fibromuscular dysplasia is a more likely cause of renal artery stenosis. This is an uncommon disorder of unknown cause. It is characterised by hypertrophy of the media (medial fibroplasia), which narrows the artery but rarely leads to total occlusion. It may be associated with disease in other arteries; for example, those who have carotid artery dissections are more likely to have renal arteries with this appearance. It most commonly presents with hypertension in patients aged 15–30 years, and women are affected more frequently than men. Irregular narrowing (beading) may occur in the distal renal artery and this sometimes extends into the intrarenal branches of the vessel. Rarely, renal artery stenosis may occur as a complication of large-vessel vasculitis, such as Takayasu’s arteritis and polyarteritis nodosa (pp. 1041 and 1042). Untreated, atheromatous renal artery stenosis is thought to progress to complete arterial occlusion in about 15% of cases. This figure increases with more severe degrees of stenosis. If the progression is gradual, collateral vessels may develop and some function may be preserved, preventing infarction and loss of kidney structure. Conversely, at least 85% of patients with renal artery stenosis will not develop progressive renal impairment, and many patients die from coronary, cerebral or other vascular disease rather than renal failure. Unfortunately, methods of predicting which patients are at risk of progression or who will respond to treatment are still imperfect. Clinical features Renal artery stenosis can present in various ways including hypertension, acute pulmonary oedema, progressive renal failure (with bilateral disease) or a deterioration in renal function when ACE inhibitors or ARBs are administered. Although many patients experience a slight drop in GFR when commencing these drugs, an increase in serum creatinine of 30% or more raises the possibility of renal artery stenosis. Acute pulmonary oedema is particularly characteristic of bilateral renovascular disease. It typically occurs at night and is associated with severe hypertension, often in the context of normal or only mildly impaired renal and cardiac function. Clinical evidence of generalised vascular disease may be observed, particularly in the legs and in older patients with atherosclerotic renal artery stenosis. Clinical features associated with an increased risk of renal artery stenosis in hypertensive patients are summarised in Box 15.22. However, given the risk of imaging and angiography in patients with renal disease (see Box 15.4, p. 390), further investigation should only be performed if intervention is being contemplated (see below). Investigations When appropriate, imaging of the renal vasculature with either CT angiography or MR angiography should be performed to confirm the diagnosis (Fig. 15.16). Both give good views of the main renal arteries, the vessels predominantly involved and the most amenable to intervention. Biochemical testing may reveal impaired renal function and an elevated plasma renin activity, sometimes with hypokalaemia due to hyperaldosteronism. Ultrasound may also reveal a discrepancy in size between the two kidneys, 15.22 Presentation and clinical features of renal artery stenosis Renal artery stenosis is more likely if: • hypertension is severe, of recent onset or difficult to control • kidneys are asymmetrical in size • flash pulmonary oedema occurs repeatedly* • there is peripheral vascular disease of the lower limbs • there is renal impairment* • renal function has deteriorated on angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers *Particularly with bilateral disease. Fig. 15.16 Renal artery stenosis. A magnetic resonance angiogram following injection of contrast. The abdominal aorta is severely irregular and atheromatous. The left renal artery is stenosed (arrow).

408 • NEPHROLOGY AND UROLOGY Diseases of small intrarenal vessels Thrombotic microangiopathies A number of conditions are associated with acute damage and occlusion of small blood vessels (arterioles and capillaries) in the kidney (Box 15.23) and other organs. A common feature of these syndromes is microangiopathic haemolytic anaemia (MAHA), in which haemolysis and red cell fragmentation arise as consequences of damage incurred to red blood cells during passage through the abnormal vessels. The red blood cell fragments (schistocytes) may be observed on blood films, together with laboratory features of intravascular haemolysis (p. 947), including an elevated unconjugated bilirubin level, raised serum LDH concentration and decreased circulating levels of haptoglobin. A reticulocytosis is often seen. Endothelial injury is pronounced, leading to increased platelet adherence and a marked reduction in the platelet count. These abnormal blood parameters should alert the physician to the possibility of a thrombotic microangiopathy and may also be useful in monitoring response to treatment. The key is to distinguish between the various aetiologies, as the management differs according to the primary cause (Box 15.23). Haemolytic uraemic syndrome Haemolytic uraemic syndrome (HUS) is characterised by thrombotic microangiopathy that predominantly affects the renal microcirculation, with involvement of other organs (including the brain) observed in more severe cases. The most common cause of HUS is infection with organisms that produce enterotoxins called Shiga-like toxin or verotoxins. The organisms most commonly implicated are enterohaemorrhagic Escherichia coli (p. 263) and Shigella dysenteriae (p. 265). The performed in atherosclerotic disease, as randomised trials such as ASTRAL and CORAL have produced no convincing evidence for overall benefit in terms of renal function, blood pressure control or cardiovascular outcomes. The risks of angioplasty and stenting include renal artery occlusion, renal infarction and atheroemboli (p. 409) from manipulations in a severely diseased aorta. Small-vessel disease distal to the stenosis may preclude substantial functional recovery. Acute renal infarction This is an uncommon condition that occurs as the result of sudden occlusion of the renal arteries. The presentation is typically with loin pain of acute onset, usually in association with non-visible haematuria, but pain may be absent in some cases. Severe hypertension is common but not universal. Blood levels of lactate dehydrogenase (LDH) and CRP are commonly raised. The condition may be caused by thrombosis of a renal artery or by thromboemboli from a distant source, when occlusion may occur in branch arteries distal to the main renal artery. This can cause multiple infarcts within the renal parenchyma of both kidneys, which may be visualised by CT scanning. If occlusion of the main renal arteries is bilateral or if there is occlusion in a single functioning kidney, the presentation is with AKI and the patient is typically anuric. Patients with bilateral occlusion usually have evidence of widespread vascular disease and may show evidence of aortic occlusion, with absent femoral pulses and reduced lower limb perfusion. Management is largely supportive, and includes anticoagulation if a source of thromboembolism is identified. It is sometimes possible to perform stenting of an acutely blocked main renal artery to try to restore renal blood flow; in most cases, however, presentation is too late to salvage renal function. 15.23 Thrombotic microangiopathies associated with acute renal damage Condition Typical features Management Primary thrombotic microangiopathies Haemolytic uraemic syndrome: Renal failure prominent in all causes Shiga toxin +ve HUS Bloody diarrhoea; check stool for Escherichia coli O157:H7 Supportive therapy Complement-mediated Positive family history; screen for complement factor mutations Plasma exchange, eculizumab Drug-induced: quinine, calcineurin and VEGF-A inhibitors Drug exposure, fever with quinine Cessation of offending drug Thrombotic thrombocytopenic purpura Neurological manifestations prominent; check ADAMTS-13 activity Plasma exchange (p. 979) Thrombotic microangiopathy associated with systemic disorders Disseminated intravascular coagulation (DIC) Clotting system involvement: elevated D-dimers, low fibrinogen, prolonged PT and APTT Treatment of primary cause (p. 979) Malignancy May occur with breast, prostate, lung, pancreas and GI tumours Treatment of tumour where possible Systemic sclerosis Cutaneous features of systemic sclerosis Blood pressure control with ACE inhibitors (p. 1037) Pre-eclampsia and HELLP syndrome Typically in third trimester; abnormal LFTs Resolution with delivery (p. 1276) Malignant hypertension Blood pressure typically very high; evidence of hypertensive retinopathy including papilloedema Blood pressure control (ACE = angiotensin-converting enzyme; ADAMTS-13 = a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13; APTT = activated partial thromboplastin time; GI = gastrointestinal; HELLP = haemolysis, elevated liver enzymes and low platelets; HUS = haemolytic uraemic syndrome; LFTs = liver function tests; PT = prothrombin time; VEGF = vascular endothelial growth factor)

Renal involvement in systemic conditions • 409

E. coli O157:H7 serotype is the best known but other serotypes that produce verotoxins may also be responsible. Although these bacteria live as commensals in the gut of cattle and other livestock, they can cause haemorrhagic diarrhoea in humans when the infection is contracted from contaminated food products, water or other infected individuals. In a proportion of cases, verotoxin produced by the organisms enters the circulation and binds to specific glycolipid receptors that are expressed on the surface of microvascular endothelial cells. Most cases are sporadic but large outbreaks related to poor sanitation may occur. In developed countries, Shiga-like toxin-associated HUS is now the most common cause of AKI in children. Recovery is good in most patients but sometimes RRT may be required for up to 14 days. No other specific treatments have been shown to accelerate renal recovery. In the absence of bloody diarrhoea, other (atypical) causes of HUS should be considered: in particular, abnormalities of the complement system. Familial forms are due to mutations in various genes that encode components or regulators of the complement cascade, including factor H (CFH), factor B (CFB), membrane co-factor protein (MCP) and complement component 3 (C3). The penetrance of familial HUS is incomplete, indicating that environmental triggers are also involved: often infection, including diarrhoea. Sporadic cases may be associated with the development of autoantibodies to complement factor H. In addition to supportive care, including RRT if necessary, management of complement-mediated HUS includes plasma exchange to replace complement component and remove pathogenic autoantibodies. Recently, impressive results have been reported with the anti-C5 monoclonal antibody, eculizumab, which binds to C5, thereby preventing activation of the terminal complement cascade. Thrombotic thrombocytopenic purpura Like HUS, thrombotic thrombocytopenic purpura (TTP) is characterised by microangiopathic haemolytic anaemia and thrombocytopenia; in contrast, however, the brain is more commonly affected in TTP and involvement of the kidney is usually less prominent. TTP is an autoimmune disorder caused by antibodies against ADAMTS-13, which is involved in regulating platelet aggregation, and a low (< 10%) serum ADAMTS-13 activity level may be useful in distinguishing TTP from HUS. This distinction is important, as early therapy with plasma exchange is crucial in TTP. More details are provided on page 979. Cholesterol emboli These present with renal impairment, haematuria, proteinuria and sometimes eosinophilia with inflammatory features that can mimic a small-vessel vasculitis. The symptoms are provoked by showers of cholesterol-containing microemboli, arising in atheromatous plaques in major arteries. The diagnosis should be suspected when these clinical features occur in patients with widespread atheromatous disease, who have undergone interventions such as surgery or arteriography. They may also be precipitated by anticoagulants and thrombolytic agents. On clinical examination, signs of large-vessel disease and microvascular occlusion in the lower limbs (ischaemic toes, livedo reticularis) are common but not invariable (Fig. 15.17). There is no specific treatment. Small-vessel vasculitis Renal disease caused by small-vessel vasculitis usually presents with a clinical picture typical of a glomerulonephritis (see Figs 15.9 and 15.12C, pp. 393 and 399). More information is given on page 410. Renal involvement in systemic conditions The kidneys may be directly involved in a number of multisystem diseases or secondarily affected by diseases of other organs. Involvement may be at a pre-renal, renal (glomerular or interstitial) or post-renal level. Many of the diseases are described in other sections of this chapter or in other chapters of the book. Diabetes mellitus Diabetic nephropathy is the most common cause of CKD in developed countries. In patients with diabetes, there is a steady advance from moderately elevated albuminuria (microalbuminuria) to dipstick-positive proteinuria, in association with evolving hypertensive and progressive renal failure, as described on page 757. Few patients require renal biopsy to establish the diagnosis, but atypical features such as very rapid progression of proteinuria/decline in renal function or the absence of other microvascular damage, including retinopathy, should lead to suspicion that an alternative condition could be present. Management with ACE inhibitors and ARBs to slow progression is described on page 757. In some patients, proteinuria may be eradicated and progression completely halted, even if renal function is abnormal, although most still have progressive disease, albeit at a slower rate. Emerging evidence suggests that SGLT2 inhibitors, such as empagliflozin, a new agent for diabetes that causes glycosuria (p. 748), may lead to improved cardiovascular and renal outcomes, at the expense of increased genital infections. Multiple myeloma In myeloma, a malignant clone of plasma cells produces a paraprotein, often a monoclonal light chain (p. 966). Renal manifestations are dominated by these toxic light chains, which may cause a variety of insults (Box 15.24). Hypercalcaemia may also occur due to bony metastases. Hepatic–renal disease Severe hepatic dysfunction may cause a haemodynamically mediated type of renal failure, hepatorenal syndrome (HRS), described on page 864. Patients with chronic liver disease are also predisposed to develop AKI (acute tubular necrosis) in response to relatively minor insults, including bleeding, diuretic therapy and infection. Differentiating true HRS from AKI can be difficult. Patients with true HRS are often difficult to treat Fig. 15.17 The foot of a patient who suffered extensive atheroembolism following coronary artery stenting.

410 • NEPHROLOGY AND UROLOGY neuropathy may also occur. Serological testing for antibodies to myeloperoxidase (MPO) and proteinase 3 (PR3) is usually positive but these are not specific and a biopsy of affected tissue should be obtained, if possible, to confirm the diagnosis. The standard treatment of glomerulonephritis associated with systemic vasculitis is high-dose glucocorticoids combined with cyclophosphamide, or mycophenolate mofetil (p. 1041). Recent studies indicate that rituximab (p. 1006), when combined with highdose glucocorticoids, is as effective as oral cyclophosphamide and high-dose glucocorticoids in the treatment of ANCA-associated vasculitis. Plasma exchange can offer additional benefit in patients with progressive renal damage who are not responding adequately to immunosuppressive therapy. Glomerulonephritis secondary to vasculitis may rarely be seen in rheumatoid arthritis, SLE and cryoglobulinaemia, although SLE usually involves the kidney in different ways (see below). Medium- to large-vessel vasculitis, such as polyarteritis nodosa (p. 1042), does not cause glomerulonephritis but can cause hypertension, renal aneurysms and infarction if the renal vessels are involved. Systemic sclerosis Renal involvement is a serious complication of systemic sclerosis, which is more likely to occur in diffuse cutaneous systemic sclerosis (DCSS) than in limited cutaneous systemic sclerosis (LCSS) (p. 1037). The renal lesion is caused by intimal cell proliferation and luminal narrowing of intrarenal arteries and arterioles. There is intense intrarenal vasospasm and plasma renin activity is markedly elevated. Renal involvement usually presents clinically with severe hypertension, microangiopathic features and progressive oliguric renal failure (‘scleroderma renal crisis’). Use of ACE inhibitors to control the hypertension has improved the 1-year survival from 20% to 75% but about 50% of patients continue to require RRT. Onset or acceleration of the syndrome after glucocorticoid use or cessation of ACE inhibitors is well described. Systemic lupus erythematosus Subclinical renal involvement, with non-visible haematuria and proteinuria but minimally impaired or normal renal function, is common in systemic lupus erythematosus (SLE). Usually, this is due to glomerular disease, although interstitial nephritis may also occur, particularly in patients with overlap syndromes such as mixed connective tissue disease and Sjögren’s syndrome (p. 1038). Almost any histological pattern of glomerular disease can be observed in SLE and the clinical presentation ranges from florid, rapidly progressive glomerulonephritis to nephrotic syndrome. The most common presentation is with subacute disease and inflammatory features (haematuria, hypertension, variable renal impairment), accompanied by heavy proteinuria that often reaches nephrotic levels. In severely affected patients, the most common histological pattern is a proliferative glomerulonephritis with substantial deposits of immunoglobulins on immunofluorescence. Randomised controlled trials have shown that the risk of ESRD in lupus nephritis is significantly reduced by high-dose glucocorticoids administered in combination with cyclophosphamide, usually given as regular intravenous pulses. Subsequently, it has been shown that the combination of glucocorticoids and mycophenolate mofetil is equally as effective, for both induction and maintenance treatment. Many patients with SLE who develop ESRD go into remission, possibly because of immunosuppression related to the ESRD. by dialysis and have a poor prognosis. Where treatment is justified – for example, if there is a good chance of recovery or of a liver transplant – slow or continuous treatments are less likely to precipitate or exacerbate hepatic encephalopathy. IgA nephropathy (p. 400) is more common in patients with chronic liver disease. Sarcoidosis The most common renal manifestation of sarcoidosis is hypercalcaemia from 1-α-vitamin D formation in granulomas. Less commonly, it may lead to a granulomatous interstitial nephritis, sometimes presenting acutely, where renal function may improve with glucocorticoid therapy. Postmortem examinations reveal a chronic interstitial nephritis in 15–30% of patients with sarcoidosis but clinically relevant disease appears to be much less common. Systemic vasculitis Small-vessel vasculitis (p. 1040) commonly affects the kidneys, with rapid and profound impairment of glomerular function. Histologically, there is a focal inflammatory glomerulonephritis, usually with focal necrosis (see Box 15.15, p. 398, and Fig. 15.12C, p. 399) and often with crescentic changes (see Fig. 15.12C). Typically, the patient is systemically unwell with an acute phase response, weight loss and arthralgia. In some patients, it presents as a kidney-limited disorder, with rapidly deteriorating renal function and crescentic nephritis (a rapidly progressive glomerulonephritis). In others, pulmonary haemorrhage may occur, which can be life-threatening. The most important cause is ANCA vasculitis (p. 1041). Two subtypes are recognised, microscopic polyangiitis (MPA) and granulomatosis with polyangiitis. Both may present with glomerulonephritis and pulmonary haemorrhage, along with constitutional symptoms. Gastrointestinal involvement and 15.24 Renal manifestations of multiple myeloma Condition Presentation Pathogenesis Cast nephropathy (‘myeloma kidney’) AKI Little/no proteinuria Light chains combine with Tamm–Horsfall protein precipitating in tubules Fanconi’s syndrome Aminoaciduria, phosphaturia, glycosuria Proximal (type II) RTA Proximal tubular injury due to light chain deposition in tubular epithelium AL (primary) amyloidosis* Proteinuria/nephrotic syndrome Renal impairment Misfolded lights chains (usually lambda) form amyloid, which is deposited in glomeruli Monoclonal immunoglobulin deposition disease* Proteinuria (may be in nephrotic range) Renal impairment Usually light chains (frequently kappa) are deposited in glomeruli, causing a nodular glomerulosclerosis Hypercalcaemia Thirst, polyuria, bony and abdominal pain, headache Bony destruction from metastases *These may also occur as primary conditions without myeloma being present. (AKI = acute kidney injury; RTA = renal tubular acidosis)

Acute kidney injury • 411

renal injury over time (several weeks). Recovery of renal function depends on the duration of obstruction and also the pre-morbid GFR. Clinical features Early recognition and intervention is important in AKI; all emergency admissions to hospital should have renal function, blood pressure, temperature and pulse checked on arrival and should undergo a risk assessment for the likelihood of developing AKI. This includes looking at coexisting diseases such as diabetes and vascular and liver disease, which make AKI more likely, as well as gathering information on drug treatments such as ACE inhibitors and NSAIDs, which may be associated with renal dysfunction. If a patient is found to have a high serum creatinine, it is important to establish whether this is an acute or acute-on-chronic phenomenon, or a sign of CKD (see Fig. 15.22, p. 416). Previous measurements of renal function can be of great value in differentiating these possibilities. Patients with AKI need to be assessed quickly to determine the likely underlying cause. Clinical features and pertinent investigations for the different causes of AKI are shown in Box 15.25. Various criteria have been proposed to classify AKI and to help identify high-risk patients, guide treatment and provide information regarding prognosis but are mostly used in a research setting to standardise diagnosis. The most commonly used are the KDIGO, AKIN and RIFLE criteria. Pre-renal AKI Patients with pre-renal AKI are typically hypotensive and tachycardic with signs of poor peripheral perfusion, such as delayed capillary return. Tachycardia and postural hypotension (a fall in blood pressure of > 20/10 mmHg from lying to standing) are valuable signs of early hypovolaemia. Many patients with sepsis Patients with ESRD caused by SLE are usually good candidates for dialysis and transplantation. Although it may recur in renal allografts, the immunosuppression required to prevent allograft rejection usually controls SLE. Sickle-cell nephropathy Improved survival of patients with sickle-cell disease (p. 951) means that a high proportion now live to develop chronic complications of microvascular occlusion. In the kidney, these changes are most pronounced in the medulla, where the vasa recta are the site of sickling because of hypoxia and hypertonicity. Loss of urinary concentrating ability and polyuria are the earliest changes; distal renal tubular acidosis and impaired potassium excretion are typical. Papillary necrosis may also occur (p. 403). A minority of patients develop ESRD. This is managed according to the usual principles, but response to recombinant erythropoietin is poor because of the haemoglobinopathy. Patients with sickle trait have an increased incidence of unexplained non-visible haematuria. Acute kidney injury Acute kidney injury (AKI), previously referred to as acute renal failure, is not a diagnosis; rather it describes the situation where there is a sudden and often reversible loss of renal function, which develops over days or weeks and is often accompanied by a reduction in urine volume. Approximately 7% of all hospitalised patients and 20% of acutely ill patients develop AKI. In uncomplicated AKI mortality is low, even when RRT is required. In AKI associated with sepsis and multiple organ failure, mortality is 50–70% and the outcome is usually determined by the severity of the underlying disorder and other complications, rather than by kidney injury itself. Elderly patients are at higher risk of developing AKI and have a worse outcome (Box 15.25). Pathophysiology There are many causes of AKI and it is frequently multifactorial. It is helpful to classify it into three subtypes: • ‘pre-renal’, when perfusion to the kidney is reduced • ‘renal’, when the primary insult affects the kidney itself • ‘post-renal’, when there is obstruction to urine flow at any point from the tubule to the urethra (Fig. 15.18). In pre-renal AKI, a reduction in perfusion reduces GFR. If the insult is not corrected, this may lead to ‘renal’ injury: namely, acute tubular necrosis (ATN). Histologically, the kidney shows inflammatory changes, focal breaks in the tubular basement membrane and interstitial oedema (see Fig. 15.13B, p. 402). Dead tubular cells may also be shed into the tubular lumen, leading to tubular obstruction. Although tubular cell damage is the dominant feature under the microscope, there may also be profound alterations in the renal microcirculation. Renal AKI may be caused by nephrotoxic drugs (p. 426), which can cause ATN or allergic interstitial nephritis. The other common ‘renal’ cause is glomerulonephritis, in which there is direct inflammatory damage to the glomeruli (p. 416). Post-renal AKI occurs as the result of obstruction to the renal tract. This leads to elevation of intraluminal ureteral pressure transmitted to the nephrons after prolonged obstruction, with a subsequent fall in GFR. If the obstruction is not relieved, the low GFR is maintained by a drop in renal blood flow rate via thromboxane A2 and angiotensin II. This leads to chronic Fig. 15.18 Causes of acute kidney injury. RENAL Glomerulonephritis Small-vessel vasculitis Acute tubular necrosis • Drugs • Toxins • Prolonged hypotension Interstitial nephritis • Drugs • Toxins • Inflammatory disease • Infection PRE-RENAL Impaired perfusion: • Cardiac failure • Sepsis • Blood loss • Dehydration • Vascular occlusion POST-RENAL Urinary calculi (bilateral) Retroperitoneal fibrosis Benign prostatic enlargement Bladder cancer Prostate cancer Cervical cancer Urethral stricture/valves Meatal stenosis/phimosis

412 • NEPHROLOGY AND UROLOGY 15.25 Categorising acute kidney injury based on history, examination and investigations Type of AKI History Examination Investigations Pre-renal Volume depletion (vomiting, diarrhoea, burns, haemorrhage) Drugs (diuretics, ACE inhibitors, ARBs, NSAIDs, calcineurin inhibitors, iodinated contrast) Liver disease Cardiac failure Low BP (including postural drop) Tachycardia Weight decrease Dry mucous membranes and increased skin turgor JVP not visible even when lying down Urine Na < 20 mmol/L Fractional excretion Na < 1% High urea:creatinine ratio Urinalysis bland Renal ATN Prolonged pre-renal state Sepsis Toxic ATN: drugs (aminoglycosides, cisplatin, tenofovir, methotrexate, iodinated contrast) Other (rhabdomyolysis, snake bite, Amanita mushrooms) Vital signs Fluid assessment Limbs for compartment syndrome Urine Na > 40 mmol/L Fractional excretion Na ≥ 1% Dense granular (‘muddy brown’) casts Creatine kinase Glomerular Rash, weight loss, arthralgia Chest symptoms (pulmonary renal syndromes) IV drug use Hypertension Oedema Purpuric rash, uveitis, arthritis Proteinuria, haematuria Red cell casts, dysmorphic red cells ANCA, anti-GBM, ANA, C3 and C4 Viral hepatitis screen, HIV Renal biopsy Tubulo-interstitial Interstitial nephritis: drugs (PPIs, penicillins, NSAIDs) Sarcoidosis Fever Rash Leucocyturia Eosinophiluria (and a peripheral eosinophilia) White cell casts Minimal proteinuria Tubular obstruction:

  1. Myeloma (cast nephropathy) Paraprotein Calcium (myeloma, sarcoidosis)
  2. Tubular crystal nephropathy: Drugs (aciclovir, indinavir, triamterene, methotrexate) Oxalate (fat malabsorption, ethylene glycol) Urate (tumour lysis) Urine microscopy for crystals Serum urate Urine collection for oxalate Vascular (including renal infarction, renal vein thrombosis, cholesterol emboli, malignant hypertension) Flank pain, trauma Anticoagulation Recent angiography (cholesterol emboli) Nephrotic syndrome (renal vein thrombosis) Systemic sclerosis (renal crisis) Diarrhoea (HUS) BP (malignant hypertension) Fundoscopy Livedo reticularis (cholesterol emboli) Sclerodactyly Normal urinalysis or some haematuria C3 and C4 (cholesterol emboli, TMA) Doppler renal ultrasound CT angiography Platelets, haemolytic screen, LDH Consider ADAMTS13 and complement genetics (if TMA) Post-renal Prostate cancer history Neurogenic bladder Cervical carcinoma Retroperitoneal fibrosis Bladder outlet symptoms Rectal examination (prostate and anal tone) Distended bladder Pelvic mass Urinalysis frequently normal (may reveal haematuria depending on cause) Renal ultrasound (hydronephrosis) Isotope renogram (delayed excretion) if ultrasound inconclusive (ACE = angiotensin-converting enzyme; ANA = antinuclear antibody; ANCA = antineutrophil cytoplasmic antibody; ARBs = angiotensin receptor blockers; BP = blood pressure; GBM = glomerular basement membrane; HIV = human immunodeficiency virus; HUS = haemolytic uraemic syndrome; JVP = jugular venous pulse; LDH = lactate dehydrogenase; Na = sodium; NSAIDs = non-steroidal anti-inflammatory drugs; PPIs = proton pump inhibitors; TMA = thrombotic microangiopathy) initially present with poor peripheral perfusion, as mentioned above, but then show evidence of peripheral vasodilatation once they have undergone initial resuscitation with intravenous fluids. However, this is accompanied by relative underfilling of the arterial tree and the kidney responds as it would to absolute hypovolaemia, with renal vasoconstriction. It is important to note that pre-renal AKI may also occur without systemic hypotension, particularly in patients taking NSAIDs or ACE inhibitors (Fig. 15.19). The cause of hypotension is often obvious, but concealed blood loss can occur into the gastrointestinal tract, retroperitoneum, following trauma (particularly with pelvic and femoral fractures), and into the pregnant uterus. Large volumes of intravascular fluid may also be lost into tissues after crush injuries or burns, and in severe inflammatory skin diseases or sepsis. Uncorrected renal hypoperfusion causing pre-renal azotaemia may progress to ATN. Renal AKI Factors that can help differentiate the various causes of intrinsic renal AKI are summarised in Box 15.25. Patients with

Acute kidney injury • 413

glomerulonephritis demonstrate haematuria and proteinuria, and may have clinical manifestations of an underlying disease, such as SLE or systemic vasculitis. Although blood tests, including an immunological screen, should be performed to clarify the diagnosis in glomerulonephritis, a renal biopsy is usually required. Drug-induced acute interstitial nephritis is harder to spot but should be suspected in a previously well patient if there is an acute deterioration of renal function coinciding with introduction of a new drug treatment. Drugs that are commonly implicated include PPIs, NSAIDs and many antibiotics. Post-renal AKI Patients should be examined clinically to look for evidence of a distended bladder and should also undergo imaging with ultrasound to detect evidence of obstruction above the level of the bladder. Post-renal AKI is usually accompanied by hydronephrosis. Management Management options common to all forms of AKI are discussed in more detail below and summarised in Box 15.26. Haemodynamic status If hypovolaemia is present, it should be corrected by replacement of intravenous fluid or blood; excessive administration of fluid should be avoided, since this can provoke pulmonary oedema and worsen outcome in AKI. Monitoring of central venous pressure may be of value in determining the rate of administration of fluid in these circumstances. Balanced crystalloid solutions, such as Plasma-Lyte, Hartmann’s or Ringer’s lactate, may be preferable to isotonic saline (0.9% NaCl) when large volumes of fluid resuscitation are required, in order to avoid hyperchloraemic acidosis, but whether this substantially influences outcome remains unclear. Administration of hydroxyethyl starch solutions should be avoided, since they have been associated with higher rates of established AKI. Critically ill patients may require inotropic drugs to restore an effective blood pressure but clinical trials do not support a specific role for low-dose dopamine. Hyperkalaemia and acidosis Hyperkalaemia is common, particularly in patients with rhabdomyolysis, burns, haemolysis or metabolic acidosis Fig. 15.19 Renal haemodynamics and autoregulation of glomerular filtration rate (GFR). It is evident from this figure how angiotensinconverting enzyme (ACE) inhibitors/angiotensin receptor blockers (ARBs) may be associated with profound drops in GFR in the context of bilateral renal artery stenosis or intravascular volume depletion (which decrease perfusion to afferent arterioles). (NSAIDs = non-steroidal anti-inflammatory drugs) Afferent arteriole Prostaglandins maintain blood flow by vasodilating NSAIDs inhibit prostaglandins Angiotensin II vasoconstricts, maintaining intraglomerular pressure ACE inhibitors/ ARBs inhibit this Efferent arteriole (p. 362). If serum K+ concentration is > 6.5 mmol/L, this should be treated immediately, as described in Box 14.17 (p. 363), to prevent life-threatening cardiac arrhythmias. Metabolic acidosis develops unless prevented by loss of hydrogen ions through vomiting. Severe acidosis can be ameliorated with sodium bicarbonate if volume status allows. Restoration of blood volume will correct acidosis by restoring kidney function. Infusions of isotonic sodium bicarbonate may also be used, if acidosis is severe, to reduce life-threatening hyperkalaemia (Box 15.26). Cardiopulmonary complications Pulmonary oedema (Fig. 15.20) may be caused by the administration of excessive amounts of fluids relative to urine 15.26 Management of acute kidney injury • Assess fluid status as this will determine fluid prescription: If hypovolaemic: optimise systemic haemodynamic status with fluid challenge and inotropic drugs if necessary Once euvolaemic, match fluid intake to urine output plus an additional 500 mL to cover insensible losses If fluid-overloaded, prescribe diuretics (loop diuretics at high dose will often be required); if the response is unsatisfactory, dialysis may be required • Administer calcium resonium to stabilise myocardium and glucose and insulin to correct hyperkalaemia if K+ > 6.5 mmol/L (see Box 14.17, p. 363) as a holding measure until a definitive method of removing potassium is achieved (dialysis or restoration of renal function) • Consider administering sodium bicarbonate (100 mmol) to correct acidosis if H+ is > 100 nmol/L (pH < 7.0) • Discontinue potentially nephrotoxic drugs and reduce doses of therapeutic drugs according to level of renal function • Ensure adequate nutritional support • Consider proton pump inhibitors to reduce the risk of upper gastrointestinal bleeding • Screen for intercurrent infections and treat promptly if present • In case of urinary tract obstruction, drain lower or upper urinary tract as necessary Fig. 15.20 Pulmonary oedema in acute kidney injury. The appearances are indistinguishable from left ventricular failure but the heart size is usually normal. Blood pressure is often high.

414 • NEPHROLOGY AND UROLOGY challenge in unstable patients. Accordingly, the decision to institute RRT should be made on an individual basis, taking account of the potential risks and benefits, comorbidity and an assessment of whether early or delayed recovery is likely. Severe uraemia with pericarditis and neurological signs (uraemic encephalopathy) is uncommon in AKI but, when present, is a strong indication for RRT; other indications are given in Box 15.35 (p. 422). The two main options for RRT in AKI are intermittent haemodialysis and CRRT (see Box 15.38, p. 424). Peritoneal dialysis is also an option if haemodialysis is not available (p. 424). Recovery from AKI Most cases of AKI will recover after the insult resolves but recovery may be impaired in pre-existing CKD or a prolonged severe insult (Fig. 15.21). Recovery is heralded by a gradual return of urine output and a steady improvement in plasma biochemistry. Initially, there is often a diuretic phase in which urine output increases rapidly and remains excessive for several days before returning to normal. This may be due in part to tubular damage and to temporary loss of the medullary concentration gradient. After a few days, urine volume falls to normal as the concentrating output and by increased pulmonary capillary permeability. If pulmonary oedema is present and urine output cannot be rapidly restored, treatment with dialysis may be required to remove excess fluid. Temporary respiratory support may also be necessary using non-invasive ventilation. Once initial resuscitation has been performed, fluid intake should be matched to urine output plus 500 mL per day to cover insensible losses, unless diarrhoea is present, in which case additional fluids may be required. Electrolyte disturbances Electrolyte disturbances, such as dilutional hyponatraemia, may occur if the patient has continued to drink freely despite oliguria or has received inappropriate amounts of intravenous dextrose. They can be avoided by paying careful attention to fluid balance and by giving intravenous fluids slowly. Modest hypocalcaemia is common but rarely requires treatment. Serum phosphate levels are usually high but may fall in patients on daily or continuous renal replacement therapy (CRRT), necessitating phosphate replacement. Dietary measures Adequate nutritional support should be ensured and it is important to give sufficient amounts of energy and adequate amounts of protein; high protein intake should be avoided. This is particularly important in patients with sepsis and burns who are hypercatabolic. Enteral or parenteral nutrition may be required (p. 707). Infection Patients with AKI are at substantial risk of intercurrent infection because humoral and cellular immune mechanisms are depressed. Regular clinical examination, supplemented by microbiological investigation where appropriate, is required to diagnose infection. If infection is discovered, it should be treated promptly according to standard principles (Ch. 6). Medications Patients with drug-induced kidney injury (p. 402) should have the offending drug withdrawn. Additionally, vasoactive medications, such as NSAIDs and ACE inhibitors, should be discontinued, as they may prolong AKI (see Fig 15.19). H2-receptor antagonists or PPIs should be given to prevent gastrointestinal bleeding. Other drug treatments should be reviewed and the doses adjusted if necessary, to take account of renal function. Non-essential drug treatments should be stopped. Renal tract obstruction In post-renal AKI, the obstruction should be relieved as soon as possible. This may involve urinary catheterisation for bladder outflow obstruction, or correction of ureteric obstruction with a ureteric stent or percutaneous nephrostomy. Renal replacement therapy Conservative management can be successful in AKI with meticulous attention to fluid balance, electrolytes and nutrition, but RRT may be required in patients who are not showing signs of recovery with these measures (Box 15.26). No specific cut-off values for serum urea or creatinine have been identified at which RRT should be commenced, and clinical trials of earlier versus later RRT in unselected patients with AKI have not shown differences in outcome. Furthermore, RRT can be a risky intervention, since it requires the placement of central venous catheters that may become infected and it may represent a major haemodynamic Fig. 15.21 Recovery from acute kidney injury (AKI). Many patients make a full recovery of renal function (1). If the insult is prolonged or prior renal function not normal, however, patients may develop progressive chronic kidney disease (2) or, rarely, irreversible, complete loss of renal function (3). (ESRD = end-stage renal disease) AKI

Full recovery AKI to ESRD Time Renal function Acute on chronic kidney disease 15.27 Acute kidney injury in old age • Physiological change: nephrons decline in number with age and average GFR falls progressively, so many elderly patients will have established CKD and less functional reserve. Small acute declines in renal function may therefore have a significant impact. • Creatinine: as muscle mass falls with age, less creatinine is produced each day. Serum creatinine can be misleading as a guide to renal function. • Renal tubular function: declines with age, leading to loss of urinary concentrating ability. • Drugs: increased drug prescription in older people (diuretics, ACE inhibitors and NSAIDs) may contribute to the risk of AKI. • Causes: infection, renal vascular disease, prostatic obstruction, hypovolaemia and severe cardiac dysfunction are common. • Mortality: rises with age, primarily because of comorbid conditions.

Chronic kidney disease • 415

Many patients diagnosed at a late stage have bilateral small kidneys; renal biopsy is rarely undertaken in this group since it is more risky, less likely to provide a histological diagnosis because of the severity of damage, and unlikely to alter management. Clinical features The typical presentation is for a raised urea and creatinine to be found incidentally during routine blood tests, often during screening of high-risk patients, such as those with diabetes or hypertension. Most patients with slowly progressive disease are asymptomatic until GFR falls below 30 mL/min/1.73 m2 and some can remain asymptomatic with much lower GFR values than this. An early symptom is nocturia, due to the loss of concentrating ability and increased osmotic load per nephron, but this is non-specific. When GFR falls below 15–20 mL/min/1.73 m2, symptoms and signs are common and can affect almost all body systems (Fig. 15.22). They typically include tiredness or breathlessness, which may, in part, be related to renal anaemia or fluid overload. With further deterioration in renal function, patients may suffer pruritus, anorexia, weight loss, nausea, vomiting and hiccups. In very advanced renal failure, respiration may be particularly deep (Kussmaul breathing) due to profound metabolic acidosis, and patients may develop muscular twitching, fits, drowsiness and coma. Investigations The recommended investigations in patients with CKD are shown in Box 15.29. Their main aims are: • to exclude AKI requiring rapid investigation; in patients with unexpectedly high urea and creatinine (when there is an increase from previous results or no prior results are available), renal function should be retested within 2 weeks to avoid missing AKI • to identify the underlying cause where possible, since this may influence the treatment • to identify reversible factors that may worsen renal function, such as hypertension or urinary tract obstruction • to screen for complications of CKD, such as anaemia and renal osteodystrophy • to screen for cardiovascular risk factors. Referral to a nephrologist is appropriate for patients with potentially treatable underlying disease and those who are likely to progress to ESRD. Suggested referral criteria are listed in Box 15.30. Management The aims of management in CKD are to: • monitor renal function • prevent or slow further renal damage • limit complications of renal failure • treat risk factors for cardiovascular disease • prepare for RRT, if appropriate (p. 420). Monitoring of renal function The rate of change in renal function varies between patients and may vary over time in each individual. Renal function should therefore be monitored every 6 months in patients with stage 3 CKD, but more frequently in patients who are deteriorating rapidly or have stage 4 or 5 CKD. A plot of GFR against time (Fig. 15.23) can demonstrate whether therapy has been successful in slowing progression, detect any unexpected increase in the rate of decline that may warrant further investigation, and help mechanism and tubular reabsorption are restored. During the recovery phase of AKI, it may be necessary to provide temporary supplementation of bicarbonate, potassium and sometimes calcium, phosphate and magnesium. AKI in old age is described in Box 15.27. Chronic kidney disease Chronic kidney disease (CKD) refers to an irreversible deterioration in renal function that usually develops over a period of years (see Box 15.3, p. 388). Initially, it manifests only as a biochemical abnormality but, eventually, loss of the excretory, metabolic and endocrine functions of the kidney leads to the clinical symptoms and signs of renal failure, collectively referred to as uraemia. When death is likely without RRT (CKD stage 5), it is called end-stage renal disease (ESRD). Epidemiology The social and economic consequences of CKD are considerable. In many countries, estimates of the prevalence of CKD stages 3–5 (eGFR < 60 mL/min/1.73 m2) are around 5–7%, mostly affecting people aged 65 years and above (see Box 15.3). The prevalence of CKD in patients with hypertension, diabetes and vascular disease is substantially higher, and targeted screening for CKD should be considered in these and other high-risk groups. More than 25% of the population aged over 75 years have an eGFR of < 60 mL/min/1.73 m2, mostly stage 3A CKD, which in this context typically reflects an increased cardiovascular risk burden. In these patients, investigation and management should be focused on cardiovascular risk prevention, as very few will ever develop ESRD. Many primary renal diseases, however, are more common in the elderly, so investigation is warranted for those with declining renal function or with haematuria/proteinuria on dipstick. Pathophysiology Common causes of CKD are shown in Box 15.28. In many cases, the underlying diagnosis is unclear, especially among the large number of elderly patients with stage 3 CKD (see Box 15.3). 15.28 Common causes of chronic kidney disease Disease Proportion Comments Diabetes mellitus 20–40% Large racial and geographical differences Interstitial diseases 20–30% Often drug-induced Glomerular diseases 10–20% IgA nephropathy is most common Hypertension 5–20% Causality controversial, much may be secondary to another primary renal disease Systemic inflammatory diseases 5–10% Systemic lupus erythematosus, vasculitis Renovascular disease 5% Mostly atheromatous, may be more common Congenital and inherited 5% Polycystic kidney disease, Alport’s syndrome Unknown 5–20%

416 • NEPHROLOGY AND UROLOGY be employed where possible; tight blood pressure control is applicable to CKD regardless of cause, however, and reducing proteinuria is a key target in those with glomerular disease. Antihypertensive therapy Lowering of blood pressure slows the rate at which renal function declines in CKD, independently of the agent used (apart from those with proteinuria; see below) and predict when ESRF will be reached to facilitate timely planning for RRT. Reduction of rate of progression Slowing the rate of progression of CKD may reduce complications and delay symptom onset and the need for RRT (Fig. 15.23). Therapies directed towards the primary cause of CKD should 15.29 Suggested investigations in chronic kidney disease Initial tests Interpretation Urea and creatinine To assess stability/progression: compare to previous results Urinalysis and quantification of proteinuria Haematuria and proteinuria may indicate glomerular disease and need for biopsy (p. 391). Proteinuria indicates risk of progressive CKD requiring preventive ACE inhibitor or ARB therapy Electrolytes To identify hyperkalaemia and acidosis Calcium, phosphate, parathyroid hormone and 25(OH)D Assessment of renal osteodystrophy Albumin Low albumin: consider malnutrition, inflammation, nephrotic syndrome Full blood count (± Fe, ferritin, folate, B12) If anaemic, exclude common non-renal explanations, then manage as renal anaemia Lipids, glucose ± HbA1c Cardiovascular risk high in CKD: treat risk factors aggressively Renal ultrasound Only if there are obstructive urinary symptoms, persistent haematuria, family history of polycystic kidney disease or progressive CKD. Small kidneys suggest chronicity. Asymmetric renal size suggests renovascular or developmental disease Hepatitis and HIV serology If dialysis or transplant is planned. Hepatitis B vaccination recommended if seronegative Other tests Consider relevant tests from Box 15.25, especially if the cause of CKD is unknown (ACE = angiotensin-converting enzyme; ARB = angiotensin II receptor blocker; 25(OH)D = 25-hydroxyvitamin D) Fig. 15.22 Physical signs in advanced chronic kidney disease. (Features of renal replacement therapy) Yellow complexion Pallor Dual-lumen central venous catheter for dialysis access (right or left) Pericardial friction rub Arteriovenous fistulae for dialysis access* Transplanted kidney (right or left) with overlying scar* ‘Brown line’ pigmentation of nails Excoriation of pruritus Bruising easily Peripheral neuropathy

Absent reflexes

Reduced sensation

Paraesthesia

‘Restless legs’ Jugular venous pressure raised in fluid overload or pericardial tamponade Pulsus paradoxus in pericardial tamponade Tenckhoff catheter for peritoneal dialysis (right or left)* Increased respiratory rate and depth in metabolic acidosis

Chronic kidney disease • 417

patients with proteinuria (PCR > 50 mg/mmol or ACR > 30 mg/ mmol) through a reduction in glomerular perfusion pressure. In addition, ACE inhibitors have been shown to reduce the risk of cardiovascular events and all-cause mortality in CKD. Accordingly, ACE inhibitors and/or ARBs should be prescribed to all patients with diabetic nephropathy and patients with CKD and proteinuria, irrespective of whether or not hypertension is present. While ACE inhibitors and ARBs are excellent drugs for patients with diabetes or CKD and proteinuria, they need to be prescribed with care in certain circumstances. Initiation of treatment with ACE inhibitors and ARBs may be accompanied by an immediate reduction in GFR; patients should therefore have their renal function checked within 7–10 days of initiating or increasing the dose of an ACE inhibitor or ARB. Treatment can be continued so long as the reduction in GFR is not greater than 25% and is not progressive. Angiotensin II is critical for autoregulation of GFR in the context of low renal perfusion (see Fig. 15.1D, p. 385), and so ACE inhibitors or ARBs may exacerbate pre-renal failure (see Fig. 15.19). Patients on ACE inhibitors/ARBs should therefore be warned to stop taking the medication if they become unwell, such as with fever, vomiting or diarrhoea, restarting once they are better. This also applies to other common medications used in patients with CKD, such as diuretics, metformin and NSAIDs, and this advice may be reinforced by providing written information such as ‘sick-day rule’ cards (Box 15.31). ACE inhibitors and ARBs increase serum potassium and should not be commenced in patients with baseline potassium > 5.5 mmol/L. In patients with serum potassium > 6.0 mmol/L, the dose of ACE inhibitors or ARBs should be reduced or discontinued entirely, but only after all other measures to reduce potassium have been considered (see below). Combination therapy with ACE inhibitors and ARBs or direct renin inhibitors has not been shown to reduce progression of kidney disease but is associated with higher rates of hyperkalaemia and AKI, and is therefore to be avoided. Fig. 15.23 Plot of estimated glomerular filtration rate (eGFR) against time in a patient with type 1 diabetes mellitus. After approximately 6 years of monitoring (blue arrow), this patient entered an aggressive treatment programme aimed at optimising blood pressure (BP) and glycaemic control. The reduction in BP was accompanied by a fall in proteinuria (protein:creatinine ratio, PCR; shown in mg/mmol). At the previous rate of decline in renal function (dashed line), he was likely to reach the level of renal function at which dialysis therapy is typically required (eGFR = 10 mL/min/1.73 m2) within 18 months; however, the relative stabilisation in his renal function (dotted line) means that this has been deferred, potentially for several years. BP 162/88 PCR 284 BP 177/104 PCR 397 BP 146/77 PCR 170

eGFR mL/min/1.73 m2 BP 207/101 PCR 367 BP 122/68 PCR 107

Time (years)

15.30 Criteria for referral of chronic kidney disease patients to a nephrologist • eGFR < 30 mL/min/1.73 m2 • Rapid deterioration in renal function (> 25% from previous or

15 mL/min/1.73 m2/year) • Significant proteinuria (PCR > 100 mg/mmol or ACR > 70 mg/ mmol), unless known to be due to diabetes and patient is already on appropriate medications • ACR > 30 mg/mmol with non-visible haematuria • Hypertension that remains poorly controlled despite at least four antihypertensive medications • Suspicion of renal involvement in multisystem disease has additional benefits in lowering the risk of hypertensive heart failure, stroke and peripheral vascular disease. No threshold for beneficial effects has been identified and any reduction of blood pressure appears to be beneficial. Various targets have been suggested, such as 140/90 mmHg for patients with CKD and no albuminuria (ACR < 3 mg/mmol). A lower target of 130/80 mmHg should be considered for those who have moderately elevated albuminuria (ACR 3–3 mg/mmol), and is recommended for those with an ACR of more than 30 mg/mmol. Even lower targets, such as 125/75 mmHg, may be prudent in patients with CKD and heavy proteinuria (PCR > 100 mg/mmol or ACR > 70 mg/ mmol). Achieving these blood pressure targets often requires multiple drugs, and therapeutic success may be limited by adverse effects and poor adherence. Reduction of proteinuria Patients with proteinuria are at higher risk of progression of renal disease, and there is strong evidence that reducing proteinuria reduces the risk of progression. ACE inhibitors and ARBs reduce proteinuria and retard the progression of CKD. These effects are partly due to the reduction in blood pressure but there is evidence for a specific beneficial effect in

418 • NEPHROLOGY AND UROLOGY The inability of the failing kidney to excrete sodium and water loads commonly leads to their accumulation, which may manifest as oedema and may drive hypertension. Patients with evidence of volume expansion should be instructed to consume a low-sodium diet (< 100 mmol/24 hrs), and in severe cases fluid intake should also be restricted. Diuretics are commonly required, and as renal function deteriorates, increasing doses of potent loop diuretics or synergistic combinations of loop, thiazide and potassium-sparing diuretics may be necessary. Occasionally, some patients with tubulo-interstitial disease can develop ‘salt-wasting’ disease and may require a high sodium and water intake, including supplements of sodium salts, to prevent fluid depletion and worsening of renal function. Acid–base balance Reduced ability to excrete organic acids in patients with CKD may lead to an anion-gap metabolic acidosis. In addition, in patients with tubulo-interstitial disease or diabetic nephropathy, there may be specific defects in acid–base regulation within the kidney, causing a non-anion-gap renal tubular acidosis (p. 365). Although acidosis is usually asymptomatic, it may be associated with increased tissue catabolism and decreased protein synthesis, and may exacerbate bone disease and the rate of decline in renal function. Hence, plasma bicarbonate concentrations should be maintained above 22 mmol/L by prescribing sodium bicarbonate supplements (starting dose of 1 g 8-hourly, increasing as required). There is some evidence that correcting acidosis may reduce the rate of decline in renal function. Renal bone disease Disturbances of calcium and phosphate metabolism are almost universal in advanced CKD (Fig. 15.24). The sequence of events that leads to renal bone disease is complex, but two primary factors are impaired excretion of phosphate and failure of the renal tubular cells to convert 25-hydroxyvitamin D to its active metabolite, 1,25-dihydroxyvitamin D. A rise in serum phosphate levels promotes production of the hormone fibroblast growth factor 23 (FGF23) from osteocytes (Fig. 24.3, p. 986) and stimulates parathyroid hormone (PTH) release and hyperplasia of the parathyroid glands. The FGF23 and PTH promote tubular phosphate excretion, thereby partly compensating for the reduced glomerular filtration of phosphate. The reduced 1,25-dihydroxyvitamin D levels impair intestinal absorption of calcium. In addition, raised levels of serum phosphate complex with calcium in the extracellular space, leading to calcium phosphate deposition. Both the reduced absorption and increased deposition of calcium cause hypocalcaemia, which also stimulates PTH production by the parathyroid glands. Hence in many patients with CKD, compensatory responses initially maintain phosphate and calcium levels at the upper and lower ends of their respective normal ranges, at the expense of an elevated PTH level (secondary hyperparathyroidism). This is associated with a gradual transfer of calcium and phosphate from the bone to other tissues, leading to bone resorption (osteitis fibrosa cystica), and in severe cases this may result in bony pain and increased risk of fractures. Conversely there is increased deposition of calcium phosphate in many tissues, most notably blood vessels and heart valves, which may contribute to the increased risk of cardiovascular disease in patients with CKD (p. 420). In some cases, tertiary hyperparathyroidism supervenes, due to autonomous production of PTH by the enlarged parathyroid glands; this presents with hypercalcaemia. Additional problems in bone metabolism include low bone turnover (adynamic bone disease) in patients who have been over-treated with vitamin D metabolites, osteomalacia with over-treatment of Treatment of complications The kidneys have many functions in addition to excretion of waste (p. 384). Treatments that substitute for all of the normal roles of the kidneys must therefore be instigated to maintain normal body homeostasis and prevent complications. Maintenance of fluid and electrolyte balance The kidneys excrete waste and regulate many electrolytes, and so patients with CKD may accumulate waste products and develop electrolyte abnormalities. Urea is a key product of protein degradation and accumulates with progressive CKD. All patients with stages 4 and 5 CKD should be given dietetic advice aimed at preventing excessive consumption of protein. Severe protein restriction is not recommended, however; there is no evidence that this reduces the rate of decline in renal function but may lead to malnutrition. Potassium often accumulates in patients with advanced CKD, who should be provided with dietary advice to reduce daily potassium intake to below 70 mmol (Box 15.32). Potassiumbinding compounds limit absorption of potassium from the gut and may be a useful adjunctive therapy. Calcium resonium is not recommended other than as a very short-term measure, as it can be associated with bowel necrosis; however, newer agents, such as zirconium cyclosilicate and patiromer, appear promising for chronic use. Other measures that may help regulate potassium include diuretic therapy and control of acidosis with sodium bicarbonate (see below). Consideration should be given to stopping or reducing drugs that elevate potassium, such as potassium-sparing diuretics and ACE inhibitors/ARBs; however, this has to be balanced against the potential benefit that such drugs may have on retarding progression of renal and cardiovascular disease, and hence withdrawal should be reserved for when other measures have failed. 15.31 Exemplar medicine sick-day card When you are unwell with vomiting, diarrhoea or fever, stop taking the following medications: • ACE inhibitors: medicines ending in ‘-pril’, e.g. lisinopril, ramipril • Angiotensin receptor blockers: medicines ending in ‘-sartan’, e.g. irbesartan, losartan, candesartan • Non-steroidal anti-inflammatory painkillers: e.g. ibuprofen (Brufen), diclofenac (Voltarol) • Diuretics: e.g. furosemide, bendroflumethiazide, indapamide, spironolactone • Metformin: a medicine for diabetes. Restart when you are well again (after 24–48 hours of eating and drinking normally). 15.32 Foods high in potassium • Fruit: bananas, avocados, figs, rhubarb • Vegetables: tomatoes, spinach, parsnips, courgettes, sprouts, potatoes (including baked, fries, wedges; boiling vegetables reduces potassium content) • Sweets/snacks: crisps, chocolate, toffee, nuts (including peanut butter) • Drinks: beer, cider, wine (spirits contain less potassium), hot chocolate, fruit juice, milk, yoghurt • Salt substitutes, such as Lo-Salt: sodium chloride is substituted with potassium chloride

Chronic kidney disease • 419

shortness of breath. Haemoglobin can be as low as 50–70 g/L in CKD stage 5, although it is often less severe or absent in patients with polycystic kidney disease. Several mechanisms are implicated, as summarised in Box 15.33. Iron deficiency is common in patients with CKD, and even more prevalent in those on haemodialysis as a result of haemolysis in the dialysis circuit. Hence many patients require iron supplements, which may be given intravenously for those with iron intolerance or in situations where adherence may be difficult. Once iron deficiency and other causes of anaemia have been excluded or corrected, recombinant human erythropoietin is very effective in correcting the anaemia of CKD and improving symptoms. Erythropoietin treatment does not influence mortality, however, and correcting haemoglobin to normal levels may carry some extra risk, including hypertension and thrombosis. The target haemoglobin is usually between 100 and 120 g/L. Erythropoietin is less effective in the presence of iron deficiency, active inflammation or malignancy, in particular myeloma. hyperphosphataemia (p. 369), and osteoporosis in patients with poor nutritional intake. The key focus in the management of renal bone disease should be directed towards the two main driving factors, hyperphosphataemia and inadequate activation of vitamin D. Hyperphosphataemia should be treated by dietary restriction of foods with high phosphate content (milk, cheese, eggs and protein-rich foods) and by the use of phosphate-binding drugs. Various drugs are available, including calcium carbonate, aluminium hydroxide, lanthanum carbonate and polymer-based phosphate binders such as sevelamer. The aim is to maintain serum phosphate values at or below 1.5 mmol/L (4.6 mg/dL) if possible, but many of these drugs are difficult to take and adherence can be a problem. Active vitamin D metabolites (either 1-α-hydroxyvitamin D or 1,25-dihydroxyvitamin D) should be administered in patients who are hypocalcaemic or have serum PTH levels more than twice the upper limit of normal. The dose should be adjusted to try to reduce PTH levels to between 2 and 4 times the upper limit of normal to limit hyperparathyroidism while avoiding over-suppression of bone turnover and adynamic bone disease, but care must be exercised in order to avoid hypercalcaemia. In patients with persistent hypercalcaemia (tertiary hyperparathyroidism), parathyroidectomy may be required. If parathyroidectomy is unsuccessful or not possible, calcimimetic agents, such as cinacalcet, may be used. These bind to the calcium-sensing receptor in the parathyroid glands and reduce PTH secretion. Anaemia Anaemia is common in patients with CKD and contributes to many of the non-specific symptoms, including fatigue and Fig. 15.24 Pathogenesis of renal osteodystrophy. Low 1,25-dihydroxyvitamin D (1,25(OH)2D) levels cause calcium malabsorption and this, combined with high phosphate levels, causes hypocalcaemia, which increases parathyroid hormone (PTH) production by the parathyroid glands. The raised level of PTH increases osteoclastic bone resorption. Although production of fibroblast growth factor 23 (FGF23) from osteocytes also increases, promoting phosphate excretion, this is insufficient to prevent hyperphosphataemia in advanced chronic kidney disease. Impaired renal function ↑Osteoclastic bone resorption Decreased conversion of 25(OH)D to 1,25(OH)2D ↑PO4 excretion ↓1,25(OH)2D FGF23 Stimulation of parathyroid glands leading to hyperplasia ↑PTH

↓PO4 excretion ↑Plasma [PO4] ↓Ca2+ absorption ↓Plasma [Ca2+] Impaired mineralisation of bone 15.33 Causes of anaemia in chronic kidney disease • Deficiency of erythropoietin • Toxic effects of uraemia on marrow precursor cells • Reduced red cell survival • Blood loss due to capillary fragility and poor platelet function • Reduced intake, absorption and utilisation of dietary iron

420 • NEPHROLOGY AND UROLOGY Renal replacement therapy Renal replacement therapy (RRT) may be required on a temporary basis in patients with AKI or on a permanent basis for those with advanced CKD. Since the advent of long-term RRT in the 1960s, the numbers of patients with ESRD who are kept alive by dialysis and transplantation have increased considerably. By the end of 2014, almost 59 000 patients were on RRT in the UK, with a median age of 65 years. After a long period of expansion, the number of patients on dialysis in the UK and USA has begun to stabilise; however, the total number of patients on RRT continues to expand, due to an increasing proportion (53%) of patients with a functional transplant. The remaining patients were on haemodialysis (41%) and peritoneal dialysis (6%). There are variations in the numbers of patients receiving RRT in different countries because of differences in the incidence of predisposing disease, as well as differences in medical practice. For example, the incidence rate for RRT in the USA was about three times higher than in the UK (363 versus 115 patients per million population), and the prevalence rate was more than twice as high (2034 versus 913 per million population). Diabetic kidney disease is the most common cause of ESRD in many countries, accounting for 26% of all ESRD in the UK and almost 50% in the USA. The large increase in the prevalence of type 2 diabetes in developing countries is resulting in a predictable rise in cases of ESRD, which is challenging already stretched health-care resources. Survival on dialysis is strongly influenced by age and presence of complications such as diabetes (Fig. 15.26). For this reason, conservative care rather than RRT may be a more appropriate option for older patients or those with extensive comorbidities Although many young patients without extrarenal disease lead Treatment of risk factors for cardiovascular disease The risk of cardiovascular disease is substantially increased in patients with a GFR below 60 mL/min/1.73 m2 and in those with proteinuria, the combination of reduced eGFR and proteinuria being particularly unfavourable. Patients with CKD have a higher prevalence of traditional risk factors for atherosclerosis, such as hypertension, hyperlipidaemia and diabetes; however, additional mechanisms of cardiovascular disease may also be implicated. Left ventricular hypertrophy is commonly found in patients with CKD, secondary to hypertension or anaemia. Calcification of the media of blood vessels, heart valves, myocardium and the conduction system of the heart is also common and may be due, in part, to the high serum phosphate levels. Reflecting this fact, serum FGF23 levels, which increase in response to serum phosphate, are an independent predictor of mortality in CKD. Both left ventricular hypertrophy and cardiac calcification may increase the risk of arrhythmias and sudden cardiac death, which is a much more common mode of death in patients with CKD than in the general population, particularly in those with more advanced disease and those on dialysis. To reduce vascular risk, patients with CKD should be encouraged to adopt a healthy lifestyle, including regular exercise, and weight loss and smoking cessation where appropriate. Lipid-lowering drugs reduce cardiovascular events in patients with CKD, although their efficacy may be less once patients require dialysis. Preparing for renal replacement therapy It is crucial for patients who are known to have progressive CKD to be prepared well in advance for the institution of RRT. This involves ensuring that they are referred to a nephrologist in a timely manner, as those who are referred late, when they are either at the stage of or very close to requiring dialysis, tend to have poorer outcomes. Several decisions need to be taken in discussion with the patient and family. The first is to decide whether RRT is an appropriate choice or whether conservative treatment might be preferable (p. 421). This is especially relevant in patients with significant comorbidity. For those who decide to go ahead with RRT, there are further choices between haemodialysis and peritoneal dialysis (Box 15.34), between hospital and home treatment, and on referral for renal transplantation. Since there is no evidence that early initiation of RRT improves outcome, the overall aim is to commence RRT when symptoms of CKD begin to impact on quality of life but before serious complications have occurred. While there is wide variation between patients, this typically occurs when the eGFR approaches 10 mL/ min/1.73 m2. This may be a useful marker to predict the timing of initiation of RRT by extrapolating from a plot of serial eGFR measurements over time (see Fig. 15.23). Preparations for starting RRT should begin at least 12 months before the predicted start date. This involves providing the patient with psychological and social support, assessing home circumstances and discussing the various choices of treatment (Fig. 15.25). Depression is common in patients who are on or approaching RRT, and support from the renal multidisciplinary team should be provided both for them and for their relatives, to explain and help them adapt to the changes to lifestyle that may be necessary once RRT starts; this may help to reduce their anxieties about these changes. Physical preparations include establishment of timely access for haemodialysis or peritoneal dialysis and vaccination against hepatitis B. 15.34 Comparison of haemodialysis and peritoneal dialysis Haemodialysis Peritoneal dialysis Efficient; 4 hrs three times per week is usually adequate Less efficient; four exchanges per day are usually required, each taking 30–60 mins (continuous ambulatory peritoneal dialysis) or 8–10 hrs each night (automated peritoneal dialysis) 2–3 days between treatments A few hours between treatments Requires visits to hospital (although home treatment is possible for some patients) Performed at home Requires adequate venous circulation for vascular access Requires an intact peritoneal cavity without major scarring from previous surgery Careful adherence to diet and fluid restrictions required between treatments Diet and fluid less restricted Fluid removal compressed into treatment periods; may cause symptoms and haemodynamic instability Slow continuous fluid removal, usually asymptomatic Infections related to vascular access may occur Peritonitis and catheter-related infections may occur Patients are usually dependent on others Patients can take full responsibility for their treatment

Renal replacement therapy • 421

slightly shorter than that of patients who undergo RRT, but they avoid the hospitalisation and interventions associated with dialysis. Patients are offered full medical, psychological and social support to optimise and sustain their existing renal function and to treat complications, such as anaemia, for as long as possible, with appropriate palliative care in the terminal phase of their disease. Many of these patients enjoy a good quality of life for several years. When quality of life on dialysis is poor, it is appropriate to consider discontinuing it, following discussion with the patient and family, and to offer palliative care. Haemodialysis Haemodialysis is the most common form of RRT in ESRD and is also used in AKI. Haemodialysis involves gaining access to the circulation, either through a central venous catheter or an arteriovenous fistula or graft. The patient’s blood is pumped through a haemodialyser, which allows bidirectional diffusion of Fig. 15.25 Options for renal replacement therapy. A In haemodialysis, there is diffusion of solutes from blood to dialysate across a semipermeable membrane down a concentration gradient. B In haemofiltration, both water and solutes are filtered across a porous semipermeable membrane by a pressure gradient. Replacement fluid is added to the filtered blood before it is returned to the patient. C In peritoneal dialysis (PD), fluid is introduced into the abdominal cavity using a catheter. Solutes diffuse from blood across the peritoneal membrane to PD fluid down a concentration gradient, and water diffuses through osmosis (see text for details). D In transplantation, the blood supply of the transplanted kidney is generally anastomosed to the external iliac vessels and the ureter to the bladder. The transplanted kidney replaces all functions of the failed kidney. Haemodialysis Dialysate Haemofiltration Ultrafiltrate Replacement fluid Peritoneal dialysis Peritoneal cavity Transplantation External iliac artery Peritoneal membrane PD fluid Catheter Transplanted kidney External iliac vein Donor artery Donor vein Donor ureter Bladder Blood from patient Blood to patient Blood to patient Blood from patient A B C D normal and active lives on RRT, those aged 30–34 have a mortality rate 25 times higher than that of age-matched controls. The aim of RRT is to replace the excretory functions of the kidney and to maintain normal electrolyte concentrations and fluid balance. Various options are available, including haemodialysis, haemofiltration, haemodiafiltration, peritoneal dialysis and renal transplantation, and each of these is discussed in more detail below. Indications for starting RRT in both AKI and CKD may be found in Box 15.35. Conservative treatment In older patients with multiple comorbidities, conservative treatment of stage 5 CKD, aimed at limiting the adverse symptoms of ESRD without commencing RRT, is increasingly viewed as a positive choice (Box 15.36). Current evidence suggests that survival of these patients without dialysis can be similar or only

422 • NEPHROLOGY AND UROLOGY In AKI, dialysis is performed through a large-bore, dual-lumen catheter inserted into the femoral or internal jugular vein (Fig. 15.27A). Subclavian lines are avoided where possible, largely due to bleeding risk. Also, thromboses or stenoses here will compromise the ability to form a functioning fistula in the arm if the patient fails to recover renal function and needs chronic dialysis. Haemodialysis in CKD In CKD, vascular access for haemodialysis is gained by formation of an arteriovenous fistula (AVF), usually in the forearm, up to a year before dialysis is contemplated (Fig. 15.27B). After 4–6 weeks, increased pressure transmitted from the artery to the vein leading from the fistula causes distension and thickening of the vessel wall (arterialisation). Large-bore needles can then be solutes between blood and the dialysate across a semipermeable membrane down a concentration gradient (Fig. 15.25A). The composition of the dialysate can be varied to achieve the desired gradient, and fluid can be removed by applying negative pressure to the dialysate side. Haemodialysis in AKI Haemodialysis offers the best rate of small solute clearance in AKI, compared with other techniques such as haemofiltration, but should be started gradually because of the risk of delirium and convulsions due to cerebral oedema (dialysis disequilibrium). Typically, 1–2 hours of dialysis is prescribed initially but, subsequently, patients with AKI who are haemodynamically stable can be treated by 4–5 hours of haemodialysis on alternate days, or 2–3 hours every day. During dialysis, it is standard practice to anticoagulate patients with heparin but the dose may be reduced if there is a bleeding risk. Epoprostenol can be used as an alternative but carries a risk of hypotension. In patients undergoing short treatments and in those with abnormal clotting, it may be possible to avoid anticoagulation altogether. Fig. 15.26 Percentage survival after commencing renal replacement therapy according to age group and presence of diabetes.

Time (years) Survival (%) 18–44 years, no diabetes 18–44 years, with diabetes 44–64 years, no diabetes 44–64 years, with diabetes ≥ 65 years, no diabetes ≥ 65 years, with diabetes

15.36 Renal replacement therapy in old age • Quality of life: age itself is not a barrier to good quality of life on RRT. • Coexisting cardiovascular disease: older people are more sensitive to fluid balance changes, predisposing to hypotension during dialysis with rebound hypertension between dialysis sessions. A failing heart cannot cope with fluid overload, and pulmonary oedema develops easily. • Provision of treatment: often only hospital-provided haemodialysis is suitable and older patients require more medical and nursing time. • Survival on dialysis: difficult to predict for an individual patient, but old age plus substantial comorbidity are associated with poor median survival. Similar survival may be achieved through conservative care, without the complications associated with dialysis. • Withdrawal from dialysis: may be appropriate whenever quality of life deteriorates irreversibly, usually in the context of severe comorbidity. • Transplantation: relative risks of surgery and immunosuppression exclude most older people from transplantation. • Conservative therapy: without dialysis but with adequate support. This is an appropriate option for patients at high risk of complications from dialysis, who have a limited prognosis and little hope of functional recovery. 15.35 Indications for dialysis with examples for AKI and CKD Indication* Acute examples Chronic examples Fluid overload Acute pulmonary oedema Intractable dependent oedema resistant to diuretics Pulmonary oedema Severe hypertension Hyperkalaemia High potassium (generally > 6.5 mmol/L) with ECG changes (especially broad QRS) Potassium resistant to dietary control and medical intervention Uraemia Pericarditis Encephalopathy Uraemic syndrome including anorexia, nausea, lethargy etc. (generally not until eGFR < 10 mL/min/1.73 m2) Metabolic acidosis Severe acidosis (H+ > 79 nmol/L; pH < 7.1) Chronic acidosis resistant to bicarbonate therapy Other (often relative indications) Bleeding diathesis considered due to uraemia-induced platelet dysfunction Intractable anaemia despite erythropoietin and iron Hyperphosphataemia despite binders *The presence of anuria in AKI will modify the above indications, as these complications will not resolve if the patient is persistently anuric. Most indications to commence chronic dialysis are relative indications; a holistic approach is taken to making this decision. (ECG = electrocardiogram; eGFR = estimated glomerular filtration rate)

Renal replacement therapy • 423

Fig. 15.27 Haemodialysis access. A A tunnelled cuffed dialysis catheter. B An arteriovenous fistula. C An arteriovenous graft. Right internal jugular vein Catheter Right atrium of heart Mixed arteriovenous blood Artery Artery Vein Arteriovenous graft Vein, expanded due to increased blood pressure Arteriovenous fistula Blood from dialysis machine Blood to dialysis machine Blood from dialysis machine Blood to dialysis machine A B C inserted into the vein to provide access for each haemodialysis treatment. Preservation of arm veins is thus very important in patients with progressive renal disease who may require haemodialysis in the future. If creation of an AVF is not possible, synthetic polytetrafluoroethylene (PTFE) grafts may be fashioned between an artery and a vein, or central venous catheters may be used for short-term access (Fig. 15.27C). These are tunnelled under the skin to reduce infection risk. All patients must be screened in advance for hepatitis B, hepatitis C and HIV, and vaccinated against hepatitis B if they are not immune. All dialysis units should have segregation facilities for hepatitis B-positive patients, given its easy transmissibility. Patients with hepatitis C and HIV are less infectious and can be treated satisfactorily using machine segregation and standard infection control measures. Haemodialysis is usually carried out for 3–5 hours three times weekly, either at home or in an outpatient dialysis unit. The intensity and frequency of dialysis should be adjusted to achieve a reduction in urea during dialysis (urea reduction ratio) of over 65%; below this level there is an associated increase in mortality. Most patients notice an improvement in symptoms during the first 6 weeks of treatment. The intensity of dialysis can be increased by: • escalating the number of standard sessions to four or more per week • performing short, frequent dialysis sessions of 2–3 hours 5–7 times per week • performing nocturnal haemodialysis, when low bloodpump speeds and single-needle dialysis are used for approximately 8 hours overnight 5–6 times per week. More frequent dialysis and nocturnal dialysis can achieve better fluid balance and phosphate control, improve left ventricular mass and possibly improve mortality, although the latter has not yet been robustly demonstrated. Box 15.37 summarises some of the problems related to haemodialysis. Haemofiltration This technique is principally used in the treatment of AKI as CRRT (Box 15.38). Large volumes of water are filtered from blood across a porous semipermeable membrane under a pressure gradient. Solutes are removed via ‘solvent drag’. Replacement fluid of a suitable electrolyte composition is added to the blood after it exits the haemofilter. If removal of fluid is required, then less fluid is added back than is removed (see Fig. 15.25B). Haemofiltration may be either intermittent or continuous, and typically 1–2 L of filtrate is replaced per hour (equivalent to a GFR of 15–30 mL/ min/1.73 m2); higher rates of filtration may be of benefit in patients with sepsis and multi-organ failure. In continuous arteriovenous haemofiltration (CAVH), the extracorporeal blood circuit is driven by the arteriovenous pressure difference, but poor filtration rates and clotting of the filter are common and this treatment has fallen out of favour. Continuous venovenous haemofiltration (CVVH) is pump-driven, providing a reliable extracorporeal circulation. Issues concerning anticoagulation are similar to those for haemodialysis, but may be more problematic because longer or continuous anticoagulation is necessary. Haemodiafiltration This technique combines haemodialysis with approximately 20–30 L of ultrafiltration (with replacement of filtrate) over a 3–5-hour treatment. It uses a large-pore membrane and combines the improved clearance of medium-sized molecules observed in haemofiltration with the higher small-solute clearance of haemodialysis. It is sometimes used in the treatment of AKI, often as continuous therapy (Box 15.38). It is increasingly favoured in the treatment of CKD but is more expensive than haemodialysis and the long-term benefits are not yet established.

424 • NEPHROLOGY AND UROLOGY Renal transplantation Renal transplantation offers the best chance of long-term survival in ESRD and is the most cost-effective treatment. All patients with ESRD should be considered for transplantation but many are not suitable due to a combination of comorbidity and advanced age (although no absolute age limit applies). Active malignancy, vasculitis, cardiovascular disease and a high risk of recurrence of renal disease (generally glomerulonephritides) are common contraindications to transplantation. Kidney grafts may be taken from a deceased donor in the UK after brain death (40%) or circulatory death (24%), or from a living donor (36%). As described on page 88, matching of a donor to a specific recipient is strongly influenced by immunological factors, since graft rejection is the major cause of transplant failure. Compatibility of ABO blood group between donor and recipient is usually required and the degree of matching for major histocompatibility (MHC) antigens, particularly human leucocyte antigen DR (HLA-DR), influences the incidence of rejection. Immediately prior to transplantation, cross-matching should be performed for anti-HLA antibodies (traditionally mixing of recipient serum with donor lymphocytes) (p. 88). Positive tests predict early rejection and worse graft survival. Although some ABO- and HLA-incompatible transplants are now possible, this involves appropriate preparation with pre-transplant plasma exchange and/or immunosuppression, so that recipient antibodies to the donor’s tissue are reduced to acceptably low levels. This option is generally only available for living donor transplants because of the preparation required. Paired exchanges, in which a donor–recipient pair who are incompatible, either in blood group or HLA, are computer-matched with another pair to overcome the mismatch, are also used to help increase the number of successful transplants that can be performed. During the transplant operation, the kidney is placed in the pelvis; the donor vessels are usually anastomosed to the recipient’s external iliac artery and vein, and the donor ureter to the bladder (see Fig. 15.25D). The native kidneys are usually left in place but may be removed pre-transplant if they are a source of repeated sepsis or to make room for a transplant in patients with very large kidneys due to adult polycystic kidney disease. Peritoneal dialysis Peritoneal dialysis is principally used in the treatment of CKD, though it may occasionally be employed in AKI. It requires the insertion of a permanent Silastic catheter into the peritoneal cavity (see Fig. 15.25C). Two types are in common use. In continuous ambulatory peritoneal dialysis (CAPD), about 2 L of sterile, isotonic dialysis fluid are introduced and left in place for approximately 4–6 hours. Metabolic waste products diffuse from peritoneal capillaries into the dialysis fluid down a concentration gradient. The fluid is then drained and fresh dialysis fluid introduced, in a continuous four-times-daily cycle. The inflow fluid is rendered hyperosmolar by the addition of glucose or glucose polymer; this results in net removal of fluid from the patient during each cycle, due to diffusion of water from the blood through the peritoneal membrane down an osmotic gradient (ultrafiltration). The patient is mobile and able to undertake normal daily activities. Automated peritoneal dialysis (APD) is similar to CAPD but uses a mechanical device to perform the fluid exchanges during the night, leaving the patient free, or with only a single exchange to perform, during the day. CAPD is particularly useful in children, as a first treatment in adults with residual renal function, and as a treatment for elderly patients with cardiovascular instability. The long-term use of peritoneal dialysis may be limited by episodes of bacterial peritonitis and damage to the peritoneal membrane, including encapsulating peritoneal sclerosis, but some patients have been treated successfully for more than 10 years. Box 15.39 summarises some of the problems related to CAPD treatment. 15.37 Problems with haemodialysis Problem Clinical features Cause Treatment During treatments Hypotension Sudden ↓BP; often leg cramps; sometimes chest pain Fluid removal and hypovolaemia Saline infusion; exclude cardiac ischaemia; quinine may help cramp Cardiac arrhythmias Hypotension; sometimes chest pain Potassium and acid–base shifts Check K+ and arterial blood gases; review dialysis prescription; stop dialysis Haemorrhage Blood loss (overt or occult); hypotension Anticoagulation Venous needle disconnection Stop dialysis; seek source; consider heparin-free treatment Air embolism Circulatory collapse; cardiac arrest Disconnected or faulty lines and equipment malfunction Stop dialysis Dialyser hypersensitivity Acute circulatory collapse Allergic reaction to dialysis membrane or sterilisant Stop dialysis; change to different artificial kidney Between treatments Pulmonary oedema Breathlessness Fluid overload Ultrafiltration ± dialysis Systemic sepsis Rigors; fever; ↓BP Usually involves vascular access devices (catheter or fistula) Blood cultures; antibiotics (BP = blood pressure) 15.38 Types of continuous renal replacement therapy (CRRT) used in AKI management* • CVVH: continuous venovenous haemofiltration • CVVHD: continuous venovenous haemodialysis • CVVHDF: continuous venovenous haemodiafiltration *Most CRRT machines may perform all of these treatments. Continuous arteriovenous treatments (i.e. continuous arteriovenous haemofiltration) have fallen out of favour.

Renal replacement therapy • 425

used initially due to impaired wound healing. Antibodies to deplete or modulate specific lymphocyte populations are increasingly used for induction and for treatment of glucocorticoid-resistant acute rejection. Basiliximab, an interleukin (IL)-2 receptor antagonist, is frequently used at induction to lower rates of rejection. Acute cellular rejection is usually treated, in the first instance, by short courses of high-dose glucocorticoids, such as intravenous methylprednisolone on three consecutive days. Anti-lymphocyte preparations (e.g. anti-thymocyte globulin, ATG) are used for glucocorticoid-resistant rejection. Antibody-mediated rejection is more difficult to treat and usually requires plasma exchange All transplant patients require regular life-long follow-up to monitor renal function and complications of immunosuppression. Allograft dysfunction is often asymptomatic and picked up during routine surveillance blood tests. The common causes at different time points post transplant are summarised in Box 15.40. Immunosuppressive therapy (see Box 4.26, p. 89) is required to prevent rejection and is more intensive in the early post-transplantation period, when rejection risk is highest. A common regimen is triple therapy with prednisolone; ciclosporin or tacrolimus; and azathioprine or mycophenolate mofetil. Sirolimus is an alternative that can be introduced later but is generally not 15.39 Problems with continuous ambulatory peritoneal dialysis Problem Clinical features Cause Treatment Peritonitis Cloudy drainage fluid; abdominal pain and systemic sepsis are variable Usually entry of skin contaminants via catheter; bowel organisms less common Culture of peritoneal dialysis fluid Intraperitoneal antibiotics, tobramycin, vancomycin Catheter removal sometimes required Catheter exit site infection Erythema and pus around exit site Usually skin organisms Antibiotics; sometimes surgical drainage Ultrafiltration failure Fluid overload Damage to peritoneal membrane, leading to rapid transport of glucose and loss of osmotic gradient Replacement of glucose with synthetic, poorly absorbed polymers for some exchanges (icodextrin) Peritoneal membrane failure Inadequate clearance of urea etc. Scarring/damage to peritoneal membrane Increase in exchange volumes; consideration of automated peritoneal dialysis or switch to haemodialysis Sclerosing peritonitis Intermittent bowel obstruction Malnutrition Unknown; typically occurs after many years Switch to haemodialysis (may still progress) Surgery and tamoxifen may be used 15.40 Common causes of renal allograft dysfunction Time post transplant Cause Risk factors Hours to days Renal artery/vein thrombosis Technically difficult surgery Thrombophilia/SLE Ureteric leak Small bladder/anuria pre-transplant Delayed graft function (i.e. transplant does not start working immediately) Prolonged cold ischaemia time* Donation after circulatory death Older, hypertensive donor with stroke as cause of death, high tacrolimus level Hyperacute rejection Pre-formed anti-HLA antibodies HLA mismatch Previous transplant Weeks Acute rejection (especially < 3 months; can occur later with non-adherence/insufficient immunosuppression) Pre-formed anti-HLA antibodies HLA mismatch Previous transplant Months BK virus nephropathy Intensive immunosuppression Ureteric stent use Renal artery stenosis Donor disease Injury at organ retrieval Years Chronic allograft injury (often antibody-mediated) Previous acute rejections Non-adherence/insufficient immunosuppression Any time Tacrolimus/ciclosporin toxicity High doses/serum levels Concurrent use of drugs that inhibit cytochrome P450 system Sepsis (opportunistic and conventional) Recurrence of disease: Early (FSGS/MCGN) Later (IgA nephropathy/membranous glomerulonephritis) Primary FSGS and MCGN Previous transplant recurrence *Time from organ retrieval in the donor, with cold perfusion occurring ex vivo, until implantation into the recipient. (FSGS = focal segmental glomerulosclerosis; HLA = human leucocyte antigen; IgA = immunoglobulin A; MCGN = mesangiocapillary glomerulonephritis; SLE = systemic lupus erythematosus)

426 • NEPHROLOGY AND UROLOGY drugs and their metabolites. Some may reach high concentrations in the renal cortex as a result of proximal tubular transport mechanisms. Others are concentrated in the medulla by the operation of the countercurrent system. The same applies to certain toxins. Toxic renal damage may occur by a variety of mechanisms (Box 15.43). Very commonly, drugs contribute to the development of acute tubular necrosis as one of multiple insults. Numerically, reactions to NSAIDs and ACE inhibitors are the most important. Haemodynamic renal impairment, acute tubular necrosis and allergic reactions are usually reversible if recognised early enough. Other types, however, especially those associated with extensive fibrosis, are less likely to be reversible. Non-steroidal anti-inflammatory drugs Impairment of renal function may develop in patients on NSAIDs, since prostaglandins play an important role in regulating renal blood flow by vasodilating afferent arterioles (see Fig. 15.19, p. 413). This is particularly likely in patients with other disorders, such as volume depletion, heart failure, cirrhosis, sepsis and pre-existing renal impairment. In addition, idiosyncratic immune reactions may occur, causing minimal change nephrotic syndrome, membranous nephropathy (p. 400) and acute interstitial nephritis (p. 402). Analgesic nephropathy (p. 403) is now a rare complication of long-term use. ACE inhibitors These abolish the compensatory angiotensin II-mediated vasoconstriction of the glomerular efferent arteriole that takes place in order to maintain glomerular perfusion pressure distal to a renal artery stenosis and in renal hypoperfusion (see Figs 15.1 and 15.19, pp. 385 and 413). Monitoring of renal function before and after initiation of therapy is essential and an expected rise in creatinine of about 20% is frequently observed. Prescribing in renal disease Many drugs and drug metabolites are excreted by the kidney and so the presence of renal impairment alters the required dose and frequency (p. 31). Infections of the urinary tract In health, bacterial colonisation is confined to the lower end of the urethra and the remainder of the urinary tract is sterile (see Ch. 6). The urinary tract can become infected with various bacteria but the most common is E. coli derived from the gastrointestinal tract. The most common presenting problem is cystitis with urethritis (generally referred to as urinary tract infection). Urinary tract infection Urinary tract infection (UTI) is the term used to describe acute urethritis and cystitis caused by a microorganism. It is a common disorder, accounting for 1–3% of consultations in general medical practice. The prevalence of UTI in women is about 3% at the age of 20, increasing by about 1% in each subsequent decade. In males, UTI is uncommon, except in the first year of life and in men over 60, when it may complicate bladder outflow obstruction. and intravenous immunoglobulin (p. 89). Complications of immunosuppression include infections and malignancy (p. 89). Approximately 50% of white patients develop skin malignancy by 15 years after transplantation. The prognosis after kidney transplantation is good. Recent UK statistics for transplants from cadaver donors indicate 96% patient survival and 93% graft survival at 1 year, and 88% patient survival and 84% graft survival at 5 years. Even better figures are obtained with living donor transplantation (91% graft survival at 5 years). Renal disease in pregnancy Pregnancy has important physiological effects on the renal system. Some diseases are more common in pregnancy (Box 15.41), the manifestations of others are modified during pregnancy, and a few diseases, such as pre-eclampsia (see Box 30.8, p. 1276), are unique to pregnancy. These are discussed in detail in Chapter 30. 15.41 Renal diseases in pregnancy • Eclampsia: severe hypertension, encephalopathy and fits • Disseminated intravascular coagulation • Thrombotic microangiopathy: may also occur post-partum (post-partum thrombotic thrombocytopenic purpura/haemolytic uraemic syndrome) • Acute fatty liver of pregnancy • ‘HELLP’ syndrome: haemolysis, elevated liver enzymes, low platelets (thrombotic microangiopathy with abnormal liver function) 15.42 Kidney disease in adolescence • Adherence: young adults moving from parental supervision may become disengaged. There may also be reduced adherence to prophylactic and therapeutic treatment. • Adverse events: there is an increased risk of transplant loss and other adverse events in young adults on renal replacement therapy. • Management: joint transition clinics should be established with the paediatric team to facilitate transfer to adult specialist clinics. Renal disease in adolescence Many causes of renal failure present during infancy or childhood, such as congenital urological malformations and inherited disorders like cystinosis and autosomal recessive polycystic kidney disease. The consequences continue throughout the patient’s life and the situation often arises whereby patients transition from paediatric to adult nephrology services. Some of the issues and challenges surrounding this transition are summarised in Box 15.42. Drugs and the kidney Drug-induced renal disease The kidney is susceptible to damage by drugs because it is the route of excretion of many water-soluble compounds, including

Infections of the urinary tract • 427

15.43 Mechanisms and examples of drug-induced renal disease/dysfunction Mechanism Drug or toxin Comments Haemodynamic NSAIDs Reduce renal blood flow due to inhibition of prostaglandin synthesis causing afferent arteriolar vasoconstriction ACE inhibitors Reduce efferent glomerular arteriolar tone, so especially problematic in the presence of renal artery stenosis and other causes of renal hypoperfusion (e.g. NSAIDs) Radiographic contrast media Multifactorial aetiology may include intense vasoconstriction Acute tubular necrosis Aminoglycosides, amphotericin In most examples there is evidence of direct tubular toxicity but haemodynamic and other factors probably contribute Paracetamol overdose May occur with or without serious hepatotoxicity Radiographic contrast media Directly toxic to proximal tubular cells Loss of tubular/collecting duct function Lithium Cisplatin Aminoglycosides, amphotericin Dose-related, partially reversible loss of concentrating ability Occurs at lower exposures than cause acute tubular necrosis Glomerulonephritis (immune-mediated) Penicillamine, gold Membranous nephropathy Penicillamine, propylthiouracil, hydralazine Crescentic or focal necrotising glomerulonephritis in association with ANCA and systemic small-vessel vasculitis NSAIDs Minimal change nephropathy, membranous nephropathy Interstitial nephritis (immune-mediated) NSAIDs, penicillins, proton pump inhibitors, many others Acute interstitial nephritis Interstitial nephritis (toxicity) Lithium As a consequence of acute toxicity Chronic interstitial nephritis Ciclosporin, tacrolimus Interstitial nephritis (with papillary necrosis) Various NSAIDs (p. 403) Ischaemic damage secondary to NSAID effects on renal blood flow Tubular obstruction (crystal formation) Aciclovir Crystals of the drug form in tubules Aciclovir is now more common than the original example of sulphonamides Chemotherapy Uric acid crystals form as a consequence of tumour lysis (typically, a first-dose effect in haematological malignancy) Nephrocalcinosis Oral sodium phosphate-containing bowel cleansing agents Precipitation of calcium phosphate occurring in 1–4% and exacerbated by volume depletion Usually mild but damage can be irreversible Retroperitoneal fibrosis Ergolinic dopamine agonists (cabergoline), methysergide*, practolol* Idiopathic retroperitoneal fibrosis is more common (p. 434) *These drugs are no longer in use in the UK. (ACE = angiotensin-converting enzyme; ANCA = antineutrophil cytoplasmic antibody; NSAIDs = non-steroidal anti-inflammatory drugs) Pathophysiology Urine is an excellent culture medium for bacteria; in addition, the urothelium of susceptible persons may have more receptors, to which virulent strains of E. coli become adherent. In women, the ascent of organisms into the bladder is easier than in men; the urethra is shorter and the absence of bactericidal prostatic secretions may be relevant. Sexual intercourse may cause minor urethral trauma and transfer bacteria from the perineum into the bladder. Instrumentation of the bladder may also introduce organisms. Multiplication of organisms then depends on a number of factors, including the size of the inoculum and virulence of the bacteria. Conditions that predispose to UTI are shown in Box 15.44. Clinical features Typical features of cystitis and urethritis include: • abrupt onset of frequency of micturition and urgency • burning pain in the urethra during micturition (dysuria) • suprapubic pain during and after voiding • intense desire to pass more urine after micturition, due to spasm of the inflamed bladder wall (strangury) • urine that may appear cloudy and have an unpleasant odour • non-visible or visible haematuria. Systemic symptoms are usually slight or absent. However, infection in the lower urinary tract can spread to cause acute pyelonephritis. This is suggested by prominent systemic symptoms with fever, rigors, vomiting, hypotension and loin pain, guarding or tenderness, and may be an indication for hospitalisation. Only about 30% of patients with acute pyelonephritis have associated symptoms of cystitis or urethritis. Prostatitis is suggested by perineal or suprapubic pain, pain on ejaculation and prostatic tenderness on rectal examination. The differential diagnosis of lower urinary tract symptoms includes urethritis due to sexually transmitted disease, notably chlamydia (p. 340) and urethritis associated with reactive arthritis (p. 1031). Some patients, usually female, have symptoms suggestive of urethritis and cystitis but no bacteria are cultured from the urine (the ‘urethral syndrome’). Possible explanations include infection with organisms not readily cultured by ordinary

428 • NEPHROLOGY AND UROLOGY of typical clinical features and abnormalities on urinalysis. Most urinary pathogens can reduce nitrate to nitrite, and neutrophils and nitrites can usually be detected in symptomatic infections by urine dipstick tests for leucocyte esterase and nitrite, respectively. The absence of both nitrites and leucocyte esterase in the urine makes UTI unlikely. Interpretation of bacterial counts in the urine, and of what is a ‘significant’ culture result, is based on probabilities. Urine taken by suprapubic aspiration should be sterile, so the presence of any organisms is significant. If the patient has symptoms and there are neutrophils in the urine, a small number of organisms is significant. In asymptomatic patients, more than 105 organisms/mL is usually regarded as significant (asymptomatic bacteriuria; see below). Typical organisms causing UTI in the community include E. coli derived from the gastrointestinal tract (about 75% of infections), Proteus spp., Pseudomonas spp., streptococci and Staphylococcus epidermidis. In hospital, E. coli still predominates but Klebsiella and streptococci are becoming more common. Certain strains of E. coli have a particular propensity to invade the urinary tract. Investigations to detect underlying predisposing factors for UTI are used selectively, most commonly in children, men or patients with recurrent infections (see Box 15.45). Management Antibiotics are recommended in all cases of proven UTI (Box 15.47). If urine culture has been performed, treatment may be started while awaiting the result. For infection of the lower urinary tract, treatment for 3 days is the norm and is less likely to induce significant alterations in bowel flora than more prolonged therapy. Trimethoprim or nitrofurantoin is the usual first choice of drug for initial treatment; however, between 10% and 40% of organisms causing UTI are resistant to trimethoprim, the lower rates being seen in community-based practice. Trimethoprim and nitrofurantoin are not recommended if eGFR is <30 mL/ min/1.73m2 due to reduced efficacy/increased risk of toxicity. In addition, trimethoprim may increase serum potassium and creatinine levels and lead to artefactual reductions in eGFR, which resolve once the drug is discontinued. Quinolone antibiotics such as ciprofloxacin and norfloxacin, and cefalexin are also generally effective. Co-amoxiclav and amoxicillin are no longer recommended as blind therapy, as up to 30% of organisms are resistant. They may be used once cultures confirm that the organism is sensitive. Penicillins and cephalosporins are safe to use in pregnancy but trimethoprim, sulphonamides, quinolones and tetracyclines should be avoided. methods (such as Chlamydia and certain anaerobes), intermittent or low-count bacteriuria, reaction to toiletries or disinfectants, symptoms related to sexual intercourse, or post-menopausal atrophic vaginitis. The differential diagnosis of acute pyelonephritis includes pyelonephrosis, acute appendicitis, diverticulitis, cholecystitis, salpingitis, ruptured ovarian cyst or ectopic pregnancy. In pyelonephrosis due to upper urinary tract obstruction, patients may become extremely ill, with fever, leucocytosis and positive blood cultures. With a perinephric abscess, there is marked pain and tenderness, and often bulging of the loin on the affected side. Urinary symptoms may be absent in this situation and urine testing negative, containing neither pus cells nor organisms. Investigations An approach to investigation is shown in Box 15.45. In an otherwise healthy woman with a single lower urinary tract infection, urine culture prior to treatment is not mandatory. Investigation is necessary, however, in patients with recurrent infection or after failure of initial treatment, during pregnancy, or in patients susceptible to serious infection, such as the immunocompromised, those with diabetes or an indwelling catheter, and older people (Box 15.46). The diagnosis can be made from the combination 15.44 Risk factors for urinary tract infection Bladder outflow obstruction • Benign prostatic enlargement • Prostate cancer • Urethral stricture Anatomical abnormalities • Vesico-ureteric reflux • Uterine prolapse • Bladder fistula Neurological problems • Multiple sclerosis • Spina bifida • Diabetic neuropathy Foreign bodies • Urethral suprapubic catheter • Ureteric stent • Nephrostomy tube • Urolithiasis Loss of host defences • Atrophic urethritis and vaginitis in post-menopausal women • Diabetes mellitus 15.45 Investigation of patients with urinary tract infection All patients • Dipstick* estimation of nitrite, leucocyte esterase and glucose • Microscopy/cytometry of urine for white blood cells, organisms • Urine culture Infants, children, and anyone with fever or complicated infection • Full blood count; urea, electrolytes, creatinine • Blood cultures Pyelonephritis: men; children; women with recurrent infections • Renal tract ultrasound or CT • Pelvic examination in women, rectal examination in men Continuing haematuria or other suspicion of bladder lesion • Cystoscopy *May substitute for microscopy and culture in simple uncomplicated infection. 15.46 Urinary infection in old age • Prevalence of asymptomatic bacteriuria: rises with age. Among the most frail in institutional care it rises to 40% in women and 30% in men. • Decision to treat: treating asymptomatic bacteriuria does not improve chronic incontinence or decrease mortality or morbidity from symptomatic urinary infection. It risks adverse effects from the antibiotic and promotion of the emergence of resistant organisms. Bacteriuria should not be treated in the absence of urinary symptoms. • Source of infection: the urinary tract is the most frequent source of bacteraemia in older patients admitted to hospital. • Incontinence: new or increased incontinence is a common presentation of UTI in older women. • Treatment: post-menopausal women with acute lower urinary tract symptoms may require longer than 3 days’ therapy.

Infections of the urinary tract • 429

} Scenario Drug Regimen Duration Comment Cystitis First choices Trimethoprim 200 mg twice daily 3 days 7–10 days in men Second choices1 Nitrofurantoin 50 mg 4 times daily Cefalexin 250 mg 4 times daily Ciprofloxacin 250 mg twice daily Pivmecillinam 400 mg 3 times daily In pregnancy Nitrofurantoin 50 mg 4 times daily 7 days Avoid trimethoprim and quinolones during pregnancy; avoid nitrofurantoin at term Cefalexin 250 mg 4 times daily Prophylactic therapy First choice Trimethoprim 100 mg at night Continuous Second choice1 Nitrofurantoin 50 mg at night Pyelonephritis First choice Cefalexin 1 g 4 times daily 14 days Admit to hospital if no response within 24 hrs Ciprofloxacin 500 mg twice daily 7 days Second choice Gentamicin2 Adjust dose according to renal function and serum levels 14 days Switch to appropriate oral agent as soon as possible Cefuroxime 750–1500 mg 3 times daily Epididymo-orchitis First choice Ciprofloxacin 500 mg twice daily 14 days Refer young men to genito-urinary department to check for Neisseria gonorrhoeae, which requires addition of a single dose of ceftriaxone 500 mg IM Young men Doxycycline 100 mg twice daily Older men Ciprofloxacin 500 mg twice daily Acute prostatitis First choice Trimethoprim 200 mg twice daily 28 days Second choice Ciprofloxacin 500 mg twice daily } 15.47 Antibiotic regimens for urinary tract infection in adults1 1In all cases, the choice of drug should take locally determined antibiotic resistance patterns into account. 2See Hartford nomogram (Fig. 6.18, p. 122). (IM = intramuscular) In more severe infection, antibiotics should be continued for 7–14 days. Seriously ill patients may require intravenous therapy with gentamicin for a few days (Box 15.47), later switching to an oral agent. A fluid intake of at least 2 L/day is usually recommended, although this is not based on evidence and may make symptoms of dysuria worse. Persistent or recurrent UTI If the causative organism persists on repeat culture despite treatment, or if there is reinfection with any organism after an interval, then an underlying cause is more likely to be present (see Box 15.44) and more detailed investigation is justified (see Box 15.45). In women, recurrent infections are common and investigation is justified only if infections are frequent (three or more per year) or unusually severe. Recurrent UTI, particularly in the presence of an underlying cause, may result in permanent renal damage, whereas uncomplicated infections rarely (if ever) do so (see chronic reflux nephropathy, p. 430). If an underlying cause cannot be treated, suppressive antibiotic therapy (see Box 15.47) can be used to prevent recurrence and reduce the risk of sepsis and renal damage. Urine should be cultured at regular intervals; a regimen of two or three antibiotics in sequence, rotating every 6 months, is often used in an attempt to reduce the emergence of resistant organisms. Other simple measures may help to prevent recurrence (Box 15.48). Trimethoprim or nitrofurantion is recommended for prophylaxis. Alternative antibiotics include cefalexin, co-amoxiclav and ciprofloxacin, but these should be avoided if possible because of adverse effects and the generation of resistance. Asymptomatic bacteriuria This is defined as more than 105 organisms/mL in the urine of apparently healthy asymptomatic patients. Approximately 1% of children under the age of 1 year, 1% of schoolgirls, 0.03% of schoolboys and men, 3% of non-pregnant adult women and 5% of pregnant women have asymptomatic bacteriuria. It is increasingly common in those aged over 65. There is no evidence that this condition causes renal scarring in adults who are not pregnant and have a normal urinary tract, and, in general, treatment is not indicated. Up to 30% will develop symptomatic infection within 1 year, however. Treatment is required in infants, pregnant women and those with urinary tract abnormalities. Catheter-related bacteriuria In patients with a urinary catheter, bacteriuria increases the risk of Gram-negative bacteraemia five-fold. Bacteriuria is common, 15.48 Prophylactic measures to be adopted by women with recurrent urinary infections • Fluid intake of at least 2 L/day • Regular complete emptying of bladder • Good personal hygiene • Emptying of bladder before and after sexual intercourse • Cranberry juice/tablets may be effective

430 • NEPHROLOGY AND UROLOGY however, and almost universal during long-term catheterisation. Treatment is usually avoided in asymptomatic patients, as this may promote antibiotic resistance. Careful sterile insertion technique is important and the catheter should be removed as soon as it is not required. Acute pyelonephritis The kidneys are infected in a minority of patients with UTI. Acute renal infection (pyelonephritis) presents as a classic triad of loin pain, fever and tenderness over the kidneys. The renal pelvis is inflamed and small abscesses are often evident in the renal parenchyma (see Fig. 15.13C, p. 402). Renal infection is almost always caused by organisms ascending from the bladder, and the bacterial profile is the same as for lower urinary tract infection (p. 428). Rarely, bacteraemia may give rise to renal or perinephric abscesses, most commonly due to staphylococci. Predisposing factors, such as cysts or renal scarring, facilitate infection. Rarely, acute pyelonephritis is associated with papillary necrosis. Fragments of renal papillary tissue are passed per urethra and can be identified histologically. They may cause ureteric obstruction and, if this occurs bilaterally or in a single kidney, it may lead to AKI. Predisposing factors include diabetes mellitus, chronic urinary obstruction, analgesic nephropathy and sickle-cell disease. A necrotising form of pyelonephritis with gas formation, ‘emphysematous pyelonephritis’, is occasionally seen in patients with diabetes mellitus. Xanthogranulomatous pyelonephritis is a chronic infection that can resemble renal cell cancer. It is usually associated with obstruction, is characterised by accumulation of foamy macrophages and generally requires nephrectomy. Infection of cysts in polycystic kidney disease (p. 405) calls for prolonged antibiotic treatment. Appropriate investigations are shown in Box 15.45 and management is described above and in Box 15.47. Intravenous rehydration may be needed in severe cases. If complicated infection is suspected or response to treatment is not prompt, urine should be re-cultured and renal tract ultrasound performed to exclude urinary tract obstruction or a perinephric collection. If obstruction is present, drainage by a percutaneous nephrostomy or ureteric stent should be considered. Tuberculosis Tuberculosis of the kidney and renal tract is secondary to tuberculosis elsewhere (p. 588) and is the result of blood-borne infection. Initially, lesions develop in the renal cortex; these may ulcerate into the renal pelvis and involve the ureters, bladder, epididymis, seminal vesicles and prostate. Calcification in the kidney and stricture formation in the ureter are typical. Clinical features may include symptoms of bladder involvement (frequency, dysuria); haematuria (sometimes macroscopic); malaise, fever, night sweats, lassitude and weight loss; loin pain; associated genital disease; and chronic renal failure as a result of urinary tract obstruction or destruction of kidney tissue. Neutrophils are present in the urine but routine urine culture may be negative (‘sterile pyuria’). Special techniques of microscopy and culture may be required to identify tubercle bacilli and are most usefully performed on early morning urine specimens. Bladder involvement should be assessed by cystoscopy. Radiology of the urinary tract and a chest X-ray to look for pulmonary tuberculosis are mandatory. Anti-tuberculous chemotherapy follows standard regimens (p. 592). Surgery to relieve urinary tract obstruction or to remove a very severely infected kidney may be required. Reflux nephropathy This condition, which was previously known as chronic pyelonephritis, is a specific type of chronic interstitial nephritis associated with vesico-ureteric reflux (VUR) in early life and with the appearance of scars in the kidney, as demonstrated by various imaging techniques. About 12% of patients in Europe requiring treatment for ESRD may have this disorder but diagnostic criteria are imprecise. Pathophysiology Reflux nephropathy is thought to be due to chronic reflux of urine from the bladder into the ureters, in association with recurrent UTI in childhood. It was previously assumed that ascending infection was necessary for progressive renal damage in patients with VUR but there is evidence to suggest that renal scars can occur, even in the absence of infection. Furthermore, epidemiological surveys and controlled trials have found that efforts to correct VUR by using surgical or other means are ineffective in halting progression of the disease. Susceptibility to VUR has a genetic component and may be associated with renal dysplasia and other congenital abnormalities of the urinary tract. It can be connected with outflow obstruction, usually caused by urethral valves, but usually occurs with an apparently normal bladder. Clinical features Usually, the renal scarring and dilatation are asymptomatic and the patient may present at any age with hypertension (sometimes severe), proteinuria or features of CKD. There may be no history of overt UTI. However, symptoms arising from the urinary tract may be present and include frequency of micturition, dysuria and aching lumbar pain. VUR may occur in children but diminishes as the child grows, and usually has disappeared by adulthood. Urinalysis often shows the presence of leucocytes and moderate proteinuria (usually < 1 g/24 hrs) but these are not invariable. The risk of renal stone formation is increased. A number of women first present with hypertension and/or proteinuria in pregnancy. Children and adults with small or unilateral renal scars have a good prognosis, provided renal growth is normal. With significant unilateral scars there is usually compensatory hypertrophy of the contralateral kidney. In patients with more severe bilateral disease, prognosis is related to the severity of renal dysfunction, hypertension and proteinuria. If the serum creatinine is normal and hypertension and proteinuria are absent, then the long-term prognosis is usually good. Investigations Renal scarring can be detected by ultrasound but it has poor sensitivity and is only capable of detecting major defects and excluding significant obstruction. Radionuclide DMSA scans are more sensitive (see Fig. 15.6, p. 390), and serial imaging by MRI or CT may be useful in assessing progression. Abnormalities may be unilateral or bilateral and of any grade of severity. Gross scarring of the kidneys, commonly at the poles, is seen, with reduced kidney size and narrowing of the cortex and medulla. Renal scars may be juxtaposed to dilated calyces. In patients who develop heavy proteinuria and hypertension, renal biopsies show glomerulomegaly and focal glomerulosclerosis, probably as a secondary response to reduced nephron numbers. Radionuclide

Urolithiasis • 431

proteins and glycoproteins. The most common types are summarised in Box 15.49. A number of risk factors have been identified for renal stone formation (Box 15.50). In developed countries, however, most calculi occur in healthy young men, in whom investigations reveal no clear predisposing cause. Renal stones vary greatly in size, from sand-like particles anywhere in the urinary tract to large, round stones in the bladder. In developing countries, bladder stones are common, particularly in children. In developed countries, the incidence of childhood bladder stones is low; renal stones in adults are more common. Staghorn calculi fill the whole renal pelvis and branch into the calyces (Fig. 15.29); they are usually associated with infection and composed largely of struvite. Deposits of calcium may be present throughout the renal parenchyma, giving rise to fine calcification within it (nephrocalcinosis), especially in patients with renal tubular acidosis, hyperparathyroidism, vitamin D intoxication and healed renal tuberculosis. Cortical nephrocalcinosis may occur in areas of cortical necrosis, typically after AKI in pregnancy or other severe AKI. Clinical features The clinical presentation is highly variable. Many patients with renal stone disease are asymptomatic, whereas others present with pain, haematuria, UTI or urinary tract obstruction. A common presentation is with acute loin pain radiating to the anterior techniques can also be used to demonstrate VUR as a noninvasive alternative to micturating cystourethrography (MCUG; the bladder is filled with contrast media through a urinary catheter and images are taken during and after micturition; Fig. 15.28). As surgical intervention for VUR has declined in popularity (see below), however, this type of imaging is used less often. Management Infection, if present, should be treated; if recurrent, it should be prevented with prophylactic therapy, as described for UTI (p. 429). If recurrent pyelonephritis occurs in an abnormal kidney with minimal function, nephrectomy may be indicated. Occasionally, hypertension is cured by the removal of a diseased kidney when the disease is predominantly or entirely unilateral. As most childhood reflux tends to disappear spontaneously and trials have shown small or no benefits from anti-reflux surgery, such intervention is now less common. Severe reflux may be managed by ureteric reimplantation or subtrigonal injection of Teflon or polysaccharide (STING) beneath the ureteric orifice. Urolithiasis Renal stone disease is common, affecting people of all countries and ethnic groups. In the UK, the prevalence is about 1.2%, with a lifetime risk of developing a renal stone by age 60–70 of approximately 7% in men. In some regions, the risk is higher, most notably in countries such as Saudi Arabia, where the lifetime risk of developing a renal stone in men aged 60–70 is just over 20%. Pathophysiology Urinary calculi consist of aggregates of crystals, usually containing calcium or phosphate in combination with small amounts of Fig. 15.28 Vesico-ureteric reflux (grade IV) shown by micturating cystogram. The bladder has been filled with contrast medium through a urinary catheter. After micturition, there was gross vesico-ureteric reflux into widely distended ureters and pelvicalyceal systems. Courtesy of Dr A.P. Bayliss and Dr P. Thorpe, Aberdeen Royal Infirmary. 15.49 Composition of renal stones Composition Percentage Calcium oxalate1 60% Calcium phosphate 15% Uric acid 10% Magnesium ammonium phosphate (struvite)2 15% Cystine and others 1% 1Stones often contain small amounts of calcium phosphate. 2Associated with urine infection. 15.50 Predisposing factors for kidney stones Environmental and dietary causes • Low urine volumes: high ambient temperatures, low fluid intake • Diet: high protein, high sodium, low calcium • High sodium excretion • High oxalate excretion • High urate excretion • Low citrate excretion Acquired causes • Hypercalcaemia of any cause (p. 661) • Ileal disease or resection (increases oxalate absorption and urinary excretion) • Renal tubular acidosis type I (distal, p. 365) Congenital and inherited causes • Familial hypercalciuria • Medullary sponge kidney • Cystinuria • Renal tubular acidosis type I (distal) • Primary hyperoxaluria

432 • NEPHROLOGY AND UROLOGY Fig. 15.29 Computed tomogram of the kidneys, ureters and bladder (CTKUB): coronal view showing a staghorn calculus in the left kidney. Courtesy of Dr I. Mendichovszky, University of Cambridge. 15.51 Investigations for renal stones Sample Test First stone Recurrent stone Stone Chemical composition1 ᅚ Blood Calcium ᅚ ᅚ Phosphate ᅚ ᅚ Uric acid ᅚ ᅚ Urea and electrolytes ᅚ ᅚ Bicarbonate ᅚ ᅚ Parathyroid hormone2 (ᅚ) Urine Dipstick test for protein, blood, glucose ᅚ ᅚ Amino acids ᅚ 24-hr urine Urea ᅚ Creatinine clearance ᅚ Sodium ᅚ Calcium ᅚ Oxalate ᅚ Uric acid ᅚ 1The most valuable test if a stone can be obtained. 2Only if serum calcium or urinary calcium excretion is high. abdominal wall, together with haematuria: a symptom complex termed renal or ureteric colic. This is most commonly caused by ureteric obstruction by a calculus but the same symptoms can occur in association with a sloughed renal papilla, tumour or blood clot. The patient is suddenly aware of pain in the loin, which radiates round the flank to the groin and often into the testis or labium, in the sensory distribution of the first lumbar nerve. The pain steadily increases in intensity to reach a peak in a few minutes. The patient is restless and generally tries unsuccessfully to obtain relief by changing position or pacing the room. There is pallor, sweating and often vomiting. Frequency, dysuria and haematuria may occur. The intense pain usually subsides within 2 hours but may continue unabated for hours or days. It is usually constant during attacks, although slight fluctuations in severity may be seen. Subsequent to an attack of renal colic, intermittent dull pain in the loin or back may persist for several hours. Investigations Patients with symptoms of renal colic should be investigated to determine whether or not a stone is present, to identify its location and to assess whether it is causing obstruction. About 90% of stones contain calcium and these can be visualised on plain abdominal X-ray (radio-opaque stones) but non-contrast CTKUB (Fig. 15.29) is the gold standard for diagnosing a stone within the kidney or ureter, as 99% are visible using this method. Ultrasound can show stones within the kidney and dilatation of the renal pelvis and ureter if the stone is obstructing urine flow; it is useful in unstable patients or young women, in whom exposure to ionising radiation is undesirable. A minimum set of investigations (Box 15.51) should be performed in patients with a first renal stone. The yield of more detailed investigation is low, and hence usually reserved for young patients, those with recurrent or multiple stones, or those with complicated or unexpected presentations. Chemical analysis of stones is often helpful in defining the underlying cause. Since most stones pass spontaneously through the urinary tract, ideally the urine should be sieved for a few days after an episode of colic in order to collect the calculus for analysis. Management The immediate treatment of renal colic is with analgesia and antiemetics. Renal colic is often unbearably painful and demands powerful analgesia; diclofenac orally or as a suppository (100 mg) is often very effective, followed by morphine (10–20 mg) or pethidine (100 mg) intramuscularly. Around 90% of stones of less than 4 mm diameter pass spontaneously, but this applies to only 10% of stones bigger than 6 mm, and these may require intervention (see below). Patients with renal or ureteric stones are at high risk of infection; if surgery is contemplated, the patient should be covered with appropriate antibiotics. Immediate action is required if infection occurs in the stagnant urine proximal to the stone (pyonephrosis), and in patients with a solitary kidney who develop anuria in association with a stone in the ureter. Stones that do not pass spontaneously through the urinary tract may need to be removed surgically, using ureteroscopy and stone fragmentation usually with a laser, or percutaneous nephrolithotomy (PCNL) and fragmentation with an ultrasonic disaggregator. Alternatively, stones can be fragmented by extracorporeal shock wave lithotripsy (ESWL), in which shock waves generated outside the body are focused on the stone, breaking it into small pieces that can pass easily down the ureter. The indications for intervention to manage or remove stones from the renal tract are summarised in Box 15.52. Procedures vary, depending on the site (Fig. 15.30). Measures to prevent further stone formation are guided by the investigations in Box 15.51. Some general principles apply to almost every patient with calcium-containing stones (Box 15.53). More specific measures apply to some types. Urate stones can be prevented by allopurinol but its role in patients with calcium

Diseases of the collecting system and ureters • 433

stones and high urate excretion is uncertain. Stones formed in cystinuria can be reduced by penicillamine therapy. It may also be helpful to attempt to alkalinise the urine with sodium bicarbonate, as a high pH discourages urate and cystine stone formation. Diseases of the collecting system and ureters Congenital abnormalities Various congenital anomalies of the urinary tract can occur (Fig. 15.31); they affect more than 10% of infants. If not immediately lethal, they can lead to complications in later life, including obstructive nephropathy and CKD. Single kidneys About 1 in 500 infants is born with only one kidney. Although this is usually compatible with normal life, it may be associated with other abnormalities. Medullary sponge kidney disease Medullary sponge kidney is a congenital disorder characterised by malformation of the papillary collecting ducts in the pericalyceal region of the renal pyramids. This leads to the formation of microscopic and large medullary cysts. Patients often present as adults with renal stones but the prognosis is generally good. The diagnosis is made by ultrasound, CT or intravenous urography, where contrast medium is seen to fill dilated or cystic tubules, which are sometimes calcified. Fig. 15.30 Options for removal of urinary stones. A A patient undergoing extracorporeal shock wave lithotripsy (ESWL). B The procedures that are used for removal of stones in the urinary tract, shown in relation to the site of the stone. (PCNL = percutaneous nephrolithotomy) A B Renal pelvis or kidney ESWL PCNL Ureteroscopy Upper ureter ESWL Ureteroscopy Bladder Cystoscopic removal or destruction Percutaneous endoscopic removal or destruction Open surgery removal or destruction Lower ureter ESWL Ureteroscopy 15.52 Indications for intervention to manage and remove stones from the urinary tract Clinical presentation Procedure Obstruction and/or anuria Emergency nephrostomy or stent Pyonephrosis associated with stone Emergency nephrostomy or stent Stone in a patient with solitary kidney Urgent PCNL, stent, ESWL or ureteroscopy* Severe pain and persistence of stone in renal tract Urgent PCNL, stent, ESWL or ureteroscopy* Pain and persistence of stone in renal tract Elective PCNL, ESWL or ureteroscopy* *Procedure depends on site of stone; see Fig. 15.30. (ESWL = extracorporeal shock wave lithotripsy; PCNL = percutaneous nephrolithotomy) 15.53 Measures to prevent calcium stone formation Diet Fluid • At least 2 L output per day (intake 3–4 L): check with 24-hr urine collections • Intake distributed throughout the day (especially before bed) Sodium • Restrict intake Protein • Moderate, not high Calcium • Maintain good calcium intake (calcium forms an insoluble salt with dietary oxalate, lowering oxalate absorption and excretion) • Avoid calcium supplements separate from meals (increase calcium excretion without reducing oxalate excretion) Oxalate • Avoid foods that are rich in oxalate (spinach, rhubarb) Drugs Thiazide diuretics • Reduce calcium excretion • Valuable in recurrent stone-formers and hypercalciuria Allopurinol • If urate excretion high (unproven except for urate stones) Avoid • Vitamin D supplements (increase calcium absorption and excretion) • Vitamin C supplementation (increases oxalate excretion)

434 • NEPHROLOGY AND UROLOGY Pelvi-ureteric junction obstruction Pelvi-ureteric junction obstruction (PUJO) causes idiopathic hydronephrosis and results from a functional obstruction at the junction of the ureter and renal pelvis. The abnormality is likely to be congenital and is often bilateral. It can be seen in very young children but gross hydronephrosis may present at any age. The common presentation is ill-defined renal pain or ache, exacerbated by drinking large volumes of liquid (Dietl’s crisis). Rarely, it is asymptomatic. The diagnosis is often suspected after ultrasound or CT scan, and can be confirmed with a 99mTc-MAG3 renogram followed by diuretic. In a PUJO, the MAG3 renogram shows a pathognomonic ‘rising curve’ as the radioisotope accumulates in the renal pelvis and still does not drain following the diuretic injection. Treatment is surgical excision of the pelvi-ureteric junction and reanastomosis (pyeloplasty), which can now be performed laparoscopically. Less invasive alternatives are also possible, including balloon dilatation and endoscopic pyelotomy, but are generally less effective. Retroperitoneal fibrosis Fibrosis of the retroperitoneal connective tissues may encircle and compress the ureter(s), causing obstruction. The fibrosis is most commonly idiopathic but can represent a reaction to infection, radiation or aortic aneurysm, or be caused by metastatic cancer. It is recognised as part of the spectrum of disorders associated with elevated IgG4 levels (p. 890). Rarely, it can be associated with inflammatory bowel disease. Patients usually present with ill-defined symptoms of ureteric obstruction. Typically, there is an acute phase response (high CRP and ESR, and polyclonal hypergammaglobulinaemia). Imaging with CT or IVU shows ureteric obstruction with medial deviation of the ureters. Idiopathic retroperitoneal fibrosis may respond well to glucocorticoids (with a reduction in inflammatory marker levels) but ureteric stenting is often necessary to relieve obstruction and preserve renal function. Failure to improve indicates the need for surgery (ureterolysis), both to relieve obstruction and to exclude malignancy. Tumours of the kidney and urinary tract Several malignant tumours can affect the kidney and urinary tract, including renal cell cancer, upper urinary tract urothelial cancers, bladder carcinoma, prostate carcinoma, and cancers of the testis and penis. The urogenital tract can also be affected by benign tumours and secondary tumour deposits, which can cause obstructive uropathy. Renal cell cancer and bladder carcinoma are described here, while prostate cancer (p. 438) and testicular tumours (p. 439) are covered later in this chapter. Renal cell cancer Renal cell cancer (RCC) is by far the most common malignant tumour of the kidney in adults, making up 2.5% of all adult cancers, with a prevalence of 16 cases per 100 000 population. It is twice as common in males. The peak incidence is between 65 and 75 years of age and it is uncommon before 40. The tumour arises from renal tubular cells. Haemorrhage and necrosis give the cut surface a characteristic mixed golden-yellow and red appearance (Fig. 15.32B). Microscopically, clear cell RCCs are the most common histological subtype (85%), with papillary, Fig. 15.31 Congenital abnormalities of the urinary tract. (PUJ = pelvi-ureteric junction) Renal agenesis/ dysplasia Ectopic kidney Single kidney PUJ obstruction Horseshoe kidney Duplex ureter Ectopic ureter Megaureter Ureterocele Urethral valves Vesico-ureteric reflux Ureterocele A ureterocele occurs behind a pin-hole ureteric orifice when the intramural part of the ureter dilates and bulges into the bladder. It can become very large and cause lower urinary tract obstruction. Incision of the pin-hole opening relieves the obstruction. Ectopic ureters and duplex kidneys Ectopic ureters occur with congenital duplication of one or both kidneys (duplex kidneys). Developmentally, the ureter has two main branches and, if this arrangement persists, the two ureters of the duplex kidneys may drain separately into the bladder. The lower pole moiety enters the bladder superiorly and laterally, while the upper pole moiety enters the bladder inferomedially to the lower pole moiety ureter or, more rarely, enters the vagina or seminal vesicle. The lower pole moiety has an ineffective valve mechanism, so that urine passes up the ureter on voiding (vesico-ureteric reflux, p. 430), whereas the upper pole moiety is often associated with a ureterocele. Megaureter A megaureter is a ureter dilated to more than 5 mm in diameter. It may be obstructed or non-obstructed and refluxing or nonrefluxing. Some 50% of cases are asymptomatic but patients may present with pain, haematuria or infection. Radiographic and pressure/flow studies may be needed to determine whether there is obstruction to urine flow. Patients with symptoms or reduced renal function are treated. Ideally, treatment is expectant with antibiotic prophylaxis. Surgery (narrowing of the ureter and/or reimplantation) may, however, be needed for recurrent symptoms, reduction of more than 10% in renal function or complications (i.e. stones).

Tumours of the kidney and urinary tract • 435

436 • NEPHROLOGY AND UROLOGY multiple angiomyolipomas (tubers) may occasionally cause renal failure in adults; they may also bleed, requiring embolisation. The von Hippel–Lindau syndrome (p. 1132) is associated with multiple renal cysts, renal adenomas and clear cell renal cell cancers. Other organs affected include the central nervous system (haemangioblastomas), pancreas and adrenals (phaeochromocytoma). Urinary incontinence Urinary incontinence is defined as any involuntary leakage of urine. It may occur in patients with a normal urinary tract, as the result of dementia or poor mobility, or transiently during an acute illness or hospitalisation, especially in older people (Box 15.54). The prevalence of any form of incontinence in all females is 25–45%, with a concomitant socioeconomic burden. Childbirth, hysterectomy, obesity, recurrent UTI, smoking, caffeine and constipation are risk factors for incontinence. Pathophysiology As urine accumulates in the bladder during the storage phase, the sphincter tone gradually increases, but there are no significant changes in vesical pressure, detrusor pressure or intra-abdominal pressure. During voiding, intravesical pressure increases as a result of detrusor contraction and the sphincter relaxes, allowing urine to flow from the bladder until it is empty. Clinical disorders associated with incontinence are connected with various abnormalities in this cycle and these are discussed in more detail below. Stress incontinence This occurs because passive bladder pressure exceeds the urethral pressure, due either to poor pelvic floor support or a weak urethral sphincter. Usually there is an element of both these factors. Stress incontinence is very common in women and seen most frequently following childbirth. It is rare in men and usually follows surgery to the prostate. The presentation is with incontinence during coughing, sneezing or exertion. In women, perineal inspection may reveal leakage of urine when the patient coughs. Urge incontinence This usually occurs because of detrusor over-activity, which produces an increased bladder pressure that overcomes the urethral sphincter. Urgency with or without incontinence may also be driven by a hypersensitive bladder resulting from UTI or a bladder stone. Detrusor over-activity is usually idiopathic, Pathophysiology Risk factors include cigarette smoking and exposure to industrial carcinogens such as aromatic amines, aniline dyes and aldehydes. Clinical features More than 80% of patients present with painless, visible haematuria. It should be assumed that such bleeding is from a tumour until proven otherwise (p. 391). Tumours of the ureter or bladder may also cause symptoms of obstruction, depending on the site of involvement, and tumours of the bladder present with dysuria or storage symptoms. Physical examination is usually unremarkable, except in patients with very advanced disease, when bimanual examination may reveal a palpable mass. Investigations Cystoscopy (usually flexible cystoscopy under a local anaesthetic) is mandatory to evaluate the bladder in cases of haematuria or suspected bladder cancer. Imaging of the upper urinary tract (CT urogram is the gold standard but IVU combined with renal ultrasound is also acceptable) is also important to rule out abnormalities of the kidney, ureters and renal pelvis in patients with haematuria. If a suspicious defect is seen on CT urography or IVU in the ureter or renal pelvis, a retrograde ureteropyelogram, ureteroscopy and biopsy are required. If evidence of a solid invasive urothelial tumour is found, CT of the abdomen, pelvis and chest should be performed to define tumour stage. Management Most bladder tumours are low-grade superficial lesions that can be successfully treated endoscopically by transurethral resection of the tumour. Intravesical chemotherapy with mitomycin C is usually administered as a one-off treatment post resection to prevent tumour recurrence, or may be given as a prolonged course to treat multiple low-grade bladder tumours. Patients with carcinoma in situ have a high risk of progression to invasive cancer. These patients often respond well to intravesical bacille Calmette–Guérin (BCG) treatment but more radical treatment may also be needed if this is unsuccessful. Following initial treatment and endoscopic clearance of bladder tumours, regular check cystoscopies are required to look for evidence of recurrence. Patients with recurrences of superficial disease can usually be treated by further resection and diathermy, but if this is unsuccessful, a cystectomy may be needed. The management of invasive bladder tumours involves radical cystectomy with urinary diversion into an incontinent ileal conduit or a continent catheterisable bowel pouch; the latter is usually reserved for patients under the age of 70 years. The prognosis of bladder tumours depends on tumour stage and grade. About 5% of patients with low-grade superficial bladder cancer progress to develop invasion of the bladder muscle, compared with about 50% of those with high-grade superficial bladder cancers. Overall, the 5-year survival for patients with muscle-invasive bladder cancer of either grade is 50–70%. Urothelial cell carcinoma of the renal pelvis and ureter is usually treated by open or laparoscopic nephro-ureterectomy, but if the tumour is solitary and low-grade, it can be treated endoscopically. Inherited tumour syndromes affecting the renal tract Some uncommon autosomal dominantly inherited conditions are associated with multiple renal tumours in adult life. In tuberous sclerosis (p. 1264), replacement of renal tissue by 15.54 Incontinence in old age • Prevalence: urinary incontinence affects 15% of women and 10% of men aged over 65 years. • Cause: incontinence may be transient and due to delirium, urinary infection, medication (such as diuretics), faecal impaction or restricted mobility, and these should be treated before embarking on further specific investigation. • Detrusor over-activity: established incontinence in old age is most commonly due to detrusor over-activity, which may be caused by damage to central inhibitory centres or local detrusor muscle abnormalities. • Catheterisation: poor manual dexterity or cognitive impairment may necessitate the help of a carer to assist with intermittent catheterisation.

Prostate disease • 437

other than in patients with neurological conditions such as spina bifida or multiple sclerosis, in whom it is neurogenic (p. 1093). The incidence of urge incontinence increases with age, occurring in 10–15% of the population aged over 65 years and in approximately 50% of patients requiring nursing home care. It is also seen in men with lower urinary tract obstruction and most often remits after the obstruction is relieved. Continual incontinence This is suggestive of a fistula, usually between the bladder and vagina (vesicovaginal), or the ureter and vagina (ureterovaginal). It is most common following gynaecological surgery but is also seen in patients with gynaecological malignancy or post radiotherapy. In parts of the world where obstetric services are scarce, prolonged obstructed labour can be a common cause of vesicovaginal fistulae. Continual incontinence may also be seen in infants with congenital ectopic ureters. Occasionally, stress incontinence is so severe that the patient leaks continuously. Overflow incontinence This occurs when the bladder becomes chronically over-distended and may lead to AKI (high-pressure chronic urinary retention). It is most commonly seen in men with benign prostatic enlargement or bladder neck obstruction (see below) but may arise in either sex as a result of failure of the detrusor muscle (atonic bladder). The latter may be idiopathic but more commonly is the result of damage to the pelvic nerves, either from surgery (commonly, hysterectomy or rectal excision), trauma or infection, or from compression of the cauda equina by disc prolapse, trauma or tumour. Incontinence due to prostatic enlargement can be regarded as a type of overflow incontinence. Post-micturition dribble This is very common in men, even in the relatively young. It is due to a small amount of urine becoming trapped in the U-bend of the bulbar urethra, which leaks out when the patient moves. Post-micturition dribble is more pronounced if associated with a urethral diverticulum or urethral stricture. It may occur in women with a urethral diverticulum and may mimic stress incontinence. Clinical features Patients should be encouraged to keep a voiding diary, including the measured volume voided, frequency of voiding, a note of incontinence pad usage, precipitating factors and associated features, such as urgency, since this can be of diagnostic value. Structured questionnaires may help objectively quantify symptoms. The patient should be assessed for evidence of cognitive impairment and impaired mobility. A neurological assessment should be performed to detect disorders such as multiple sclerosis that may affect the nervous supply of the bladder, and the lumbar spine should be inspected for features of spina bifida occulta. Perineal sensation and anal sphincter tone should be assessed. Rectal examination is needed to assess the prostate in men and to exclude faecal impaction as a cause of incontinence. Genital examination should be done to identify phimosis or paraphimosis in men, and vaginal mucosal atrophy, cystoceles or rectoceles in women. Investigations Urinalysis and culture should be performed in all patients. Ultrasound examination can be helpful in identifying patients with overflow incontinence who have incomplete bladder emptying, as they may reveal a significant amount of fluid in the bladder (> 100 mL) post micturition. Urine flow rates and full urodynamic assessment by cystometrography may be required to diagnose the type of incontinence and are indicated in selected cases when the diagnosis is unclear on clinical grounds. A CT scan and cystoscopy should be performed in patients with continual incontinence who are suspected of having a fistula. Imaging with MRI is indicated when a urethral diverticulum is suspected. Management Weight reduction in obese patients will aid resolution of incontinence. Women with stress incontinence respond well to physiotherapy. The mainstay of treatment for urge incontinence is bladder retraining, which involves teaching patients to hold more urine voluntarily in their bladder, assisted by anticholinergic medication. Surgery may be required in patients who have severe daytime incontinence despite conservative treatment. The treatment of incontinence secondary to fistula formation is surgical. Patients with overflow incontinence due to bladder obstruction should be treated surgically or with long-term catheterisation (intermittent or continuous). Incontinence secondary to neurological diseases can be managed by intermittent self-catheterisation. Prostate disease Prostatitis This results from inflammation of the prostate gland. Acute or chronic bacterial prostatitis can be caused by infection with the same bacteria that are associated with UTI (p. 426) but prostatitis can also be ‘non-bacterial’, in which case no organism can be cultured from the urine. This is also known as chronic pelvic pain syndrome. Clinical features of prostatitis include frequency, dysuria, painful ejaculation, perineal or groin pain, difficulty passing urine and, in acute disease, considerable systemic disturbance. The prostate is enlarged and tender. Bacterial prostatitis is confirmed by a positive culture from urine or from urethral discharge obtained after prostatic massage, and the treatment of choice is a quinolone antibiotic. A 4–6-week course of antibiotics is required (see Box 15.47, p. 429). Treatment of chronic pelvic pain syndrome is challenging but some patients respond to a combination of α-blockers, NSAIDs and amitriptyline. Benign prostatic enlargement Benign prostatic enlargement (BPE) is extremely common. It has been estimated that about half of all men aged 80 years and over will have lower urinary tract symptoms associated with bladder outlet obstruction (BOO) due to BPE. Benign prostatic hyperplasia (BPH) is the histological abnormality that underlies BPE. Pathophysiology The prostate gland increases in volume by 2.4 cm3 per year on average from 40 years of age. The process begins in the periurethral (transitional) zone and involves both glandular and stromal tissue to a variable degree. The cause is unknown, although BPE does not occur in patients with hypogonadism, suggesting that hormonal factors may be important. Clinical features The primary symptoms of BPE arise because of difficulty in voiding urine due to obstruction of the urethra by the prostate; these voiding symptoms consist of hesitancy, poor urinary flow and a sensation of incomplete emptying. Other storage

438 • NEPHROLOGY AND UROLOGY post-void residual volume of urine assessed with ultrasound, and prostate volume by transrectal ultrasound scan (TRUS). Objective assessment of obstruction is possible by urodynamics but this is seldom required. If symptoms or signs, such as a palpable bladder, nocturnal enuresis, recurrent UTI or a history of renal stones, are present, renal function should be assessed; if it is abnormal, screening should be conducted for evidence of obstructive uropathy by ultrasound examination. Management Patients who present with acute retention require urgent treatment and should undergo immediate catheterisation to relieve the obstruction. Those with mild to moderate symptoms can be treated by medication (Box 15.56). The first-line treatments are α1A-adrenoceptor blockers such as tamsulosin, which reduce the tone of smooth muscle cells in the prostate and bladder neck, thereby reducing the obstruction. The 5α-reductase inhibitors finasteride and dutasteride inhibit conversion of testosterone to the nine times more potent dihydrotestosterone in the prostate and so cause the prostate to reduce in size. This class of drugs is indicated in patients with an estimated prostate size of more than 30 g or a prostate-specific antigen (PSA) level of more than 1.4 ng/mL. Patients who fail to respond to a single drug may be treated with a combination of α-blockers and 5α-reductase inhibitors, since this is more efficacious than either agent alone. Symptoms that are resistant to medical therapy require surgical treatment to remove some of the prostate tissue that is causing urethral obstruction. This is usually achieved by transurethral resection of the prostate (TURP) but enucleation of the prostate by holmium laser or vaporisation by potassium-titanyl-phosphate (KTP) laser (Greenlight laser) is equally effective and has potentially fewer complications. Open surgery is rarely needed, unless the gland is very large. Prostate cancer Prostate cancer is the most common malignancy in men in the UK, with a prevalence of 105 per 100 000 population. It is also common in northern Europe and the USA (particularly in the African American population) but is rare in China and Japan. It is uncommon in India but the incidence is increasing. Prostate cancer rarely occurs before the age of 50 and has a mean age at presentation of 70 years. Pathophysiology Prostate cancers tend to arise within the peripheral zone of the prostate and almost all are adenocarcinomas. Metastatic spread to pelvic lymph nodes occurs early and metastases to bone, mainly the lumbar spine and pelvis, are common. Genetic factors are known to play an important role in pathogenesis, symptoms include urinary frequency, urgency of micturition and urge incontinence, although these are not specific to BPE. Some patients present suddenly with acute urinary retention, when they are unable to micturate and develop a painful, distended bladder. This is often precipitated by excessive alcohol intake, constipation or prostatic infection. Severity of symptoms can be ascertained by using the International Prostate Symptom Score (IPSS) questionnaire (Box 15.55), which serves as a valuable starting point for assessment of the patient. Once a baseline value is established, any improvement or deterioration may be monitored on subsequent visits. The IPSS may be combined with a quality-of-life score, in which patients are asked the following question: ‘If you were to spend the rest of your life with your urinary condition the way it is now, how would you feel about that?’ Responses range from 0 (delighted) to 6 (terrible). Patients may also present with chronic urinary retention. Here, the bladder slowly distends due to inadequate emptying over a long period of time. Patients with chronic retention can also develop acute retention: so-called acute-on-chronic retention. This condition is characterised by pain-free bladder distension, which may result in hydroureter, hydronephrosis and renal failure (high-pressure chronic retention, of which nocturnal incontinence is a pathognomonic symptom). On digital rectal examination (DRE), patients with BPE have evidence of prostatic enlargement with a smooth prostate gland. Abdominal examination may also reveal evidence of bladder enlargement in patients with urinary retention. Investigations The diagnosis of BOO secondary to BPE is a clinical one but flow rates can be accurately measured with a flow meter, 15.55 The International Prostate Symptom Score (IPSS) Symptom Question Example score Straining How often have you had to push or strain to begin urination?

Urgency How often have you found it difficult to postpone urination?

Hesitancy How often have you found that you stopped and started again several times when you urinated?

Incomplete emptying How often have you had a sensation of not emptying your bladder completely after you finished urinating?

Frequency How often have you had to urinate again less than 2 hours after you finished urinating?

Weak stream How often have you had a weak urinary stream?

Nocturia How many times did you most typically get up to urinate from the time you went to bed at night until the time you got up in the morning?

Total score

0 = not at all; 1 = less than one-fifth of the time; 2 = less than half the time; 3 = about half of the time; 4 = more than half of the time; 5 = almost always. A score of 0–7 indicates mild symptoms, 8–19 moderate symptoms and 20–35 severe symptoms. In the example shown, the patient had moderate symptoms. 15.56 Treatment for benign prostatic enlargement Medical • Prostate < 30 g: α-adrenoceptor blockers • Prostate > 30 g: 5α-reductase inhibitors ± α-adrenoceptor blockers Surgical • Transurethral resection of the prostate (TURP) • Laser enucleation • Laser vaporisation • Open prostatectomy

Testicular tumours • 439

the presence and extent of local involvement. An isotope bone scan should be carried out if distant metastases are suspected (rare if the PSA is below 20 ng/mL); very high levels of serum PSA (> 100 ng/mL) almost always indicate distant bone metastases. Following diagnosis, serial assessment of PSA levels is useful for monitoring response to treatment and disease progression. Management Tumour confined to the prostate is potentially curable by radical prostatectomy, radical radiotherapy or brachytherapy (implantation of small radioactive particles into the prostate). These options should be considered only in patients with more than 10 years’ life expectancy. Patients who are found to have small-volume, low-grade disease do not appear to require specific treatment but should be followed up periodically with PSA testing, DRE and a schedule of biopsies; this is known as active surveillance. Prostatic cancer, like breast cancer, is sensitive to steroid hormones; metastatic prostate cancer is treated by androgen depletion, involving either surgery (orchidectomy) or, more commonly, androgen-suppressing drugs. Androgen receptor blockers, such as bicalutamide or cyproterone acetate, may also prevent tumour cell growth. Gonadotrophin-releasing hormone (GnRH) analogues, such as goserelin, continuously occupy pituitary receptors, preventing them from responding to the GnRH pulses that normally stimulate luteinising hormone (LH) and follicle-stimulating hormone (FSH) release. This initially causes an increase in testosterone before producing a prolonged reduction, and for this reason the initial dose must be covered with an androgen receptor blocker to prevent a tumour flare. A small proportion of patients fail to respond to endocrine treatment. A larger number respond for a year or two but then the disease progresses. Chemotherapy with docetaxel can then be effective and provide a modest (around 3 months) survival advantage. Radiotherapy is useful for localised bone pain but the basis of treatment remains pain control by analgesia (p. 1331). Provided that patients do not die of another cause, the 10-year survival rate of patients with tumours localised to the prostate is 95%, but if metastases are present, this falls to 10%. Life expectancy is not reduced in patients with small foci of tumour. Testicular tumours Testicular tumours are uncommon, with a prevalence of 5 cases per 100 000 population. They occur mainly in young men aged between 20 and 40 years. They often secrete α-fetoprotein (AFP) and β-human chorionic gonadotrophin (β-hCG), which are useful biochemical markers for both diagnosis and prognosis. Seminoma and teratoma account for 85% of all tumours of the testis. Leydig cell tumours are less common. Seminomas arise from seminiferous tubules and represent a relatively low-grade malignancy. Metastases can occur through lymphatic spread, however, and typically involve the lungs. Teratomas arise from primitive germinal cells and tend to occur at a younger age than seminomas. They may contain cartilage, bone, muscle, fat and a variety of other tissues, and are classified according to the degree of differentiation. Welldifferentiated tumours are the least aggressive; at the other extreme, trophoblastic teratoma is highly malignant. Occasionally, teratoma and seminoma occur together. Leydig cell tumours are usually small and benign but secrete oestrogens, leading to presentation with gynaecomastia (p. 657). and multiple genetic loci have been found to predispose to the disease in genome-wide association studies. A family history of prostate cancer greatly increases a man’s chances of developing the disease. Clinical features Most patients either are asymptomatic or present with lower urinary tract symptoms indistinguishable from BPE. On DRE the prostate may feel nodular and stony-hard, and the median sulcus may be lost, but up to 45% of tumours are impalpable. Symptoms and signs due to metastases are much less common at the initial presentation but may include back pain, weight loss, anaemia and obstruction of the ureters. Investigations Measurement of PSA levels in a peripheral blood sample, together with DRE, is the cornerstone of diagnosis. Prior to a PSA test, men should be given careful counselling about the limitations of the test: namely, a normal level does not exclude prostate cancer, while a high value does not confirm the diagnosis but will open a discussion about biopsy and possible future treatments with potential side-effects (Box 15.57). The need for radical treatment of localised prostate cancer is still not established; radical treatments have significant potential morbidity and mortality, yet early identification and treatment of prostate cancer may save lives. Current evidence suggests that population-based screening for prostate cancer with PSA is of limited value, due in part to the fact that over 700 patients would need to be screened to cure 1 man of prostate cancer. Individuals suspected of having prostate cancer, based on an elevated PSA and/or abnormal DRE, should undergo transrectal ultrasound-guided prostate biopsies. About 40% of patients with a serum PSA of 4.0–10 ng/mL or more will have prostate cancer on biopsy, although 25% of patients with a PSA of less than 4 ng/mL may also have prostate cancer. Occasionally, a small focus of tumour is found incidentally in patients undergoing TURP for benign hyperplasia. If the diagnosis of prostate cancer is confirmed, staging should be performed by pelvic MRI to assess 15.57 Advantages and disadvantages of prostate-specific antigen (PSA) testing in order to identify men with prostate cancer Advantages • Identification of prostate cancer at a treatable stage, which otherwise may not have been identified* Disadvantages • High false-positive rate: 50–60% of men with an elevated PSA will not have prostate cancer • High false-negative rate: 25% of men with a normal PSA have prostate cancer • Leads to further invasive tests (biopsy) with morbidity (e.g. sepsis or bleeding) • May lead to diagnosis of prostate cancer, which is often over-treated by surgery or radiotherapy with associated side-effects (e.g. impotence or incontinence) • If PSA is elevated but biopsy is normal, there is a potential need for further testing and associated anxiety *The advantages of identifying prostate cancer earlier than would be the case if the man developed symptomatic disease must be considered against the limitations of PSA testing.

440 • NEPHROLOGY AND UROLOGY discuss matters frankly with the patient, and to establish whether there are associated features of hypogonadism (p. 655) and if erections occur at any other time. If the patient has erections on wakening, vascular and neuropathic causes are much less likely and a psychological cause should be suspected. Investigations Blood should be taken for glucose, lipids, thyroid function tests, prolactin, testosterone, LH and FSH. A number of further tests are available but are rarely employed because they do not usually influence management. These include nocturnal tumescence monitoring (using a plethysmograph placed around the shaft of the penis overnight) to establish whether blood supply and nerve function are sufficient to allow erections to occur during sleep; intracavernosal injection of prostaglandin E1 to test the adequacy of blood supply; internal pudendal artery angiography; and tests of autonomic and peripheral sensory nerve conduction. Management First-line therapy is usually with oral phosphodiesterase type 5 inhibitors, such as sildenafil, which elevate cyclic guanosine monophosphate (cGMP) levels in vascular smooth muscle cells of the corpus cavernosum, causing vasodilatation and penile erection. Co-administration of these drugs with nitric oxide donors, such as glycerol trinitrate, is contraindicated because of the risk of severe hypotension. Other treatments for impotence include self-administered intracavernosal injection or urethral administration of prostaglandin E1; vacuum devices that achieve an erection maintained by a tourniquet around the base of the penis; and prosthetic implants, either of a fixed rod or an inflatable reservoir. Psychotherapy involving the patient and sexual partner may be helpful for psychological problems. Erectile dysfunction associated with peripheral neuropathy and vascular disease is difficult to treat. If hypogonadism is detected, it should be managed as described on page 655. Further information Websites edren.org Renal Unit, Royal Infirmary of Edinburgh; information about individual diseases, protocols for immediate in-hospital management and more. edrep.org/resources Educational resources. nephron.com The links under ‘Physicians’ include useful urology pages, eGFR and other calculators, and other resources. renal.org/ckd UK Renal Association; current UK guidelines on the detection, referral and management of CKD. renalfellow.blogspot.co.uk/ Educational blog written by renal trainees for trainees. uroweb.org/guidelines European Association of Urology guidelines; current European guidelines on the management of all common urological conditions. Clinical features and investigations The common presentation is incidental discovery of a painless testicular lump, although some patients complain of a testicular ache. All suspicious scrotal lumps should be imaged by ultrasound. Serum levels of AFP and β-hCG are elevated in extensive disease. Oestradiol may be elevated, suppressing LH, FSH and testosterone. Accurate staging is based on CT of the lungs, liver and retroperitoneal area. Management and prognosis The primary treatment is surgical orchidectomy. Subsequent treatment depends on the histological type and stage. Radiotherapy is the treatment of choice for early-stage seminoma. Teratoma confined to the testes may be managed conservatively, but more advanced cancers are treated with chemotherapy, usually the combination of bleomycin, etoposide and cisplatin. Follow-up is by CT and assessment of AFP and β-hCG. Retroperitoneal lymph node dissection is now performed only for residual or recurrent nodal masses. The 5-year survival rate for patients with seminoma is 90–95%. For teratomas, the 5-year survival varies between 60% and 95%, depending on tumour type, stage and volume. Erectile dysfunction Causes of erectile failure are shown in Box 15.58. Vascular, neuropathic and psychological causes are most common. Exclusion of previously unrecognised cardiovascular disease is important in men presenting with erectile dysfunction. With the exception of diabetes mellitus, endocrine causes are relatively uncommon and are characterised by loss of libido, as well as erectile dysfunction. Erectile dysfunction and reduced libido occur in over 50% of men with advanced CKD or those on dialysis, and is a markedly under-diagnosed problem. It is important to 15.58 Causes of erectile dysfunction With reduced libido • Hypogonadism • Depression With intact libido • Psychological problems, including anxiety • Vascular insufficiency (atheroma) • Neuropathic causes (diabetes mellitus, alcohol excess, multiple sclerosis) • Drugs (β-blockers, thiazide diuretics)

Ch04-3 Clinical Medicine

06-16 Cardiology

16 Cardiology

Cardiology DE Newby NR Grubb Clinical examination of the cardiovascular system 442 Functional anatomy and physiology 444 Anatomy 444 Physiology 446 Investigation of cardiovascular disease 448 Electrocardiogram 448 Cardiac biomarkers 450 Chest X-ray 450 Echocardiography 451 Computed tomography 452 Magnetic resonance imaging 452 Cardiac catheterisation 453 Electrophysiology 454 Radionuclide imaging 454 Presenting problems in cardiovascular disease 454 Chest pain on exertion 454 Severe prolonged chest pain 455 Breathlessness 455 Syncope 455 Palpitation 455 Cardiac arrest 456 Abnormal heart sounds 457 Heart failure 461 Cardiac arrhythmias 468 Principles of management of cardiac arrhythmias 479 Anti-arrhythmic drugs 479 Non-pharmacological treatments 482 Coronary artery disease 484 Angina pectoris 487 Acute coronary syndrome 493 Non-cardiac surgery in patients with heart disease 501 Peripheral arterial disease 502 Diseases of the aorta 505 Aortic aneurysm 505 Aortic dissection 506 Aortitis 508 Marfan’s syndrome 508 Coarctation of the aorta 508 Hypertension 508 Diseases of the heart valves 514 Rheumatic heart disease 515 Mitral valve disease 517 Aortic valve disease 521 Tricuspid valve disease 525 Pulmonary valve disease 526 Prosthetic valves 526 Infective endocarditis 527 Congenital heart disease 531 Diseases of the myocardium 538 Myocarditis 538 Cardiomyopathy 538 Cardiac tumours 541 Diseases of the pericardium 542

442 • CARDIOLOGY Clinical examination of the cardiovascular system Insets (Splinter haemorrhage, jugular venous pulse, malar flush, tendon xanthomas) From Newby D, Grubb N. Cardiology: an illustrated colour text. Edinburgh: Churchill Livingstone, Elsevier Ltd; 2005. Observation Hands Clubbing Splinter haemorrhages and other stigmata of infective endocarditis Radial pulse Rate Rhythm Blood pressure Carotid pulses Volume Character Bruits (see opposite) Jugular venous pulse (see opposite) Height Waveform Face, mouth and eyes Pallor Central cyanosis Dental caries Fundi (retinopathy) Stigmata of hyperlipidaemia and thyroid disease Precordium Inspect Palpate (see opposite) Auscultation (see opposite) Back Lung crepitations Sacral oedema Femoral pulses Radio-femoral delay Bruits Abdomen Hepatomegaly Ascites Aortic aneurysm Bruits

Symptoms and well-being • Breathlessness • Distress etc. Body habitus • Body mass (obesity, cachexia) • Marfan’s and other syndromes Tissue perfusion • Skin temperature • Sweating • Urine output Legs Peripheral pulses Oedema

Poor oral hygiene in a patient with infective endocarditis Xanthelasma Vasculitis in a patient with infective endocarditis Cyanosis and clubbing in a patient with complex cyanotic congenital heart disease Peripheral oedema in a patient with congestive cardiac failure Splinter haemorrhage Jugular venous pulse Malar flush Tendon xanthomas (hyperlipidaemia)

Clinical examination of the cardiovascular system • 443

Distinguishing venous/arterial pulsation in the neck • The venous pulse has two peaks in each cardiac cycle; the arterial pulse has one peak. • The height of the venous pulse varies with respiration (falls on inspiration) and position. • Abdominal compression causes the venous pulse to rise. • The venous pulse is not easily palpable and can be occluded with light pressure. 4 Examination of the arterial pulse • The character of the pulse is determined by stroke volume and arterial compliance, and is best assessed by palpating a major artery, such as the carotid or brachial artery. • Aortic regurgitation, anaemia, sepsis and other causes of a large stroke volume typically produce a bounding pulse with a high amplitude and wide pulse pressure (panel A). • Aortic stenosis impedes ventricular emptying. If severe, it causes a slow-rising, weak and delayed pulse (panel A). • Sinus rhythm produces a pulse that is regular in time and force. Arrhythmias may cause irregularity. Atrial fibrillation produces a pulse that is irregular in time and volume (panel B). B Normal pulse Aortic regurgitation Aortic stenosis A 5 Examination of the jugular venous pulse The internal jugular vein, superior vena cava and right atrium are in continuity, so the height of the jugular venous pulsation reflects right atrial pressure. When the patient is placed at 45°, with the head supported and turned to the left, the jugular venous pulse is visible along the line of the sternocleidomastoid muscle (see opposite). In health it is normally just visible above the clavicle. • The height of the jugular venous pulse is determined by right atrial pressure and is therefore elevated in right heart failure and reduced in hypovolaemia. • If the jugular venous pulse is not easily seen, it may be exposed by applying firm pressure over the abdomen. • In sinus rhythm, the two venous peaks, the a and v waves, approximate to atrial and ventricular systole, respectively. • The x descent reflects atrial relaxation and apical displacement of the tricuspid valve ring. The y descent reflects atrial emptying early in diastole. These signs are subtle. • Tricuspid regurgitation produces giant v waves that coincide with ventricular systole. Ventricular Systole Diastole a c x v y a c x 8 Auscultation of the heart • Use the diaphragm to examine at the apex, lower left sternal edge (tricuspid area) and upper left (pulmonary area) and right (aortic area) sternal edges. • Use the bell to examine low-pitched noises, particularly at the apex for the mid-diastolic murmur of mitral stenosis. • Time the sounds and murmurs by feeling the carotid pulse; the first heart sound (S1) just precedes the upstroke of the pulse and the second heart sound (S2) is out of step with it. If present, a third heart sound (S3) immediately follows S2, and a fourth heart sound (S4) just precedes S1. Systolic murmurs are synchronous with the pulse. • Listen for radiation of systolic murmurs, over the base of the neck (aortic stenosis) and in the axilla (mitral incompetence). • Listen over the left sternal border with the patient sitting forward (aortic incompetence), then at the apex with the patient rolled on to the left side (mitral stenosis).

7 Palpation of the precordium Technique • Place fingertips over apex (1) to assess for position and character. Place heel of hand over left sternal edge (2) for a parasternal heave or ‘lift’. Assess for thrills in all areas, including the aortic and pulmonary areas (3). Normal position is the 5th or 6th intercostal space, at the mid-clavicular line. Common abnormalities of the apex beat • Volume overload, such as mitral or aortic regurgitation: displaced, thrusting • Pressure overload, such as aortic stenosis, hypertension: discrete, heaving • Dyskinetic, such as left ventricular aneurysm: displaced, incoordinate Other abnormalities • Palpable S1 (tapping apex beat: mitral stenosis) • Palpable P2 (severe pulmonary hypertension) • Left parasternal heave or ‘lift’ felt by heel of hand (right ventricular hypertrophy) • Palpable thrill (aortic stenosis) The haemodynamic effects of respiration are discussed on page 447, and the analysis and interpretation of heart sounds and murmurs on page 457.

444 • CARDIOLOGY aorta. The right atrium (RA) receives blood from the superior and inferior venae cavae and the coronary sinus. The LA receives blood from four pulmonary veins, two from each of the left and right lungs. The ventricles are thick-walled structures, adapted to circulating blood through large vascular beds under pressure. The atria and ventricles are separated by the annulus fibrosus, which forms the skeleton for the atrioventricular (AV) valves and electrically insulates the atria from the ventricles. The right ventricle (RV) is about 2–3 mm thick and triangular in shape. It extends from the annulus fibrosus to near the cardiac apex and sits anterior and to the right of the left ventricle (LV). The anterosuperior surface of the RV is rounded and convex, and its posterior extent is bounded by the interventricular septum, which bulges into the chamber. Its upper extent is conical, forming the conus arteriosus or outflow tract, from which the pulmonary artery arises. The LV is more conical in shape and in cross-section is nearly circular. It extends from the LA to the apex of the heart. The LV myocardium is normally around 10 mm thick because it pumps blood at a higher pressure than the RV. Normally, the heart occupies less than 50% of the transthoracic diameter in the frontal plane, as seen on a chest X-ray. On the patient’s left, the cardiac silhouette is formed by the aortic arch, the pulmonary trunk, the left atrial appendage and the LV. On the right, the silhouette is formed by the RA and the superior and inferior venae cavae, and the lower right border is formed by the RV (Fig. 16.2). In disease states or congenital cardiac abnormalities, the silhouette may change as a result of hypertrophy or dilatation. Coronary circulation The left main and right coronary arteries arise from the left and right sinuses of the aortic root, distal to the aortic valve (Fig. 16.3). Within 2.5 cm of its origin, the left main coronary artery divides into the left anterior descending artery (LAD), which runs in the anterior interventricular groove, and the left circumflex artery (CX), which runs posteriorly in the atrioventricular groove. Fig. 16.1 Direction of blood flow through the heart. The blue arrows show deoxygenated blood moving through the right heart to the lungs. The red arrows show oxygenated blood moving from the lungs to the systemic circulation. The normal pressures are shown for each chamber in mmHg. Pulmonary artery Systolic 15–30 Diastolic 5–15 Mean 10–20 Superior vena cava Inferior vena cava Systolic 90–140 Diastolic 60–90 Mean 70–105 Aorta Left atrium 4–12 Left ventricle Systolic End-diastolic 90–140 4–12 Right atrium 0–5 Right ventricle Systolic End-diastolic 15–30 0–5 Cardiovascular disease is the most frequent cause of adult death in the Western world. In the UK, one-third of men and one-quarter of women will die as a result of ischaemic heart disease. In many developed countries, the incidence of ischaemic heart disease has been falling for the last two or three decades, but it is rising in Eastern Europe and Asia. Cardiovascular disease will soon become the leading cause of death on all continents. Strategies for the treatment and prevention of heart disease can be highly effective and have been subjected to rigorous evaluation. The evidence base for the treatment of cardiovascular disease is stronger than for almost any other disease group. Valvular heart disease is common but the aetiology varies in different parts of the world. On the Indian subcontinent and in Africa, it is predominantly due to rheumatic fever, whereas calcific aortic valve disease is the most common problem in developed countries. Prompt recognition of the development of heart disease is limited by two key factors. Firstly, it is often latent; coronary artery disease can proceed to an advanced stage before the patient notices any symptoms. Secondly, the diversity of symptoms attributable to heart disease is limited, so different pathologies may frequently present with the same symptoms. Functional anatomy and physiology Anatomy The heart acts as two serial pumps that share several electrical and mechanical components. The right heart circulates blood to the lungs where it is oxygenated, and the left heart circulates it to the rest of the body (Fig. 16.1). The atria are thin-walled structures that act as priming pumps for the ventricles, which provide most of the energy required to maintain the circulation. The atria are situated posteriorly within the mediastinum where the left atrium (LA) sits anterior to the oesophagus and descending

Functional anatomy and physiology • 445

to coronary thrombosis, results in infarction of the inferior part of the LV and often the RV. Abrupt occlusion of the LAD or CX causes infarction in the corresponding territory of the LV, and occlusion of the left main coronary artery is usually fatal. The venous system follows the coronary arteries but drains into the coronary sinus in the atrioventricular groove, and then to the RA. An extensive lymphatic system drains into vessels that travel with the coronary vessels and then into the thoracic duct. Conduction system The SA node is situated at the junction of the superior vena cava and RA (Fig. 16.4). It comprises specialised atrial cells that depolarise at a rate influenced by the autonomic nervous system and by circulating catecholamines. During normal (sinus) rhythm, this depolarisation wave propagates through both atria via sheets of atrial myocytes. The annulus fibrosus forms a conduction barrier between atria and ventricles, and the only pathway through it is the AV node. This is a midline structure, extending from the right side of the interatrial septum, penetrating the annulus fibrosus anteriorly. The AV node conducts relatively slowly, producing a necessary time delay between atrial and ventricular contraction. The His–Purkinje system is composed of the bundle of His extending from the AV node into the interventricular septum, the right and left bundle branches passing along the ventricular septum and into the respective ventricles, the anterior and posterior fascicles of the left bundle branch, and the smaller Purkinje fibres that ramify through the ventricular myocardium. The tissues of the His–Purkinje system conduct very rapidly and allow near-simultaneous depolarisation of the entire ventricular myocardium. Nerve supply of the heart The heart is innervated by both sympathetic and parasympathetic fibres. Adrenergic nerves from the cervical sympathetic chain supply muscle fibres in the atria and ventricles, and the electrical conducting system. Activation of β1-adrenoceptors in the heart results in positive inotropic and chronotropic effects, whereas activation of β2-adrenoceptors in vascular smooth muscle causes vasodilatation. Parasympathetic pre-ganglionic fibres and sensory fibres reach the heart through the vagus nerves. Cholinergic nerves supply the AV and SA nodes via muscarinic (M2) receptors. Fig. 16.2 Surface anatomy of the heart. The positions of the major cardiac chambers and heart valves are shown. (LV = left ventricle; RA = right atrium; RV = right ventricle) RA RV LV Superior vena cava Aortic valve Tricuspid valve Pulmonary artery Pulmonary valve Left atrial appendage Aorta Base of the heart Apex of the heart Inferior vena cava Mitral valve Fig. 16.3 The coronary arteries: anterior view. Aorta Circumflex artery (CX) Right coronary artery (RCA) Sinoatrial node Left main coronary artery Left coronary artery Pulmonary artery and valve Left anterior descending artery (LAD) Apex Obtuse marginal Inferior vena cava Superior vena cava Atrioventricular node Posterior descending Diagonal branches Septal perforator branches Fig. 16.4 The cardiac conduction system. Depolarisation starts in the sinoatrial node and spreads through the atria (blue arrows), and then through the atrioventricular node (black arrows). Depolarisation then spreads through the bundle of His and the bundle branches to reach the ventricular muscle (red arrows). Repolarisation spreads from epicardium to endocardium (green arrows). Sinoatrial node Bundle of His Atrioventricular (AV) node Right bundle branch Right ventricle Left atrium Left bundle branch Left anterior fascicle Left posterior fascicle Purkinje fibres Left ventricle The LAD gives branches to supply the anterior part of the septum (septal perforators) and the anterior, lateral and apical walls of the LV. The CX gives marginal branches that supply the lateral, posterior and inferior segments of the LV. The right coronary artery (RCA) runs in the right atrioventricular groove, giving branches that supply the RA, RV and inferoposterior aspects of the LV. The posterior descending artery runs in the posterior interventricular groove and supplies the inferior part of the interventricular septum. This vessel is a branch of the RCA in approximately 90% of people (dominant right system) and is supplied by the CX in the remainder (dominant left system). The coronary anatomy varies greatly from person to person and there are many normal variants. The RCA supplies the sinoatrial (SA) node in about 60% of individuals and the AV node in about 90%. Proximal occlusion of the RCA therefore often results in sinus bradycardia and may also cause AV nodal block. Abrupt occlusion of the RCA, due

446 • CARDIOLOGY (ATPase), which breaks down adenosine triphosphate (ATP) to provide the energy for contraction (Fig. 16.5E). Two chains of actin molecules form a helical structure, with a second molecule, tropomyosin, in the grooves of the actin helix, and a further molecule complex, troponin, attached to every seventh actin molecule (Fig. 16.5D). During the plateau phase of the action potential, calcium ions enter the cell and are mobilised from the sarcoplasmic reticulum. They bind to troponin and thereby precipitate contraction by shortening of the sarcomere through the interdigitation of the actin and myosin molecules. The force of cardiac muscle contraction, or inotropic state, is regulated by the influx of calcium ions through ‘slow calcium channels’. The extent to which the sarcomere can shorten determines stroke volume of the ventricle. It is maximally shortened in response to powerful inotropic drugs or marked exercise. However, the enlargement of the heart seen in heart failure is due to slippage of the myofibrils and adjacent cells rather than lengthening of the sarcomere. Cardiac peptides Cardiomyocytes secrete peptides that have humoral effects on the vasculature and kidneys. Atrial natriuretic peptide (ANP) is a Under resting conditions, vagal inhibitory activity predominates and the heart rate is slow. Adrenergic stimulation, associated with exercise, emotional stress, fever and so on, causes the heart rate to increase. In disease states, the nerve supply to the heart may be affected. For example, in heart failure the sympathetic system may be up-regulated, and in diabetes mellitus the nerves themselves may be damaged by autonomic neuropathy (p. 758) so that there is little variation in heart rate. Physiology Myocardial contraction Myocardial cells (myocytes) are about 50–100 μm long; each cell branches and interdigitates with adjacent cells. An intercalated disc permits electrical conduction via gap junctions, and mechanical conduction via the fascia adherens, to adjacent cells (Fig. 16.5A). The basic unit of contraction is the sarcomere (2 μm long), which is aligned to those of adjacent myofibrils, giving a striated appearance due to the Z-lines (Fig. 16.5B and C). Actin filaments are attached at right angles to the Z-lines and interdigitate with thicker parallel myosin filaments. The cross-links between actin and myosin molecules contain myofibrillar adenosine triphosphatase Fig. 16.5 Schematic of myocytes and the contraction process within a muscle fibre. A Myocytes are joined together through intercalated discs. B Within the myocytes, myofibrils are composed of longitudinal and transverse tubules extending from the sarcoplasmic reticulum. C The expanded section shows a schematic of an individual sarcomere with thick filaments composed of myosin and thin filaments composed primarily of actin. D Actin filaments are composed of troponin, tropomyosin and actin subunits. E The three stages of contraction, resulting in shortening of the sarcomere. (1) The actin-binding site is blocked by tropomyosin. (2) ATP-dependent release of calcium ions, which bind to troponin, displacing tropomyosin. The binding site is exposed. (3) Tilting of the angle of attachment of the myosin head, resulting in fibre shortening. (ADP = adenosine diphosphate; ATP = adenosine triphosphate) Intercalated disc Myocyte 10 μm Sarcoplasmic reticulum Transverse tubules Mitochondrion Muscle fibre Mitochondrion T-tubule Z-line Sarcolemma Actin subunit Tropomyosin Troponin

Tropomyosin Actin Myosin body Z-line Troponin complex Myosin head ATP ADP Ca2+ E C A B D Myofibril-like unit (1.0 μm diameter)

Functional anatomy and physiology • 447

stimulation also causes modest dilatation of normal coronary arteries. Because of these homeostatic mechanisms that regulate vessel tone, narrowing or stenosis in a coronary artery does not limit flow, even during exercise, until the cross-sectional area of the vessel is reduced by at least 70%. Endothelium The endothelium plays a vital role in the control of vascular homeostasis. It synthesises and releases many vasoactive mediators that cause vasodilatation, including nitric oxide, prostacyclin and endothelium-derived hyperpolarising factor, and vasoconstriction, including endothelin-1 and angiotensin II. A balance exists whereby the release of such factors contributes to the maintenance and regulation of vascular tone and BP. Damage to the endothelium may disrupt this balance and lead to vascular dysfunction, tissue ischaemia and hypertension. The endothelium has a major influence on key regulatory steps in the recruitment of inflammatory cells and on the formation and dissolution of thrombus. Once activated, the endothelium expresses surface receptors such as E-selectin, intercellular adhesion molecule type 1 (ICAM-1) and platelet–endothelial cell adhesion molecule type 1 (PECAM-1), which mediate rolling, adhesion and migration of inflammatory leucocytes into the subintima. The endothelium also stores and releases the multimeric glycoprotein von Willebrand factor, which promotes thrombus formation by linking platelet adhesion to denuded surfaces, especially in the arterial vasculature. In contrast, once intravascular thrombus forms, tissue plasminogen activator is rapidly released from a dynamic storage pool within the endothelium to induce fibrinolysis and thrombus dissolution. These processes are critically involved in the development and progression of atherosclerosis, and endothelial function and injury are seen as central to the pathogenesis of many cardiovascular disease states. Respiration Cardiac output, BP and pulse rate change with respiration as the result of changes in blood flow to the right and left heart, as summarised in Box 16.1. During inspiration the fall in intrathoracic pressure causes increased return of venous blood into the chest and right side of the heart, which increases cardiac output from the RV. A substantial amount of blood is sequestered in the lungs, however, due to increased capacitance of the pulmonary vascular bed, which causes a reduction in blood flow to the left side of the heart. This causes a reduction in cardiac output from the LV and a slight fall in BP. With expiration the opposite sequence of events occurs; there is a fall in venous return to the right heart with a reduction in RV output, and a rise in the venous return to the left side of the heart with an increase in LV output. As the result of these changes, BP normally falls during inspiration 28-amino acid peptide, which includes an amino acid ring that acts as a vasodilator, thereby reducing blood pressure (BP), and acts as a diuretic by promoting renal excretion of water and sodium. It is released by atrial myocytes in response to stretch. Brain natriuretic peptide (BNP), which was originally identified in extracts of porcine brain, is a 32-amino acid polypeptide produced by ventricular cardiomyocytes in response to stretch, as occurs in heart failure. Like ANP, it has diuretic properties. Neprilysin is an enzyme present in the circulation that is produced by the kidney and other tissues. It breaks down ANP, BNP and other proteins and, in so doing, acts as a vasoconstrictor. It forms a therapeutic target in patients with heart failure (p. 466). Circulation The RA receives deoxygenated blood from the superior and inferior venae cavae and discharges blood to the RV, which in turn pumps it into the pulmonary artery. Blood passes through the pulmonary arterial and alveolar capillary bed, where it is oxygenated, then drains through the pulmonary veins into the LA. Blood then passes into the LV, which pumps it into the aorta (see Fig. 16.1). During ventricular contraction (systole), the tricuspid valve in the right heart and the mitral valve in the left heart close, and the pulmonary and aortic valves open. In diastole, the pulmonary and aortic valves close, and the two AV valves open. Collectively, these atrial and ventricular events constitute the cardiac cycle of filling and ejection of blood from one heart beat to the next. Blood passes from the heart through the large central elastic arteries into muscular arteries before encountering the resistance vessels, and ultimately the capillary bed, where there is exchange of nutrients, oxygen and waste products of metabolism. The central arteries, such as the aorta, are predominantly composed of elastic tissue with little or no vascular smooth muscle cells. When blood is ejected from the heart, the compliant aorta expands to accommodate the volume of blood before the elastic recoil sustains BP and flow following cessation of cardiac contraction. This is called the Windkessel effect and it prevents excessive rises in systolic BP while sustaining diastolic BP, thereby reducing cardiac afterload and maintaining coronary perfusion. These benefits are lost with progressive arterial stiffening, which occurs with ageing and advanced renal disease. Passing down the arterial tree, vascular smooth muscle cells progressively play a greater role until the resistance arterioles are encountered. Although all vessels contribute, the resistance vessels (diameter 50–200 μm) provide the greatest contribution to systemic vascular resistance, with small changes in radius having a marked influence on blood flow; resistance is inversely proportional to the fourth power of the radius (Poiseuille’s Law). The tone of these resistance vessels is tightly regulated by humoral, neuronal and mechanical factors. Neurogenic constriction operates via α-adrenoceptors on vascular smooth muscle, and dilatation via muscarinic and β2-adrenoceptors. In addition, systemic and locally released vasoactive substances influence tone; vasoconstrictors include noradrenaline (norepinephrine), angiotensin II and endothelin-1, whereas adenosine, bradykinin, prostaglandins and nitric oxide are vasodilators. Resistance to blood flow rises with viscosity and is mainly influenced by the haematocrit. Coronary blood vessels receive sympathetic and parasympathetic innervation. While stimulation of α-adrenoceptors causes vasoconstriction and stimulation of β2-adrenoceptors causes vasodilatation, the predominant effect of sympathetic stimulation in coronary arteries is vasodilatation. Parasympathetic 16.1 Haemodynamic effects of respiration Inspiration Expiration Jugular venous pressure Falls Rises Blood pressure Falls (up to 10 mmHg) Rises Heart rate Accelerates Slows Second heart sound Splits* Fuses* *Inspiration prolongs right ventricular ejection, delaying P2, and shortens left ventricular ejection, bringing forward A2; expiration produces the opposite effects.

448 • CARDIOLOGY the QRS complex is larger than the P wave. The interval between the onset of the P wave and the onset of the QRS complex is termed the ‘PR interval’ and largely reflects the duration of AV nodal conduction. Injury to the left or right bundle branch delays ventricular depolarisation, widening the QRS complex. Selective injury of one of the left fascicles (hemiblock, p. 479) affects the electrical axis. Repolarisation is slower and spreads from the epicardium to the endocardium. Atrial repolarisation does not cause a detectable signal but ventricular repolarisation produces the T wave. The QT interval represents the total duration of ventricular depolarisation and repolarisation. The 12-lead ECG The 12-lead ECG (Box 16.2) is generated from 10 electrodes that are attached to the skin. One electrode is attached to each limb and six electrodes are attached to the chest. In addition, the left arm, right arm and left leg electrodes are attached to a central terminal acting as an additional virtual electrode in the centre of the chest (the right leg electrode acts as an earthing electrode). The 12 ‘leads’ of the ECG refer to recordings made from pairs or sets of these electrodes. They comprise three groups: three dipole limb leads, three augmented voltage limb leads and six unipole chest leads. Leads I, II and III are the dipole limb leads and refer to recordings obtained from pairs of limb electrodes. Lead I records but rises during expiration. These changes are exaggerated in patients with severe airways obstruction secondary to asthma or chronic obstructive pulmonary disease (COPD) leading to pulsus paradoxus, which describes an exaggerated fall in BP during inspiration. As well as being found in airways obstruction, pulsus paradoxus is also characteristic of cardiac tamponade (p. 544). Here, cardiac filling is constrained by external pressure, and on inspiration compression of the RV impedes the normal increase in flow through it on inspiration. The interventricular septum then moves to the left, impeding left ventricular filling and cardiac output. This produces a marked fall in BP (> 10 mmHg fall during inspiration). Investigation of cardiovascular disease Several investigations may be required in the diagnosis of cardiac disease and assessment of its severity. Basic tests, such as electrocardiography, chest X-ray and echocardiography, can be performed in an outpatient clinic or at the bedside, whereas more complex procedures such as cardiac catheterisation, radionuclide imaging, computed tomography (CT) and magnetic resonance imaging (MRI) require specialised facilities. Electrocardiogram The electrocardiogram (ECG) is used to assess cardiac rhythm and conduction, and is the main test used in the diagnosis of myocardial ischaemia and infarction. The physiological basis of an ECG recording is the fact that electrical depolarisation of myocardial tissue produces a small dipole current, which can be detected by electrode pairs on the body surface. These signals are amplified and either printed or displayed on a monitor (Fig. 16.6). During sinus rhythm, the SA node triggers atrial depolarisation, producing a P wave. Depolarisation proceeds slowly through the AV node, which is too small to produce a depolarisation wave detectable from the body surface. The bundle of His, bundle branches and Purkinje system are then activated, initiating ventricular myocardial depolarisation, which produces the QRS complex. The muscle mass of the ventricles is much larger than that of the atria, so Fig. 16.6 The electrocardiogram. The components correspond to depolarisation and repolarisation, as depicted in Figure 16.4. The upper limit of the normal range for each interval is given in brackets. QRS width (0.10 sec) P wave (0.12 sec) PR interval (0.20 sec) QT interval (0.42 sec at rate of 60/min) P Q S T wave: ventricular repolarisation P wave: atrial depolarisation T R QRS complex: ventricular depolarisation 16.2 How to read a 12-lead electrocardiogram: examination sequence Rhythm strip (lead II) To determine heart rate and rhythm Cardiac axis Normal if QRS complexes +ve in leads I/II P-wave shape Tall P waves denote right atrial enlargement (P pulmonale) and notched P waves denote left atrial enlargement (P mitrale) PR interval Normal = 0.12–0.20 sec. Prolongation denotes impaired atrioventricular nodal conduction. A short PR interval occurs in Wolff–Parkinson– White syndrome (p. 474) QRS duration If > 0.12 sec, ventricular conduction is abnormal (left or right bundle branch block) QRS amplitude Large QRS complexes occur in slim young patients and in patients with left ventricular hypertrophy Q waves May signify previous myocardial infarction ST segment ST elevation may signify myocardial infarction, pericarditis or left ventricular aneurysm; ST depression may signify ischaemia or infarction T waves T-wave inversion has many causes, including myocardial ischaemia or infarction, and electrolyte disturbances QT interval Normal < 0.42 sec. QT prolongation may occur with congenital long QT syndrome, low K+, Mg2+ or Ca2+, and some drugs (see Box 16.26, p. 476) ECG conventions Depolarisation towards electrode: +ve deflection Depolarisation away from electrode: −ve deflection Sensitivity: 10 mm = 1 mV Paper speed: 25 mm per sec Each large (5 mm) square = 0.2 sec Each small (1 mm) square = 0.04 sec Heart rate = 1500/RR interval (mm) (i.e. 300 ÷ number of large squares between beats)

Investigation of cardiovascular disease • 449

average vector of ventricular depolarisation is known as the frontal cardiac axis. When the vector is at right angles to a lead, the depolarisation in that lead is equally negative and positive (isoelectric). In Figure 16.7A, the QRS complex is isoelectric in aVL, negative in aVR and most strongly positive in lead II; the main vector or axis of depolarisation is therefore 60°. The normal cardiac axis lies between −30° and +90°. Examples of left and right axis deviation are shown in Figures 16.7B and C. There are six chest leads, V1–V6, derived from electrodes placed on the anterior and lateral left side of the chest, over the heart. Each lead records the signal between the corresponding chest electrode (positive) and the central terminal (negative). Leads V1 and V2 lie approximately over the RV, V3 and V4 over the interventricular septum, and V5 and V6 over the LV (Fig. 16.8). The LV has the greater muscle mass and contributes the major component of the QRS complex. The shape of the QRS complex varies across the chest leads. Depolarisation of the interventricular septum occurs first and moves from left to right; this generates a small initial negative deflection in lead V6 (Q wave) and an initial positive deflection in lead V1 (R wave). The second phase of depolarisation is activation of the body of the LV, which creates a large positive deflection or R wave in V6 (with reciprocal changes in V1). The third and final phase involves the RV and produces a small negative deflection or S wave in V6. Exercise ECG In exercise or stress electrocardiography a 12-lead ECG is recorded during exercise on a treadmill or bicycle ergometer. It is similar to a resting ECG, except that the limb electrodes are placed on the shoulders and hips rather than the wrists and ankles. The Bruce Protocol is the most commonly used. During an exercise ECG, BP is recorded and symptoms are assessed. Common indications for exercise testing are shown in Box 16.3. The test is considered positive if angina occurs, BP falls or fails to increase, or if there are ST segment shifts of more than 1 mm (see Fig. 16.57, p. 490). Exercise testing is useful in confirming the diagnosis of coronary artery disease in patients with suspected angina, and under these circumstances has good sensitivity and specificity (Box 16.3). False-negative the signal between the right (negative) and left (positive) arms. Lead II records the signal between the right arm (negative) and left leg (positive). Lead III records the signal between the left arm (negative) and left leg (positive). These three leads thus record electrical activity along three different axes in the frontal plane. Leads aVR, aVL and aVF are the augmented voltage limb leads. These record electrical activity between a limb electrode and a modified central terminal. For example, lead aVL records the signal between the left arm (positive) and a central (negative) terminal, formed by connecting the right arm and left leg electrodes (Fig. 16.7). Similarly augmented signals are obtained from the right arm (aVR) and left leg (aVF). These leads also record electrical activity in the frontal plane, with each lead 120° apart. Lead aVF thus examines activity along the axis +90°, and lead aVL along the axis −30°, and so on. When depolarisation moves towards a positive electrode, it produces a positive deflection in the ECG; depolarisation in the opposite direction produces a negative deflection. The Fig. 16.7 The appearance of the ECG from different leads in the frontal plane. A Normal. B Left axis deviation, with negative deflection in lead II and positive in lead I. C Right axis deviation, with negative deflection in lead I and positive in lead II. III (120°) aVF (90°) II (60°) I (0°) 120° I (0°) I (0°) A B C II (60°) II (60°) aVR (210°) aVL (−30°) Fig. 16.8 The sequence of activation of the ventricles. A Activation of the septum occurs first (red arrows), followed by spreading of the impulse through the left ventricle (LV, blue arrows) and then the right ventricle (RV, green arrows). B Normal electrocardiographic complexes from leads V1 and V6. Right bundle AV node Left bundle Bundle of His RV LV V1 V1 V2 V3 V4 V5 V6 V6 1 3

A B

450 • CARDIOLOGY preference to BNP since it has a longer half-life. Measurements of NT-proBNP are indicated for the diagnosis of LV dysfunction and to assess prognosis and response to therapy in patients with heart failure (p. 461). Cardiac troponins Troponin I and troponin T are structural cardiac muscle proteins (see Fig. 16.5) that are released during myocyte damage and necrosis, and represent the cornerstone of the diagnosis of acute myocardial infarction (MI, Box 16.47, p. 493). Modern assays are extremely sensitive, however, and can detect minor degrees of myocardial damage, so that elevated plasma troponin concentrations may be observed in conditions other than acute MI, such as pulmonary embolus, septic shock and pulmonary oedema. Chest X-ray This is useful for determining the size and shape of the heart, and the state of the pulmonary blood vessels and lung fields. Most information is given by a postero-anterior (PA) projection taken in full inspiration. Anteroposterior (AP) projections can be performed when patient movement is restricted but result in magnification of the cardiac shadow. An estimate of overall heart size can be made by comparing the maximum width of the cardiac outline with the maximum internal transverse diameter of the thoracic cavity. The term cardiomegaly is used to describe an enlarged cardiac silhouette when the ratio of cardiac width to the width of the lung fields is greater than 0.5. Cardiomegaly can be caused by chamber dilatation, especially left ventricular dilatation, or by a pericardial effusion, but may also be due to a mediastinal mass or pectus excavatum (p. 628). Cardiomegaly is not a sensitive indicator of left ventricular systolic dysfunction since the cardiothoracic ratio is normal in many patients with poor left ventricular function and is not specific, since many patients with cardiomegaly on chest X-ray have normal echocardiograms. Dilatation of individual cardiac chambers can be recognised by the characteristic alterations to the cardiac silhouette (Fig. 16.9): • Left atrial dilatation results in prominence of the left atrial appendage, creating the appearance of a straight left heart border, a double cardiac shadow to the right of the sternum, and widening of the angle of the carina (bifurcation of the trachea) as the left main bronchus is pushed upwards. • Right atrial enlargement projects from the right heart border towards the right lower lung field. • Left ventricular dilatation causes prominence of the left heart border and enlargement of the cardiac silhouette. Left ventricular hypertrophy produces rounding of the left heart border (Fig. 16.10). • Right ventricular dilatation increases heart size, displaces the apex upwards and straightens the left heart border. Lateral or oblique projections may be useful for detecting pericardial calcification in patients with constrictive pericarditis (p. 543) or a calcified thoracic aortic aneurysm, as these abnormalities may be obscured by the spine on the PA view. The lung fields on the chest X-ray may show congestion and oedema in patients with heart failure (see Fig. 16.27, p. 464), and an increase in pulmonary blood flow (‘pulmonary plethora’) in those with left-to-right shunt. Pleural effusions may also occur in heart failure. results can, however, occur in patients with coronary artery disease, and not all patients with a positive test have coronary disease. This is especially true in low-risk individuals, such as asymptomatic young or middle-aged women, in whom an abnormal response is more likely to represent a false-positive than a true-positive test. Stress testing is contraindicated in the presence of acute coronary syndrome, decompensated heart failure and severe hypertension. Ambulatory ECG Ambulatory ECG recordings can be obtained using a portable digital recorder. These devices usually provide limb lead ECG recordings only, on a continuous basis for periods of between 1 and 7 days. The main indication for ambulatory ECG is in the investigation of patients with suspected arrhythmia, such as those with intermittent palpitation, dizziness or syncope. In this situation a standard ECG provides only a snapshot of the cardiac rhythm and is unlikely to detect an intermittent arrhythmia, so a longer period of recording is required (see Fig. 16.32, p. 469). Ambulatory ECG can also be used to assess rate control in patients with atrial fibrillation, and to detect transient myocardial ischaemia using ST segment analysis. If symptoms are infrequent, special recorders can be issued that can be activated by the patient when a symptom episode occurs and placed on the chest wall to record the cardiac rhythm at that point in time. With some devices, the recording can be transmitted to hospital electronically. If the symptoms are very infrequent but potentially serious, such as syncope, implantable ‘loop recorders’ resembling a leadless pacemaker can be used and implanted subcutaneously to record cardiac rhythm for prolonged periods of between 1 and 3 years. Cardiac biomarkers Several biomarkers are available that can be measured in peripheral blood to assess myocardial dysfunction and ischaemia. Brain natriuretic peptide Brain natriuretic peptide (BNP) is a peptide hormone of 32 amino acids with diuretic properties. It is secreted by the LV as a 108amino acid prohormone, which is cleaved to produce active BNP, and an inactive 76-amino acid N-terminal fragment (NT-proBNP). Circulating levels are elevated in conditions associated with LV systolic dysfunction. Generally, NT-proBNP is measured in 16.3 Exercise testing Indications • To confirm the diagnosis of angina • To evaluate stable angina • To assess prognosis following myocardial infarction • To assess outcome after coronary revascularisation, e.g. coronary angioplasty • To diagnose and evaluate the treatment of exercise-induced arrhythmias High-risk findings • Low threshold for ischaemia (within stage 1 or 2 of the Bruce Protocol) • Fall in blood pressure on exercise • Widespread, marked or prolonged ischaemic ECG changes • Exercise-induced arrhythmia

Investigation of cardiovascular disease • 451

Doppler echocardiography Doppler echocardiography provides information on blood flow within the heart and the great vessels. It is based on the Doppler principle that sound waves reflected from moving objects, such as red blood cells, undergo a frequency shift. Doppler echocardiography can therefore detect the speed and direction of blood flow in the heart chambers and great vessels. The greater the frequency shift, the faster the blood is moving. The information can be presented either as a plot of blood velocity against time for a particular point in the heart (Fig. 16.11) or as Echocardiography Transthoracic echocardiography Transthoracic echocardiography, commonly referred to as ‘echo’, is obtained by placing an ultrasound transducer on the chest wall to image the heart structures as a real-time two-dimensional ‘slice’. This can be used for rapid evaluation of various aspects of cardiac structure and function. Common indications for echocardiography are shown in Box 16.4. Fig. 16.9 Chest X-ray of a patient with mitral stenosis and regurgitation indicating enlargement of the LA and prominence of the pulmonary artery trunk. Splaying of carina Distended pulmonary veins Enlarged left atrium ‘Double shadow’ of left atrial enlargement Enlarged pulmonary trunk Fig. 16.10 Chest X-ray of a patient with aortic regurgitation, left ventricular enlargement and dilatation of the ascending aorta. Normal-sized aortic arch Large left ventricle Dilated ascending aorta 16.4 Common indications for echocardiography • Assessment of left ventricular function • Diagnosis and quantification of severity of valve disease • Identification of vegetations in endocarditis • Identification of structural heart disease in atrial fibrillation, cardiomyopathies or congenital heart disease • Detection of pericardial effusion • Identification of structural heart disease or intracardiac thrombus in systemic embolism Fig. 16.11 Doppler echocardiography in aortic stenosis. A The aortic valve is imaged and a Doppler beam passed directly through the left ventricular outflow tract and the aorta into the turbulent flow beyond the stenosed valve. B The velocity of the blood cells is recorded to determine the maximum velocity and hence the pressure gradient across the valve. In this example, the peak velocity is approximately 450 cm/sec (4.5 m/sec), indicating severe aortic stenosis (peak gradient of 81 mmHg). Transducer Chest wall LV LA Turbulent flow Stenosed aortic valve A B

452 • CARDIOLOGY Stress echocardiography Stress echocardiography is used to investigate patients with suspected coronary artery disease who are unsuitable for exercise stress testing, such as those with mobility problems or pre-existing bundle branch block. A two-dimensional echo is performed before and after infusion of a moderate to high dose of an inotrope, such as dobutamine. Myocardial segments with poor perfusion become ischaemic and contract poorly under stress, manifesting as a wall motion abnormality on the scan. Stress echocardiography is sometimes used to examine myocardial viability in patients with impaired left ventricular function. Low-dose dobutamine can induce contraction in ‘hibernating’ myocardium; such patients may benefit from bypass surgery or percutaneous coronary intervention. Computed tomography Computed tomography (CT) is useful for imaging the cardiac chambers, great vessels, pericardium, and mediastinal structures and masses. Multidetector scanners can acquire up to 320 slices per rotation, allowing very high-resolution imaging in a single heart beat. CT is often performed using a timed injection of X-ray contrast to produce clear images of blood vessels and associated pathologies. Contrast scans are very useful for imaging the aorta in suspected aortic dissection (see Fig. 16.74, p. 507), and the pulmonary arteries and branches in suspected pulmonary embolism (p. 619). Some centres use cardiac CT scans for quantification of coronary artery calcification, which may serve as an index of cardiovascular risk. However, modern multidetector scanning allows non-invasive coronary angiography (Fig. 16.13) with a spatial resolution approaching that of conventional coronary arteriography and at a lower radiation dose. CT coronary angiography is particularly useful in the initial assessment of patients with chest pain and a low or intermediate likelihood of disease, since it has a high negative predictive value in excluding coronary artery disease. Modern volume scanners are also able to assess myocardial perfusion, often at the same sitting. Magnetic resonance imaging Magnetic resonance imaging (MRI) can be used to generate crosssectional images of the heart, lungs and mediastinal structures. It provides better differentiation of soft tissue structures than CT Fig. 16.12 Echocardiographic illustration of the principal cardiac structures in the ‘four-chamber’ view. Colour-flow Doppler has been used to demonstrate mitral regurgitation: a flame-shaped (yellow/blue) turbulent jet into the left atrium. Tricuspid valve Right ventricle Left ventricle (dilated) Mitral valve (regurgitant) Right atrium Left atrium Fig. 16.13 Computed tomography coronary angiography, demonstrating normal coronary arteries (arrows). A Threedimensional image. B Two-dimensional image. A B a colour overlay on a two-dimensional real-time echo picture (colour-flow Doppler, Fig. 16.12). Doppler echocardiography is useful in the detection of valvular regurgitation, where the direction of blood flow is reversed and turbulence is seen, and is also used to detect pressure gradients across stenosed valves. For example, the normal resting systolic flow velocity across the aortic valve is approximately 1 m/sec; in the presence of aortic stenosis, this is increased as blood accelerates through the narrow orifice. In severe aortic stenosis, the peak aortic velocity may be increased to 5 m/sec (see Fig. 16.11). An estimate of the pressure gradient across a valve or lesion is given by the modified Bernoulli equation: Pressure gradient mmHg peak velocity in m/sec ( ) ( )

×

Advanced techniques include three-dimensional echocardiography, intravascular ultrasound (defines vessel wall abnormalities and guides coronary intervention), intracardiac ultrasound (provides high-resolution images), tissue Doppler imaging (quantifies myocardial contractility and diastolic function) and speckle tracking (assesses myocardial motion and strain). Transoesophageal echocardiography Transoesophageal echocardiography (TOE) involves passing an endoscope-like ultrasound probe into the oesophagus and upper stomach under light sedation and positioning it behind the LA. It is particularly useful for imaging structures such as the left atrial appendage, pulmonary veins, thoracic aorta and interatrial septum, which may be poorly visualised by transthoracic echocardiography, especially if the patient is overweight or has obstructive airway disease. The high-resolution images that can be obtained makes TOE particularly valuable for investigating patients with prosthetic (especially mitral) valve dysfunction, congenital abnormalities such as atrial septal defects, aortic dissection, infective endocarditis (vegetations that are too small to be detected by transthoracic echocardiography) and systemic embolism (intracardiac thrombus or masses).

Investigation of cardiovascular disease • 453

help in selecting patients for revascularisation procedures, or in identifying those with myocardial infiltration, such as that seen with sarcoid heart disease and arrhythmogenic right ventricular cardiomyopathy. Cardiac catheterisation This involves passing a specialised catheter through a peripheral vein or artery into the heart under X-ray guidance. Cardiac catheterisation allows BP and oxygen saturation to be measured in the cardiac chambers and great vessels, and is used to perform angiograms by injecting contrast media into a chamber or blood vessel. Left heart catheterisation involves accessing the arterial circulation, usually through the radial artery, to allow catheterisation of the aorta, LV and coronary arteries. Coronary angiography is the most widely performed procedure, in which the left and right coronary arteries are selectively imaged, providing information about the extent and severity of coronary stenoses, thrombus and calcification (Fig. 16.15). Additional anatomical but is poor at demonstrating calcification. MRI scans need to be ‘gated’ to the ECG, allowing the scanner to produce moving images of the heart and mediastinal structures throughout the cardiac cycle. MRI is very useful for imaging the aorta, including suspected dissection (see Fig. 16.73, p. 507), and can define the anatomy of the heart and great vessels in patients with congenital heart disease. It is also useful for detecting infiltrative conditions affecting the heart and for evaluation of the RV that is difficult to image by echocardiography. Physiological data can be obtained from the signal returned from moving blood, which allows quantification of blood flow across regurgitant or stenotic valves. It is also possible to analyse regional wall motion in patients with suspected coronary disease or cardiomyopathy. Myocardial perfusion and viability can also be readily assessed by MRI. When enhanced by gadolinium-based contrast media, areas of myocardial hypoperfusion can be identified with better spatial resolution than nuclear medicine techniques. Later redistribution of this contrast, so-called delayed enhancement, can be used to identify myocardial scarring and fibrosis: this is a particular strength of cardiac MRI (Fig. 16.14). This can Fig. 16.14 Cardiac magnetic resonance imaging. A Recent inferior myocardial infarction with black area of microvascular obstruction (arrow). B Old anterior myocardial infarction with large area of subendocardial delayed gadolinium enhancement (white area, arrows). B A Fig. 16.15 The left anterior descending and circumflex coronary arteries with a stenosis (arrow) in the left anterior descending vessel. A Coronary artery angiogram. B Schematic of the vessels and branches. Diagnostic catheter Left main stem artery Circumflex artery Left anterior descending artery Stenosis A B

454 • CARDIOLOGY Presenting problems in cardiovascular disease Cardiovascular disease gives rise to a relatively limited range of symptoms. Making the correct diagnosis depends on careful analysis of the factors that provoke symptoms, the subtle differences in how they are described by the patient, the clinical findings and the results of investigations. A close relationship between symptoms and exercise is the hallmark of heart disease. The New York Heart Association (NYHA) functional classification is used to grade disability (Box 16.5). Chest pain on exertion There are many other non-cardiac causes of chest pain, as discussed in Chapter 10. This section will focus on exertional chest pain, which is a typical presenting symptom of coronary artery disease. Clinical assessment A careful history is crucial in determining whether chest pain is cardiac or not. Chest pain on effort is the hallmark of angina pectoris (Fig. 16.16). The reproducibility, predictability and relationship to physical exertion (and occasionally emotion) of the chest pain are the most important features. The duration of symptoms should be noted because patients with recent-onset angina are at greater risk than those with long-standing and unchanged symptoms. Physical examination is often normal but (intravascular ultrasound, optical coherence tomography) or functional (pressure wire) assessments are sometimes used to define plaque characteristics and severity more precisely. This permits planning of percutaneous coronary intervention and coronary artery bypass graft surgery. Left ventriculography can be performed during the procedure to determine the size and function of the LV and to demonstrate mitral regurgitation. Aortography defines the size of the aortic root and thoracic aorta, and can help quantify aortic regurgitation. Left heart catheterisation is a day-case procedure and is relatively safe, with serious complications occurring in only approximately 1 in 1000 cases. Right heart catheterisation is used to assess right heart and pulmonary artery pressures, and to detect intracardiac shunts by measuring oxygen saturations in different chambers. For example, a step up in oxygen saturation from 65% in the RA to 80% in the pulmonary artery is indicative of a large left-to-right shunt that might be due to a ventricular septal defect. Cardiac output can also be measured using thermodilution techniques. Left atrial pressure can be measured directly by puncturing the interatrial septum from the RA with a special catheter. For most purposes, however, a satisfactory approximation to left atrial pressure can be obtained by ‘wedging’ an end-hole or balloon catheter in a branch of the pulmonary artery. Swan–Ganz balloon catheters are often used to monitor pulmonary ‘wedge’ pressure as a guide to left heart filling pressure in critically ill patients (p. 206). Electrophysiology Patients with known or suspected arrhythmia are investigated by percutaneous placement of electrode catheters into the heart via the femoral and neck veins. An electrophysiology study (EPS) is most commonly performed to evaluate patients for catheter ablation and is normally done at the same time as the ablation procedure. EPS is occasionally used for risk stratification of patients suspected of being at risk of ventricular arrhythmias. Radionuclide imaging Radionuclide imaging can be used to evaluate cardiac function but is declining in popularity due to the availability of MRI, which does not involve exposure to radiation and provides equivalent or superior quality data to radionuclide imaging. Blood pool imaging The patient is given an intravenous injection of radioisotopelabelled blood cells, and after 4–5 minutes the distribution of isotope in the heart is evaluated by a gamma camera at different phases of the cardiac cycle, thereby permitting the calculation of ventricular ejection fractions. It also allows the assessment of the size and ‘shape’ of the cardiac chambers. Myocardial perfusion scanning The patient is given an intravenous injection of a radioactive isotope, such as 99technetium tetrofosmin, and scintiscans of the myocardium are subsequently obtained by gamma camera at rest and during stress (see Fig. 16.58, p. 490). Either exercise stress or pharmacological stress (using the inotrope dobutamine or the vasodilator dipyridamole) can be used. More sophisticated quantitative information can be obtained with positron emission tomography (PET), which can also be used to assess myocardial metabolism, but this is available in only a few centres. Fig. 16.16 Typical ischaemic cardiac pain. Characteristic hand gestures used to describe cardiac pain. Typical radiation of pain is shown in the schematic. 16.5 New York Heart Association (NYHA) functional classification Class I • No limitation during ordinary activity Class II • Slight limitation during ordinary activity Class III • Marked limitation of normal activities without symptoms at rest Class IV • Unable to undertake physical activity without symptoms; symptoms may be present at rest

Presenting problems in cardiovascular disease • 455

Management The differential diagnosis and management of acute coronary syndrome are described in more detail on pages 494 and 498. Breathlessness Cardiac causes of breathlessness include cardiac arrhythmias, acute and chronic heart failure, acute coronary syndrome, valvular disease, cardiomyopathy and constrictive pericarditis, all discussed later in this chapter. The differential diagnosis of breathlessness is wide, however, and has many other non-cardiac causes. These are discussed in more detail on pages 179 and 557. Syncope The term ‘syncope’ refers to loss of consciousness due to reduced cerebral perfusion. The differential diagnosis, investigation and management of syncope are discussed on page 181. Palpitation Palpitation is a common and sometimes frightening symptom that is usually due to a disorder of cardiac rhythm. Patients use the term to describe many sensations, including an unusually erratic, fast, slow or forceful heart beat, or even chest pain or breathlessness. Clinical assessment Initial evaluation should concentrate on determining the likely mechanism of palpitation and whether or not there is significant underlying heart disease. A detailed description of the sensation is essential and patients should be asked to describe their symptoms clearly, or to demonstrate the sensation of rhythm by tapping with their hand. A provisional diagnosis can usually be made on the basis of a thorough history (Box 16.6 and Fig. 16.17). Recurrent but short-lived bouts of an irregular heart beat are usually due to atrial or ventricular extrasystoles (ectopic beats). Some patients will describe the experience as a ‘flip’ or a ‘jolt’ in the chest, while others report dropped or missed beats. Extrasystoles are often more frequent during periods of stress or debility; they can be triggered by alcohol or nicotine. Episodes of a pounding, forceful and relatively fast (90–120/ min) heart beat are a common manifestation of anxiety. These may also reflect a hyperdynamic circulation, such as anaemia, pregnancy and thyrotoxicosis, and can occur in some forms of valve disease such as aortic regurgitation. Discrete bouts of a may reveal evidence of risk factors for cardiovascular disease, such as xanthoma or xanthelasma indicating hyperlipidaemia (p. 373). Signs of anaemia (p. 923) or thyrotoxicosis (p. 635) may be identified, both of which can exacerbate angina. Cardiovascular examination may reveal evidence of left ventricular dysfunction (p. 442) or cardiac murmurs in patients with aortic valve disease and hypertrophic cardiomyopathy. Other manifestations of arterial disease, such as bruits and loss of peripheral pulses, may also be observed. Investigations A full blood count, fasting blood glucose, lipids, thyroid function tests and a 12-lead ECG are the most important baseline investigations. An exercise ECG is helpful in identifying high-risk patients who require further investigation and treatment but cannot reliably exclude the presence of coronary artery disease (p. 449). In patients with chest pain where the exercise ECG is normal but where there is a suspicion of coronary artery disease, CT coronary angiography should be performed. If a murmur is found, echocardiography should be performed to check for valve disease or hypertrophic cardiomyopathy. Severe prolonged chest pain Severe prolonged cardiac chest pain may be due to acute myocardial infarction or to unstable angina (p. 493). These are known collectively as the acute coronary syndromes. Clinical assessment Acute coronary syndrome is suggested by a previous history of stable angina but an episode of acute severe chest pain at rest can be the first presentation of coronary artery disease. Making the correct diagnosis depends on analysing the character of the pain and its associated features. Physical examination may reveal signs of risk factors for coronary artery disease as described for exertional chest pain, and pallor or sweating, which is indicative of autonomic disturbance and typical of acute coronary syndrome. Other features, such as arrhythmia, hypotension and heart failure, may occur. Patients presenting with symptoms consistent with an acute coronary syndrome require admission to hospital and urgent investigation because there is a high risk of avoidable complications. Investigations A 12-lead ECG is mandatory and is the most useful method of initial triage, along with measurement of serum troponin I or T. The diagnosis of an acute coronary syndrome is supported by ST segment elevation or depression on ECG and an elevated level of troponin I or T, which demonstrates that there has been myocardial damage. If the diagnosis remains unclear after initial investigation, repeat ECG recordings should be performed and are particularly useful if they can be obtained during an episode of pain. If the plasma troponin concentrations are normal at baseline, repeat measurements should be made 6–12 hours after the onset of symptoms or admission to hospital. New ECG changes or an elevated plasma troponin concentration confirm the diagnosis of an acute coronary syndrome. If the pain settles and does not recur, there are no new ECG changes and troponin concentrations remain normal, the patient can be discharged from hospital but further investigations may be indicated to look for evidence of coronary artery disease, as discussed on page 484. 16.6 How to evaluate palpitation • Is the palpitation continuous or intermittent? • Is the heart beat regular or irregular? • What is the approximate heart rate? • Do symptoms occur in discrete attacks? Is the onset abrupt? How do attacks terminate? • Are there any associated symptoms? Chest pain, lightheadedness, polyuria (a feature of supraventricular tachycardia, p. 473) • Are there any precipitating factors, such as exercise or alcohol excess? • Is there a history of structural heart disease, such as coronary artery disease or valvular heart disease?

456 • CARDIOLOGY in the first few hours of MI and many victims die before medical help is sought. Up to one-third of people developing MI die before reaching hospital, emphasising the importance of educating the public to recognise symptoms and to seek medical help quickly. Acute myocardial ischaemia in the absence of infarction can also cause these arrhythmias, but less commonly. Patients with a history of previous MI are at increased risk of sudden arrhythmic death, especially if there is extensive left ventricular scarring and impairment, or if there is ongoing myocardial ischaemia. Cardiac arrest may be caused by ventricular fibrillation (Fig. 16.18), pulseless ventricular tachycardia (p. 457), asystole or pulseless electrical activity. These can complicate many types of heart disease, including cardiomyopathies, and sometimes can occur in the absence of recognised structural abnormalities. The causes are listed in Box 16.7. Sudden death less often occurs because of an acute mechanical catastrophe such as cardiac rupture or aortic dissection (pp. 496 and 506). Clinical assessment and management Basic life support When a patient with suspected cardiac arrest is encountered, the ABCDE approach to management should be followed; this involves prompt assessment and restoration of the Airway, maintenance of ventilation using rescue Breathing (‘mouth-tomouth’ breathing), and maintenance of the Circulation using chest compressions; Disability, in resuscitated patients, refers to assessment of neurological status, and Exposure entails removal of clothes to enable defibrillation, auscultation of the chest, and assessment for a rash caused by anaphylaxis, for injuries and so on (Fig. 16.19). The term basic life support (BLS) very rapid (over 120/min) heart beat are more likely to be due to a paroxysmal supraventricular or ventricular tachycardia. In contrast, episodes of atrial fibrillation typically present with irregular and usually rapid palpitation. Investigation If initial assessment suggests that the palpitation is due to an arrhythmia, the diagnosis should be confirmed by an ECG recording during an episode using an ambulatory ECG monitor or a patient-activated ECG recorder. Additional investigations may be required depending on the nature of the arrhythmia, as discussed on page 468. Management Palpitation is usually benign and even if the patient’s symptoms are due to an arrhythmia, the outlook is good if there is no underlying structural heart disease. Most cases are due to an awareness of the normal heart beat, a sinus tachycardia or benign extrasystoles, in which case an explanation and reassurance may be all that is required. Palpitation associated with pre-syncope or syncope (p. 181) may reflect more serious structural or electrical disease and should be investigated without delay. Other arrhythmias may require treatment, as discussed in more detail on page 479. Cardiac arrest Cardiac arrest describes the sudden and complete loss of cardiac output due to asystole, ventricular tachycardia or fibrillation, or loss of mechanical cardiac contraction (pulseless electrical activity). The clinical diagnosis is based on the victim being unconscious and pulseless; breathing may take some time to stop completely after cardiac arrest. Death is virtually inevitable, unless effective treatment is given promptly. Sudden cardiac death is usually caused by a catastrophic arrhythmia and accounts for 25–30% of deaths from cardiovascular disease, claiming an estimated 70 000 to 90 000 lives each year in the UK. Many of these deaths are potentially preventable. Pathogenesis Coronary artery disease is the most common cause of cardiac arrest. Ventricular fibrillation or ventricular tachycardia is common Fig. 16.18 Ventricular fibrillation. A bizarre chaotic rhythm, initiated in this case by two ventricular ectopic beats in rapid succession. 16.7 Causes of sudden arrhythmic death Coronary artery disease (85%) • Myocardial ischaemia • Acute myocardial infarction • Prior myocardial infarction with myocardial scarring Structural heart disease (10%) • Aortic stenosis (p. 521) • Hypertrophic cardiomyopathy (p. 539) • Dilated cardiomyopathy (p. 539) • Arrhythmogenic right ventricular dysplasia (p. 540) • Congenital heart disease (p. 531) No structural heart disease (5%) • Long QT syndrome (p. 476) • Brugada syndrome (p. 477) • Wolff–Parkinson–White syndrome (p. 474) • Adverse drug reactions (torsades de pointes, p. 476) • Severe electrolyte abnormalities Fig. 16.17 A simple approach to the diagnosis of palpitation. Consider Ectopic beats Atrial fibrillation Consider Supraventricular tachycardia Ventricular tachycardia Consider Sinus tachycardia High stroke volume, e.g. anaemia, anxiety, valve disease Is the heart beat regular? No No Yes Yes Are there discrete attacks of tachycardia? (> 120/min)

Presenting problems in cardiovascular disease • 457

of intravenous amiodarone, especially if ventricular fibrillation or ventricular tachycardia re-initiates after successful defibrillation. Ventricular fibrillation of low amplitude, or ‘fine VF’, may mimic asystole. If asystole cannot be confidently diagnosed, the patient should be treated for VF and defibrillated. If an electrical rhythm is observed that would be expected to produce a cardiac output, ‘pulseless electrical activity’ is present. Pulseless electrical activity should be treated by continuing CPR and adrenaline (epinephrine) administration while seeking such causes. Asystole should be treated similarly, with the additional support of atropine and sometimes external or transvenous pacing in an attempt to generate an electrical rhythm. There are many potentially reversible causes of cardiac arrest; the main ones can be easily remembered as a list of four Hs and four Ts (Fig. 16.20). The Chain of Survival This term refers to the sequence of events that is necessary to maximise the chances of a cardiac arrest victim surviving (Fig. 16.21). Survival is most likely if all links in the chain are strong: that is, if the arrest is witnessed, help is called immediately, basic life support is administered by a trained individual, the emergency medical services respond promptly, and defibrillation is achieved within a few minutes. Good training in both basic and advanced life support is essential and should be maintained by regular refresher courses. In recent years, public access defibrillation has been introduced in places of high population density, particularly where traffic congestion may impede the response of emergency services, such as railway stations, airports and sports stadia. Designated individuals can respond to a cardiac arrest using BLS and an automated external defibrillator. Survivors of cardiac arrest Patients who survive a cardiac arrest caused by acute MI need no specific treatment beyond that given to those recovering from an uncomplicated infarct, since their prognosis is similar (p. 498). Those with reversible causes, such as exercise-induced ischaemia or aortic stenosis, should have the underlying cause treated if possible. Survivors of ventricular tachycardia or ventricular fibrillation arrest in whom no reversible cause can be identified may be at risk of another episode, and should be considered for an implantable cardiac defibrillator (p. 483) and anti-arrhythmic drug therapy. In these patients, the risk is reduced by treatment of heart failure with β-adrenoceptor antagonists (β-blockers) and angiotensin-converting enzyme (ACE) inhibitors, and by coronary revascularisation. Abnormal heart sounds The first indication of heart disease may be the discovery of an abnormal sound on auscultation (Box 16.8). This may be incidental – for example, during a routine childhood examination – or may be prompted by symptoms of heart disease. Clinical assessment The aims of clinical assessment are, firstly, to determine if the abnormal sound is cardiac; secondly, to determine if it is pathological; and thirdly, to try to determine its cause. Is the sound cardiac? Additional heart sounds and murmurs demonstrate a consistent relationship to a specific part of the cardiac cycle, whereas extracardiac sounds, such as a pleural rub or venous hum, Fig. 16.19 Algorithm for adult basic life support. For further information, see www.resus.org.uk. (CPR = cardiopulmonary resuscitation) From Resuscitation Council (UK) guidelines: https://www.resus.org.uk/ resuscitation-guidelines/in-hospital-resuscitation/. In-hospital resuscitation Collapsed / sick patient Shout for HELP and assess patient Signs of life? YES Assess ABCDE Recognise and treat Oxygen, monitoring, IV access Call resuscitation team if appropriate Handover to resuscitation team NO Call resuscitation team CPR 30:2 with oxygen and airway adjuncts Apply pads/monitor Attempt defibrillation if appropriate Advanced life support when resuscitation team arrives encompasses manœuvres that aim to maintain a low level of circulation until more definitive treatment with advanced life support can be given. Chest compression-only (‘hands-only’) cardiopulmonary resuscitation (CPR) is easier for members of the public to learn and administer, and is now advocated in public education campaigns. Advanced life support Advanced life support (ALS) (Fig. 16.20) aims to restore normal cardiac rhythm by defibrillation when the cause of cardiac arrest is a tachyarrhythmia, or to restore cardiac output by correcting other reversible causes of cardiac arrest. The initial priority is to assess the patient’s cardiac rhythm by attaching a defibrillator or monitor. Once that this has been done, treatment should be instituted based on the clinical findings. Ventricular fibrillation or pulseless ventricular tachycardia should be treated with immediate defibrillation. Defibrillation is more likely to be effective if a biphasic shock defibrillator is used, where the polarity of the shock is reversed midway through its delivery. Defibrillation is usually administered using a 150-joule biphasic shock, and CPR resumed immediately for 2 minutes without attempting to confirm restoration of a pulse because restoration of mechanical cardiac output rarely occurs immediately after successful defibrillation. If, after 2 minutes, a pulse is not restored, a further biphasic shock of 150–200 joules should be given. Thereafter, additional biphasic shocks of 150–200 joules are given every 2 minutes after each cycle of CPR. During resuscitation, adrenaline (epinephrine, 1 mg IV) should be given every 3–5 minutes and consideration given to the use

458 • CARDIOLOGY Fig. 16.20 Algorithm for adult advanced life support. For further information, see www.resus.org.uk. (CPR = cardiopulmonary resuscitation: PEA = pulseless electrical activity; VF = ventricular fibrillation; VT = ventricular tachycardia) From Resuscitation Council (UK) guidelines: https://www.resus.org.uk/resuscitation-guidelines/adult-advanced-life-support/. Advanced life support Unresponsive and not breathing normally? CPR 30:2 Attach defibrillator/monitor Minimise interruptions Assess rhythm Call resuscitation team Non-shockable (PEA/Asystole) Immediately resume CPR for 2 mins Minimise interruptions Immediately resume CPR for 2 mins Minimise interruptions Shockable (VF/Pulseless VT) Return of spontaneous circulation Immediate post-cardiac arrest treatment • Use ABCDE approach • Aim for SaO2 of 94–98% • Aim for normal PaCO2 • 12-lead ECG • Treat precipitating cause • Targeted temperature management During CPR • Ensure high-quality chest compressions • Minimise interruptions to compressions • Give oxygen • Use waveform capnography • Perform continuous compressions when advanced airway in place • Gain vascular access (intravenous or interosseous) • Give adrenaline (epinephrine) every 3–5 min • Give amiodarone after 3 shocks Treat reversible causes Hypoxia Hypovolaemia Hypo-/hyperkalaemia/metabolic Hypothermia/hyperthermia Consider • Ultrasound imaging • Mechanical chest compressions to facilitate transfer/treatment • Coronary angiography and percutaneous coronary intervention • Extracorporeal CPR Thrombosis – coronary or pulmonary Tension pneumothorax Tamponade – cardiac Toxins 1 shock Minimise interruptions Fig. 16.21 The Chain of Survival in cardiac arrest. (ALS = advanced life support; CPR = cardiopulmonary resuscitation) t o

g e t h e l p E a rl y

A C C E S S t o

g e t h e l p E a rl y

A C C E S S t o

b u y ti m e E a rl y C P R t o r e s t a r t h e a r t E a r l y

D E F I B R I L L A T I O N t o

s t a b il i s e E a rl y

A L S

Presenting problems in cardiovascular disease • 459

the murmur, such as the ‘blowing’ murmur of mitral regurgitation or the ‘rasping’ murmur of aortic stenosis. The position of a murmur in relation to the cardiac cycle is crucial and should be assessed by timing it with the heart sounds, carotid pulse and apex beat (Figs 16.22 and 16.23). Systolic murmurs Ejection systolic murmurs are associated with ventricular outflow tract obstruction and occur in mid-systole with a do not. Pericardial friction produces a characteristic scratching noise termed a pericardial rub, which may have two components corresponding to atrial and ventricular systole, and may vary with posture and respiration. Is the sound pathological? Pathological sounds and murmurs are the product of turbulent blood flow or rapid ventricular filling due to abnormal loading conditions. Some added sounds are physiological but may also occur in pathological conditions; for example, a third sound is common in young people and in pregnancy but is also a feature of heart failure (Box 16.8). Similarly, a systolic murmur due to turbulence across the right ventricular outflow tract may occur in hyperdynamic states such as anaemia or pregnancy, but may also be due to pulmonary stenosis or an intracardiac shunt leading to volume overload of the RV, such as an atrial septal defect. Benign murmurs do not occur in diastole (Box 16.9), and systolic murmurs that radiate or are associated with a thrill are almost always pathological. What is the origin of the sound? Timing, intensity, location, radiation and quality are all useful clues to the origin and nature of an additional sound or murmur (Box 16.10). Radiation of a murmur is determined by the direction of turbulent blood flow and is detectable only when there is a high-velocity jet, such as in mitral regurgitation (radiation from apex to axilla) or aortic stenosis (radiation from base to neck). Similarly, the pitch and quality of the sound can help to distinguish 16.10 How to assess a heart murmur When does it occur? • Time the murmur using heart sounds, carotid pulse and the apex beat. Is it systolic or diastolic? • Does the murmur extend throughout systole or diastole or is it confined to a shorter part of the cardiac cycle? How loud is it? (intensity) • Grade 1: very soft (audible only in ideal conditions) • Grade 2: soft • Grade 3: moderate • Grade 4: loud with associated thrill • Grade 5: very loud • Grade 6: heard without stethoscope Note: Diastolic murmurs are very rarely above grade 4 Where is it heard best? (location) • Listen over the apex and base of the heart, including the aortic and pulmonary areas Where does it radiate? • Listen at the neck, axilla or back What does it sound like? (pitch and quality) • Pitch is determined by flow (high pitch indicates high-velocity flow) • Is the intensity constant or variable? 16.9 Features of a benign or innocent heart murmur • Soft • Mid-systolic • Heard at left sternal edge • No radiation • No other cardiac abnormalities 16.8 Normal and abnormal heart sounds Sound Timing Characteristics Mechanisms Variable features First heart sound (S1) Onset of systole Usually single or narrowly split Closure of mitral and tricuspid valves Loud: hyperdynamic circulation (anaemia, pregnancy, thyrotoxicosis); mitral stenosis Soft: heart failure; mitral regurgitation Second heart sound (S2) End of systole Split on inspiration Single on expiration (p. 447) Closure of aortic and pulmonary valve A2 first P2 second Fixed wide splitting with atrial septal defect Wide but variable splitting with delayed right heart emptying (right bundle branch block) Reversed splitting due to delayed left heart emptying (left bundle branch block) Third heart sound (S3) Early in diastole, just after S2 Low pitch, often heard as ‘gallop’ From ventricular wall due to abrupt cessation of rapid filling Physiological: young people, pregnancy Pathological: heart failure, mitral regurgitation Fourth heart sound (S4) End of diastole, just before S1 Low pitch Ventricular origin (stiff ventricle and augmented atrial contraction) related to atrial filling Absent in atrial fibrillation A feature of severe left ventricular hypertrophy Systolic clicks Early or mid-systole Brief, high-intensity sound Valvular aortic stenosis Valvular pulmonary stenosis Floppy mitral valve Prosthetic heart sounds from opening and closing of normally functioning mechanical valves Click may be lost when stenotic valve becomes thickened or calcified Prosthetic clicks lost when valve obstructed by thrombus or vegetations Opening snap (OS) Early in diastole High pitch, brief duration Opening of stenosed leaflets of mitral valve Prosthetic heart sounds Moves closer to S2 as mitral stenosis becomes more severe. May be absent in calcific mitral stenosis

460 • CARDIOLOGY occur in mitral valve prolapse, if the mitral regurgitation is confined to late systole, and hypertrophic obstructive cardiomyopathy, if dynamic obstruction occurs late in systole. Diastolic murmurs These are due to accelerated or turbulent flow across the mitral or tricuspid valves. They are low-pitched noises that are often difficult to hear and should be evaluated with the bell of the stethoscope. A mid-diastolic murmur may be due to mitral stenosis (located at the apex and axilla), tricuspid stenosis (located at the left sternal edge), increased flow across the mitral valve (for example, the to-and-fro murmur of severe mitral regurgitation) or increased flow across the tricuspid valve (for example, a left-to-right shunt through a large atrial septal defect). Early diastolic murmurs have a soft, blowing quality with a decrescendo pattern and should be evaluated with the diaphragm of the stethoscope. They are due to regurgitation across the aortic or pulmonary valves and are best heard at the left sternal edge, with the patient sitting forwards in held expiration. crescendo–decrescendo pattern, reflecting the changing velocity of blood flow (Box 16.11). Pansystolic murmurs maintain a constant intensity and extend from the first heart sound throughout systole to the second heart sound, sometimes obscuring it. They occur when blood leaks from a ventricle into a low-pressure chamber at an even or constant velocity. Mitral regurgitation, tricuspid regurgitation and ventricular septal defect are the only causes of a pansystolic murmur. Late systolic murmurs are unusual but may Fig. 16.22 The relationship of the cardiac cycle to the ECG, the left ventricular pressure wave and the position of heart sounds. Opening snap in mitral stenosis or mitral prosthesis Ejection click, or opening sound of aortic prosthesis Aortic pressure Left ventricular pressure 4th sound 1st sound 2nd sound 3rd sound Left atrial pressure DIASTOLE SYSTOLE DIASTOLE Mid-systolic click Clicks Sounds ECG Fig. 16.23 The timing and pattern of cardiac murmurs. Pansystolic murmur (mitral regurgitation, tricuspid regurgitation, ventricular septal defect) Late systolic murmur (mitral valve prolapse) S1 S2 Click Opening snap Mid-diastolic murmur (mitral stenosis, tricuspid stenosis, mitral or tricuspid flow murmurs) Early diastolic murmur (aortic or pulmonary regurgitation) Ejection systolic murmur (aortic stenosis, pulmonary stenosis, aortic or pulmonary flow murmurs) 16.11 Features of some common systolic murmurs Condition Timing and duration Quality Location and radiation Associated features Aortic stenosis Mid-systolic Loud, rasping Base and left sternal edge, radiating to suprasternal notch and carotids Single second heart sound Ejection click (in young patients) Slow rising pulse Left ventricular hypertrophy (pressure overload) Mitral regurgitation Pansystolic Blowing Apex, radiating to axilla Soft first heart sound Third heart sound Left ventricular hypertrophy (volume overload) Ventricular septal defect Pansystolic Harsh Lower left sternal edge, radiating to whole precordium Thrill Biventricular hypertrophy Benign Mid-systolic Soft Left sternal edge, no radiation No other signs of heart disease

Presenting problems in cardiovascular disease • 461

aged 80–89 years. In the UK, most patients admitted to hospital with heart failure are more than 70 years old; they typically remain hospitalised for a week or more and may be left with chronic disability. Although the outlook depends, to some extent, on the underlying cause of the problem, untreated heart failure generally carries a poor prognosis; approximately 50% of patients with severe heart failure due to left ventricular dysfunction will die within 2 years because of either pump failure or malignant ventricular arrhythmias. The most common causes are coronary artery disease and myocardial infarction but almost all forms of heart disease can lead to heart failure, as summarised in Box 16.12. An accurate diagnosis is important because treatment of the underlying cause may reverse heart failure or prevent its progression. Pathogenesis Heart failure occurs when cardiac output fails to meet the demands of the circulation. Cardiac output is determined by preload (the volume and pressure of blood in the ventricles at the end of diastole), afterload (the volume and pressure of blood in the ventricles during systole) and myocardial contractility, forming the basis of Starling’s Law (Fig. 16.24). The causes of heart failure are discussed below. Continuous murmurs These result from a combination of systolic and diastolic flow, such as occurs with a persistent ductus arteriosus, and must be distinguished from extracardiac noises such as bruits from arterial shunts, venous hums (high rates of venous flow in children) and pericardial friction rubs. Investigations If clinical evaluation suggests that the additional sound is cardiac and likely to be pathological, then echocardiography is indicated to determine the underlying cause. Management Management of patients with additional cardiac sounds depends on the underlying cause. More details are provided in the sections on specific valve defects and congenital anomalies later in this chapter (pp. 514 and 531). Heart failure Heart failure describes the clinical syndrome that develops when the heart cannot maintain adequate output, or can do so only at the expense of elevated ventricular filling pressure. In mild to moderate forms of heart failure, symptoms occur only when the metabolic demand increases during exercise or some other form of stress. In severe heart failure, symptoms may be present at rest. In clinical practice, heart failure may be diagnosed when a patient with significant heart disease develops the signs or symptoms of a low cardiac output, pulmonary congestion or systemic venous congestion at rest or on exercise. Three types of heart failure are recognised. Left heart failure This is characterised by a reduction in left ventricular output and an increase in left atrial and pulmonary venous pressure. If left heart failure occurs suddenly – for example, as the result of an acute MI – the rapid increase in left atrial pressure causes pulmonary oedema. If the rise in atrial pressure is more gradual, as occurs with mitral stenosis, there is reflex pulmonary vasoconstriction, which protects the patient from pulmonary oedema. However, the resulting increase in pulmonary vascular resistance causes pulmonary hypertension, which in turn impairs right ventricular function. Right heart failure This is characterised by a reduction in right ventricular output and an increase in right atrial and systemic venous pressure. The most common causes are chronic lung disease, pulmonary embolism and pulmonary valvular stenosis. The term ‘cor pulmonale’ is used to describe right heart failure that is secondary to chronic lung disease. Biventricular heart failure In biventricular failure, both sides of the heart are affected. This may occur because the disease process, such as dilated cardiomyopathy or ischaemic heart disease, affects both ventricles or because disease of the left heart leads to chronic elevation of the left atrial pressure, pulmonary hypertension and right heart failure. Epidemiology Heart failure predominantly affects the elderly; the prevalence rises from 1% in those aged 50–59 years to over 10% in those Fig. 16.24 Starling’s Law. Normal (A), mild (B), moderate (C) and severe (D) heart failure. Ventricular performance is related to the degree of myocardial stretching. An increase in preload (end-diastolic volume, end-diastolic pressure, filling pressure or atrial pressure) will therefore enhance function; however, overstretching causes marked deterioration. In heart failure, the curve moves to the right and becomes flatter. An increase in myocardial contractility or a reduction in afterload will shift the curve upwards and to the left (green arrow). Cardiac output or ventricular performance Contractility Afterload A B C D Preload Ventricular dysfunction Ventricular dysfunction is the most common cause of heart failure. This can occur because of impaired systolic contraction due to myocardial disease, or diastolic dysfunction where there is abnormal ventricular relaxation due to a stiff, non-compliant ventricle. This is most commonly found in patients with left ventricular hypertrophy. Systolic dysfunction and diastolic dysfunction often coexist, particularly in patients with coronary artery disease. Ventricular dysfunction reduces cardiac output, which, in turn, activates the sympathetic nervous system (SNS) and renin–angiotensin–aldosterone system (RAAS). Under normal circumstances, activation of the SNS and RAAS supports cardiac function but, in the setting of impaired ventricular function, the consequences are negative and lead to an increase in both afterload and preload (Fig. 16.25). A vicious circle may then be

462 • CARDIOLOGY 16.12 Mechanisms of heart failure Cause Examples Features Reduced ventricular contractility Myocardial infarction (segmental dysfunction) In coronary artery disease, ‘akinetic’ or ‘dyskinetic’ segments contract poorly and may impede the function of normal segments by distorting their contraction and relaxation patterns Myocarditis/cardiomyopathy (global dysfunction) Progressive ventricular dilatation Ventricular outflow obstruction (pressure overload) Hypertension, aortic stenosis (left heart failure) Pulmonary hypertension, pulmonary valve stenosis (right heart failure) Initially, concentric ventricular hypertrophy allows the ventricle to maintain a normal output by generating a high systolic pressure. Later, secondary changes in the myocardium and increasing obstruction lead to failure with ventricular dilatation and rapid clinical deterioration Ventricular inflow obstruction Mitral stenosis, tricuspid stenosis Small, vigorous ventricle; dilated, hypertrophied atrium. Atrial fibrillation is common and often causes marked deterioration because ventricular filling depends heavily on atrial contraction Ventricular volume overload Left ventricular volume overload (mitral or aortic regurgitation) Ventricular septal defect Right ventricular volume overload (atrial septal defect) Increased metabolic demand (high output) Dilatation and hypertrophy allow the ventricle to generate a high stroke volume and help to maintain a normal cardiac output. However, secondary changes in the myocardium lead to impaired contractility and worsening heart failure Arrhythmia Atrial fibrillation Tachycardia does not allow for adequate filling of the heart, resulting in reduced cardiac output and back pressure Tachycardia Prolonged tachycardia causes myocardial fatigue Complete heart block Bradycardia limits cardiac output, even if stroke volume is normal Diastolic dysfunction Constrictive pericarditis Marked fluid retention and peripheral oedema, ascites, pleural effusions and elevated jugular veins Restrictive cardiomyopathy Bi-atrial enlargement (restrictive filling pattern and high atrial pressures). Atrial fibrillation may cause deterioration Left ventricular hypertrophy and fibrosis Cardiac tamponade Good systolic function but poor diastolic filling Hypotension, elevated jugular veins, pulsus paradoxus, poor urine output Fig. 16.25 Neurohumoral activation and compensatory mechanisms in heart failure. There is a vicious circle in progressive heart failure. Myocyte loss Heart failure Reduced cardiac output Myocardial fibrosis Neurohumoral activation Sympathetic nervous system Renin – angiotensin system Vasopressin system Endothelin system Increased blood pressure and cardiac work Increased blood pressure and cardiac work Increased intravascular volume Sodium and water retention Increased afterload Vasoconstriction established because any additional fall in cardiac output causes further activation of the SNS and RAAS, and an additional increase in peripheral vascular resistance. Activation of the RAAS causes vasoconstriction and sodium and water retention. This is primarily mediated by angiotensin II, a potent constrictor of arterioles, in both the kidney and the systemic circulation (Fig. 16.25). Activation of the SNS also occurs and can initially sustain cardiac output through increased myocardial contractility and heart rate. Prolonged sympathetic stimulation has negative effects, however, causing cardiac myocyte apoptosis, cardiac hypertrophy and focal myocardial necrosis. Sympathetic stimulation also contributes to vasoconstriction and predisposes to arrhythmias. Sodium and water retention is further enhanced by the release of aldosterone, endothelin-1 (a potent vasoconstrictor peptide with marked effects on the renal vasculature) and, in severe heart failure, vasopressin (antidiuretic hormone, ADH). Natriuretic peptides are released from the atria in response to atrial dilatation and compensate to an extent for the sodium-conserving effect of aldosterone, but this mechanism is overwhelmed in heart failure. Pulmonary and peripheral oedema occurs because of high left and right atrial pressures, and is compounded by sodium and water retention, caused by impairment of renal perfusion and by secondary hyperaldosteronism. If the underlying cause is a myocardial infarction, cardiac contractility is impaired and SNS and RAAS activation causes hypertrophy of noninfarcted segments, with thinning, dilatation and expansion of the infarcted segment (see Fig. 16.64, p. 496). This leads to further deterioration in ventricular function and worsening heart failure.

Presenting problems in cardiovascular disease • 463

is severe. There may be an expiratory wheeze. Patients with acute-on-chronic heart failure may have additional features of chronic heart failure (see below). Potential precipitants, such as an upper respiratory tract infection or inappropriate cessation of diuretic medication, may be identified on clinical examination or history-taking. Chronic heart failure Patients with chronic heart failure commonly follow a relapsing and remitting course, with periods of stability and episodes of decompensation, leading to worsening symptoms that may necessitate hospitalisation. The clinical picture depends on the nature of the underlying heart disease, the type of heart failure that it has evoked, and the changes in the SNS and RAAS that have developed (see Box 16.12 and Fig. 16.26). Low cardiac output causes fatigue, listlessness and a poor effort tolerance; the peripheries are cold and the BP is low. To maintain perfusion of vital organs, blood flow is diverted away from skeletal muscle and this may contribute to fatigue and weakness. Poor renal perfusion leads to oliguria and uraemia. Pulmonary oedema due to left heart failure presents with dyspnoea and inspiratory crepitations over the lung bases. In contrast, right heart failure produces a high JVP with hepatic congestion and dependent peripheral oedema. In ambulant patients the oedema affects the ankles, whereas in bed-bound patients it collects around the thighs and sacrum. Ascites or pleural effusion may occur (Fig. 16.26). Heart failure is not the only cause of oedema (Box 16.14). High-output failure Sometimes cardiac failure can occur in patients without heart disease due to a large arteriovenous shunt, or where there is an excessively high cardiac output due to beri-beri (p. 714), severe anaemia or thyrotoxicosis. Valvular disease Heart failure can also be caused by valvular disease in which there is impaired filling of the ventricles due to mitral or tricuspid stenosis; where there is obstruction to ventricular outflow, as occurs in aortic and tricuspid stenosis and hypertrophic cardiomyopathy; or as the result of ventricular overload secondary to valvular regurgitation. Clinical assessment Heart failure may develop suddenly, as in MI, or gradually, as in valvular heart disease. When there is gradual impairment of cardiac function, several compensatory changes take place. The term compensated heart failure is sometimes used to describe the condition of those with impaired cardiac function, in whom adaptive changes have prevented the development of overt heart failure. However, a minor event, such as an intercurrent infection or development of atrial fibrillation, may precipitate acute heart failure in these circumstances (Box 16.13). Similarly, acute heart failure sometimes supervenes as the result of a decompensating episode, on a background of chronic heart failure; this is called acute-on-chronic heart failure. Acute left heart failure Acute left heart failure presents with a sudden onset of dyspnoea at rest that rapidly progresses to acute respiratory distress, orthopnoea and prostration. Often there is a clear precipitating factor, such as an acute MI, which may be apparent from the history. The patient appears agitated, pale and clammy. The peripheries are cool to the touch and the pulse is rapid, but in some cases there may be an inappropriate bradycardia that may contribute to the acute episode of heart failure. The BP is usually high because of SNS activation, but may be normal or low if the patient is in cardiogenic shock. The jugular venous pressure (JVP) is usually elevated, particularly with associated fluid overload or right heart failure. In acute heart failure, there has been no time for ventricular dilatation and the apex is not displaced. A ‘gallop’ rhythm, with a third heart sound, is heard quite early in the development of acute left-sided heart failure. A new systolic murmur may signify acute mitral regurgitation or ventricular septal rupture. Chest examination may reveal crepitations at the lung bases if there is pulmonary oedema, or crepitations throughout the lungs if this 16.13 Factors that may precipitate or aggravate heart failure in pre-existing heart disease • Myocardial ischaemia or infarction • Intercurrent illness • Arrhythmia • Inappropriate reduction of therapy • Administration of a drug with negative inotropic (β-blocker) or fluid-retaining properties (non-steroidal anti-inflammatory drugs, glucocorticoids) • Pulmonary embolism • Conditions associated with increased metabolic demand (pregnancy, thyrotoxicosis, anaemia) • Intravenous fluid overload Fig. 16.26 Clinical features of left and right heart failure. (JVP = jugular venous pressure) Left heart failure Raised JVP +/++ Pleural effusions Pulmonary oedema Cardiomegaly Pitting oedema +/++ Right heart failure Raised JVP +++ Hepatomegaly Ascites Peripheral pitting oedema +++ 16.14 Differential diagnosis of peripheral oedema • Cardiac failure: right or combined left and right heart failure, pericardial constriction, cardiomyopathy • Chronic venous insufficiency: varicose veins • Hypoalbuminaemia: nephrotic syndrome, liver disease, proteinlosing enteropathy; often widespread, can affect arms and face • Drugs: Sodium retention: fludrocortisone, non-steroidal anti- inflammatory drugs Increasing capillary permeability: nifedipine, amlodipine • Idiopathic: women > men • Chronic lymphatic obstruction

464 • CARDIOLOGY B’ lines). More advanced changes due to alveolar oedema cause a hazy opacification spreading from the hilar regions, and pleural effusions. Echocardiography is very useful and should be considered in all patients with heart failure in order to: • determine the aetiology • detect hitherto unsuspected valvular heart disease, such as occult mitral stenosis, and other conditions that may be amenable to specific remedies • identify patients who will benefit from long-term drug therapy. Serum urea, creatinine and electrolytes, haemoglobin and thyroid function may help to establish the nature and severity of the underlying heart disease and detect any complications. BNP is elevated in heart failure and is a prognostic marker, as well as being useful in differentiating heart failure from other causes of breathlessness or peripheral oedema. Management of acute heart failure Acute heart failure with pulmonary oedema is a medical emergency that should be treated urgently. The patient should initially be kept rested, with continuous monitoring of cardiac rhythm, BP and Chronic heart failure is sometimes associated with marked weight loss (cardiac cachexia), caused by a combination of anorexia and impaired absorption due to gastrointestinal congestion, poor tissue perfusion due to a low cardiac output, and skeletal muscle atrophy due to immobility. Complications of heart failure Several complications may occur in advanced heart failure, as described below. • Renal failure is caused by poor renal perfusion due to low cardiac output and may be exacerbated by diuretic therapy, ACE inhibitors and angiotensin receptor blockers (ARBs). • Hypokalaemia may be the result of treatment with potassium-losing diuretics or hyperaldosteronism caused by activation of the renin–angiotensin system and impaired aldosterone metabolism due to hepatic congestion. Most of the body’s potassium is intracellular and there may be substantial depletion of potassium stores, even when the plasma concentration is in the reference range. • Hyperkalaemia may be due to the effects of drugs that promote renal resorption of potassium, in particular the combination of ACE inhibitors, ARBs and mineralocorticoid receptor antagonists. These effects are amplified if there is renal dysfunction due to low cardiac output or atherosclerotic renal vascular disease. • Hyponatraemia is a feature of severe heart failure and is a poor prognostic sign. It may be caused by diuretic therapy, inappropriate water retention due to high vasopressin secretion, or failure of the cell membrane ion pump. • Impaired liver function is caused by hepatic venous congestion and poor arterial perfusion, which frequently cause mild jaundice and abnormal liver function tests; reduced synthesis of clotting factors can make anticoagulant control difficult. • Thromboembolism. Deep vein thrombosis and pulmonary embolism may occur due to the effects of a low cardiac output and enforced immobility. Systemic emboli occur in patients with atrial fibrillation or flutter, or with intracardiac thrombus complicating conditions such as mitral stenosis, MI or left ventricular aneurysm. • Atrial and ventricular arrhythmias are very common and may be related to electrolyte changes such as hypokalaemia and hypomagnesaemia, the underlying cardiac disease, and the pro-arrhythmic effects of sympathetic activation. Atrial fibrillation occurs in approximately 20% of patients with heart failure and causes further impairment of cardiac function. Ventricular ectopic beats and runs of non-sustained ventricular tachycardia are common findings in patients with heart failure and are associated with an adverse prognosis. • Sudden death occurs in up to 50% of patients with heart failure and is most probably due to ventricular fibrillation. Investigations A chest X-ray should be performed in all cases. This may show abnormal distension of the upper lobe pulmonary veins with the patient in the erect position (Fig. 16.27). Vascularity of the lung fields becomes more prominent and the right and left pulmonary arteries dilate. Subsequently, interstitial oedema causes thickened interlobular septa and dilated lymphatics. These are evident as horizontal lines in the costophrenic angles (septal or ‘Kerley Fig. 16.27 Radiological features of heart failure. A Chest X-ray of a patient with pulmonary oedema. B Enlargement of lung base showing septal or ‘Kerley B’ lines (arrow). A B Prominence of upper lobe blood vessels Enlarged hilar vessels Septal or ‘Kerley B’ lines Reticular shadowing of alveolar oedema Enlarged cardiac silhouette; usually with coexisting chronic heart failure

Presenting problems in cardiovascular disease • 465

pulse oximetry. Intravenous opiates can be of value in distressed patients but must be used sparingly, as they may cause respiratory depression and exacerbation of hypoxaemia and hypercapnia. The key elements of management are summarised in Box 16.15. If these measures prove ineffective, inotropic agents such as dobutamine (2.5–10 μg/kg/min) may be required to augment cardiac output, particularly in hypotensive patients. Insertion of an intra-aortic balloon pump may be beneficial in patients with acute cardiogenic pulmonary oedema and shock. Following management of the acute episode, additional measures must be instituted to control heart failure in the longer term, as discussed below. Management of chronic heart failure The aims of treatment in chronic heart failure are to improve cardiac function by increasing contractility, optimising preload or decreasing afterload, and controlling cardiac rate and rhythm (see Fig. 16.25). This can be achieved by a combination of drug treatment or non-drug treatments, as discussed below. Education Education of patients and their relatives about the causes and treatment of heart failure can improve adherence to a management plan (Box 16.16). Some patients may need to weigh themselves daily, as a measure of fluid load, and adjust their diuretic therapy accordingly. Drug treatment A wide variety of drug treatments are now available for the treatment of heart failure. Drugs that reduce preload are appropriate in patients with high end-diastolic filling pressures and evidence of pulmonary or systemic venous congestion, whereas those that reduce afterload or increase myocardial contractility are more useful in patients with signs and symptoms of a low cardiac output. Diuretics Diuretics promote urinary sodium and water excretion, leading to a reduction in blood plasma volume (p. 354), which in turn reduces preload and improves pulmonary and systemic venous congestion. They may also reduce afterload and ventricular volume, leading to a fall in ventricular wall tension and increased cardiac efficiency. Although a fall in preload (ventricular filling pressure) normally reduces cardiac output, patients with heart failure are beyond the apex of the Starling curve, so there may Fig. 16.28 The effect of treatment on ventricular performance curves in heart failure. Diuretics and venodilators (A), angiotensinconverting enzyme (ACE) inhibitors and mixed vasodilators (B), and positive inotropic agents (C). Normal Heart failure C A B Cardiac output or ventricular performance Preload Forward failure Fatigue Backward failure Dyspnoea/oedema 16.16 General measures for the management of heart failure Education • Explanation of nature of disease, treatment and self-help strategies Diet • Good general nutrition and weight reduction for the obese • Avoidance of high-salt foods and added salt, especially for patients with severe congestive heart failure Alcohol • Moderation or elimination of alcohol consumption; alcohol-induced cardiomyopathy requires abstinence Smoking • Cessation Exercise • Regular moderate aerobic exercise within limits of symptoms Vaccination • Consideration of influenza and pneumococcal vaccination 16.15 Management of acute pulmonary oedema Action Effect Sit the patient up Reduces preload Give high-flow oxygen Corrects hypoxia Ensure continuous positive airway pressure (CPAP) of 5–10 mmHg by tight-fitting mask Reduces preload and pulmonary capillary hydraulic gradient Administer nitrates:* IV glyceryl trinitrate (10–200 μg/min) Buccal glyceryl trinitrate 2–5 mg Reduces preload and afterload Administer a loop diuretic: Furosemide (50–100 mg IV) Combats fluid overload *The dose of nitrate should be titrated upwards every 10 mins until there is an improvement or systolic blood pressure is < 110 mmHg. be a substantial and beneficial fall in filling pressure with either no change or an improvement in cardiac output (see Figs 16.24 and 16.28). Nevertheless, the dose of diuretics needs to be titrated carefully so as to avoid excessive volume depletion, which can cause a fall in cardiac output with hypotension, lethargy and renal failure. This is especially likely in patients with a marked diastolic component to their heart failure. Oedema may persist, despite oral loop diuretic therapy, in some patients with severe chronic heart failure, particularly if there is renal impairment. Under these circumstances an intravenous infusion of furosemide (5–10 mg/hr) may initiate a diuresis. Combining a loop diuretic with a thiazide diuretic such as bendroflumethiazide (5 mg daily) may also prove effective but care must be taken to avoid an excessive diuresis. Mineralocorticoid receptor antagonists, such as spironolactone and eplerenone, are potassium-sparing diuretics that are of particular benefit in patients with heart failure with severe left ventricular systolic dysfunction. They have been shown to improve long-term clinical outcome in individuals with severe heart failure or heart failure following acute MI but may cause hyperkalaemia, particularly when used with an ACE inhibitor.

466 • CARDIOLOGY the community. In other patients, however, it is usually advisable to withhold diuretics for 24 hours before starting treatment with a small dose of a long-acting agent, preferably given at night (Box 16.18). Renal function and serum potassium must be monitored and should be checked 1–2 weeks after starting therapy. Angiotensin receptor blockers ARBs act by blocking the action of angiotensin II on the heart, peripheral vasculature and kidney. In heart failure, they produce beneficial haemodynamic changes that are similar to the effects of ACE inhibitors (Fig. 16.29) but are generally better tolerated. They have comparable effects on mortality and are a useful alternative for patients who cannot tolerate ACE inhibitors. Like ACE inhibitors they should be started at a low dose and titrated upwards, depending on response (Box 16.18). Unfortunately, they share all the more serious adverse effects of ACE inhibitors, including renal dysfunction and hyperkalaemia. ARBs are normally used as an alternative to ACE inhibitors, but the two can be combined in patients with resistant or recurrent heart failure. Neprilysin inhibitors The only drug currently in this class is sacubitril, a small-molecule inhibitor of neprilysin, which is Angiotensin-converting enzyme inhibitors ACE inhibitors play a central role in the management of heart failure since they interrupt the vicious circle of neurohumoral activation that is characteristic of the disease by preventing the conversion of angiotensin I to angiotensin II. This, in turn, reduces peripheral vasoconstriction, activation of the sympathetic nervous system (Fig. 16.29), and salt and water retention due to aldosterone release, as well as preventing the activation of the renin–angiotensin system caused by diuretic therapy. In moderate and severe heart failure, ACE inhibitors can produce a substantial improvement in effort tolerance and in mortality. They can also improve outcome and prevent the onset of overt heart failure in patients with poor residual left ventricular function following MI. Adverse effects of ACE inhibitors include symptomatic hypotension and impairment of renal function, especially in patients with bilateral renal artery stenosis or those with pre-existing renal disease. An increase in serum potassium concentration may also occur, which can be beneficial in offsetting the hypokalaemia associated with loop diuretic therapy. Short-acting ACE inhibitors can cause marked falls in BP, particularly in the elderly or when started in the presence of hypotension, hypovolaemia or hyponatraemia. In stable patients without hypotension (systolic BP over 100 mmHg), ACE inhibitors can usually be safely started in 16.17 Congestive cardiac failure in old age • Incidence: rises with age and affects 5–10% of those in their eighties. • Common causes: coronary artery disease, hypertension and calcific degenerative valvular disease. • Diastolic dysfunction: often prominent, particularly in those with a history of hypertension. • ACE inhibitors: improve symptoms and mortality but are more frequently associated with postural hypotension and renal impairment than in younger patients. • Loop diuretics: usually required but may be poorly tolerated in those with urinary incontinence and men with prostate enlargement. Fig. 16.29 Neurohumoral activation and sites of action of drugs used in the treatment of heart failure. Angiotensinogen Angiotensin I Angiotensin II Vasoconstriction Renin (kidney) Angiotensinconverting enzyme (ACE) Non-ACE pathways Bradykinin Inactive peptides Vasodilatation ACE inhibitors Aldosterone Enhanced sympathetic activity Salt and water retention β-blockers Mineralocorticoid receptor antagonists Diuretics Angiotensin receptor blockers 16.18 Dosages of ACE inhibitors, β-blockers and angiotensin receptor blockers in heart failure Starting dose Target dose ACE inhibitors Enalapril 2.5 mg twice daily 10 mg twice daily Lisinopril 2.5 mg daily 20 mg daily Ramipril 1.25 mg daily 10 mg daily Angiotensin receptor blockers Losartan 25 mg daily 100 mg daily Candesartan 4 mg daily 32 mg daily Valsartan 40 mg daily 160 mg daily β-blockers Bisoprolol 1.25 mg daily 10 mg daily Metoprolol 25 mg twice daily 100 mg twice daily Carvedilol 3.125 mg twice daily 25 mg twice daily

Presenting problems in cardiovascular disease • 467

areas of the myocardium that are ‘hibernating’ because of inadequate blood supply, and can be used to treat carefully selected patients with heart failure and coronary artery disease. If necessary, ‘hibernating’ myocardium can be identified by stress echocardiography and specialised nuclear or magnetic resonance imaging. Cardiac transplantation Cardiac transplantation is an established and successful treatment for patients with intractable heart failure. Coronary artery disease and dilated cardiomyopathy are the most common indications. The use of transplantation is limited by the efficacy of modern drug and device therapies, as well as the availability of donor hearts, so it is generally reserved for young patients with severe symptoms despite optimal therapy. Conventional heart transplantation is contraindicated in patients with pulmonary vascular disease due to long-standing left heart failure, complex congenital heart disease such as Eisenmenger’s syndrome, or primary pulmonary hypertension because the RV of the donor heart may fail in the face of high pulmonary vascular resistance. However, heart–lung transplantation can be successful in patients with Eisenmenger’s syndrome, and lung transplantation has been used for primary pulmonary hypertension. Although cardiac transplantation usually produces a dramatic improvement in the recipient’s quality of life, serious complications may occur: • Rejection. In spite of routine therapy with ciclosporin A, azathioprine and glucocorticoids, episodes of rejection are common and may present with heart failure, arrhythmias or subtle ECG changes. Cardiac biopsy is often used to confirm the diagnosis before starting treatment with high-dose glucocorticoids. • Accelerated atherosclerosis. Recurrent heart failure is often due to progressive atherosclerosis in the coronary arteries of the donor heart. This is not confined to patients who underwent transplantation for coronary artery disease and is probably a manifestation of chronic rejection. Angina is rare because the heart has been denervated. Fig. 16.30 Chest X-ray of a biventricular pacemaker and defibrillator (cardiac resynchronisation therapy). The right ventricular lead (RV) is in position in the ventricular apex and is used for both pacing and defibrillation. The left ventricular lead (LV) is placed via the coronary sinus, and the right atrial lead (RA) is placed in the right atrial appendage; both are used for pacing only. RA RV LV responsible for the breakdown of the endogenous diuretics ANP and BNP. Used in combination with the ARB valsartan (sacubitril–valsartan), it has been shown to produce additional symptomatic and mortality benefit over ACE inhibition and is now recommended in the management of resistant heart failure. Vasodilators These drugs are valuable in chronic heart failure, when ACE inhibitors or ARBs are contraindicated. Venodilators, such as nitrates, reduce preload, and arterial dilators, such as hydralazine, reduce afterload (see Fig. 16.28). Their use is limited by pharmacological tolerance and hypotension. Beta-adrenoceptor blockers Beta-blockade helps to counteract the deleterious effects of enhanced sympathetic stimulation and reduces the risk of arrhythmias and sudden death. When initiated in standard doses β-blockers may precipitate acute-on-chronic heart failure, but when given in small incremental doses they can increase ejection fraction, improve symptoms, reduce the frequency of hospitalisation and reduce mortality in patients with chronic heart failure. A typical regimen is bisoprolol, starting at a dose of 1.25 mg daily and increased gradually over a 12-week period to a target maintenance dose of 10 mg daily. Beta-blockers are more effective at reducing mortality than ACE inhibitors, with a relative risk reduction of 33% versus 20%, respectively. Ivabradine Ivabradine acts on the If inward current in the SA node, resulting in reduction of heart rate. It reduces hospital admission and mortality rates in patients with heart failure due to moderate or severe left ventricular systolic impairment. In trials, its effects were most marked in patients with a relatively high heart rate (over 77/min), so ivabradine is best suited to patients who cannot take β-blockers or whose heart rate remains high despite β-blockade. It is ineffective in patients with atrial fibrillation. Digoxin Digoxin (p. 482) can be used to provide rate control in patients with heart failure and atrial fibrillation. In patients with severe heart failure (NYHA class III–IV, see Box 16.5), digoxin reduces the likelihood of hospitalisation for heart failure, although it has no effect on long-term survival. Amiodarone This is a potent anti-arrhythmic drug (p. 481) that has little negative inotropic effect and may be valuable in patients with poor left ventricular function. It is effective only in the treatment of symptomatic arrhythmias and should not be used as a preventative agent in asymptomatic patients. Amiodarone is used for prevention of symptomatic atrial arrhythmias and of ventricular arrhythmias when other pharmacological options have been exhausted. Non-pharmacological treatments Implantable cardiac defibrillators These devices are indicated in patients with symptomatic ventricular arrhythmias and heart failure, since they improve prognosis and survival (p. 483). Resynchronisation devices In patients with marked intraventricular conduction delay, prolonged depolarisation may lead to uncoordinated left ventricular contraction. When this is associated with severe symptomatic heart failure, cardiac resynchronisation devices may be helpful. Here, both the LV and RV are paced simultaneously (Fig. 16.30) to generate a more coordinated left ventricular contraction and improve cardiac output. This is associated with improved symptoms and survival. Coronary revascularisation Coronary artery bypass surgery or percutaneous coronary intervention may improve function in

468 • CARDIOLOGY atria, atrioventricular junction or ventricles, often in response to catecholamines. Single depolarisations lead to atrial, junctional or ventricular premature (ectopic) beats. Repeated depolarisation leads to atrial, junctional or ventricular tachycardia. • Re-entry. The tachycardia is initiated by an ectopic beat and sustained by a re-entry circuit (Fig. 16.31). Most tachyarrhythmias are caused by re-entry. • Triggered activity. This can cause ventricular arrhythmias in patients with coronary artery disease. It is a form of secondary depolarisation arising from an incompletely repolarised cell membrane. Arrhythmias may be supraventricular (sinus, atrial or junctional) or ventricular in origin. Supraventricular rhythms usually produce narrow QRS complexes because the ventricles are depolarised in their normal sequence via the AV node, the bundle of His and associated Purkinje fibres. In contrast, ventricular rhythms produce broad, bizarre QRS complexes because the ventricles are activated in an abnormal sequence. Occasionally, supraventricular tachycardia can mimic ventricular tachycardia and present as a broad-complex tachycardia due to coexisting bundle branch block or the presence of an additional atrioventricular connection (accessory pathway, see below). Bradycardia may be due to reduced automaticity of the SA node or abnormalities of conduction through the AV node. If the sinus rate becomes unduly slow, another, more distal part of the conducting system may assume the role of pacemaker. This is known as an escape rhythm and may arise in the AV node or His bundle (junctional rhythm) or in the ventricles (idioventricular rhythm). Clinical features Many arrhythmias are asymptomatic but sustained tachycardias typically present with rapid palpitation, dizziness, chest discomfort or breathlessness. Extreme tachycardias can also cause syncope because the heart is unable to contract or relax properly at extreme rates. Bradycardias tend to cause symptoms that reflect low cardiac output, including fatigue, lightheadedness and syncope. Extreme bradycardias or tachycardias can precipitate sudden death or cardiac arrest. Investigations The first-line investigation is a standard 12-lead ECG, which can be diagnostic in many cases. If arrhythmias are intermittent and the resting ECG is normal, an attempt should be made to capture the abnormal rhythm using an ambulatory ECG or a patient-activated ECG. • Infection. Opportunistic infection with organisms such as cytomegalovirus or Aspergillus remains a major cause of death in transplant recipients. Ventricular assist devices Because of the limited supply of donor organs, ventricular assist devices (VAD) may be employed as a bridge to cardiac transplantation and as short-term restoration therapy following a potentially reversible insult such as viral myocarditis. In some patients, VADs may be used as a long-term therapy if no other options exist. These devices assist cardiac output by using a roller, centrifugal or pulsatile pump that, in some cases, is implantable and portable. They withdraw blood through cannulae inserted in the atria or ventricular apex and pump it into the pulmonary artery or aorta. They are designed not only to unload the ventricles but also to provide support to the pulmonary and systemic circulations. Their more widespread application is limited by high complication rates (haemorrhage, systemic embolism, infection, neurological and renal sequelae), although some improvements in survival and quality of life have been demonstrated in patients with severe heart failure. Cardiac arrhythmias A cardiac arrhythmia is defined as a disturbance of the electrical rhythm of the heart. Cardiac arrhythmias are often a manifestation of structural heart disease but may also occur because of abnormal conduction or depolarisation in an otherwise healthy heart. There are many types of cardiac arrhythmia, as discussed later in this section. By convention, however, a heart rate of more than 100/min is called a tachycardia, and a heart rate of less than 60/min is called a bradycardia. Pathogenesis Cardiac arrhythmias usually occur as the result of pathology affecting the conduction system of the heart. The cardiac cycle is normally initiated by an electrical discharge from the SA node. The atria and ventricles then activate sequentially as electrical depolarisation passes through specialised conducting tissues (see Fig. 16.4, p. 445). The sinus node acts as a pacemaker and its intrinsic rate is regulated by the autonomic nervous system; vagal activity decreases the heart rate and sympathetic activity increases heart rate through cardiac sympathetic nerves and circulating catecholamines. There are three main mechanisms of tachycardia: • Increased automaticity. The tachycardia is produced by spontaneous depolarisation of an ectopic focus in the Fig. 16.31 The mechanism of re-entry. Re-entry can occur when there are two alternative pathways with different conducting properties, such as the atrioventricular node and an accessory pathway, or an area of normal and an area of ischaemic tissue. Here, pathway A conducts slowly and recovers quickly, while pathway B conducts rapidly and recovers slowly. (1) In sinus rhythm, each impulse passes down both pathways before entering a common distal pathway. (2) As the pathways recover at different rates, a premature impulse may find pathway A open and B closed. (3) Pathway B may recover while the premature impulse is travelling selectively down pathway A. The impulse can then travel retrogradely up pathway B, setting up a closed loop or re-entry circuit. (4) This may initiate a tachycardia that continues until the circuit is interrupted by a change in conduction rates or electrical depolarisation. A A A A B B B B 1 Sinus rhythm 2 Premature impulse 3 Re-entry 4 Tachycardia Refractory tissue

Cardiac arrhythmias • 469

Management Features of individual arrhythmias are discussed below. Management depends on the nature of the arrhythmia and the general principles of medical management are discussed on page 479. Sinus arrhythmia This is defined as a cyclical alteration of the heart rate during respiration, with an increase during inspiration and a decrease during expiration. Sinus arrhythmia is a normal phenomenon and can be quite pronounced in children. Absence of this normal variation in heart rate with breathing or with changes in posture may be a feature of diabetic neuropathy (p. 758), autonomic involvement in patients with diseases of peripheral nerves (p. 1138) or increased sympathetic drive. Sinus arrhythmia does not require treatment. Sinus bradycardia This may occur in healthy people at rest and is a common finding in athletes. Some pathological causes are listed in Box 16.19. If sinus bradycardia is asymptomatic, then no treatment is required. Symptomatic sinus bradycardia may occur acutely during an MI and can be treated with intravenous atropine (0.6–1.2 mg). Patients with recurrent or persistent symptomatic sinus bradycardia should be considered for pacemaker implantation. Sinus tachycardia Sinus tachycardia is usually due to an increase in sympathetic activity associated with exercise, emotion and pregnancy. Healthy young adults can produce a rapid sinus rate, up to 200/min, during intense exercise. Sinus tachycardia does not require treatment but sometimes may reflect an underlying disease, as summarised in Box 16.19. Sick sinus syndrome Sick sinus syndrome can occur at any age but is most common in older people. It is caused by fibrosis, degenerative changes or ischaemia of the SA node and is characterised by a variety of arrhythmias (Box 16.20). The typical presentation is with 16.20 Common features of sinoatrial disease • Sinus bradycardia • Sinoatrial block (sinus arrest) • Paroxysmal atrial fibrillation • Paroxysmal atrial tachycardia • Atrioventricular block 16.19 Some pathological causes of sinus bradycardia and tachycardia Sinus bradycardia • Myocardial infarction • Sinus node disease (sick sinus syndrome) • Hypothermia • Hypothyroidism • Cholestatic jaundice • Raised intracranial pressure • Drugs (β-blockers, digoxin, verapamil) Sinus tachycardia • Anxiety • Fever • Anaemia • Heart failure • Thyrotoxicosis • Phaeochromocytoma • Drugs (β-agonists) Fig. 16.32 Sinoatrial disease (sick sinus syndrome). A continuous rhythm strip from a 24-hour ECG tape recording illustrating periods of sinus rhythm, atrial ectopics, junctional beats, sinus bradycardia, sinus arrest and paroxysmal atrial fibrillation. Sinus beat Junctional beat Sinus bradycardia Sinus arrest Atrial fibrillation Atrial ectopic beat palpitation, dizzy spells or syncope, due to intermittent tachycardia, bradycardia, or pauses with no atrial or ventricular activity (SA block or sinus arrest) (Fig. 16.32). A permanent pacemaker may benefit patients with troublesome symptoms due to spontaneous bradycardias, or those with symptomatic bradycardias induced by drugs required to prevent tachyarrhythmias. Atrial pacing may prevent episodes of atrial fibrillation. Pacing improves symptoms but not prognosis, and is not indicated in patients who are asymptomatic. Atrial ectopic beats Atrial ectopic beats usually cause no symptoms but can give the sensation of a missed beat or an abnormally strong beat. The ECG (Fig. 16.33) shows a premature but otherwise normal QRS complex; if visible, the preceding P wave has a different morphology because the atria activate from an abnormal site. In most cases these are of no consequence, although very frequent atrial ectopic beats may herald the onset of atrial fibrillation.

470 • CARDIOLOGY Atrial fibrillation Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia, with an overall prevalence of 0.5% in the adult population of the UK. The prevalence rises with age, affecting 1% of those aged 60–64 years, increasing to 9% of those aged over 80 years. It is associated with significant morbidity and a twofold increase in mortality. This is mainly because of its association with underlying heart disease but also because of its association with systemic embolism and stroke. Pathogenesis AF is a complex arrhythmia characterised by both abnormal automatic firing and the presence of multiple interacting re-entry circuits looping around the atria. Episodes of AF are initiated by rapid bursts of ectopic beats arising from conducting tissue in the pulmonary veins or from diseased atrial tissue. It becomes sustained because of re-entrant conduction within the atria or sometimes because of continuous ectopic firing (Fig. 16.36). Re-entry is more likely to occur in atria that are enlarged or in which conduction is slow, as is the case in many forms of heart disease. During episodes of AF, the atria beat rapidly but in an uncoordinated and ineffective manner. The ventricles are activated irregularly at a rate determined by conduction through the AV node. This produces the characteristic ‘irregularly irregular’ pulse. The ECG (Fig. 16.37) shows normal but irregular QRS complexes; there are no P waves but the baseline may show irregular fibrillation waves. Commonly, AF is classified as paroxysmal (intermittent episodes that self-terminate within 7 days), persistent Fig. 16.33 Atrial ectopic beats. The first, second and fifth complexes are normal sinus beats. The third, fourth and sixth complexes are atrial ectopic beats with identical QRS complexes and abnormal (sometimes barely visible) P waves. Treatment is rarely necessary but β-blockers can be used if symptoms are intrusive. Atrial tachycardia Atrial tachycardia may be a manifestation of increased atrial automaticity, sinoatrial disease or digoxin toxicity. It produces a narrow-complex tachycardia with abnormal P-wave morphology, sometimes associated with AV block if the atrial rate is rapid. It may respond to β-blockers, which reduce automaticity, or class I or III anti-arrhythmic drugs (see Box 16.30 below). The ventricular response in rapid atrial tachycardias may be controlled by AV node-blocking drugs. Catheter ablation (p. 484) can be used to target the ectopic site and should be offered as an alternative to anti-arrhythmic drugs in patients with recurrent atrial tachycardia. Atrial flutter Atrial flutter is characterised by a large (macro) re-entry circuit, usually within the right atrium encircling the tricuspid annulus. The atrial rate is approximately 300/min, and is usually associated with 2 : 1, 3 : 1 or 4 : 1 AV block (with corresponding heart rates of 150, 100 or 75/min). Rarely, in young patients, every flutter wave is conducted, producing a rate of 300/min and, potentially, haemodynamic compromise. The ECG shows saw-tooth flutter waves (Fig. 16.34). When there is regular 2 : 1 AV block, it may be difficult to identify flutter waves that are buried in QRS complexes and T waves. Atrial flutter should always be suspected when there is a narrow-complex tachycardia of 150/min. Carotid sinus pressure or intravenous adenosine may help to establish the diagnosis by temporarily increasing the degree of AV block and revealing flutter waves (Fig. 16.35). Management Medical management with digoxin, β-blockers or verapamil is often successful in controlling the ventricular rate (p. 479). In many cases, however, it may be preferable to try to restore sinus rhythm by direct current (DC) cardioversion. Following cardioversion, β-blockers or amiodarone can be used to prevent recurrent episodes of atrial flutter. Class Ic anti-arrhythmic drugs such as flecainide are contraindicated because there is a risk of slowing the flutter circuit, facilitating 1 : 1 AV nodal conduction and producing a paradoxical extreme tachycardia and haemodynamic compromise. Catheter ablation is a highly effective treatment, offering a greater than 90% chance of complete cure, and is the treatment of choice for patients with persistent symptoms. Anticoagulant management in patients with atrial flutter, including management around cardioversion, is identical to that of patients with atrial fibrillation (p. 471). Fig. 16.34 Atrial flutter. Simultaneous recording showing atrial flutter with 4 : 1 atrioventricular block. Flutter waves are visible only in leads II and III. II III I Fig. 16.35 Carotid sinus pressure in atrial flutter: continuous trace. The diagnosis of atrial flutter with 2 : 1 block was established when carotid sinus pressure produced temporary atrioventricular block, revealing the flutter waves. Carotid sinus pressure

Cardiac arrhythmias • 471

of loss of atrial function and heart rate control. A fall in BP may cause lightheadedness, and chest pain may occur with underlying coronary artery disease. In older patients, AF may not be associated with a rapid ventricular rate and may be asymptomatic, only to be discovered as a result of a routine examination or an ECG. Asymptomatic AF may also present with systemic embolism and is a major cause of stroke in the elderly. Investigations Assessment of patients with newly diagnosed AF should include a full history, physical examination, a 12-lead ECG, echocardiogram and thyroid function tests to exclude thyrotoxicosis. This is an unusual but potentially treatable cause of AF. Additional investigations may be needed to determine the nature and extent of any underlying heart disease. In particular echocardiographic assessment is useful to identify any structural heart disease, particularly mitral valve disease. Management Management depends on whether the AF is transient or persistent and whether there is a clear precipitating factor. When AF complicates an acute illness such as a chest infection or pulmonary embolism, treatment of the underlying disorder will often restore sinus rhythm. Where AF does not resolve, the main objectives are to control heart rate during periods of AF, restore sinus rhythm, prevent recurrence of AF and reduce the risk of thromboembolism. Management of paroxysmal and persistent AF is discussed below. Paroxysmal atrial fibrillation Occasional attacks of AF that are well tolerated do not necessarily require treatment. Beta-blockers are normally used as first-line therapy if symptoms are troublesome, since they reduce the ectopic firing that normally initiates the arrhythmia. They are particularly useful for treating patients with AF associated with coronary artery disease, hypertension and cardiac failure. Class Ic drugs (see Box 16.30), such as propafenone or flecainide, are also effective at preventing episodes but should not be given to patients with coronary artery disease or left ventricular dysfunction. Flecainide is seldom used alone, since it can precipitate atrial flutter, and is usually prescribed with a rate-limiting β-blocker. Class III drugs can also be used; amiodarone is the most effective agent for preventing AF but side-effects restrict its use to when other measures fail. Dronedarone is an effective alternative but is contraindicated in patients with heart failure or significant left ventricular impairment. Digoxin and verapamil are not effective for the prevention of AF but can help with rate control by slowing conduction through the AV node. Catheter ablation can be considered where anti-arrhythmic drug therapy is ineffective or causes side-effects. Ablation can disconnect the pulmonary veins from the LA electrically, preventing ectopic triggering of AF. In addition, lines of conduction block can be created Fig. 16.36 Mechanisms initiating atrial fibrillation. (1) Ectopic beats, often arising from the pulmonary veins, trigger atrial fibrillation. (2) Re-entry within the atria maintains atrial fibrillation, with multiple interacting re-entry circuits operating simultaneously.

Fig. 16.37 Two examples of atrial fibrillation. The QRS complexes are irregular and there are no P waves. A There is usually a fast ventricular rate, between 120 and 160/min, at the onset of atrial fibrillation. B In chronic atrial fibrillation, the ventricular rate may be much slower, due to the effects of medication and AV nodal fatigue. A B 16.21 Common causes of atrial fibrillation • Coronary artery disease (including acute MI) • Valvular heart disease, especially rheumatic mitral valve disease • Hypertension • Sinoatrial disease • Hyperthyroidism • Alcohol • Cardiomyopathy • Congenital heart disease • Chest infection • Pulmonary embolism • Pericardial disease • Idiopathic (lone atrial fibrillation) (prolonged episodes that can be terminated by electrical or pharmacological cardioversion) or permanent. It can be difficult to identify what type of AF patients have at first presentation but this usually becomes clearer as time progresses. Unfortunately for many patients, paroxysmal AF becomes permanent as the underlying disease process progresses. This is partly because of electrophysiological changes that occur in the atria within a few hours of the onset of AF and which tend to maintain fibrillation: a process called electrical remodelling. When AF persists for a period of months, structural remodelling also occurs, leading to atrial fibrosis and dilatation that predispose to chronicity of the AF. Early treatment of AF can sometimes prevent the arrhythmia from becoming persistent. Many forms of heart disease can present with AF (Box 16.21), particularly those that are associated with enlargement or dilatation of the atria. Alcohol excess, hyperthyroidism and chronic lung disease are also common causes of AF, although multiple predisposing factors may coexist, such as the combination of alcohol, hypertension and coronary artery disease. About 50% of all patients with paroxysmal AF and 20% of patients with persistent or permanent AF have structurally normal hearts; this is known as ‘lone atrial fibrillation’. Clinical features The typical presentation is with palpitation, breathlessness and fatigue. In patients with poor ventricular function or valve disease, AF may precipitate or aggravate cardiac failure because

472 • CARDIOLOGY Patients undergoing cardioversion to restore sinus rhythm require temporary anticoagulation to reduce the risk of systemic embolus. This can be achieved with warfarin, aiming for an international normalised ratio (INR) target of 2.0–3.0. Increasingly, direct-acting oral anticoagulant drugs (see below) are used as an alternative. Anticoagulation should be started for at least 4 weeks before cardioversion and should be maintained for at least 3 months following successful cardioversion. In patients with chronic AF, the annual risk of stroke is influenced by many factors and a decision has to be made in which the risk of stroke is balanced against the risk of bleeding with anticoagulation. Patients with AF secondary to mitral valve disease should always be anticoagulated because the risk is so high. In other patients, clinical scoring systems can be used to assess the risk of stroke and bleeding. The risk of stroke is usually assessed by the CHA2DS2-VASc score (Box 16.23), whereas the HAS-BLED score can be used to estimate the bleeding risk (Box 16.24). Patients with a HAS-BLED score of 3 or more points may require more careful monitoring if anticoagulated. In patients with intermittent AF, stroke risk is similar to that in patients with persistent AF when adjusted for CHA2DS2-VASc score. The risk of embolism is only weakly related to the frequency and duration of AF episodes, so stroke prevention guidelines do not distinguish between those with paroxysmal, persistent and permanent AF. Several agents can be used to reduce stroke risk in AF. Warfarin therapy adjusted to a target INR of 2.0–3.0 reduces the risk of stroke by about two-thirds at the cost of an annual risk of bleeding of 1–1.5% and is indicated for patients with a CHA2DS-VASc score of 2 or more, unless there are coexisting clinical risk factors that increase the risk of bleeding. These include peptic ulcer, uncontrolled hypertension, alcohol misuse, frequent falls, poor adherence and the use of other drugs that might interact with warfarin. If bleeding does occur in warfarin-treated patients, anticoagulation can be reversed by administering vitamin K or clotting factors. The factor Xa inhibitors rivaroxaban, apixaban and edoxaban, and the direct thrombin inhibitor dabigatran (collectively referred within the atria to prevent re-entry. Ablation prevents AF in approximately 75% of patients with prior drug-resistant episodes, although a repeat procedure is sometimes required before this is achieved. Ablation for AF is an attractive treatment when drugs are ineffective or poorly tolerated but may be complicated by cardiac tamponade, stroke, phrenic nerve injury and, rarely, pulmonary vein stenosis. Persistent atrial fibrillation There are two options for treating persistent AF. One is to attempt to restore and maintain sinus rhythm and the second is to accept the presence of AF and to try to control the ventricular rate. With both options prophylaxis against thromboembolism is required on either a short-term or long-term basis. Rhythm control An attempt to restore sinus rhythm is particularly appropriate if the arrhythmia causes troublesome symptoms and if there is a modifiable or treatable underlying cause. Electrical DC cardioversion (p. 482) or pharmacological cardioversion may be used. Cardioversion is initially successful in most patients but relapse is frequent (25–50% at 1 month and 70–90% at 1 year). Attempts to restore and maintain sinus rhythm are most successful if AF has been present for less than 3 months, the patient is young and there is no important structural heart disease. Immediate cardioversion is appropriate if AF has been present for less than 48 hours. In stable patients with no history of structural heart disease, intravenous flecainide (2 mg/kg over 30 mins, maximum dose 150 mg) can be used for pharmacological cardioversion and will restore sinus rhythm in 75% of patients within 8 hours. In patients with structural or ischaemic heart disease, intravenous amiodarone can be given through a central venous catheter. Cardioversion is an alternative treatment and is often effective when drugs fail. If AF has been present for 48 hours or longer, or if there is doubt about its duration, DC cardioversion should be deferred until the patient has been established on effective oral anticoagulation for a minimum of 4 weeks and any underlying problems, such as hypertension or alcohol excess, have been corrected. Consideration should be given to prophylactic treatment with amiodarone to reduce the risk of recurrence. Catheter ablation is sometimes used to restore and maintain sinus rhythm in resistant cases but is a less effective treatment than for paroxysmal AF. Rate control If sinus rhythm cannot be restored, treatment should be directed at maintaining an appropriate heart rate. Digoxin, β-blockers and rate-limiting calcium antagonists, such as verapamil or diltiazem (p. 479), reduce the ventricular rate by slowing AV conduction. This alone may produce a striking improvement in cardiac function, particularly in patients with mitral stenosis. Beta-blockers and rate-limiting calcium antagonists are more effective than digoxin at controlling the heart rate during exercise and have additional benefits in patients with hypertension or structural heart disease. Combination therapy with digoxin and a β-blocker can help with rate control but calcium channel antagonists should not be used with β-blockers because of the risk of bradycardia. In exceptional cases, poorly controlled and symptomatic AF can be treated by implanting a permanent pacemaker and then deliberately inducing complete AV nodal block with catheter ablation. This is known as the ‘pace and ablate’ strategy. Thromboprophylaxis Loss of atrial contraction and left atrial dilatation cause stasis of blood in the LA and may lead to thrombus formation in the left atrial appendage. This predisposes patients to stroke and other forms of systemic embolism. 16.22 Atrial fibrillation in old age • Prevalence: rises with age, reaching 9% in those over 80 years. • Symptoms: sometimes asymptomatic but often accompanied by diastolic heart failure. • Hyperthyroidism: atrial fibrillation may emerge as the dominant feature of otherwise silent or occult hyperthyroidism. • Cardioversion: followed by high rates (~70% at 1 year) of recurrent atrial fibrillation. • Stroke: atrial fibrillation is an important cause of cerebral embolism, found in 15% of all stroke patients and 2–8% of those with transient ischaemic attacks (TIAs). • Anticoagulation: although the risk of thromboembolism rises, the hazards of anticoagulation also become greater with age because of increased comorbidity, particularly cognitive impairment and falls. • Target INR: if anticoagulation is recommended in those over 75 years, care should be taken to maintain an INR below 3.0 because of the increased risk of intracranial haemorrhage. • Directly acting oral anticoagulants: alternatives to warfarin. No blood monitoring is required, there are fewer drug interactions, and fixed dosing may aid adherence. Dabigatran dose is reduced from 150 mg twice daily to 110 mg twice daily in those over 80 or if creatinine clearance is less than 30 mL/min. Rivaroxaban dose is reduced from 20 mg once daily to 15 mg once daily if creatinine clearance is 30–49 mL/min, and is contraindicated below 30 mL/min.

Cardiac arrhythmias • 473

16.23 CHA2DS2-VASc stroke risk scoring system for non-valvular atrial fibrillation Parameter Score C Congestive heart failure 1 point H Hypertension history 1 point A2 Age ≥ 75 years 2 points D Diabetes mellitus 1 point S2 Previous stroke or transient ischemic attack (TIA) 2 points V Vascular disease 1 point A Age 65–74 years 1 point Sc Sex category female 1 point Maximum total score 9 points Annual stroke risk 0 points = 0% (no prophylaxis required) 1 point = 1.3% (oral anticoagulant recommended in males only) 2+ points = > 2.2% (oral anticoagulant recommended) From European Society of Cardiology Clinical practice guidelines: atrial fibrillation (management of) 2010 and focused update (2012). Eur Heart J 2012; 33:2719–2747. 16.24 HAS-BLED bleeding risk scoring system for patients receiving oral anticoagulation Parameter Score H Hypertension; current systolic blood pressure

160 mmHg 1 point A Abnormal liver function (cirrhosis OR bilirubin > twice upper limit of reference range or transaminases three times upper limit of reference range 1 point Abnormal renal function (creatinine > 200 μmol/L (2.26 mg/dL) 1 point S Stroke history 1 point B Bleeding: prior major event 1 point L Labile INR on warfarin 1 point E Elderly: age ≥ 65 years 1 point D Drugs: Use of antiplatelet drugs High alcohol consumption 1 point 1 point Maximum total score 9 points HAS-BLED score of ≥ 3 points requires close patient monitoring Fig. 16.38 Supraventricular tachycardia. The rate is 180/min and the QRS complexes are normal. similar appearance on ECG. These are usually narrow-complex tachycardias and are characterised by a re-entry circuit or automatic focus involving the atria. The three principal types are atrioventricular nodal re-entrant tachycardia (AVNRT), atrioventricular re-entrant tachycardia (AVRT) and atrial tachycardia. The term SVT is technically incorrect as, in many cases, the ventricles also form part of the re-entry circuit. Atrioventricular nodal re-entrant tachycardia AVNRT is a type of SVT caused by re-entry in a circuit involving the AV node and its two right atrial input pathways: a superior ‘fast’ pathway and an inferior ‘slow’ pathway (see Fig. 16.39A below). This produces a regular tachycardia with a rate of 120–240/ min. It tends to occur in the absence of structural heart disease and episodes may last from a few seconds to many hours. The patient is usually aware of a rapid, very forceful, regular heart beat and may experience chest discomfort, lightheadedness or breathlessness. Polyuria, mainly due to the release of ANP, is sometimes a feature. The ECG (Fig. 16.38) usually shows a tachycardia with normal QRS complexes but occasionally there may be rate-dependent bundle branch block. Management Treatment is not always necessary. However, an acute episode may be terminated by carotid sinus pressure or by the Valsalva manœuvre. Adenosine (3–12 mg rapidly IV in incremental doses until tachycardia stops) or verapamil (5 mg IV over 1 min) will restore sinus rhythm in most cases. Intravenous β-blocker or flecainide can also be used. In rare cases, when there is severe haemodynamic compromise, the tachycardia should be terminated by DC cardioversion (p. 482). In patients with recurrent SVT, catheter ablation (p. 484) is the most effective therapy and will permanently prevent SVT in more than 90% of cases. Alternatively, prophylaxis with oral β-blocker, verapamil or flecainide may be used but commits predominantly young patients to long-term drug therapy and can create difficulty in female patients, as these drugs are normally avoided during pregnancy. Atrioventricular re-entrant tachycardia In this condition there is an abnormal band of conducting tissue that connects the atria and ventricles. This so-called accessory pathway comprises rapidly conducting fibres that resemble Purkinje tissue, in that they conduct very rapidly and are rich in sodium channels. In about 50% of cases, this pathway conducts only in the retrograde direction (from ventricles to atria) and thus does not alter the appearance of the ECG in sinus rhythm. This is known as a concealed accessory pathway. In the rest, the pathway also conducts in an antegrade direction (from atria to ventricles), so AV conduction in sinus rhythm is mediated via both the AV node and the accessory pathway, distorting the QRS complex. Premature ventricular activation via the pathway shortens the PR interval and produces a ‘slurred’ initial deflection to as directly acting oral anticoagulants, or DOACs), can be used as an alternative. They are at least as effective as warfarin at preventing thrombotic stroke and are associated with a lower risk of intracranial haemorrhage. Other advantages include the lack of requirement for monitoring and the fact that they have fewer drug interactions. Agents that reverse the effects of DOACs have been developed. These include idarucizumab, which binds to dabigatran and allows acute bleeding complications to be managed more effectively. Aspirin should not be used since it has little or no effect on embolic stroke and is associated with significant bleeding risk. Supraventricular tachycardia The term supraventricular tachycardia (SVT) describes the occurrence of a group of regular tachycardias that have a

474 • CARDIOLOGY Ventricular premature beats Ventricular premature beats (VPBs) are frequently found in healthy people and their prevalence increases with age. Ectopic beats in patients with otherwise normal hearts are more prominent at rest and disappear with exercise. Sometimes VPBs are a manifestation of subclinical coronary artery disease or cardiomyopathy but also may occur in patients with established heart disease following an MI. Most patients with VPBs are asymptomatic but some present with an irregular heart beat, missed beats or abnormally strong beats, due to increased cardiac output of the post-ectopic sinus beat. On examination the pulse is irregular, with weak or missed beats as a result of the fact that the stroke volume is low because left ventricular contraction occurs before filling is complete (Fig. 16.40). The ECG shows broad and bizarre complexes because the ventricles are activated sequentially rather than simultaneously. The complexes may be unifocal (identical beats arising from a single ectopic focus) or multifocal (varying morphology with multiple foci, Fig. 16.40). ‘Couplet’ and ‘triplet’ are the terms used to describe two or three successive ectopic beats. A run of alternating sinus and ventricular ectopic beats is known as ventricular ‘bigeminy’. The significance depends on the presence or absence of underlying heart disease. Management Treatment may not be necessary, unless the patient is highly symptomatic, in which case β-blockers or, in some situations, of the QRS complex, called a delta wave (Fig. 16.39B). This is known as a manifest accessory pathway. As the AV node and accessory pathway have different conduction speeds and refractory periods, a re-entry circuit can develop, causing tachycardia (Fig. 16.39C); when associated with symptoms, the condition is known as Wolff–Parkinson–White syndrome. The ECG during this tachycardia is almost indistinguishable from that of AVNRT (Fig. 16.39A). Management Carotid sinus pressure or intravenous adenosine can terminate the tachycardia. If AF occurs, it may produce a dangerously rapid ventricular rate because the accessory pathway lacks the rate-limiting properties of the AV node (Fig. 16.39D). This is known as pre-excited atrial fibrillation and may cause collapse, syncope and even death. It should be treated as an emergency, usually with DC cardioversion. Catheter ablation is first-line treatment in symptomatic patients and is nearly always curative. Alternatively, prophylactic antiarrhythmic drugs, such as flecainide or propafenone (p. 481), can be used to slow conduction in, and prolong the refractory period of, the accessory pathway. Long-term drug therapy is not the preferred treatment for most patients and amiodarone should not be used, as its side-effect profile cannot be justified and ablation is safer and more effective. Digoxin and verapamil shorten the refractory period of the accessory pathway and should not be used. Fig. 16.39 Atrioventricular nodal re-entrant tachycardia (AVNRT) and Wolff–Parkinson–White (WPW) syndrome. A AV node re-entrant tachycardia. The mechanism of AVNRT occurs via two right atrial AV nodal input pathways: the slow (S) and fast (F) pathways. Antegrade conduction occurs via the slow pathway; the wavefront enters the AV node and passes into the ventricles, at the same time re-entering the atria via the fast pathway. In WPW syndrome, there is a strip of accessory conducting tissue that allows electricity to bypass the AV node and spread from the atria to the ventricles rapidly and without delay. When the ventricles are depolarised through the AV node the ECG is normal, but when the ventricles are depolarised through the accessory conducting tissue the ECG shows a very short PR interval and a broad QRS complex. B Sinus rhythm. In sinus rhythm, the ventricles are depolarised through (1) the AV node and (2) the accessory pathway, producing an ECG with a short PR interval and broadened QRS complexes; the characteristic slurring of the upstroke of the QRS complex is known as a delta wave. The degree of pre-excitation (the proportion of activation passing down the accessory pathway) and therefore the ECG appearances may vary a lot, and at times the ECG can look normal. C Orthodromic tachycardia. This is the most common form of tachycardia in WPW. The re-entry circuit passes antegradely through the AV node and retrogradely through the accessory pathway. The ventricles are therefore depolarised in the normal way, producing a narrow-complex tachycardia that is indistinguishable from other forms of supraventricular tachycardia. D Atrial fibrillation. In this rhythm, the ventricles are largely depolarised through the accessory pathway, producing an irregular broad-complex tachycardia that is often more rapid than the example shown. AV nodal re-entrant tachycardia S F

A Wolff–Parkinson–White syndrome: orthodromic tachycardia C Wolff–Parkinson–White syndrome: atrial fibrillation D Wolff–Parkinson–White syndrome: sinus rhythm B

Cardiac arrhythmias • 475

catheter ablation can be used. There is no evidence that antiarrhythmic therapy improves prognosis but the discovery of very frequent VPBs in a patient not known to have heart disease should prompt further investigations with echocardiography and an exercise ECG to screen for structural heart disease and ischaemic heart disease. It is common for VPBs to occur during the course of an acute MI. Persistent, frequent VPBs (over 10/ hr) in patients who have survived the acute phase of MI indicate a poorer long-term outcome. In this situation, anti-arrhythmic drugs do not improve and may even worsen prognosis. The exception is β-blockers, which should be prescribed for other reasons (p. 500). Similarly, heart failure of any cause is associated with VPBs. While they indicate an adverse prognosis, this is not improved by anti-arrhythmic drugs. Effective treatment of the heart failure may suppress the ectopic beats. VPBs are also a feature of digoxin toxicity. Ventricular tachycardia Ventricular tachycardia (VT) occurs most commonly in the settings of acute MI, chronic coronary artery disease and cardiomyopathy. It is associated with extensive ventricular disease, impaired left ventricular function and ventricular aneurysm. In these settings, VT may cause haemodynamic compromise or degenerate into ventricular fibrillation (p. 456). VT is caused by abnormal automaticity or triggered activity in ischaemic tissue, or by re-entry within scarred ventricular tissue. Patients may complain of palpitation or symptoms of low cardiac output, including dyspnoea, lightheadedness and syncope. The ECG shows tachycardia and broad, abnormal QRS complexes with a rate of more than 120/min (Fig. 16.41). It may be difficult to distinguish VT from SVT with bundle branch block or pre-excitation (WPW syndrome) on ECG but features in favour of VT are listed in Box 16.25. A 12-lead ECG (Fig. 16.42) or electrophysiology study (p. 454) may help establish the diagnosis. When there is doubt, it is safer to manage the problem as VT. Patients recovering from MI sometimes have periods of idioventricular rhythm (‘slow’ VT) at a rate only slightly above the preceding sinus rate and below 120/min. These episodes often reflect reperfusion of the infarct territory and may be a good sign. They are usually self-limiting and asymptomatic, and do not require treatment. Other forms of sustained VT require treatment, often as an emergency. Fig. 16.40 Ventricular ectopic beats. A There are broad, bizarre QRS complexes (arrows) with no preceding P wave in between normal sinus beats. Their configuration varies, so these are multifocal ectopics. B A simultaneous arterial pressure trace is shown. The ectopic beats result in a weaker pulse (arrows), which may be perceived as a ‘dropped beat’. A B Fig. 16.41 Ventricular tachycardia: fusion beat (arrow). In ventricular tachycardia, there is independent atrial and ventricular activity. Occasionally, a P wave is conducted to the ventricles through the AV node, producing a normal sinus beat in the middle of the tachycardia (a capture beat); more commonly, however, the conducted impulse fuses with an impulse from the tachycardia (a fusion beat). This can occur only when there is atrioventricular dissociation and is therefore diagnostic of ventricular tachycardia. 16.25 Features more in keeping with ventricular tachycardia • History of myocardial infarction • Atrioventricular dissociation (pathognomonic) • Capture/fusion beats (pathognomonic; see Fig. 16.41) • Extreme left axis deviation • Very broad QRS complexes (> 140 msecs) • No response to carotid sinus massage or intravenous adenosine Occasionally, VT occurs in patients with otherwise healthy hearts (‘normal heart VT’), usually because of abnormal automaticity in the right ventricular outflow tract or one of the fascicles of the left bundle branch. Management Prompt action to restore sinus rhythm is required and should usually be followed by prophylactic therapy. Synchronised DC cardioversion is the treatment of choice if systolic BP is less than 90 mmHg. If the arrhythmia is well tolerated, intravenous amiodarone may be given as a bolus, followed by a continuous infusion (p. 481). Intravenous lidocaine can be used but may depress left ventricular function, causing hypotension or acute heart failure. Hypokalaemia, hypomagnesaemia, acidosis and hypoxia should be corrected if present. Beta-blockers are effective at preventing VT by reducing ventricular automaticity. Amiodarone can be added if additional

476 • CARDIOLOGY Fig. 16.42 Ventricular tachycardia: 12-lead ECG. There are typically very broad QRS complexes and marked left axis deviation. There is also atrioventricular dissociation; some P waves are visible and others are buried in the QRS complexes (arrows). I aVR V1 II aVL III aVF Rhythm strip V4 V2 V5 V3 V6 Torsades de pointes This form of polymorphic VT is a complication of prolonged ventricular repolarisation (prolonged QT interval). The ECG shows rapid irregular complexes that seem to twist around the baseline as the mean QRS axis changes (Fig. 16.43). The arrhythmia is usually non-sustained and repetitive, but may degenerate into ventricular fibrillation. During periods of sinus rhythm, the ECG will usually show a prolonged QT interval (> 0.44 sec in men, > 0.46 sec in women when corrected to a heart rate of 60/min). Some of the common causes are listed in Box 16.26. The arrhythmia is more common in women and is often triggered by a combination of factors, such as administration of QT-prolonging medications and hypokalaemia. The congenital long QT syndromes are a family of genetic disorders that are characterised by mutations in genes that code for cardiac sodium or potassium channels. Long QT syndrome subtypes have different triggers, which are important when counselling patients. Adrenergic stimulation through vigorous exercise is a common trigger in long QT type 1, and a sudden noise may trigger arrhythmias in long QT type 2. Arrhythmias are more common during sleep in type 3. Management Intravenous magnesium (8 mmol over 15 mins, then 72 mmol over 24 hrs) should be given in all cases. If this is ineffective, Fig. 16.43 Torsades de pointes. A bradycardia with a long QT interval is followed by polymorphic ventricular tachycardia that is triggered by an R on T ectopic. Many other drugs that are not shown can be associated with prolongation of the QT interval. See www.crediblemeds.org for a complete list. 16.26 Causes of long QT interval and torsades de pointes Bradycardia • Bradycardia compounds other factors that cause torsades de pointes Electrolyte disturbance • Hypokalaemia • Hypomagnesaemia • Hypocalcaemia Drugs • Disopyramide, flecainide and other class Ia, Ic anti-arrhythmic drugs (p. 479) • Sotalol, amiodarone and other class III anti-arrhythmic drugs • Amitriptyline and other tricyclic antidepressants • Chlorpromazine and other phenothiazines • Erythromycin and other macrolides Congenital syndromes • Long QT1: gene affected KCNQI: K+ channel, 30–35% • Long QT2: gene affected HERG: K+ channel, 25–30% • Long QT3: gene affected SCNSA: Na+ channel, 5–10% • Long QT4–12: rare; various genes implicated control is needed. Class Ic anti-arrhythmic drugs should not be used for prevention of VT in patients with coronary artery disease or heart failure because they depress myocardial function and can increase the likelihood of a dangerous arrhythmia. In patients with poor left ventricular function or where VT is associated with haemodynamic compromise, the use of an implantable cardiac defibrillator is recommended (p. 483). Rarely, surgery with resection of a ventricular aneurysm or catheter ablation can be used to interrupt the arrhythmia focus or circuit in patients with VT associated with a myocardial infarct scar. The treatment of choice for VT occurring in a normal heart is catheter ablation, which often can be curative.

Cardiac arrhythmias • 477

progressive lengthening of successive PR intervals, culminating in a dropped beat. The cycle then repeats itself. This is known as the Wenckebach phenomenon and is usually due to impaired conduction in the AV node itself. The phenomenon may be physiological and is sometimes observed at rest or during sleep in athletic young adults with high vagal tone. In Mobitz type II second-degree AV block (Fig. 16.46), the PR interval of the conducted impulses remains constant but some P waves are not conducted. This is usually caused by disease of the His–Purkinje system and carries a risk of asystole. In 2 : 1 AV block (Fig. 16.47), alternate P waves are conducted, so it is impossible to distinguish between Mobitz type I and type II block. Third-degree atrioventricular block In third-degree AV block, conduction fails completely and the atria and ventricles beat independently. This is known as AV dissociation, as shown in Fig. 16.48. Ventricular activity is maintained by an escape rhythm arising in the AV node or bundle of His (narrow QRS complexes) or the distal Purkinje tissues (broad QRS complexes). Distal escape rhythms tend to be slower and less reliable. Complete AV block (Box 16.27) produces a slow (25–50/min), regular pulse that does not vary with exercise, except in the case of congenital complete AV block. There is usually a compensatory increase in stroke volume, producing a large-volume pulse. Cannon waves may be visible in the neck and the intensity of the first heart sound varies due to the loss of AV synchrony. Clinical features The typical presentation is with recurrent syncope or ‘Stokes– Adams’ attacks. These episodes are characterised by sudden atrial pacing should be tried, since it can suppress the arrhythmia through rate-dependent shortening of the QT interval. Intravenous isoprenaline is a reasonable alternative to pacing but should be avoided in patients with the congenital long QT syndromes. Once initial control has been achieved, efforts should be made to identify and treat the underlying cause or stop medications that predispose to the arrhythmia. If the underlying cause cannot be corrected or the arrhythmia is the result of an inherited syndrome, then long-term pharmacological therapy may be necessary. Beta-blockers are effective at preventing syncope in patients with congenital long QT syndrome. Some patients, particularly those with extreme QT interval prolongation (> 500 msecs) or certain high-risk genotypes, should be considered for an implantable defibrillator. Left stellate ganglion block may be of value in patients with resistant arrhythmias. Brugada syndrome is a related genetic disorder that may present with polymorphic VT or sudden death. It is characterised by a defect in sodium channel function and an abnormal ECG (right bundle branch block and ST elevation in V1 and V2 but not usually prolongation of the QT interval). The only known effective treatment is an implantable defibrillator. Atrioventricular block This usually occurs as the result of disease affecting the AV node. AV block can be intermittent, however, and may become evident only when the conducting tissue is stressed by a rapid atrial rate. Reflecting this fact, atrial tachyarrhythmias are often associated with AV block (see Fig. 16.37). Episodes of ventricular asystole may also complicate complete heart block or Mobitz type II second-degree AV block. Several types of AV block are recognised. First-degree atrioventricular block In this condition, AV conduction is delayed and so the PR interval is prolonged (> 0.20 sec; Fig. 16.44). It rarely causes symptoms and does not usually require treatment. Second-degree atrioventricular block Here dropped beats occur because some impulses from the atria fail to conduct to the ventricles. Two subtypes are recognised. In Mobitz type I second-degree AV block (Fig. 16.45), there is Fig. 16.44 First-degree atrioventricular block. The PR interval is prolonged and measures 0.26 sec. Fig. 16.45 Second-degree atrioventricular block (Mobitz type I – the Wenckebach phenomenon). The PR interval progressively increases until a P wave is not conducted. The cycle then repeats itself. In this example, conduction is at a ratio of 4 : 3, leading to groupings of three ventricular complexes in a row. P P P P P P P P P P P P P Fig. 16.46 Second-degree atrioventricular block (Mobitz type II). The PR interval of conducted beats is normal but some P waves are not conducted. The constant PR interval distinguishes this from the Wenckebach phenomenon. P P P P P P P P P P P

478 • CARDIOLOGY Patients with symptomatic bradyarrhythmias associated with AV block should be treated with a permanent pacemaker. Asymptomatic first-degree or Mobitz type I second-degree AV block (Wenckebach phenomenon) does not require treatment but may be an indication of underlying heart disease. A permanent pacemaker is usually indicated in patients with asymptomatic Mobitz type II second-degree AV block or third-degree AV heart block because of the risk of asystole and sudden death. Pacing improves prognosis. Bundle branch block Damage to the right or left bundle branch of the conducting system can occur as a result of many pathologies, including ischaemic heart disease, hypertensive heart disease and cardiomyopathy. However, right bundle branch block (RBBB) can occur as a normal variant in healthy individuals (Box 16.28). In left bundle branch block (LBBB) and RBBB, depolarisation proceeds through a slow myocardial route in the affected ventricle rather than through the rapidly conducting Purkinje tissues that constitute the bundle branches. This causes delayed conduction into the LV or RV, broadens the QRS complex (≥ 0.12 sec) and produces characteristic alterations in QRS morphology (Figs 16.49 and loss of consciousness that occurs without warning and results in collapse. A brief anoxic seizure (due to cerebral ischaemia) may occur if there is prolonged asystole. There is pallor and a death-like appearance during the attack, but when the heart starts beating again there is a characteristic flush. In distinction to epilepsy, recovery is rapid. Sinoatrial disease and neurocardiogenic syncope (p. 181) may cause similar symptoms. Management This depends on the clinical circumstances. Acute inferior MI is often complicated by transient AV block because the right coronary artery (RCA) supplies the AV node. There is usually a reliable escape rhythm and, if the patient remains well, no treatment is required. Symptomatic second- or third-degree AV block may respond to atropine (0.6 mg IV, repeated as necessary) or, if this fails, a temporary pacemaker. In most cases, the AV block will resolve within 7–10 days. Second- or third-degree AV heart block complicating acute anterior MI indicates extensive ventricular damage involving both bundle branches and carries a poor prognosis. Asystole may ensue and a temporary pacemaker should be inserted promptly. If the patient presents with asystole, intravenous atropine (3 mg) or intravenous isoprenaline (2 mg in 500 mL 5% dextrose, infused at 10–60 mL/hr) may help to maintain the circulation until a temporary pacing electrode can be inserted. Temporary pacing can provide effective rhythm support in the short term. 16.28 Common causes of bundle branch block Right bundle branch block • Normal variant • Right ventricular hypertrophy or strain, e.g. pulmonary embolism • Congenital heart disease, e.g. atrial septal defect • Coronary artery disease Left bundle branch block • Coronary artery disease • Hypertension • Aortic valve disease • Cardiomyopathy Fig. 16.47 Second-degree atrioventricular block with fixed 2 : 1 block. Alternate P waves are not conducted. This may be due to Mobitz type I or II block. P P P P P P P Fig. 16.48 Complete (third-degree) atrioventricular block. There is complete dissociation of atrial and ventricular complexes. The atrial rate is 80/min and the ventricular rate is 38/min. P P P P P P P 16.27 Causes of complete atrioventricular block Congenital Acquired • Idiopathic fibrosis • Myocardial infarction/ ischaemia • Inflammation: Infective endocarditis Sarcoidosis Chagas’ disease • Trauma • Drugs: Digoxin β-blockers Calcium antagonists Fig. 16.49 Right bundle branch block. Note the wide QRS complexes with ‘M’-shaped configuration in leads V1 and V2 and a wide S wave in lead I. V1 aVR aVL aVF V4 V2 V5 V3 V6 III II I

Principles of management of cardiac arrhythmias • 479

Fig. 16.50 Left bundle branch block. Note the wide QRS complexes with loss of the Q wave or septal vector in lead I and ‘M’-shaped QRS complexes in V5 and V6. I aVR V1 V4 II aVL V2 V5 III aVF V3 V6 Some drugs such as digoxin, ivabradine and adenosine have no place in this classification, while others such as amiodarone have properties in more than one class. 16.29 Classification of anti-arrhythmic drugs by effect on the intracellular action potential Class I: membrane-stabilising agents (sodium channel blockers) (a) Block Na+ channel and prolong action potential • Quinidine, disopyramide (b) Block Na+ channel and shorten action potential • Lidocaine, mexiletine (c) Block Na+ channel with no effect on action potential • Flecainide, propafenone Class II: β-adrenoceptor antagonists (β-blockers) • Atenolol, bisoprolol, metoprolol Class III: drugs whose main effect is to prolong the action potential • Amiodarone, dronedarone, sotalol Class IV: slow calcium channel blockers • Verapamil, diltiazem 16.50). Damage to the left bundle can also occur after it divides into anterior and posterior fascicles, when it is called hemiblock. In this case, the QRS complex is not broadened but the direction of ventricular depolarisation is changed, causing left axis deviation in left anterior hemiblock and right axis deviation in left posterior hemiblock (see Fig. 16.7, p. 449). The combination of RBBB and left anterior or posterior hemiblock is known as bifascicular block. LBBB usually signifies important underlying heart disease and also causes ventricular incoordination, which may aggravate symptoms in patients with heart failure. This can be treated in selected patients by cardiac resynchronisation therapy (p. 484). Principles of management of cardiac arrhythmias Cardiac arrhythmias can be managed with either anti-arrhythmic drug therapy or external devices that depolarise the heart by passing an electric current through it. These strategies are relevant across a range of indications and are discussed in more detail here. Anti-arrhythmic drugs Traditionally, the Vaughan Williams system has been used to categorise anti-arrhythmic drugs based on their effects on the action potential. More recently, increased understanding of the mechanisms of action has allowed further subclassification, based on the cardiac ion channels and receptors on which they act (Box 16.29 and Fig. 16.51). The individual agents, dosages and most common side-effects are summarised in Box 16.30 and the general principles of use are summarised in Box 16.31. Fig. 16.51 Classification of anti-arrhythmic drugs by site of action. Atria, ventricles and accessory conducting tissues Disopyramide Flecainide Propafenone Amiodarone Sinoatrial node β-blockers Atropine Verapamil Diltiazem Ventricles Lidocaine Mexiletine β-blockers AV node Adenosine β-blockers Digoxin Verapamil Diltiazem Class I drugs Class I drugs act principally by suppressing excitability and slowing conduction in atrial or ventricular muscle. They block sodium channels, of which there are several types in cardiac tissue. These drugs should generally be avoided in patients with heart failure because they depress myocardial function, and class Ia and Ic drugs are often pro-arrhythmic. Class Ia drugs These prolong cardiac action potential duration and increase the tissue refractory period. They are used to prevent both atrial and ventricular arrhythmias. Disopyramide This is an effective drug but causes anticholinergic side-effects, such as urinary retention, and can precipitate glaucoma. It can

480 • CARDIOLOGY Lidocaine This must be given intravenously and has a very short plasma half-life. Mexiletine This can be given intravenously or orally but has many side-effects. Class Ic drugs These affect the slope of the action potential without altering its duration or refractory period. They are used mainly for prophylaxis of AF but are effective in prophylaxis and treatment depress myocardial function and should be avoided in cardiac failure. Quinidine Now rarely used, quinidine increases mortality and causes gastrointestinal upset. Class Ib drugs These shorten the action potential and tissue refractory period. They act on channels found predominantly in ventricular myocardium and so are used to treat or prevent VT and VF. Drug Main uses Route Dose (adult) Important side-effects Class I Disopyramide Prevention and treatment of atrial and ventricular tachyarrhythmias IV 2 mg/kg at 30 mg/min, then 0.4 mg/kg/hr (max 800 mg/day) Myocardial depression, hypotension, dry mouth, urinary retention Oral 300–800 mg daily in divided dosage Lidocaine Treatment and short-term prevention of VT and VF IV Bolus 50–100 mg, 4 mg/min for 30 mins, then 2 mg/min for 2 hrs, then 1 mg/min for 24 hrs Myocardial depression, delirium, convulsions Mexiletine Prevention and treatment of ventricular tachyarrhythmias IV Loading dose: 100–250 mg at 25 mg/min, then 250 mg in 1 hr, then 250 mg in 2 hrs Myocardial depression, gastrointestinal irritation, delirium, dizziness, tremor, nystagmus, ataxia Oral Maintenance therapy: 0.5 mg/min 200–250 mg 3 times daily Flecainide Prevention and treatment of atrial and ventricular tachyarrhythmias IV 2 mg/kg over 10 mins, then if required 1.5 mg/kg/hr for 1 hr, then 0.1 mg/kg/hr Myocardial depression, dizziness Oral 50–100 mg twice daily Propafenone Prevention and treatment of atrial and ventricular tachyarrhythmias Oral 150 mg 3 times daily for 1 week, then 300 mg twice daily Myocardial depression, dizziness Class II Atenolol Bisoprolol Metoprolol Treatment and prevention of SVT and AF, prevention of VEs and exercise-induced VF IV Oral Oral IV 2.5 mg at 1 mg/min, repeated at 5-min intervals (max 10 mg) 25–100 mg daily 2.5–10 mg daily 5 mg over 2 mins to a maximum of 15 mg Myocardial depression, bradycardia, bronchospasm, fatigue, depression, nightmares, cold peripheries Class III Amiodarone Serious or resistant atrial and ventricular tachyarrhythmias IV 5 mg/kg over 20–120 mins, then up to 15 mg/kg/24 hrs Photosensitivity skin discoloration, corneal deposits, thyroid dysfunction, alveolitis, nausea and vomiting, hepatotoxicity, peripheral neuropathy, torsades de pointes; potentiates digoxin and warfarin Oral Initially 600–1200 mg/day, then 100–400 mg daily Dronedarone Paroxysmal atrial fibrillation Oral 400 mg twice daily Renal and hepatic dysfunction requiring regular blood monitoring Sotalol* AF, rarely ventricular tachyarrhythmias IV 10–20 mg slowly Can cause torsades de pointes Oral 40–160 mg twice daily Class IV Verapamil Teatment of SVT, control of AF IV 5–10 mg over 30 secs Myocardial depression, hypotension. bradycardia, constipation Oral 40–120 mg 3 times daily or 240 mg SR daily Other Atropine Treatment of bradycardia and/or hypotension due to vagal overactivity IV 0.6–3 mg Dry mouth, thirst, blurred vision, atrial and ventricular extrasystoles Adenosine Teatment of SVT, aid to diagnosis in unidentified tachycardia IV 3 mg over 2 secs, followed if necessary by 6 mg, then 12 mg at intervals of 1–2 mins Flushing, dyspnoea, chest pain Avoid in asthma Digoxin Treatment and prevention of SVT, rate control of AF IV Loading dose: 0.5–1 mg (total), 0.5 mg over 30 mins, then 0.25–0.5 mg after 4–6 hrs Gastrointestinal disturbance, xanthopasia, arrhythmias See Box 16.33 Oral 0.5 mg repeated after 6 hrs, then 0.0625–0.25 mg daily *Sotalol also has class II activity as a β-blocker. (AF = atrial fibrillation; IV = intravenous; SR = sustained-release formulation; SVT = supraventricular tachycardia; VE = ventricular ectopic; VF = ventricular fibrillation; VT = ventricular tachycardia) 16.30 Uses, dosages and side-effects of anti-arrhythmic drugs

Principles of management of cardiac arrhythmias • 481

16.31 Anti-arrhythmic drugs: principles of use Anti-arrhythmic drugs are potentially toxic and should be used carefully according to the following principles: • Many arrhythmias are benign and do not require specific treatment • Precipitating or causal factors should be corrected if possible: Alcohol excess Caffeine consumption Myocardial ischaemia Hyperthyroidism Acidosis Hypokalaemia Hypomagnesaemia • If drug therapy is required, it is best to use as few drugs as possible • In difficult cases, programmed electrical stimulation (electrophysiological study) may help to identify the optimum therapy • When managing life-threatening arrhythmias, it is essential to ensure that prophylactic treatment is effective. Ambulatory monitoring and exercise testing may be of value • Patients on long-term anti-arrhythmic drugs should be reviewed regularly and attempts made to withdraw therapy if the factors that precipitated the arrhythmias are no longer operative • For patients with recurrent supraventricular tachycardia, radiofrequency ablation is often preferable to long-term drug therapy Sotalol This is a racemic mixture of two isomers with non-selective β-blocker (mainly l-sotalol) and class III (mainly d-sotalol) activity. It may cause torsades de pointes. Class III drugs Class III drugs act by prolonging the plateau phase of the action potential, thus lengthening the refractory period. These drugs are very effective at preventing atrial and ventricular tachyarrhythmias. They cause QT interval prolongation and can predispose to torsades de pointes and VT, especially in patients with other predisposing risk factors (see Box 16.26). Disopyramide and sotalol have some class III activity but the main drug in this class is amiodarone, as discussed below. Amiodarone While amiodarone is primarily considered a class III drug, it also has class I, II and IV activity. It is probably the most effective drug currently available for controlling paroxysmal AF. It is also used to prevent episodes of recurrent VT, particularly in patients with poor left ventricular function or those with implantable defibrillators (to prevent unnecessary DC shocks). Amiodarone has a very long tissue half-life (25–110 days). An intravenous or oral loading regime is often used to achieve therapeutic tissue concentrations rapidly. The drug’s effects may last for weeks or months after treatment has been stopped. Sideeffects are common (up to one-third of patients), numerous and potentially serious. Drug interactions are also common (see Box 16.30). Dronedarone Dronedarone is related to amiodarone but has a short tissue half-life and fewer side-effects. It has recently been shown to be effective at preventing episodes of atrial flutter and AF. It is contraindicated in patients with permanent AF, or if there is heart failure or left ventricular impairment, because it increases mortality. Regular liver function test monitoring is required. Class IV drugs These block the ‘slow calcium channel’, which is important for impulse generation and conduction in atrial and nodal tissue, although it is also present in ventricular muscle. Their main indications are prevention of SVT (by blocking the AV node) and rate control in patients with AF. Verapamil This is the most widely used drug in this class. Intravenous verapamil may cause profound bradycardia or hypotension, and should not be used in conjunction with β-blockers. Diltiazem This has similar properties to verapamil. Other anti-arrhythmic drugs Atropine sulphate Atropine is a muscarinic receptor antagonist that increases the sinus rate and SA and AV conduction. It is the treatment of choice for severe bradycardia or hypotension due to vagal over-activity. It is used for initial management of symptomatic bradyarrhythmias complicating inferior MI, and in cardiac arrest due to asystole. The usual dose is 0.6 mg IV, repeated if necessary of supraventricular or ventricular arrhythmias. They are useful for WPW syndrome because they block conduction in accessory pathways. They should not be used in patients with previous MI because they increase the risk of arrhythmia in this setting. Flecainide This is effective for prevention of AF, and an intravenous infusion may be used for pharmacological cardioversion of AF of less than 24 hours’ duration. Since flecainide can cause slow atrial flutter with a paradoxically rapid ventricular rate, it should be prescribed along with an AV node-blocking drug such as a β-blocker to control the ventricular rate. Propafenone This also has some β-blocker (class II) properties. Important interactions with digoxin, warfarin and cimetidine have been described. Class II drugs This group comprises the β-adrenoceptor antagonists (β-blockers). These agents reduce the rate of SA node depolarisation and cause relative block in the AV node, making them useful for rate control in atrial flutter and AF. They can be used to prevent VT and SVT. They reduce myocardial excitability and the risk of arrhythmic death in patients with coronary artery disease and heart failure. Non-selective β-blockers These act on both β1 and β2 receptors. Beta2-blockade causes sideeffects, such as bronchospasm and peripheral vasoconstriction. Propranolol is non-selective and is subject to extensive firstpass metabolism in the liver. The effective oral dose is therefore unpredictable and must be titrated after treatment is started with a small dose. Other non-selective drugs include nadolol and carvedilol. Cardioselective β-blockers These act mainly on myocardial β1 receptors and are relatively well tolerated. Bisoprolol and metoprolol are examples of cardioselective β-blockers.

482 • CARDIOLOGY 16.32 Response to intravenous adenosine Arrhythmia Response Supraventricular tachycardia Termination Atrial fibrillation, atrial flutter, atrial tachycardia Transient atrioventricular block Ventricular tachycardia No effect 16.33 Digoxin toxicity Extracardiac manifestations • Anorexia, nausea, vomiting • Diarrhoea • Altered colour vision (xanthopsia) Cardiac manifestations • Bradycardia • Multiple ventricular ectopics • Ventricular bigeminy (alternate ventricular ectopics) • Atrial tachycardia (with variable block) • Ventricular tachycardia • Ventricular fibrillation to a maximum of 3 mg. Repeat dosing may be necessary because the drug disappears rapidly from the circulation after parenteral administration. Side-effects are listed in Box 16.30. Adenosine This works by binding to A1 receptors in conducting tissue, producing a transient AV block lasting a few seconds. It is used to terminate SVTs when the AV node is part of the re-entry circuit, or to help establish the diagnosis in difficult arrhythmias, such as atrial flutter with 2 : 1 AV block (see Fig. 16.35) or broad-complex tachycardia (Boxes 16.30 and 16.32). Adenosine is given as an intravenous bolus, initially 3 mg over 2 secs (see Box 16.30). If there is no response after 1–2 minutes, 6 mg should be given; if necessary, after another 1–2 minutes the maximum dose of 12 mg may be given. Patients should be warned to expect short-lived and sometimes distressing flushing, breathlessness and chest pain. Adenosine can cause bronchospasm and should be avoided in patients with asthma; its effects are greatly potentiated by dipyridamole and inhibited by theophylline and other xanthines. Digoxin Digoxin is a glycoside purified from the European foxglove, Digitalis lanata, which slows conduction and prolongs the refractory period in the AV node. This effect helps to control the ventricular rate in AF and may interrupt SVTs involving the AV node. Digoxin also shortens refractory periods and enhances excitability and conduction in other parts of the heart, including accessory conduction pathways. It may therefore increase atrial and ventricular ectopic activity and can lead to more complex atrial and ventricular tachyarrhythmias. Digoxin is largely excreted by the kidneys, and the maintenance dose (see Box 16.30) should be reduced in children, older people and those with renal impairment. It is widely distributed and has a long tissue half-life (36 hours), so that effects may persist for several days. Measurement of plasma digoxin concentration helps identify digoxin toxicity or under-treatment (Box 16.33). Non-pharmacological treatments A variety of non-pharmacological treatments are available for the treatment of arrhythmias. These include the use of electrical devices that work by passing an electric current through the heart, and catheter-based strategies that disrupt abnormal conduction tissues responsible for the generation of arrhythmias. Electrical cardioversion Electrical cardioversion, also known as direct current (DC) cardioversion, is useful for terminating an organised rhythm, such as AF or VT. The electric current interrupts the arrhythmia and produces a brief period of asystole, which is usually followed by the resumption of sinus rhythm. Cardioversion is usually carried out as an elective procedure under general anaesthesia. The electric shock is delivered immediately after the R wave because, if it is applied during ventricular repolarisation (on the T wave), it may provoke VF. High-energy shocks may cause chest wall pain post-procedure, so, if there is no urgency, it is appropriate to begin with a lower-amplitude shock of about 50 joules initially, going on to larger shocks if necessary. Defibrillation Defibrillators deliver a DC, high-energy, short-duration shock via two large electrodes or paddles coated with conducting jelly or a gel pad, positioned over the upper right sternal edge and the apex. Defibrillators are primarily used in the management of cardiac arrest due to VF and deliver an unsynchronised shock, since the precise timing of the discharge is not important in this situation. Modern units deliver a biphasic shock, during which the shock polarity is reversed mid-shock. This reduces the total shock energy required to depolarise the heart. In VF and other emergencies, the energy of the first and second shocks should be 150 joules and thereafter up to 200 joules; there is no need for an anaesthetic, as the patient is unconscious. Temporary pacemakers Temporary pacing involves delivery of an electrical impulse into the heart to initiate tissue depolarisation and to trigger cardiac contraction. This is achieved by inserting a bipolar pacing electrode through the internal jugular, subclavian or femoral vein and positioning it at the apex of the RV, using fluoroscopic imaging. The electrode is connected to an external pacemaker with an adjustable energy output and pacing rate. The ECG of right ventricular pacing is characterised by regular broad QRS complexes with a left bundle branch block pattern. Each complex is immediately preceded by a ‘pacing spike’ (Fig. 16.52). Nearly all pulse generators are used in the ‘demand’ mode, so that the pacemaker will operate only if the heart rate falls below a preset level. Occasionally, temporary atrial or dual-chamber pacing (see below) is used. Temporary pacing is indicated in the management of transient AV block and other arrhythmias complicating acute MI or cardiac surgery, to maintain the rhythm in other situations of reversible bradycardia (such as metabolic disturbance or drug overdose), or as a bridge to permanent pacing. Complications include pneumothorax, brachial plexus or subclavian artery injury, local infection or sepsis (usually with Staphylococcus aureus), and pericarditis. Failure of the system may be due to lead displacement or a progressive increase in the threshold (exit block) caused by tissue oedema. Complication rates increase with time and so a temporary pacing system should ideally not be used for more than 7 days. Transcutaneous pacing is administered by delivering an electrical stimulus through two large adhesive gel pad electrodes

Principles of management of cardiac arrhythmias • 483

Fig. 16.52 Dual-chamber pacing. The first three beats show atrial and ventricular pacing with narrow pacing spikes in front of each P wave and QRS complex. The last four beats show spontaneous P waves with a different morphology and no pacing spike; the pacemaker senses or tracks these P waves and maintains atrioventricular synchrony by pacing the ventricle after an appropriate interval. 16.34 International generic pacemaker code Chamber paced Chamber sensed Response to sensing O = none O = none O = none A = atrium A = atrium T = triggered V = ventricle V = ventricle I = inhibited D = both D = both D = both 16.35 Key indications for implantable cardiac defibrillator therapy Primary prevention • After myocardial infarction, if the left ventricular ejection fraction is < 30% • Mild to moderate symptomatic heart failure on optimal drug therapy, with left ventricular ejection fraction < 35% • Some patients with inherited cardiac conditions (long QT syndrome, cardiomyopathy) Secondary prevention • Survivors of ventricular fibrillation or ventricular tachycardia cardiac arrest not having a transient or reversible cause • Ventricular tachycardia with haemodynamic compromise or significant left ventricular impairment (left ventricular ejection fraction < 35%) placed over the apex and upper right sternal edge, or over the anterior and posterior chest. It is easy and quick to set up, but causes discomfort because it induces forceful pectoral and intercostal muscle contraction. Modern external cardiac defibrillators often incorporate a transcutaneous pacing system that can be used during an emergency until transvenous pacing is established. Permanent pacemakers Permanent pacemakers are small, flat, metal devices that are implanted under the skin, usually in the pectoral area. They contain a battery, a pulse generator, and programmable electronics that allow adjustment of pacing and memory functions. Pacing electrodes (leads) can be placed via the subclavian or cephalic veins into the RV (usually at the apex), the right atrial appendage or, to maintain AV synchrony, both. Permanent pacemakers are controlled using an external programmer through a wireless telemetry system, allowing rate, output, timing and other parameters to be adjusted. This allows the device settings to be tailored to the patient’s needs. Aside from their therapeutic role, pacemakers store useful diagnostic data about the patient’s heart rate trends and the occurrence of tachyarrhythmias, such as VT. Single-chamber atrial pacing is indicated in patients with SA disease without AV block and also in patients with continuous AF and bradycardia. Here the pacemaker acts as an external sinus node. Dual-chamber pacing is most often used in patients with second- or third-degree AV block. Here, the atrial electrode is used to detect spontaneous atrial activity and trigger ventricular pacing (Fig. 16.52), thereby preserving AV synchrony and allowing the ventricular rate to increase, together with the sinus node rate, during exercise and other forms of stress. Dual-chamber pacing has many advantages over ventricular pacing, including superior haemodynamics and better effort tolerance; a lower prevalence of atrial arrhythmias in patients with SA disease; and avoidance of ‘pacemaker syndrome’, in which a fall in BP and dizziness occur due to loss of AV synchrony. A code is used to signify the pacing mode (Box 16.34). For example, a system that paces the atrium, senses the atrium and is inhibited if it senses spontaneous activity is designated AAI. Most dual-chamber pacemakers are programmed to a mode termed DDD; in this case, ventricular pacing is triggered by a sensed sinus P wave and inhibited by a sensed spontaneous QRS complex. A fourth letter, ‘R’, is added if the pacemaker has a rate response function. For example, the letters AAIR indicate an atrial demand pacemaker with a rate response function. Rate-responsive pacemakers are used in patients with chronotropic incompetence, who are unable to increase their heart rate during exercise. These devices have a sensor that triggers an increase in heart rate in response to movement or increased respiratory rate. The sensitivity of the sensor is programmable, as is the maximum paced heart rate. Early complications of permanent pacing include pneumothorax, cardiac tamponade, infection and lead displacement. Late complications include infection (which usually necessitates removing the pacing system), erosion of the generator or lead, chronic pain related to the implant site, and lead fracture due to mechanical fatigue. Implantable cardiac defibrillators In addition to the functions of a permanent pacemaker, implantable cardiac defibrillators (ICDs) can also detect and terminate lifethreatening ventricular tachyarrhythmias. ICDs are larger than pacemakers mainly because of the need for a large battery and capacitor to enable cardioversion or defibrillation. ICD leads are similar to pacing leads but have one or two shock coils along the length of the lead, used for delivering defibrillation. ICDs treat ventricular tachyarrhythmias using overdrive pacing, cardioversion or defibrillation. They are implanted in a similar manner to pacemakers and carry a similar risk of complications. In addition, patients can be prone to psychological problems and anxiety, particularly if they have experienced repeated shocks from their device. The evidence-based indications for ICD implantation are shown in Box 16.35. These can be divided into secondary prevention indications, when patients have already had a potentially lifethreatening ventricular arrhyth mia, and primary prevention indications, when patients are considered to be at significant future risk of arrhythmic death. A common primary prevention indication is in patients with inherited conditions associated with a high risk of sudden cardiac death, such as long QT syndrome (p. 476), hypertrophic cardiomyopathy (p. 539) and arrhythmogenic right ventricular dysplasia (p. 540). Treatment with ICDs is expensive

484 • CARDIOLOGY during the ablation procedure. Serious complications are rare (< 1%) but include complete heart block requiring pacemaker implantation, and cardiac tamponade. For many arrhythmias, radiofrequency ablation is very attractive because it offers the prospect of a lifetime cure, thereby eliminating the need for long-term drug therapy. The technique has revolutionised the management of many arrhythmias and is now the treatment of choice for AVNRT and AV re-entrant (accessory pathway) tachycardias, when it is curative in over 90% of cases. Focal atrial tachycardias and atrial flutter can also be treated by radiofrequency ablation, although some patients subsequently experience episodes of AF. The applications of the technique are expanding and it can now be used to treat some forms of VT. Catheter ablation techniques are also employed to prevent AF. This involves ablation at two sites: the ostia of the pulmonary veins, from which ectopic beats may trigger paroxysms of arrhythmia, and in the LA itself, where re-entry circuits maintain AF, once established. This is effective at reducing episodes of AF in around 70–80% of younger patients with structurally normal hearts, and tends to be reserved for patients with drug-resistant AF because the procedure carries a risk of cardiac tamponade, and rarely stroke or death. In patients with permanent AF and poor rate control, in whom drugs are ineffective or are not tolerated, rate control can be achieved by implantation of a permanent pacemaker, followed by ablation of the AV node to induce complete AV block and bradycardia, thus allowing the pacemaker to assume control of the heart rate. Coronary artery disease Coronary artery disease (CAD) is the most common cause of angina and acute coronary syndrome and the most common cause of death worldwide. The World Health Organisation (WHO) has estimated that 3.8 million men and 3.4 million women die from cardiovascular disease (CVD) each year, and since 1990, more people have died from CVD than any other cause. It also has a devastating effect on quality of life. Disability-adjusted life years, a measure of healthy years of life lost, can be used to indicate the burden of disease rather than the resulting deaths. It has been estimated that CAD is responsible for 10% of disability-adjusted life years in low-income countries and 18% in high-income ones. In the UK, 1 in 3 men and 1 in 4 women die from CAD, an estimated 188 000 people have a myocardial infarct each year, and approximately 2.3 million people are living with CAD. The death rates from CAD in the UK are among the highest in Western Europe (more than 70 000 people) but are falling, particularly in younger age groups; over the last 50 years, CAD mortality has more than halved. In Eastern Europe and much of Asia, however, the rates of CAD are rapidly rising. Occult CAD is common in those who present with other forms of atherosclerotic vascular disease, such as intermittent claudication or stroke, and is an important cause of morbidity and mortality in these patients. Pathogenesis In the vast majority of patients, CAD is caused by atherosclerosis (Box 16.36) but rarely it can occur as the result of aortitis (p. 508), vasculitis (p. 1040) and autoimmune connective tissue diseases (p. 1034). Atherosclerosis is a progressive inflammatory disorder of the arterial wall that is characterised by focal lipid-rich deposits of atheroma that remain clinically silent until they become large enough to impair tissue perfusion, or until ulceration and disruption and so the indications for which the devices are routinely implanted depend on the health-care resources available. Cardiac resynchronisation therapy Cardiac resynchronisation therapy (CRT) is a useful treatment for selected patients with heart failure, in whom cardiac function is impaired by the presence of left bundle branch block. This conduction defect is associated with poorly coordinated left ventricular contraction that can aggravate heart failure in susceptible patients. The systems used to deliver CRT comprise a right atrial lead, a right ventricular lead, and a third lead that is placed via the coronary sinus into one of the veins on the epicardial surface of the LV (see Fig. 16.30, p. 467). Simultaneous septal and left ventricular epicardial pacing resynchronises left ventricular contraction. CRT improves symptoms and quality of life, and reduces mortality in patients with moderate to severe (NYHA class III–IV) heart failure who are in sinus rhythm, with left bundle branch block and left ventricular ejection fraction of 35% or less. CRT also prevents heart failure progression in similar patients with mild (NYHA class I–II) heart failure symptoms. These devices are more effective in patients in sinus rhythm than in those with AF. Most devices are also defibrillators (CRT-D) because many patients with heart failure are predisposed to ventricular arrhythmias. CRT pacemakers (CRT-P) are used when the focus is palliation of symptoms rather than prolonging life. Catheter ablation therapy Catheter ablation therapy is the treatment of choice for patients with SVT or atrial flutter, and is a useful treatment for some patients with AF or ventricular arrhythmias (Fig. 16.53). It involves inserting a series of catheter electrodes into the heart through the venous system. These are used to record the activation sequence of the heart in sinus rhythm, during tachycardia and after pacing manœuvres. Once the arrhythmia focus or circuit, such as an accessory pathway in WPW syndrome, has been identified, a catheter is used to ablate the culprit tissue. This can be done either by using heat, which is termed radiofrequency ablation, or by freezing, which is termed cryoablation. The procedure takes approximately 1–4 hours and does not require a general anaesthetic, although the patient may experience some discomfort Fig. 16.53 Radiofrequency ablation. Ablation of the accessory conducting pathway in Wolff–Parkinson–White syndrome (see text for details). (AV = atrioventricular node) Trans-septal puncture Sinus node AV node Accessory pathway ablation via catheter

Coronary artery disease • 485

16.36 Coronary artery disease: clinical manifestations and pathology Clinical problem Pathology Stable angina Ischaemia due to fixed atheromatous stenosis of one or more coronary arteries Unstable angina Ischaemia caused by dynamic obstruction of a coronary artery due to plaque rupture or erosion with superimposed thrombosis Myocardial infarction Myocardial necrosis caused by acute occlusion of a coronary artery due to plaque rupture or erosion with superimposed thrombosis Heart failure Myocardial dysfunction due to infarction or ischaemia Arrhythmia Altered conduction due to ischaemia or infarction Sudden death Ventricular arrhythmia, asystole or massive myocardial infarction until the sixth, seventh or eighth decade. During evolution of an atherosclerotic plaque, monocytes and other inflammatory cells bind to receptors expressed by endothelial cells. Subsequently, they migrate into the intima, and take up oxidised low-density lipoprotein (LDL) particles by phagocytosis to become lipid-laden macrophages or foam cells. Extracellular lipid pools appear in the intimal space when foam cells die and release their contents (Fig. 16.54). In response to cytokines and growth factors produced by activated macrophages, smooth muscle cells migrate from the media of the arterial wall into the intima, and change from a contractile to a fibroblastic phenotype, which can stabilise the atherosclerotic lesion. If this is successful, the lipid core will be covered by smooth muscle cells and matrix, producing a stable atherosclerotic plaque that will remain asymptomatic until it becomes large enough to obstruct arterial flow. In an established atherosclerotic plaque, macrophages mediate inflammation and smooth muscle cells promote repair. If inflammation predominates, the plaque becomes active or unstable and may be complicated by ulceration and thrombosis. Cytokines, such as interleukin-1, tumour necrosis factor-alpha, interferon-gamma, platelet-derived growth factors and matrix metalloproteinases, are released by activated macrophages. They cause the intimal smooth muscle cells overlying the plaque to become senescent and the collagen cross-links within the plaque to degrade. This results in thinning of the protective fibrous cap, making the lesion vulnerable to mechanical stress that ultimately causes erosion, fissuring or rupture of the plaque surface (Fig. 16.54). Any breach in the integrity of the plaque will expose its contents to blood and will trigger platelet aggregation and of the lesion result in thrombotic occlusion or distal embolisation of the vessel. Atherosclerosis begins early in life with deposits of lipids in the vessel wall, which tend to occur at sites of altered arterial shear stress, such as bifurcations, and are associated with abnormalities of endothelial function at that site. Abnormalities of arterial function have been detected among high-risk children and adolescents, such as cigarette smokers and those with familial hyperlipidaemia or hypertension. Early lesions have been found in the arteries of victims of accidental death in the second and third decades of life but clinical manifestations often do not appear Fig. 16.54 The six stages of atherosclerosis. American Heart Association classification. From Stary HC, Chandler B, Dinsmore RE et al. A definition of advanced types of atherosclerotic lesions and a histological classification of atherosclerosis. Circulation 1995; 92:1355–1374. © 1995 American Heart Association. Sequences in progression I II IV V VI Nomenclature and main histology Type I (initial) lesion Isolated macrophage foam cells Main growth mechanism Earliest onset Clinical correlation Type II (fatty streak) lesion Mainly intracellular lipid accumulation Type III (intermediate) lesion Type II changes and small extracellular lipid pools Type IV (atheroma) lesion Type II changes and core of extracellular lipid Type V (fibroatheroma) lesion Lipid core and fibrotic layer, or multiple lipid cores and fibrotic layers, or mainly calcific, or mainly fibrotic Type VI (complicated) lesion Surface defect, haematoma-haemorrhage, thrombus Thrombosis, haematoma Accelerated smooth muscle and collagen increase Growth mainly by lipid accumulation From fourth decade Clinically silent or overt Clinically silent From third decade From first decade III

486 • CARDIOLOGY Antihypertensive therapy reduces cardiovascular mortality, stroke and heart failure. Hypercholesterolaemia The risk of atherosclerosis rises with serum cholesterol concentrations and lowering serum total and LDL cholesterol concentrations reduces the risk of cardiovascular events. Diabetes mellitus This is a potent risk factor for all forms of atherosclerosis, especially type 2 diabetes mellitus. It is often associated with diffuse disease that is difficult to treat. Insulin resistance (normal glucose homeostasis with high levels of insulin) is associated with obesity and physical inactivity, and is also a risk factor for CAD (p. 730). Glucose intolerance makes a major contribution to the high incidence of ischaemic heart disease in people from the Indian subcontinent and some other ethnic groups. Haemostatic factors Platelet activation and high plasma fibrinogen concentrations are associated with an increased risk of coronary thrombosis, whereas antiphospholipid antibodies are associated with recurrent arterial thromboses (p. 977). Physical activity Regular exercise (brisk walking, cycling or swimming for 20 minutes two or three times a week) has a protective effect, whereas inactivity roughly doubles the risk of CAD and is a major risk factor for stroke. Obesity Obesity, particularly if central or truncal, is an independent risk factor, although it is often associated with other adverse factors such as hypertension, diabetes mellitus and physical inactivity. Alcohol Excess alcohol consumption is associated with hypertension and cerebrovascular disease. Diet Diets deficient in fresh fruit, vegetables and polyunsaturated fatty acids are associated with an increased risk of cardiovascular disease. The introduction of a Mediterranean-style diet reduces cardiovascular events. However, dietary supplements, such as vitamins C and E, beta-carotene, folate and fish oils, do not reduce cardiovascular events and, in some cases, have been associated with harm. Personality While certain personality traits are associated with an increased risk of coronary disease there is no evidence to support the popular belief that stress is a major cause of CAD. Social deprivation Social deprivation is strongly related to cardiovascular disease. This may be partly due to associations with lifestyle risk factors, such as smoking and alcohol excess, which are more common in socially deprived individuals. Social deprivation does appear to be an independent risk factor for cardiovascular disease, however. Current guidelines recommend that treatment thresholds should be lowered for patients from socially deprived areas. thrombosis that extend into the atheromatous plaque and the arterial lumen. This may cause partial or complete obstruction at the site of the lesion or distal embolisation, resulting in infarction or ischaemia of the affected organ. This common mechanism underlies acute coronary syndromes, as well as other manifestations of atherosclerotic disease such as lower limb ischaemia (p. 502) and stroke (Ch. 26). The number and complexity of arterial plaques increase with age and risk factors (see below) but the rate of progression of individual plaques is variable. There is a complex and dynamic interaction between mechanical wall stress and atherosclerotic lesions. Vulnerable plaques are characterised by a lipid-rich core, a thin fibrocellular cap, speckled calcification and an increase in inflammatory cells that release specific enzymes to degrade matrix proteins. In contrast, stable plaques are typified by a small lipid pool, a thick fibrous cap, heavy calcification and plentiful collagenous cross-links. Fissuring or rupture tends to occur at sites of maximal mechanical stress, particularly the margins of an eccentric plaque, and may be triggered by a surge in BP, such as during exercise or emotional stress. Surprisingly, most plaque events are subclinical and heal spontaneously, although this may allow thrombus to be incorporated into the lesion, producing plaque growth and further obstruction to flow. Atherosclerosis may induce complex changes in the media that lead to arterial remodelling. Some arterial segments may slowly constrict (negative remodelling), while others may gradually enlarge (positive remodelling). These changes are important because they may amplify or minimise the degree to which atheroma encroaches into the arterial lumen. Many risk factors have been identified for atherosclerosis but the causes are incompletely understood, since unknown factors account for up to 40% of the variation in risk from one person to the next. Age and sex Age is the most powerful independent risk factor for atherosclerosis and gender also plays a role. Pre-menopausal women have lower rates of disease than men, although the gender difference disappears after the menopause. Hormone replacement therapy (HRT) is not effective in the prevention of CAD, and HRT in post-menopausal women is associated with an increased risk of cardiovascular events. Genetics Atherosclerotic CAD often runs in families and a positive family history is common in patients with early-onset disease (age < 50 in men and < 55 in women). Twin studies have shown that a monozygotic twin of an affected individual has an eightfold increased risk and a dizygotic twin a fourfold increased risk of dying from CAD, compared to the general population due to a combination of shared genetic, environmental and lifestyle factors. The most common risk factors, such as hypertension, hyperlipidaemia and diabetes mellitus, are inherited in a polygenic manner. Smoking There is a strong relationship between cigarette smoking and CAD, especially in younger (< 70 years) individuals, and this is probably the most important modifiable risk factor. Hypertension The incidence of atherosclerosis increases as BP rises, and this is related to systolic and diastolic BP, as well as pulse pressure.

Coronary artery disease • 487

16.37 Population-based strategies to prevent coronary disease • Do not smoke • Take regular exercise (minimum of 20 mins, three times per week) • Maintain an ‘ideal’ body weight • Eat a mixed diet rich in fresh fruit and vegetables • Aim to get no more than 10% of energy intake from saturated fat in different countries. In the UK and North America, current guidelines recommend initiation of cholesterol and BP-lowering therapies in individuals with a 10-year cardiovascular risk of 7.5–10%. Secondary prevention This involves targeting interventions at individuals who already have evidence of cardiovascular disease. Patients who recover from a clinical event such as an MI are usually keen to help themselves and are particularly receptive to lifestyle advice, such as dietary modification and smoking cessation. Additional interventions that should be introduced in patients with angina pectoris or an acute coronary syndrome are discussed in more detail below. Angina pectoris Angina pectoris is a symptom complex caused by transient myocardial ischaemia, which occurs whenever there is an imbalance between myocardial oxygen supply and demand (Box 16.38). Pathogenesis Atherosclerosis is by far the most common cause of angina pectoris. Angina may also occur in aortic valve disease and hypertrophic cardiomyopathy, and when the coronary arteries are involved with vasculitis or aortitis. The underlying mechanisms and risk factors for atherosclerosis have already been discussed. Approximately 10% of patients who report stable angina on effort have normal coronary arteries on angiography. The main causes are discussed in more detail below. Coronary artery spasm Angina may result from vasospasm of the coronary arteries. This may coexist with atherosclerosis, especially in unstable angina (see below), but may occur as an isolated phenomenon in less than 1% of cases, in patients with normal coronary arteries on angiography. This is sometimes known as variant angina; when it is accompanied by transient ST elevation on the ECG, it is termed Prinzmetal’s angina. Syndrome X The constellation of typical angina on effort, objective evidence of myocardial ischaemia on stress testing, and normal coronary arteries on angiography is sometimes known as syndrome X. Many of these patients are women and the mechanism of their The effect of risk factors can be multiplicative rather than additive. People with a combination of risk factors are at greatest risk and so assessment should take account of all identifiable risk factors. It is important to distinguish between relative risk (the proportional increase in risk) and absolute risk (the actual chance of an event). For example, a man of 35 years with a plasma cholesterol of 7 mmol/L (approximately 170 mg/dL), who smokes 40 cigarettes a day, is much more likely to die from coronary disease within the next decade than a non-smoking man of the same age with a normal cholesterol, but the absolute likelihood of his dying during this time is still small (high relative risk, low absolute risk). Management Two approaches can be employed. Primary prevention aims to introduce lifestyle changes or therapeutic interventions to prevent CAD and other forms of atherosclerosis in the whole population or in healthy individuals with an elevated risk of disease. Secondary prevention involves initiating treatment in patients who already have had an event, with the aim of reducing the risk of subsequent events. Primary prevention The population-based strategy aims to modify the risk factors of the whole population through diet and lifestyle advice, on the basis that even a small reduction in smoking or average cholesterol, or modification of exercise and diet will produce worthwhile benefits (Box 16.37). Some risk factors, such as obesity and smoking, are also associated with a higher risk of other diseases and should be actively discouraged through public health measures. The effectiveness of this approach has been demonstrated by introduction of legislation to restrict smoking in public places, which has been associated with reductions in rates of MI. The targeted strategy aims to identify and treat high-risk individuals, who usually have a combination of risk factors that can be quantified by composite scoring systems. It is important to consider the absolute risk of atheromatous cardiovascular disease that an individual is facing before initiating treatment, since this will help to determine whether the potential benefits of intervention are likely to outweigh the expense, inconvenience and possible side-effects of treatment. For example, a 65-year-old man with an average BP of 150/90 mmHg, who smokes and has diabetes mellitus with a total:high-density lipoprotein (HDL) cholesterol ratio of 8, has a 10-year risk of MI or stroke of 56%. Conversely, a 55-year-old woman who has an identical BP, is a non-smoker, does not have diabetes mellitus, and has a total:HDL cholesterol ratio of 6 has a much better outlook, with a 10-year coronary MI or stroke risk of 5.7%. Lowering cholesterol will reduce the risk in both of these individuals by 30% and lowering BP will produce a further 20% reduction. In combination, both strategies would reduce the risk of an event from 56% to 25% in the male patient and from 5.7% to 2.5% in the female patient. Thresholds for treatment vary 16.38 Factors influencing myocardial oxygen supply and demand Oxygen demand: cardiac work • Heart rate • Blood pressure • Myocardial contractility • Left ventricular hypertrophy • Valve disease Oxygen supply: coronary blood flow* • Duration of diastole • Coronary perfusion pressure (aortic diastolic minus coronary sinus or right atrial diastolic pressure) • Coronary vasomotor tone • Oxygenation: Haemoglobin Oxygen saturation *Coronary blood flow occurs mainly in diastole.

488 • CARDIOLOGY 16.41 Risk stratification in stable angina* High risk Low risk Post-infarct angina Predictable exertional angina Poor effort tolerance Good effort tolerance Ischaemia at low workload Ischaemia only at high workload Left main or three-vessel disease Single-vessel or two-vessel disease Poor left ventricular function Good left ventricular function *Patients may fall between these two categories. 16.39 Activities precipitating angina Common • Physical exertion • Cold exposure • Heavy meals • Intense emotion Uncommon • Vivid dreams (nocturnal angina) • Lying flat (decubitus angina) 16.40 Canadian Cardiovascular Society (CCS) angina score Class I • Angina only during strenuous or prolonged physical activity Class II • Slight limitation, with angina only during vigorous physical activity Class III • Moderate limitation where symptoms occur with everyday activities Class IV • Inability to perform any activity without angina or angina at rest, i.e. severe limitation symptoms is often unclear. This disorder is poorly understood; it carries a good prognosis but may respond to anti-anginal therapy. Other causes Angina can occur in association with aortic stenosis, hypertrophic obstructive cardiomyopathy and aortitis, all of which are discussed in more detail later in this chapter. It may also rarely be found in association with vasculitis (p. 1040). Clinical features The history is the most important factor in making the diagnosis (p. 454). Stable angina is characterised by central chest pain, discomfort or breathlessness that is predictably precipitated by exertion or other forms of stress (Box 16.39), and is promptly relieved by rest (see Fig. 10.1, p. 178). Some patients find the discomfort comes when they start walking and that later it does not return despite greater effort (‘warm-up angina’). The Canadian Cardiovascular Society (CCS) scoring system is commonly used to grade the severity of angina (Box 16.40). This is of clinical value, not only in documenting the severity of angina but also in assessing prognosis (p. 493). Physical examination is frequently unremarkable but should include a careful search for evidence of valve disease (particularly aortic), important risk factors (hypertension, diabetes mellitus), left ventricular dysfunction (cardiomegaly, gallop rhythm), other manifestations of arterial disease (carotid bruits, peripheral arterial disease), and unrelated conditions that may exacerbate angina (anaemia, thyrotoxicosis). Investigations Symptoms are a poor guide to the extent of CAD. Because of this, stress testing and non-invasive imaging are advisable in patients who are potential candidates for revascularisation. An algorithm for the investigation and treatment of patients with stable angina is shown in Figure 16.55. The first-line investigation is an exercise ECG, which should be performed using a standard treadmill or bicycle ergometer protocol (p. 449) while monitoring the patient’s pulse, BP and general condition. Planar or downsloping ST segment depression of 1 mm or more is indicative of ischaemia (Fig. 16.56). Up-sloping ST depression is less specific; it often occurs in normal individuals and false-positive results can occur with digoxin therapy, left ventricular hypertrophy, bundle branch block and WPW syndrome. The amount of exercise that can be tolerated and the extent of ST segment change (Fig. 16.57) that occurs can be of value in identifying high-risk individuals with severe coronary disease in combination with other clinical features (Box 16.41). However, exercise testing may be normal in a significant proportion of patients with CAD or may be inconclusive because an adequate heart rate cannot be achieved due to reduced mobility or other non-cardiac problems. Accordingly, if clinical suspicion is high and the exercise ECG is normal or inconclusive, further imaging with myocardial perfusion scanning or stress echocardiography is indicated. A perfusion defect present during stress but not at rest provides evidence of reversible myocardial ischaemia (Fig. 16.58), whereas a persistent perfusion defect seen during both phases of the study is usually indicative of previous MI. Increasingly, CT coronary arteriography is being used to document the presence or absence of CAD in patients with suspected angina. It can clarify the diagnosis, help to guide optimal treatment and avoid the need for cardiac catheterisation in patients who do not have CAD or who have mild disease only (see Fig. 16.55). Coronary angiography provides detailed anatomical information about the extent and nature of CAD (see Fig. 16.15, p. 453). It is usually performed when coronary artery bypass graft surgery or percutaneous coronary intervention is being considered (p. 491). Management This should begin with a careful explanation of the problem and a discussion of the lifestyle and medical interventions that can be deployed to relieve symptoms and improve prognosis (Box 16.42). Anxiety and misconceptions often contribute to disability; for example, some patients avoid all forms of exertion because they believe that each attack of angina is a ‘mini-heart attack’ that results in permanent damage. Education and reassurance can dispel these misconceptions and make a huge difference to the patient’s quality of life. The principles of management involve: • a careful assessment of the extent and severity of arterial disease • identification and treatment of risk factors • advice on smoking cessation • introduction of drug treatment for symptom control • identification of high-risk patients for treatment to improve life expectancy.

Coronary artery disease • 489

Fig. 16.55 A scheme for the investigation and treatment of stable angina on effort. This scheme is best adopted for patients without prior known coronary artery disease. For patients with known coronary artery disease, further stress imaging (echocardiography, radionuclide perfusion or magnetic resonance perfusion) rather than computed tomography coronary angiography is recommended. Clinical consultation History and examination Blood tests and 12-lead ECG Consider chest X-ray and echocardiography Consider exercise ECG Clear diagnosis of angina? Non-anginal chest pain and normal ECG? Yes Yes No No Computed tomography Coronary angiography Non-obstructive coronary artery disease Consider preventative therapies No coronary artery disease Consider alternative diagnoses Obstructive coronary artery disease Preventative therapies Anti-anginal therapy Consider invasive coronary angiography ± revascularisation Fig. 16.56 Forms of exercise-induced ST depression. A Planar ST depression is usually indicative of myocardial ischaemia. B Down-sloping depression also usually indicates myocardial ischaemia. C Up-sloping depression may be a normal finding. B C A All patients with angina secondary to CAD should receive antiplatelet therapy. Low-dose (75 mg) aspirin should be prescribed for all patients and continued indefinitely since it reduces the risk of MI. Clopidogrel (75 mg daily) is an equally effective alternative if aspirin causes dyspepsia or other sideeffects. Similarly, all patients should be prescribed a statin, even if cholesterol is normal. Anti-anginal drug therapy The goal of anti-anginal therapy is to control symptoms using a regimen that is as simple as possible and does not cause sideeffects. Five groups of drug can be used in the prevention and treatment of angina but there is little evidence that one group is more effective than another. It is conventional to start therapy with sublingual glyceryl trinitrate (GTN) and a β-blocker, and then add a calcium channel antagonist or a long-acting nitrate if needed. If the combination of two drugs fails to achieve an acceptable symptomatic response, revascularisation should be considered Nitrates Nitrates act directly on vascular smooth muscle to produce venous and arteriolar dilatation. Several preparations are available, 16.42 Advice to patients with stable angina • Do not smoke • Aim for an ideal body weight • Take regular exercise (exercise up to, but not beyond, the point of chest discomfort is beneficial and may promote collateral vessels) • Avoid severe unaccustomed exertion, and vigorous exercise after a heavy meal or in very cold weather • Take sublingual nitrate before undertaking exertion that may induce angina

490 • CARDIOLOGY Fig. 16.58 A myocardial perfusion scan showing reversible anterior myocardial ischaemia. The images are cross-sectional tomograms of the left ventricle. The resting scans (left) show even uptake of the 99technetium-labelled tetrofosmin and look like doughnuts. During stress there is reduced uptake of technetium, particularly along the anterior wall (arrows), and the scans look like crescents (right). At rest During stress Fig. 16.57 A positive exercise test (chest leads only). The resting 12-lead ECG shows some minor T-wave changes in the inferolateral leads but is otherwise normal. After 3 minutes’ exercise on a treadmill, there is marked planar ST depression in leads V4 and V5 (right-hand offset). Subsequent coronary angiography revealed critical three-vessel coronary artery disease. V3 V6 V5 V2 V1 V4 as shown in Box 16.43. They help angina by lowering preload and afterload, which reduces myocardial oxygen demand, and by increasing myocardial oxygen supply through coronary vasodilatation. Sublingual GTN, administered from a metered-dose aerosol (400 μg per spray) or as a tablet (300 or 500 μg), is indicated for acute attacks and will usually relieve an attack in 2–3 minutes. Patients should also be encouraged to use the drug prophylactically before taking exercise that is liable to provoke symptoms. Sublingual GTN has a short duration of action and side-effects include headache, symptomatic hypotension and, rarely, syncope. A more prolonged therapeutic effect can be achieved by giving GTN transcutaneously as a patch (5–10 mg daily) or as a slow-release buccal tablet (1–5 mg 4 times daily). Isosorbide dinitrate (10–20 mg 3 times daily) and isosorbide mononitrate (20–60 mg once or twice daily) can be given by mouth, unlike GTN, which undergoes extensive metabolism in the liver. Headache is common with oral nitrates but tends to diminish if the patient perseveres with the treatment. Continuous nitrate therapy can cause pharmacological tolerance but this can be avoided by a 6–8-hour nitrate-free period, best achieved at night when the patient is inactive. If nocturnal angina is a predominant symptom, long-acting nitrates can be given at the end of the day. Beta-blockers These lower myocardial oxygen demand by reducing heart rate, BP and myocardial contractility, but they may provoke bronchospasm in patients with asthma. The properties and side-effects of β-blockers are discussed on page 500. In theory, non-selective β-blockers may aggravate coronary vasospasm by blocking coronary artery β2-adrenoceptors, and so a once-daily cardioselective preparation such as slow-release metoprolol (50–200 mg daily) or bisoprolol (5–15 mg daily) is preferable. Beta-blockers should not be withdrawn abruptly, as rebound effects may precipitate dangerous arrhythmias, worsening angina or MI. This is known as the β-blocker withdrawal syndrome. Calcium channel antagonists These drugs lower myocardial oxygen demand by reducing BP and myocardial contractility. Since dihydropyridine calcium antagonists, such as nifedipine and amlodipine, may cause a reflex tachycardia, it is best to use them in combination with a β-blocker. In contrast, verapamil and diltiazem can be used as monotherapy because they slow SA node firing, inhibit conduction through the AV node and tend to cause bradycardia. They are particularly useful when β-blockers are contraindicated. Calcium channel antagonists reduce myocardial contractility and must be used with care in patients with poor LV function, since they can 16.43 Duration of action of some nitrate preparations Preparation Peak action Duration of action Sublingual GTN 4–8 mins 10–30 mins Buccal GTN 4–10 mins 30–300 mins Transdermal GTN 1–3 hrs Up to 24 hrs Oral isosorbide dinitrate 45–120 mins 2–6 hrs Oral isosorbide mononitrate 45–120 mins 6–10 hrs (GTN = glyceryl trinitrate)

Coronary artery disease • 491

aggravate or precipitate heart failure. Other unwanted effects include peripheral oedema, flushing, headache and dizziness (Box 16.44). Potassium channel activators Nicorandil (10–30 mg twice daily orally) is the only drug in this class that is currently available for clinical use. It acts as a vasodilator with effects on the arterial and venous systems, and has the advantage that it does not exhibit the tolerance seen with nitrates. If channel antagonist Ivabradine is the first of this class of drug. It induces bradycardia by modulating ion channels in the sinus node. It does not inhibit myocardial contractility and appears to be safe in patients with heart failure. Ranolazine This drug inhibits the late inward sodium current in coronary artery smooth muscle cells, with a secondary effect on calcium flux and vascular tone, reducing angina symptoms. Non-pharmacological treatments Percutaneous coronary intervention Percutaneous coronary intervention (PCI) involves passing a fine guidewire across a coronary stenosis under radiographic control and using it to position a balloon, which is then inflated to dilate the stenosis (Fig. 16.59). This can be combined with deployment of a coronary stent, which is a piece of metallic ‘scaffolding’ that can be impregnated with drugs with antiproliferative properties and that helps to maximise and maintain dilatation of a stenosed vessel. The routine use of stents in appropriate vessels reduces both acute complications and the incidence of clinically important restenosis (Fig. 16.60). Treatment with PCI often provides excellent symptom control but it does not improve survival in patients with chronic stable angina. It is mainly used in single- or two-vessel disease. Stenoses in bypass grafts can be dilated, as well as those in the native coronary arteries. The technique is often used to provide palliative therapy for patients with recurrent angina after coronary artery bypass grafting. The main acute complications of PCI are occlusion of the target vessel or a side branch by thrombus or a loose flap of intima (coronary artery dissection), and consequent myocardial 16.44 Calcium channel antagonists used for the treatment of angina Drug Dose Feature Nifedipine 5–20 mg 3 times daily* May cause marked tachycardia Nicardipine 20–40 mg 3 times daily May cause less myocardial depression than the other calcium antagonists Amlodipine 2.5–10 mg daily Ultra-long-acting Verapamil 40–80 mg 3 times daily* Commonly causes constipation; useful anti-arrhythmic properties (p. 481) Diltiazem 60–120 mg 3 times daily* Similar anti-arrhythmic properties to verapamil *Once- or twice-daily slow-release preparations are available. Fig. 16.59 Percutaneous coronary intervention. A guidewire is advanced from the radial (or femoral) artery to the coronary artery under radiographic control (1). A fine balloon catheter is then advanced over the guidewire to the stenotic coronary artery and the balloon is inflated to dilate the stenosis (2). When this has been achieved, a stent is usually placed at the site of the stenosis to maintain patency of the artery (3) (see text for more details).

damage. This occurs in about 2–5% of procedures and can often be corrected by deploying a stent, although emergency coronary artery bypass grafting may occasionally be required if stenting is unsuccessful. Minor myocardial damage, as indicated by elevation of sensitive intracellular markers (p. 497), occurs in up to 10% of cases. The main long-term complication of PCI is restenosis, in up to one-third of cases. This is due to a combination of elastic recoil and smooth muscle proliferation and tends to occur within 3 months. Stenting substantially reduces the risk of restenosis, probably because it allows the operator to achieve more complete dilatation. Drug-eluting stents reduce this risk further by allowing an antiproliferative drug, such as sirolimus or paclitaxel, to elute slowly from the coating and prevent neo-intimal hyperplasia and in-stent restenosis. These are especially indicated in diabetic patients, or in patients with long or calcific lesions, or small target-vessel diameter. Recurrent angina (affecting up to 5–10% of patients receiving an intracoronary stent at 6 months) may require further PCI or bypass grafting. The risk of complications and the likely success of the procedure are closely related to the morphology of the stenoses, the experience of the operator and the presence of important comorbidity, such as diabetes and peripheral arterial disease. A good outcome is less likely if the target lesion is complex, long, eccentric or calcified, lies on a bend or within a tortuous vessel, involves a branch or contains thrombus. Adjunctive therapy with a potent platelet inhibitor such as the P2Y12 receptor antagonists (clopidogrel, prasugrel or ticagrelor) in combination with aspirin and heparin improves the outcome following PCI. Coronary artery bypass grafting The internal mammary arteries, radial arteries or reversed segments of the patient’s own saphenous vein can be used to bypass coronary artery stenoses (Fig. 16.61). This usually involves major surgery under cardiopulmonary bypass but, in some cases, grafts can be applied to the beating heart: ‘off-pump’ surgery. The operative mortality is approximately 1.5% but risks are higher in elderly patients, those with poor left ventricular function and those with significant comorbidity, such as renal failure. Approximately 90% of patients are free of angina 1 year after coronary artery bypass grafting (CABG), but fewer than 60% of patients are asymptomatic after 5 or more years. Early post-operative angina is usually due to graft failure arising from technical problems during the operation, or poor ‘run-off’ due

492 • CARDIOLOGY Fig. 16.60 Primary percutaneous coronary intervention. A Acute right coronary artery occlusion. B Initial angioplasty demonstrates a large thrombus filling defect (arrows). C Complete restoration of normal flow following intracoronary stenting. A B C should be prescribed indefinitely. Intensive lipid-lowering therapy slows the progression of disease in the native coronary arteries and bypass grafts, and reduces clinical cardiovascular events. There is substantial excess cardiovascular morbidity and mortality in patients who continue to smoke after bypass grafting. Persistent smokers are twice as likely to die in the 10 years following surgery than those who give up at surgery. Survival is improved by CABG in symptomatic patients with left main stem stenosis or three-vessel coronary disease when the LAD, CX and right coronary arteries are involved, or two-vessel disease involving the proximal LAD coronary artery. Improvement in survival is most marked in those with impaired left ventricular function or positive stress testing prior to surgery and in those who have undergone left internal mammary artery grafting. Neurological complications are common, with a 1–5% risk of perioperative stroke. Between 30% and 80% of patients develop Fig. 16.61 Coronary artery bypass graft surgery. A Narrowed or stenosed arteries are bypassed using saphenous vein grafts connected to the aorta or by utilising the internal mammary artery. B Threedimensional reconstruction of multidetector CT of the heart. The image shows the patent saphenous vein grafts (SVG) to the right coronary artery (RCA), obtuse marginal branch (OM) and diagonal branch (LADD), and left internal mammary artery graft (LIMA) to the left anterior descending (LAD) coronary artery. Saphenous vein bypass graft Blocked artery Internal mammary artery bypass graft A LIMA-LAD SVG-RCA SVG-OM SVG-LADD B to disease in the distal native coronary vessels. Late recurrence of angina may be caused by progressive disease in the native coronary arteries or graft degeneration. Fewer than 50% of vein grafts are patent 10 years after surgery. Arterial grafts have a much better long-term patency rate, however, with more than 80% of internal mammary artery grafts patent at 10 years. This has led many surgeons to consider total arterial revascularisation during CABG surgery. Aspirin (75–150 mg daily) and clopidogrel (75 mg daily) both improve graft patency, and one or the other

Coronary artery disease • 493

Acute coronary syndrome Acute coronary syndrome is a term that encompasses both unstable angina and myocardial infarction. Unstable angina is characterised by new-onset or rapidly worsening angina (crescendo angina), angina on minimal exertion or angina at rest in the absence of myocardial damage. Myocardial infarction differs from unstable angina, since there is evidence of myocardial necrosis. The term acute myocardial infarction (MI) should be used when there is evidence of myocardial necrosis in a clinical setting consistent with acute myocardial ischaemia. Under these conditions, any one of the criteria shown in Box 16.47 fulfils the criteria for the diagnosis of an acute MI. The diagnosis of a previous MI can be made when any one of the features shown in Box 16.48 is present. Acute coronary syndrome may present as a new phenomenon in patients with no previous history of heart disease or against a background of chronic stable angina. Approximately 12% of patients with acute coronary syndrome die within 1 month and 20% within 6 months of the index event. The risk markers that are indicative of an adverse prognosis include recurrent ischaemia, extensive ECG changes at rest or during pain, raised troponin I or T levels, arrhythmias and haemodynamic complications short-term cognitive impairment that typically resolves within 6 months. There are also reports of long-term cognitive decline that may be evident in more than 30% of patients at 5 years. PCI and CABG are compared in Box 16.45. Prognosis The prognosis of CAD is related to the number of diseased vessels and the degree of left ventricular dysfunction. A patient with single-vessel disease and good left ventricular function has a 5-year survival of more than 90%. In contrast, a patient with severe left ventricular dysfunction and extensive threevessel disease has a 5-year survival of less than 30% unless revascularisation is performed. Symptoms are a poor guide to prognosis, since spontaneous improvement in angina due to the development of collateral vessels is common. Nevertheless, the 5-year mortality of patients with severe angina (CCS angina scale III or IV, see Box 16.40) is nearly double that of patients with mild symptoms. 16.45 Comparison of percutaneous coronary intervention (PCI) and coronary artery bypass grafting (CABG) PCI CABG Death < 0.5% < 1.5% Myocardial infarction* 2% 10% Hospital stay 12–36 hrs 5–8 days Return to work 2–5 days 6–12 weeks Recurrent angina 15–20% at 6 months 10% at 1 year Repeat revascularisation 10–20% at 2 years 2% at 2 years Neurological complications Rare Common (see text) Other complications Emergency CABG Vascular damage related to access site Diffuse myocardial damage Infection (chest, wound) Wound pain *Defined as CK-MB > 2 × normal (p. 497). 16.46 Angina in old age • Incidence: coronary artery disease increases in old age and affects women almost as often as men. • Comorbid conditions: anaemia and thyroid disease are common and may worsen angina. • Calcific aortic stenosis: common and should be sought in all older people with angina. • Atypical presentations: when myocardial ischaemia occurs, age-related changes in myocardial compliance and diastolic relaxation can cause the presentation to be with symptoms of heart failure, such as breathlessness, rather than with chest discomfort. • Angioplasty and coronary artery bypass surgery: provide symptomatic relief, although with increased procedure-related morbidity and mortality. Outcome is determined by the number of diseased vessels, severity of cardiac dysfunction and the number of concomitant diseases, as much as by age itself. Adapted from Thygesen K, Alpert JS, Jaffe AS et al. Third universal definition of myocardial infarction. Eur Heart J 2012; 33:2551–2267. 16.47 Criteria for diagnosis of an acute myocardial infarction (MI) • Detection of a rise and/or fall of cardiac biomarker values (preferably cardiac troponin (cTn)), with at least one value above the 99th centile upper reference limit (URL) and with at least one of the following:

  1. Symptoms of ischaemia
  2. New or presumed new significant ST segment–T wave (ST–T) changes or new left bundle branch block (LBBB)
  3. Development of pathological Q waves in the ECG
  4. Imaging evidence of new loss of viable myocardium or new regional wall motion abnormality
  5. Identification of an intracoronary thrombus by angiography or postmortem • Cardiac death with symptoms suggestive of myocardial ischaemia and presumed new ischaemic ECG changes or new LBBB, but death occurred before cardiac biomarkers were obtained, or before cardiac biomarker values would be increased • Percutaneous coronary intervention (PCI)-related MI is arbitrarily defined by elevation of cTn values (> 5 × 99th centile URL) in patients with normal baseline values (≤ 99th centile URL) or a rise of cTn values > 20% if the baseline values are elevated and are stable or falling. In addition, either (i) symptoms suggestive of myocardial ischaemia, or (ii) new ischaemic ECG changes, or (iii) angiographic findings consistent with a procedural complication, or (iv) imaging demonstration of new loss of viable myocardium or new regional wall motion abnormality are required • Stent thrombosis associated with MI when detected by coronary angiography or postmortem in the setting of myocardial ischaemia and with a rise and/or fall of cardiac biomarker values with at least one value above the 99th centile URL • Coronary artery bypass grafting (CABG)-related MI is arbitrarily defined by elevation of cardiac biomarker values (> 10 × 99th centile URL) in patients with normal baseline cTn values (≤ 99th centile URL). In addition, either (i) new pathological Q waves or new LBBB, or (ii) angiographic documented new graft or new native coronary artery occlusion, or (iii) imaging evidence of new loss of viable myocardium or new regional wall motion abnormality is required

494 • CARDIOLOGY Adapted from Thygesen K, Alpert JS, Jaffe AS et al. Third universal definition of myocardial infarction. Eur Heart J 2012; 33:2551–2267. 16.48 Criteria for diagnosis of a prior myocardial infarction • Pathological Q waves with or without symptoms in the absence of non-ischaemic causes • Imaging evidence of a region of loss of viable myocardium that is thinned and fails to contract, in the absence of a non-ischaemic cause • Pathological findings of a prior myocardial infarction Fig. 16.62 Risk stratification in the acute coronary syndrome: the GRACE score. Killip class refers to a categorisation of the severity of heart failure based on easily obtained clinical signs. The main clinical features are as follows: class I = no heart failure; class II = crackles audible halfway up the chest; class III = crackles heard in all the lung fields; class IV = cardiogenic shock. To convert creatinine in μmol/L to mg/dL, divide by 88.4. (SBP = systolic blood pressure) From Scottish Intercollegiate Guidelines Network (SIGN) Guideline no. 93 – Acute coronary syndromes; February 2007.

  1. Find points for each predictive factor
  2. Sum points for all predictive factors Killip class Points I II III IV

SBP (mmHg) Points ≤ 80 80–99 100–119 120–139

140–159

160–199

≥ 200 Heart rate (beats/min) Points ≤ 50 50–69 70–89 90–109

110–149

150–199

≥ 200 Age (years) Points ≤ 30 30–39 40–49 50–59

60–69

70–79

80–89

≥ 90 Serum creatinine level (μmol/L) Killip class + + + + + + + SBP Heart rate Age Creatinine level Cardiac arrest at admission ST-segment deviation

Elevated cardiac enzyme levels Total points 3. Look up risk corresponding to total points Total points Probability of in-hospital death (%) ≤ 60 ≤ 0.2

0.3

0.4

0.6

0.8

1.1

1.6

2.1

2.9

3.9

5.4

7.3

9.8

≥ 250 ≥ 52 Other risk factors Cardiac arrest at admission

ST-segment deviation

Elevated cardiac enzyme levels

Points Points 0–34 35–70 71–105 106–140

141–176

177–353

≥ 353 Examples A patient has Killip class II, SBP of 99 mmHg, heart rate of 100 beats/min, is 65 years of age, has a serum creatinine level of 76 μmol/L, did not have a cardiac arrest at admission but did have ST-segment deviation and elevated enzyme levels. His score would be: 20 + 53 + 15 + 58 + 7 + 0 + 28 + 14 = 195. This gives about a 16% risk of having an in-hospital death. Similarly, a patient with Killip class I, SBP of 80 mmHg, heart rate of 60 beats/min, who is 55 years of age, has a serum creatinine level of 30 μmol/L, and no risk factors would have the following score: 0 + 58 + 3 + 41 + 1 = 103. This gives about a 0.9% risk of having an in-hospital death. (hypotension, mitral regurgitation) during episodes of ischaemia. Careful assessment and risk stratification are important because these guide the use of more complex pharmacological and interventional treatments (Figs 16.62 and 16.70), which can improve outcome (p. 501). Pathogenesis Acute coronary syndrome almost always occurs in patients who have atherosclerosis. The culprit lesion that precipitates the acute event is usually a complex ulcerated or fissured atheromatous plaque with adherent platelet-rich thrombus and local coronary artery spasm (see Fig. 16.54). These vascular changes during an acute coronary syndrome are dynamic, such that the degree of obstruction may either increase, leading to complete vessel occlusion, or regress due to the effects of platelet disaggregation and endogenous fibrinolysis. In acute MI, occlusive thrombus is almost always present at the site of rupture or erosion of an atheromatous plaque. The thrombus may undergo spontaneous lysis over the course of the next few days, although, by this time, irreversible myocardial damage has occurred. Without treatment, the artery responsible for the MI remains permanently occluded in 20–30% of patients. Since the process of infarction progresses over several hours (Fig. 16.63), most patients present when it is still possible to salvage myocardium and improve outcome. Clinical features The differential diagnosis of acute coronary syndrome is wide and includes most causes of central chest pain or collapse (p. 176). Chest pain at rest is the cardinal symptom but breathlessness, vomiting and collapse are also common features (Box 16.49).

Coronary artery disease • 495

Arrhythmias Arrhythmias are common in patients with acute coronary syndrome (Box 16.50) but are often transient and of no haemodynamic or prognostic importance. The risk of arrhythmia can be minimised by adequate pain relief, rest and the correction of hypokalaemia. VF occurs in 5–10% of patients who reach hospital and is thought to be the major cause of death in those who die before receiving medical attention. Prompt defibrillation restores sinus rhythm and is life-saving. The prognosis of patients with early VF (within the first 48 hours) who are successfully and promptly resuscitated is identical to that of patients who do not suffer VF. The presence of ventricular arrhythmias during the convalescent phase of acute coronary syndrome may be a marker of poor ventricular function and may herald sudden death. Selected patients may benefit from electrophysiological testing and specific anti-arrhythmic therapy (including ICDs, p. 483). AF is a common but frequently transient arrhythmia, and usually does not require emergency treatment. However, if it causes a rapid ventricular rate with hypotension or circulatory collapse, prompt cardioversion is essential. In other situations, digoxin or a β-blocker is usually the treatment of choice. AF may be a feature of impending or overt left ventricular failure, and therapy may be ineffective if heart failure is not recognised and treated appropriately. Anticoagulation is required if AF persists. Bradycardia may occur but does not require treatment unless there is hypotension or haemodynamic deterioration, in which case atropine (0.6–1.2 mg IV) may be given. Inferior MI may be complicated by AV block, which is usually temporary and often resolves following reperfusion therapy. If there is clinical deterioration due to second-degree or complete AV block, a temporary pacemaker should be considered. AV block complicating anterior infarction is more serious because asystole may suddenly supervene. A prophylactic temporary pacemaker should be inserted in these patients (p. 482). Recurrent angina Patients who develop recurrent angina at rest or on minimal exertion following an acute coronary syndrome are at high risk and should be considered for prompt coronary angiography with a view to revascularisation. Patients with dynamic ECG changes and ongoing pain should be treated with intravenous glycoprotein IIb/IIIa receptor antagonists. Patients with resistant pain or marked haemodynamic changes should be considered for intra-aortic balloon counterpulsation and emergency coronary revascularisation. Post-infarct angina occurs in up to 50% of patients treated with thrombolysis. Most patients have a residual stenosis in the infarct-related vessel, despite successful thrombolysis, and this may cause angina if there is still viable myocardium downstream. For this reason, all patients who have received successful thrombolysis should be considered for early (within the first 6–24 hours) coronary angiography with a view to coronary revascularisation. 16.50 Common arrhythmias in acute coronary syndrome • Ventricular fibrillation • Ventricular tachycardia • Accelerated idioventricular rhythm • Ventricular ectopics • Atrial fibrillation • Atrial tachycardia • Sinus bradycardia (particularly after inferior myocardial infarction) • Atrioventricular block The pain occurs in the same sites as angina but is usually more severe and lasts longer; it is often described as a tightness, heaviness or constriction in the chest. In acute MI the pain can be excruciating, and the patient’s expression and pallor may vividly convey the seriousness of the situation. Most patients are breathless and, in some, this is the only symptom. Painless or ‘silent’ MI may also occur and is particularly common in older patients or those with diabetes mellitus. If syncope occurs, it is usually caused by an arrhythmia or profound hypotension. Vomiting and sinus bradycardia are often due to vagal stimulation and are particularly common in patients with inferior MI. Nausea and vomiting may also be caused or aggravated by opiates given for pain relief. Sometimes infarction occurs in the absence of physical signs. Sudden death, from ventricular fibrillation or asystole, may occur immediately and often within the first hour. If the patient survives this most critical stage, the liability to dangerous arrhythmias remains, but diminishes as each hour goes by. It is vital that patients know not to delay calling for help if symptoms occur. Complications may occur in all forms of acute coronary syndrome but have become less frequent in the modern era of immediate or early coronary revascularisation. Specific complications of acute coronary syndromes and their management are discussed below. 16.49 Clinical features of acute coronary syndromes Symptoms • Prolonged cardiac pain: chest, throat, arms, epigastrium or back • Anxiety and fear of impending death • Nausea and vomiting • Breathlessness • Collapse/syncope Physical signs Signs of sympathetic activation • Pallor • Sweating • Tachycardia Signs of vagal activation • Vomiting • Bradycardia Signs of impaired myocardial function • Hypotension, oliguria, cold peripheries • Narrow pulse pressure • Raised jugular venous pressure • Third heart sound • Quiet first heart sound • Diffuse apical impulse • Lung crepitations Low-grade fever Complications • Mitral regurgitation • Pericarditis Fig. 16.63 The time course of myocardial infarction. The relative proportion of ischaemic, infarcting and infarcted tissue slowly changes over a period of 12 hours. In the early stages of myocardial infarction, a significant proportion of the myocardium in jeopardy is potentially salvageable. Ischaemia Infarction 4 hours 8 hours 1 hour

496 • CARDIOLOGY Fig. 16.64 Infarct expansion and ventricular remodelling. Fullthickness myocardial infarction causes thinning and stretching of the infarcted segment (infarct expansion), which leads to increased wall stress with progressive dilatation and hypertrophy of the remaining ventricle (ventricular remodelling).

I n f a r c t

e x p a n s i o n Increased wall stress Acute heart failure Acute heart failure usually reflects extensive myocardial damage and is associated with a poor prognosis. All the other complications of MI are more likely to occur when acute heart failure is present. The assessment and management of heart failure is discussed in more detail on pages 463 and 465. Pericarditis This only occurs following infarction and is particularly common on the second and third days. The patient may recognise that a different pain has developed, even though it is at the same site, and that it is positional and tends to be worse or sometimes present only on inspiration. A pericardial rub may be audible. Opiate-based analgesia should be used. Non-steroidal (NSAIDs) and steroidal anti-inflammatory drugs may increase the risk of aneurysm formation and myocardial rupture in the early recovery period, and should be avoided. Dressler’s syndrome This syndrome is characterised by persistent fever, pericarditis and pleurisy, and is probably due to autoimmunity. The symptoms tend to occur a few weeks or even months after MI and often subside after a few days. If the symptoms are prolonged or severe, treatment with high-dose aspirin, NSAIDs or even glucocorticoids may be required. Papillary muscle rupture This typically presents with acute pulmonary oedema and shock due to the sudden onset of severe mitral regurgitation. Examination usually reveals a pansystolic murmur and third heart sound but the murmur may be quiet or absent in patients with severe mitral regurgitation. The diagnosis is confirmed by echocardiography, and emergency valve replacement may be necessary. Lesser degrees of mitral regurgitation due to papillary muscle dysfunction are common and may be transient. Ventricular septum rupture This usually presents with sudden haemodynamic deterioration accompanied by a new and loud pansystolic murmur radiating to the right sternal border, which may be difficult to distinguish from acute mitral regurgitation. Rupture of the intraventricular septum causes left-to-right shunting through a ventricular septal defect, which tends to cause acute right heart failure rather than pulmonary oedema. Doppler echocardiography and right heart catheterisation will confirm the diagnosis. Treatment is by emergency surgical repair; without this, the condition is usually fatal. Ventricular rupture Rupture of the ventricle may lead to cardiac tamponade and is usually fatal (p. 544), although it is occasionally possible to support a patient with an incomplete rupture until emergency surgery can be performed. Embolism Thrombus often forms on the endocardial surface of freshly infarcted myocardium. This can lead to systemic embolism and occasionally causes a stroke or ischaemic limb. Venous thrombosis and pulmonary embolism may occur but have become less common with the use of prophylactic anticoagulants and early mobilisation. Ventricular remodelling This is a potential complication of an acute transmural MI due to thinning and stretching of the infarcted segment. This leads to an increase in wall stress with progressive dilatation and hypertrophy of the remaining ventricle (ventricular remodelling, Fig. 16.64). As the ventricle dilates, it becomes less efficient and heart failure may supervene. Infarct expansion occurs over a few days and weeks but ventricular remodelling can take years. ACE inhibitor and mineralocorticoid receptor antagonist therapies reduce late ventricular remodelling and can prevent the onset of heart failure (p. 465). Ventricular aneurysm Ventricular aneurysm develops in approximately 10% of patients with MI and is particularly common when there is persistent occlusion of the infarct-related vessel. Heart failure, ventricular arrhythmias, mural thrombus and systemic embolism are all recognised complications of aneurysm formation. Other features include a paradoxical impulse on the chest wall, persistent ST elevation on the ECG, and sometimes an unusual bulge from the cardiac silhouette on the chest X-ray. Echocardiography is diagnostic. Surgical removal of a left ventricular aneurysm carries a high morbidity and mortality but is sometimes necessary. Investigations Electrocardiogram The standard 12-lead ECG is central to confirming the diagnosis but may be difficult to interpret if there is bundle branch block or previous MI. The initial ECG may be normal or non-diagnostic in one-third of cases. Repeated ECGs are important, especially where the diagnosis is uncertain or the patient has recurrent or persistent symptoms. The earliest ECG change is usually ST-segment deviation. With proximal occlusion of a major coronary artery, ST-segment elevation (or new bundle branch block) is seen initially, with later diminution in the size of the R wave and, in transmural (full-thickness) infarction, development of a Q wave. Subsequently, the T wave becomes inverted because of a change in ventricular repolarisation; this change persists after the ST segment has returned to normal. These sequential features (Fig. 16.65) are sufficiently reliable for the approximate age of the infarct to be deduced. In non-ST segment elevation acute coronary syndrome, there is partial occlusion of a major vessel or complete occlusion of

Coronary artery disease • 497

V1 to V4, while anterolateral infarction produces changes from V4 to V6, in aVL and in lead I. Inferior infarction is best shown in leads II, III and aVF, while, at the same time, leads I, aVL and the anterior chest leads may show ‘reciprocal’ changes of ST depression (Figs 16.67 and 16.68). Infarction of the posterior wall of the LV does not cause ST elevation or Q waves in the standard leads, but can be diagnosed by the presence of reciprocal changes (ST depression and a tall R wave in leads V1–V4). Some infarctions (especially inferior) also involve the RV. This may be identified by recording from additional leads placed over the right precordium. Cardiac biomarkers Serial measurements of serum troponin should be taken. In unstable angina, there is no detectable rise in troponin and the diagnosis is made on the basis of the clinical history and ECG changes. In contrast, MI causes a rise in plasma troponin T and I concentrations and other cardiac muscle enzymes (p. 450; Fig. 16.69 and see Box 16.47). Levels of troponins T and I increase within 3–6 hours, peak at about 36 hours and remain elevated for up to 2 weeks. A full blood count may reveal the presence of a leucocytosis, which reaches a peak on the first day. The erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) are also elevated. Lipids should be measured within 24 hours of presentation because there is often a transient fall in cholesterol in the 3 months following infarction. Radiography A chest X-ray should be performed since this may demonstrate pulmonary oedema that is not evident on clinical examination (see Fig. 16.27, p. 464). The heart size is often normal but Fig. 16.65 The serial evolution of ECG changes in transmural myocardial infarction. A Normal ECG complex. B Acute ST elevation (‘the current of injury’). C Progressive loss of the R wave, developing Q wave, resolution of the ST elevation and terminal T-wave inversion. D Deep Q wave and T-wave inversion. E Old or established infarct pattern; the Q wave tends to persist but the T-wave changes become less marked. The rate of evolution is very variable but, in general, stage B appears within minutes, stage C within hours, stage D within days and stage E after several weeks or months. This should be compared with the 12-lead ECGs in Figures 16.66–16.68. A B C D E Fig. 16.66 Recent anterior non-ST elevation (subendocardial) myocardial infarction. This ECG demonstrates deep symmetrical T-wave inversion, together with a reduction in the height of the R wave in leads V1, V2, V3 and V4. aVR V1 V4 aVL V2 V5 aVF V3 V6 III II I a minor vessel, causing unstable angina or partial-thickness (subendocardial) MI. This is usually associated with ST-segment depression and T-wave changes. In the presence of infarction, this may be accompanied by some loss of R waves in the absence of Q waves (Fig. 16.66). The ECG changes are best seen in the leads that ‘face’ the ischaemic or infarcted area. When there has been anteroseptal infarction, abnormalities are found in one or more leads from Fig. 16.67 Acute transmural anterior myocardial infarction. This ECG was recorded from a patient who had developed severe chest pain 6 hours earlier. There is ST elevation in leads I, aVL, V2, V3, V4, V5 and V6, and there are Q waves in leads V3, V4 and V5. Anterior infarcts with prominent changes in leads V2, V3 and V4 are sometimes called ‘anteroseptal’ infarcts, as opposed to ‘anterolateral’ infarcts, in which the ECG changes are predominantly found in V4, V5 and V6. aVR V1 V4 aVL V2 V5 aVF V3 V6 III II I

498 • CARDIOLOGY event, including those who fail to settle on medical therapy, those with extensive ECG changes, those with an elevated plasma troponin and those with severe pre-existing stable angina (Fig. 16.70). This often reveals disease that is amenable to PCI or urgent CABG (see below). Management All patients with suspected acute coronary syndrome should be admitted urgently to hospital because there is a significant risk of death or recurrent myocardial ischaemia during the early unstable phase. Appropriate medical therapy can reduce the incidence of these complications by at least 60%. The key elements of immediate in-hospital management are shown in Figure 16.70. Patients should ideally be managed in a dedicated cardiac unit, where the necessary expertise, monitoring and resuscitation facilities are available. Clinical risk factor analysis using tools such as the GRACE score (see Fig. 16.62) should be performed to identify patients that should be selected for intensive therapy, and specifically early inpatient coronary angiography (thresholds vary, but a score of 140 points or more indicates early intervention). If there are no complications and risk factor analysis shows that angiography is not required, the patient can be mobilised from the second day and discharged after 2–3 days. Low-risk patients without spontaneous angina should undergo an exercise tolerance test approximately 4 weeks after the acute coronary syndrome. This will help to identify those individuals with residual myocardial ischaemia who require further investigation, and may help to boost the confidence of the remainder. Management of the acute event is discussed below and the principles of long-term management are summarised in Box 16.51. Analgesia Adequate analgesia is essential, not only to relieve distress but also to lower adrenergic drive and thereby reduce vascular resistance, BP, infarct size and susceptibility to ventricular arrhythmias. Intravenous opiates (initially, morphine sulphate 5–10 mg or diamorphine 2.5–5 mg) and antiemetics (initially, metoclopramide 10 mg) should be administered, and titrated by giving repeated small aliquots until the patient is comfortable. Intramuscular injections should be avoided because the clinical effect may be delayed by poor skeletal muscle perfusion, and a painful haematoma may form following thrombolytic or antithrombotic therapy. Fig. 16.68 Acute transmural inferolateral myocardial infarction. This ECG was recorded from a patient who had developed severe chest pain 4 hours earlier. There is ST elevation in inferior leads II, III and aVF and lateral leads V4, V5 and V6. There is also ‘reciprocal’ ST depression in leads aVL and V2. aVR V1 V4 V2 V5 aVL V3 V6 aVF III II I Fig. 16.69 Changes in plasma cardiac biomarker concentrations after myocardial infarction. Creatine kinase (CK) and troponins T (Tn-T) and I (Tn-I) are the first to rise, followed by aspartate aminotransferase (AST) and then lactate (hydroxybutyrate) dehydrogenase (LDH). In patients treated with reperfusion therapy, a rapid rise in plasma creatine kinase (curve CK(R)) occurs, due to a washout effect. Hours after coronary occlusion LDH

Tn-T/Tn-I AST CK(R) Normal plasma activity 0 6 12

there may be cardiomegaly due to pre-existing myocardial damage. Echocardiography Echocardiography is normally performed before discharge from hospital and is useful for assessing ventricular function and for detecting important complications, such as mural thrombus, cardiac rupture, ventricular septal defect, mitral regurgitation and pericardial effusion. Coronary angiography Coronary arteriography should be considered with a view to revascularisation in all patients at moderate or high risk of a further 16.51 Late management of myocardial infarction Risk stratification and further investigation (see text) Lifestyle modification • Diet (weight control, lipid-lowering, ‘Mediterranean diet’) • Cessation of smoking • Regular exercise Secondary prevention drug therapy • Antiplatelet therapy (aspirin and/or clopidogrel) • β-blocker • ACE inhibitor/ARB • Statin • Additional therapy for control of diabetes and hypertension • Mineralocorticoid receptor antagonist Rehabilitation Devices • Implantable cardiac defibrillator (high-risk patients) (ACE = angiotensin-converting enzyme; ARB = angiotensin receptor blocker)

Coronary artery disease • 499

performed as soon as practically possible. Patients should be considered for PCI within the first 24 hours, even if they have reperfused spontaneously or with thrombolytic therapy. Coronary artery patency is restored in over 95% of patients undergoing PCI. The procedure preserves left ventricular function with a marked reduction in the progression to heart failure, more than halves rates of recurrent MI and dramatically improves mortality with more than 95% 1-year survival rates in clinical trials. Successful therapy is also associated with rapid pain relief, resolution of acute ST elevation and occasional transient arrhythmias. Reperfusion therapy Immediate reperfusion therapy with PCI (see Fig. 16.60) is indicated when the ECG shows new bundle branch block or characteristic ST-segment elevation in two contiguous leads of 1 mm or more in the limb leads or 2 mm or more in the chest leads. This procedure has revolutionised the outcomes for these patients and is the treatment of choice for those presenting within 12 hours of symptom onset (Fig. 16.70). If PCI cannot be performed within 120 minutes for any reason, and thrombolysis is contraindicated, the procedure should be Fig. 16.70 Summary of treatment for acute coronary syndrome (ACS). *Not required following PCI. For details of the GRACE score, see Figure 16.62. (ACE = angiotensin-converting enzyme; ECG = electrocardiogram; GP = glycoprotein; IV = intravenous; LMW = low-molecular-weight; PCI = percutaneous coronary intervention; PO = by mouth; SC = subcutaneous) Adapted from SIGN 93, Feb 2007, and updated in SIGN 148, April 2016. Immediate clinical assessment ECG Troponin ST segment elevation ACS? No No No No No Yes Yes Yes Yes Presenting < 12 hrs from symptom onset? Yes Thrombolysis IV + fondaparinux or LMW heparin IV Is delayed PCI possible? Yes No Mediumto high-risk ACS? No Recurrent symptoms? No Yes Failed reperfusion? Calculate GRACE score: In-hospital death Low risk < 1% Medium risk 1–9% High risk > 9% Early in-hospital coronary angiography

500 • CARDIOLOGY successful thrombolysis. Anticoagulation can be achieved using unfractionated heparin, fractioned (low-molecular-weight) heparin or a pentasaccharide such as subcutaneous fondaparinux (2.5 mg daily). Comparative clinical trials show that the pentasaccharides have the best safety and efficacy profile but low-molecular-weight heparin, such as subcutaneous enoxaparin (1 mg/kg twice daily), is a reasonable alternative. Anticoagulation should be continued for 8 days or until discharge from hospital or coronary revascularisation has been completed. A period of treatment with warfarin should be considered if there is persistent AF or evidence of extensive anterior infarction with mural thrombus because these patients are at increased risk of systemic thromboembolism. Anti-anginal therapy Sublingual glyceryl trinitrate (300–500 μg) is a valuable firstaid measure in unstable angina or threatened infarction, and intravenous nitrates (glyceryl trinitrate 0.6–1.2 mg/hr or isosorbide dinitrate 1–2 mg/hr) are useful for the treatment of left ventricular failure and the relief of recurrent or persistent ischaemic pain. Intravenous β-blockers (atenolol 5–10 mg or metoprolol 5–15 mg given over 5 mins) relieve pain, reduce arrhythmias and improve short-term mortality in patients who present within 12 hours of the onset of symptoms (Fig. 16.70). However, they should be avoided if there is heart failure (pulmonary oedema), hypotension (systolic BP < 105 mmHg) or bradycardia (heart rate < 65/min). Nifedipine or amlodipine can be added to the β-blocker if there is persistent chest discomfort but these drugs may cause tachycardia if used alone. Verapamil and diltiazem should be used if a β-blocker is contraindicated. In the longer term, treatment with an oral β-blocker reduces long-term mortality by approximately 25% among the survivors of an acute MI. Patients with heart failure, irreversible COPD or peripheral arterial disease derive similar, if not greater, secondary preventative benefits from β-blocker therapy and should receive maintenance therapy unless it is poorly tolerated. Unfortunately, a minority of patients do not tolerate β-blockers because of bradycardia, AV block, hypotension or asthma. Renin–angiotensin blockade Long-term treatment with ACE inhibitors such as enalapril (10 mg twice daily) or ramipril (2.5–5 mg twice daily) can counteract ventricular remodelling, prevent the onset of heart failure, improve survival, reduce recurrent MI and avoid rehospitalisation. The Selected medium- to high-risk patients do benefit from in-hospital coronary angiography and coronary revascularisation but this does not need to take place in the first 12 hours unless there are high-risk features, such as ongoing chest pain or ECG changes. Reperfusion therapy with PCI confers no immediate mortality benefit in patients with non-ST segment elevation acute coronary syndrome. Thrombolytic therapy If primary PCI cannot be achieved in a timely manner (see Fig. 16.70), thrombolytic therapy should be administered. Although the survival advantage is not as good as primary PCI, mortality is reduced and this is maintained for at least 10 years. The benefit of thrombolytic therapy is greatest in those patients who receive treatment within the first 12 hours and especially the first 2 hours. Modern thrombolytic agents, such as tenecteplase (TNK) and reteplase (rPA), are analogues of human tissue plasminogen activator and can be given as an intravenous bolus, assisting prompt treatment in the emergency department or in the prehospital setting. The major hazard of thrombolytic therapy is bleeding. Cerebral haemorrhage causes 4 extra strokes per 1000 patients treated, and the incidence of other major bleeds is between 0.5% and 1%. Accordingly, the treatment should be withheld if there is a significant risk of serious bleeding (Box 16.52). For some patients, thrombolytic therapy is contraindicated or fails to achieve coronary arterial reperfusion (Fig. 16.70). Emergency PCI may then be considered, particularly where there is evidence of cardiogenic shock. Even where thrombolysis successfully achieves reperfusion, PCI should be considered within 24 hours to prevent recurrent infarction and improve outcome. Antithrombotic therapy Oral administration of 75–325 mg aspirin daily improves survival, with a 25% relative risk reduction in mortality. The first tablet (300 mg) should be given orally within the first 12 hours and therapy should be continued indefinitely if there are no side-effects. A P2Y12 receptor antagonist should be given in combination with aspirin for up to 12 months. The strongest evidence is for ticagrelor (180 mg, followed by 90 mg twice daily) but prasugrel (60 mg, followed by 10 mg daily) is an alternative. If the patient is intolerant of aspirin, clopidogrel is a suitable alternative (300 mg, followed by 75 mg daily). Glycoprotein IIb/IIIa receptor antagonists, such as tirofiban and abciximab, block the final common pathway of platelet aggregation and are potent inhibitors of platelet-rich thrombus formation. They are of particular benefit in high-risk patients with acute coronary syndromes who undergo PCI, especially those with a high thrombus burden at angiography or who have received inadequate prior antiplatelet therapy. These intravenous agents are administered in addition to oral aspirin and a P2Y12 inhibitor such as clopidogrel. Anticoagulation further reduces the risk of thromboembolic complications, and prevents re-infarction in the absence of reperfusion therapy or after 16.52 Relative contraindications to thrombolytic therapy • Active internal bleeding • Previous subarachnoid or intracerebral haemorrhage • Uncontrolled hypertension • Recent surgery (within 1 month) • Recent trauma (including traumatic resuscitation) • High probability of active peptic ulcer • Pregnancy 16.53 Myocardial infarction in old age • Atypical presentation: often with anorexia, fatigue, weakness, delirium or falls rather than chest pain. • Case fatality: rises steeply. Hospital mortality exceeds 25% in those over 75 years old, which is five times greater than that seen in those aged less than 55 years. • Survival benefit of treatments: not influenced by age. The absolute benefit of evidence-based treatments may therefore be greatest in older people. • Hazards of treatments: rise with age (for example, increased risk of intracerebral bleeding after thrombolysis) and are due partly to increased comorbidity. • Quality of evidence: older patients, particularly those with significant comorbidity, were under-represented in many of the randomised controlled clinical trials that helped to establish the treatment of myocardial infarction. The balance of risk and benefit for many treatments, such as thrombolysis and primary percutaneous transluminal coronary angiography, in frail older people is uncertain.

Coronary artery disease • 501

information and counselling. Formal rehabilitation programmes, based on graded exercise protocols with individual and group counselling, are often very successful and, in some cases, have been shown to improve the long-term outcome. Implantable defibrillators ICDs are of benefit in preventing sudden cardiac death in patients who have severe left ventricular impairment (ejection fraction ≤ 30%) after MI (p. 483). Prognosis The prognosis of patients who have survived an acute coronary syndrome is related to the extent of residual myocardial ischaemia, the degree of myocardial damage and the presence of ventricular arrhythmias. In almost one-quarter of all cases of MI, death occurs within a few minutes without medical care. Half the deaths occur within 24 hours of the onset of symptoms and about 40% of all affected patients die within the first month. The prognosis of those who survive to reach hospital is much better, with a 28-day survival of more than 85%. Patients with unstable angina have a mortality of approximately half that of patients with MI. Early death is usually due to an arrhythmia and is independent of the extent of MI. However, late outcomes are determined by the extent of myocardial damage, and unfavourable features include poor left ventricular function, AV block and persistent ventricular arrhythmias. The prognosis is worse for anterior than for inferior infarcts. Bundle branch block and high cardiac marker levels both indicate extensive myocardial damage. Old age, depression and social isolation are also associated with a higher mortality. Of those who survive an acute attack, more than 80% live for a further year, about 75% for 5 years, 50% for 10 years and 25% for 20 years. Non-cardiac surgery in patients with heart disease Non-cardiac surgery, particularly major vascular, abdominal or thoracic surgery, can precipitate serious perioperative cardiac complications, such as MI and death, in patients with CAD and other forms of heart disease. Careful pre-operative cardiac assessment may help to determine the balance of benefit versus risk on an individual basis, and identify measures that minimise the operative risk (Box 16.54). A hypercoagulable state is part of the normal physiological response to surgery, and may promote coronary thrombosis leading to an acute coronary syndrome in the early post-operative period. Patients with a history of recent PCI or acute coronary syndrome are at greatest risk and, whenever possible, elective non-cardiac surgery should be avoided for 3 months after such an event. Where possible, antiplatelet agents, statins and β-blocker therapies should be continued throughout the perioperative period. benefits are greatest in those with overt heart failure (clinical or radiological) but extend to patients with asymptomatic left ventricular dysfunction and those with preserved left ventricular function. They should therefore be considered in all patients with acute coronary syndrome. Caution must be exercised in hypovolaemic or hypotensive patients because ACE inhibition may exacerbate hypotension and impair coronary perfusion. In patients intolerant of ACE inhibitors, ARBs such as valsartan (40–160 mg twice daily) or candesartan (4–16 mg daily) are alternatives and are better tolerated. Mineralocorticoid receptor antagonists Patients with acute MI and left ventricular dysfunction (ejection fraction < 35%) and either pulmonary oedema or diabetes mellitus further benefit from additional mineralocorticoid receptor antagonism (eplerenone 25–50 mg daily, or spironolactone 25–50 mg daily). Lipid-lowering therapy The benefits of lowering serum cholesterol following acute coronary syndrome have been demonstrated in several large-scale randomised trials. All patients should receive therapy with HMG CoA reductase enzyme inhibitors (statins) after acute coronary syndrome, irrespective of serum cholesterol concentrations. Patients with serum LDL cholesterol concentrations above 3.2 mmol/L (approximately 120 mg/dL) benefit from more intensive therapy, such as atorvastatin (80 mg daily). Other agents, such as ezetimibe, fibrates, anion exchange resins and injectable PCSK9 inhibitors, may be used in cases where total cholesterol or LDL cholesterol cannot be lowered adequately using statins alone. Smoking cessation The 5-year mortality of patients who continue to smoke cigarettes is double that of those who quit smoking at the time of their acute coronary syndrome. Giving up smoking is the single most effective contribution a patient can make to his or her future. The success of smoking cessation can be increased by supportive advice and pharmacological therapy (p. 94). Diet and exercise Maintaining an ideal body weight, eating a Mediterranean-style diet, taking regular exercise, and achieving good control of hypertension and diabetes mellitus may all improve the long-term outlook. Rehabilitation The necrotic muscle of an acute myocardial infarct takes 4–6 weeks to be replaced with fibrous tissue and it is conventional to restrict physical activities during this period. When there are no complications, the patient can mobilise on the second day, return home in 2–3 days and gradually increase activity, with the aim of returning to work in 4 weeks. The majority of patients may resume driving after 1–4 weeks, although, in most countries, drivers of heavy goods and public service vehicles require special assessment before returning to work. Emotional problems, such as denial, anxiety and depression, are common and must be addressed. Some patients are severely and even permanently incapacitated as a result of the psychological effects of acute coronary syndrome rather than the physical ones, and all benefit from thoughtful explanation, counselling and reassurance. Many patients mistakenly believe that stress was the cause of their heart attack and may restrict their activity inappropriately. The patient’s spouse or partner will also require emotional support, 16.54 Major risk factors for cardiac complications of non-cardiac surgery • Recent (< 6 months) myocardial infarction or unstable angina • Severe coronary artery disease: left main stem or three-vessel disease • Severe stable angina on effort • Severe left ventricular dysfunction • Severe valvular heart disease (especially aortic stenosis)

502 • CARDIOLOGY 16.55 Factors influencing the clinical manifestations of peripheral arterial disease (PAD) Anatomical site Cerebral circulation • TIA, amaurosis fugax, vertebrobasilar insufficiency Renal arteries • Hypertension and renal failure Mesenteric arteries • Mesenteric angina, acute intestinal ischaemia Limbs (legs Ԡ arms) • Intermittent claudication, critical limb ischaemia, acute limb ischaemia Collateral supply • In a patient with a complete circle of Willis, occlusion of one carotid artery may be asymptomatic • In a patient without cross-circulation, stroke is likely Speed of onset • Where PAD develops slowly, a collateral supply will develop • Sudden occlusion of a previously normal artery is likely to cause severe distal ischaemia Mechanism of injury Haemodynamic • Plaque must reduce arterial diameter by 70% (‘critical stenosis’) to reduce flow and pressure at rest. On exertion a moderate stenosis may become ‘critical’. This mechanism tends to have a relatively benign course due to collateralisation Thrombotic • Occlusion of a long-standing critical stenosis may be asymptomatic due to collateralisation. However, acute rupture and thrombosis of a non-haemodynamically significant plaque usually has severe consequences Atheroembolic • Symptoms depend on embolic load and size • Carotid (TIA, amaurosis fugax or stroke) and peripheral arterial (blue toe/finger syndrome) plaque are common examples Thromboembolic • Usually secondary to atrial fibrillation • The consequences are usually dramatic, as the thrombus load is often large and occludes a major, previously healthy, noncollateralised artery suddenly and completely (TIA = transient ischaemic attack) Careful attention to fluid balance during and after surgery is particularly important in patients with impaired left ventricular function and valvular heart disease because vasopressin is released as part of the normal physiological response to surgery and, in these circumstances, the over-zealous administration of intravenous fluids can easily precipitate heart failure. Patients with severe valvular heart disease, particularly aortic stenosis and mitral stenosis, are also at increased risk because they may not be able to increase their cardiac output in response to the stress of surgery. AF may be triggered by hypoxia, myocardial ischaemia or heart failure, and is a common post-operative complication in patients with pre-existing heart disease. It usually terminates spontaneously when the precipitating factors have been eliminated, but digoxin or β-blockers can be prescribed to control the heart rate. Peripheral arterial disease Peripheral arterial disease (PAD) has been estimated to affect about 20% of individuals aged 55–75 years in the UK. Only 25% of patients present with symptoms, the most common of which is intermittent claudication (IC). About 1–2% of patients with IC per year progress to a point where amputation and/or revascularisation are required. However, the annual mortality rate of people with IC is about 5%, which is 2–3 times higher than the general population of the same age and gender. The cause of death is typically an MI or stroke, reflecting the fact that IC nearly always occurs in association with widespread atherosclerosis. Pathogenesis In developed countries, almost all PAD is due to atherosclerosis and the risk factors are the same as described in patients with CAD. As with CAD, plaque rupture is responsible for the most serious manifestations of PAD, and not infrequently occurs in a plaque that hitherto has been asymptomatic. The clinical manifestations depend on the anatomical site, the presence or absence of a collateral supply, the speed of onset and the mechanism of injury (Box 16.55). Approximately 5–10% of patients with PAD have diabetes but this proportion increases to 30–40% in those with severe limb ischaemia. The mechanism of PAD in diabetes is atheroma affecting the medium-sized to large arteries rather than obstructive microangiopathy and so diabetes is not a contraindication to lower limb revascularisation. Nevertheless, diabetic patients with PAD pose a number of particular problems (Box 16.56). Clinical features Symptomatic PAD affects the legs about eight times more commonly than the arms. Several locations may be affected, including the aortoiliac vessels, the femoropopliteal vessels and the infrapopliteal vessels. One or more of these segments may be affected in a variable and asymmetric manner. In the arm, the subclavian artery is the most common site of disease. Peripheral artery disease can present clinically in a variety of ways, as detailed below. Intermittent claudication This is the most common presentation of PAD affecting the lower limbs. It is characterised by ischaemic pain affecting the muscles of the leg. The pain is usually felt in the calf because the disease most commonly affects the superficial femoral artery, but it may be felt in the thigh or buttock if the iliac arteries are involved. Typically, the pain comes on after walking, often once a specific distance has been covered, and rapidly subsides on resting. Resumption of walking leads to a return of the pain. Most patients describe a cyclical pattern of exacerbation and resolution due to the progression of disease and the subsequent development of collaterals. When PAD affects the upper limbs, arm claudication may occur, although this is uncommon. Critical limb ischaemia Critical limb ischaemia (CLI) is defined as rest pain requiring opiate analgesia, and/or ulceration or gangrene that has been present for more than 2 weeks, in the presence of an ankle BP of less than 50 mmHg. The typical progression of symptoms in CLI is summarised in Figure 16.71. Rest pain only, with ankle pressures above 50 mmHg, is known as subcritical limb ischaemia (SCLI). The term severe limb ischaemia (SLI) is used to describe

Peripheral arterial disease • 503

the situation where either CLI and SCLI occurs. Whereas IC is usually due to single-segment plaque, SLI is always due to multilevel disease. Many patients with SLI have not previously sought medical advice, principally because they have other comorbidity that prevents them from walking to a point where IC develops. Patients with SLI are at high risk of losing their limb, and sometimes their life, in a matter of weeks or months without surgical bypass or endovascular revascularisation by angioplasty or stenting. Treatment of these patients is difficult, however, because most are elderly with extensive and severe disease and significant multisystem comorbidities. Acute limb ischaemia This is most frequently caused by acute thrombotic occlusion of a pre-existing stenotic arterial segment, thromboembolism, and trauma that may be iatrogenic. The typical presentation is with paralysis (inability to wiggle toes/fingers) and paraesthesia (loss of light touch over the dorsum of the foot/hand), the so-called ‘Ps of acute ischaemia’ (Box 16.57). These features are nonspecific, however, and inconsistently related to its severity. Pain on squeezing the calf indicates muscle infarction and impending irreversible ischaemia. All patients with suspected acutely ischaemic limbs must be discussed immediately with a vascular surgeon; a few hours can make the difference between death/amputation and complete recovery of limb function. If there are no contraindications (acute aortic dissection or 16.56 Peripheral vascular disease in diabetes Feature Difficulty Arterial calcification Spuriously high ABPI due to incompressible ankle vessels. Inability to clamp arteries for the purposes of bypass surgery. Resistant to angioplasty Immunocompromise Prone to rapidly spreading cellulitis, gangrene and osteomyelitis Multisystem arterial disease Coronary and cerebral arterial disease increase the risks of intervention Distal disease Diabetic vascular disease has a predilection for the calf vessels. Although vessels in the foot are often spared, performing a satisfactory bypass or angioplasty to these small vessels is a technical challenge Sensory neuropathy Even severe ischaemia and/or tissue loss may be completely painless. Diabetic patients often present late with extensive destruction of the foot. Loss of proprioception leads to abnormal pressure loads and worsens joint destruction (Charcot joints) Motor neuropathy Weakness of the long and short flexors and extensors leads to abnormal foot architecture, abnormal pressure loads, callus formation and ulceration Autonomic neuropathy Leads to a dry foot deficient in sweat that normally lubricates the skin and is antibacterial. Scaling and fissuring create a portal of entry for bacteria. Abnormal blood flow in the bones of the ankle and foot may also contribute to osteopenia and bony collapse (ABPI = ankle–brachial pressure index) Fig. 16.71 Progressive night pain and the development of tissue loss. Pain develops, typically in forefoot, about an hour after patient goes to bed because: • beneficial effects of gravity on perfusion are lost • patient’s blood pressure and cardiac output fall during sleep Severe pain awakens patient Pain relieved by hanging limb out of bed. In due course patient has to get up and walk about, with resulting loss of sleep Patient takes to sleeping in chair, leading to dependent oedema. Interstitial tissue pressure is increased so arterial perfusion is further reduced. Vicious circle of increasing pain and sleep loss Trivial injury fails to heal, and entry of bacteria leads to infection and increase in metabolic demands of foot. Rapid development of ulcers and gangrene trauma, particularly head injury), an intravenous bolus of heparin (3000–5000 U) should be administered to limit propagation of thrombus and protect the collateral circulation. Distinguishing thrombosis from embolism is frequently difficult but is important because treatment and prognosis are different (Box 16.58). Acute limb ischaemia due to thrombosis in situ can usually be treated medically in the first instance with intravenous heparin (target activated partial thromboplastin time (APTT) 2.0–3.0), antiplatelet agents, high-dose statins, intravenous fluids to avoid dehydration, correction of anaemia, oxygen and sometimes prostaglandins, such as iloprost. Embolism will normally result in extensive tissue necrosis within 6 hours unless the limb is revascularised. The indications for thrombolysis, if any, remain controversial. Irreversible ischaemia mandates early amputation or palliative care. Atheroembolism This may be a presenting feature of PAD affecting the subclavian arteries. The presentation is with blue fingers, which are due to Symptoms/signs Comment Pain Pallor Pulselessness May be absent in complete acute ischaemia, and can be present in chronic ischaemia Perishing cold Unreliable, as the ischaemic limb takes on the ambient tempetature Paraesthesia Paralysis Important features of impending irreversible ischaemia } } 16.57 Symptoms AND signs of acute limb ischaemia

504 • CARDIOLOGY lipids to check for evidence of hyperlipidaemia; and measurement of blood glucose to check for evidence of diabetes. Management Key elements of medical management are summarised in Box 16.60. This consists of smoking cessation (if applicable), taking regular exercise, antiplatelet therapy with low-dose aspirin or clopidogrel, therapy with a statin, and treatment of coexisting disease such as diabetes, hypertension or polycythaemia. Recently, the antiplatelet drug vorapaxar, a selective antagonist of the protease-activated receptor 1 (PAR-1) that regulates platelet activation, has been licensed in combination with either aspirin or clopidogrel in patients with PAD. The peripheral vasodilator cilostazol has been shown to improve walking distance and should be considered in patients who do not respond adequately to best medical therapy. Intervention with angioplasty, stenting, endarterectomy or bypass is usually considered only after medical therapy has been given at least 6 months to effect symptomatic improvement, and then just in patients who are severely disabled or whose livelihood is threatened by their disability. Subclavian artery disease is usually treated by means of angioplasty and stenting, as carotid–subclavian bypass surgery can be technically difficult. Buerger’s disease Buerger’s disease or thromboangiitis obliterans is an inflammatory disease of the arteries that is distinct from atherosclerosis and usually presents in young (20–30 years) male smokers. It is most common in those from the Mediterranean and North Africa. It characteristically affects distal arteries, giving rise to claudication in the feet or rest pain in the fingers or toes. Wrist and ankle pulses are absent but brachial and popliteal pulses are present. It may also affect the veins, giving rise to superficial thrombophlebitis. It often remits if the patient stops smoking. Symptomatic therapy with vasodilators such as prostacyclin and calcium antagonists or sympathectomy may also be helpful. Major limb amputation is the most frequent outcome if patients continue to smoke. Raynaud’s syndrome This common disorder affects 5–10% of young women aged 15–30 years in temperate climates. It does not progress to ulceration or infarction, and significant pain is unusual. The underlying cause is unclear and no investigation is necessary. The patient should be reassured and advised to avoid exposure to cold. Usually, no other treatment is required, although 16.58 Distinguishing features of embolism and thrombosis in peripheral arteries Clinical features Embolism Thrombosis Severity Complete (no collaterals) Incomplete (collaterals) Onset Seconds or minutes Hours or days Limb Leg 3 : 1 arm Leg 10 : 1 arm Multiple sites Up to 15% Rare Embolic source Present (usually atrial fibrillation) Absent Previous claudication Absent Present Palpation of artery Soft, tender Hard, calcified Bruits Absent Present Contralateral leg pulses Present Absent Diagnosis Clinical Angiography Treatment Embolectomy, warfarin Medical, bypass, thrombolysis Prognosis Loss of life > loss of limb Loss of limb > loss of life small emboli lodging in digital arteries. This may be confused with Raynaud’s phenomenon (p. 1035) but the symptoms of atheroembolism are typically unilateral rather than bilateral as in Raynaud’s. Subclavian steal This can be a feature of PAD affecting the upper limbs. The presentation is with dizziness, cortical blindness and/or collapse, which occurs when the arm is used and is thought to be caused by diversion (or steal) of blood from the brain to the limbs via the vertebral artery. Investigations The presence and severity of ischaemia can usually be determined by clinical examination (Box 16.59) and measurement of the ankle–brachial pressure index (ABPI), which is the ratio between the highest systolic ankle and brachial blood pressures. In health, the ABPI is over 1.0, in IC typically 0.5–0.9 and in CLI usually less than 0.5. Further investigation with duplex ultrasonography, MRI or CT with intravenous injection of contrast agents may be used to characterise the sites of involvement further. Intra-arterial digital subtraction angiography (IA-DSA) is usually reserved for those undergoing endovascular revascularisation. Other investigations should include a full blood count to look for evidence of treatable secondary causes, such as thrombocythaemia; measurement of 16.60 Medical therapy for peripheral arterial disease • Smoking cessation • Regular exercise (30 mins of walking, three times per week) • Antiplatelet agent (aspirin 75 mg or clopidogrel 75 mg daily) • Reduction of cholesterol: Statins Diet Weight loss • Diagnosis and treatment of diabetes mellitus • Diagnosis and treatment of associated conditions: Hypertension Anaemia Heart failure 16.59 Clinical features of chronic lower limb ischaemia • Pulses: diminished or absent • Bruits: denote turbulent flow but bear no relationship to the severity of the underlying disease • Reduced skin temperature • Pallor on elevation and rubor on dependency (Buerger’s sign) • Superficial veins that fill sluggishly and empty (‘gutter’) on minimal elevation • Muscle-wasting • Skin and nails: dry, thin and brittle • Loss of hair

Diseases of the aorta • 505

Investigations Ultrasound is the best way of establishing the diagnosis of an abdominal aneurysm and of following up patients with asymptomatic aneurysms that are not yet large enough to warrant surgical repair. In the UK, a national screening programme for men over 65 years of age has been introduced using ultrasound scanning. For every 10 000 men scanned, 65 ruptures are prevented and 52 lives saved. CT provides more accurate information about the size and extent of the aneurysm, the surrounding structures and the presence of any other intraabdominal pathology. It is the standard pre-operative investigation but is not suitable for surveillance because of the high cost and radiation dose. Management The risks of surgery generally outweigh the risks of rupture until an asymptomatic AAA has reached a maximum of 5.5 cm in diameter. All symptomatic AAAs should be considered for repair, not only to rid the patient of symptoms but also because pain often predates rupture. Distal embolisation is a strong indication for repair, regardless of size, because otherwise limb loss is common. Most patients with a ruptured AAA do not survive to reach hospital, but if they do and surgery is thought to be appropriate, there must be no delay in getting them to the operating theatre to clamp the aorta. Open AAA repair has been the treatment of choice in both the elective and the emergency settings, and entails replacing the aneurysmal segment with a prosthetic (usually Dacron) graft. The 30-day mortality for this procedure is approximately 5–8% for elective asymptomatic AAA, 10–20% for emergency symptomatic AAA and 50% for ruptured AAA. However, patients who survive the operation to leave hospital have a long-term survival approaching that of the normal population. Increasingly, endovascular aneurysm repair (EVAR), using a stent graft introduced via the femoral arteries in the groin, is vasodilators such as nifedipine can may be helpful if symptoms are troublesome. More severe Raynaud’s syndrome can also occur in association with digital ulceration in patients with connective tissue disease. This is discussed in more detail on page 1035. Diseases of the aorta Aortic aneurysm Aortic aneurysm is defined to exist when there is an abnormal dilatation of the aortic lumen. The most common site is the infrarenal abdominal aorta. The suprarenal abdominal aorta and a variable length of the descending thoracic aorta may be affected in 10–20% of patients but the ascending aorta is usually spared. Abdominal aortic aneurysms (AAAs) affect men three times more commonly than women and are estimated to occur in about 5% of men over the age of 60 years. Pathogenesis The most common cause of aortic aneurysm is atherosclerosis, the risk factors for which have previously been described (p. 484). Genetic factors that predispose to hypertension, hyperlipidaemia and diabetes all play a role in the pathogenesis of aortic aneurysm but there appears to be an additional and specific genetic component since aortic aneurysm tends to run in families. This may explain in part why only some patients with risk factors for atheroma develop aneurysmal disease. Marfan’s syndrome is an inherited disorder of connective tissue that is associated with aortic aneurysm and aortic dissection (p. 508). The features and management of this disorder are discussed on page 508. Clinical features The clinical presentation is dependent on the site of the aneurysm. Thoracic aneurysms may typically present with acute severe chest pain (p. 176) but other features, including aortic regurgitation, compressive symptoms such as stridor (trachea, bronchus), hoarseness (recurrent laryngeal nerve) and superior vena cava syndrome, may occur (Fig. 16.72A). If the aneurysm erodes into an adjacent structure, such as the oesophagus or bronchus, the presentation may be with massive bleeding. AAAs affect the infrarenal segment of the aorta. They can present in a number of ways, as summarised in Box 16.62. The usual age at presentation is 65–75 years for elective presentations and 75–85 years for emergency presentations. 16.61 Atherosclerotic vascular disease in old age • Prevalence: related almost exponentially to age in developed countries, although atherosclerosis is not considered part of the normal ageing process. • Statin therapy: no role in the primary prevention of atherosclerotic disease in those over 75 years but reduces cardiovascular events in those with established vascular disease, albeit with no reduction in overall mortality. • Presentation in the frail: frequently with advanced multisystem arterial disease, along with a host of other comorbidities. • Intervention in the frail: in those with extensive disease and limited life expectancy, the risks of surgery may outweigh the benefits, and symptomatic care is all that should be offered. 16.62 Abdominal aortic aneurysm (AAA): common presentations Incidental • On physical examination, plain X-ray or, most commonly, abdominal ultrasound • Even large AAAs can be difficult to feel, so many remain undetected until they rupture • Studies are currently under way to determine whether screening will reduce the number of deaths from rupture Pain • In the central abdomen, back, loin, iliac fossa or groin Thromboembolic complications • Thrombus within the aneurysm sac may be a source of emboli to the lower limbs • Less commonly, the aorta may undergo thrombotic occlusion Compression • Surrounding structures such as the duodenum (obstruction and vomiting) and the inferior vena cava (oedema and deep vein thrombosis) Rupture • Into the retroperitoneum, the peritoneal cavity or surrounding structures (most commonly the inferior vena cava, leading to an aortocaval fistula)

506 • CARDIOLOGY Fig. 16.72 Types of aortic disease and their complications. A Types of aortic aneurysm. B Types of aortic dissection. DILATED THORACIC ABDOMINAL Expansion Thrombus Embolism Aortic regurgitation Compression, e.g. of bronchus Coronary occlusion Aortic regurgitation Loss of arm pulse Neurological deficit Renal or mesenteric occlusion Loss of leg pulse Type A Type B Aortic dissection Aortic aneurysm A B Diaphragm SACCULAR THORACIC the left pleural space or pericardium with fatal consequences. The peak incidence is in the sixth and seventh decades but dissection can occur in younger patients, usually in association with Marfan’s syndrome, pregnancy or trauma; men are affected twice as frequently as women. Pathogenesis The primary event is often a spontaneous or iatrogenic tear in the intima of the aorta; multiple tears or entry points are common. Other dissections are triggered by primary haemorrhage in the media of the aorta, which then ruptures through the intima into the true lumen. This form of spontaneous bleeding from the vasa vasorum is sometimes confined to the aortic wall, when it may present as a painful intramural haematoma. Aortic disease and hypertension are the most important aetiological factors but other conditions may also be implicated (Box 16.63). Chronic dissections may lead to aneurysmal dilatation of the aorta, and thoracic aneurysms may be complicated by dissection. It can therefore be difficult to identify the primary pathology. replacing open surgery. It is cost-effective and likely to become the treatment of choice for infrarenal AAA. It is possible to treat many suprarenal and thoraco-abdominal aneurysms by EVAR too. If the aneurysm is secondary to Marfan’s syndrome, treatment with β-blockers reduces the rate of aortic dilatation and the risk of rupture. Elective replacement of the ascending aorta may also be considered in patients with evidence of progressive aortic dilatation but carries a mortality of 5–10%. Aortic dissection Aortic dissection occurs when a breach in the integrity of the aortic wall allows arterial blood to enter the media, which is then split into two layers, creating a false lumen alongside the existing or true lumen (Fig. 16.72B). The aortic valve may be damaged and the branches of the aorta may be compromised. Typically, the false lumen eventually re-enters the true lumen, creating a double-barrelled aorta, but it may also rupture into

Diseases of the aorta • 507

16.63 Risk factors for aortic dissection • Hypertension (in 80%) • Atherosclerosis • Coarctation • Genetic: Marfan’s syndrome Ehlers–Danlos syndrome • Fibromuscular dysplasia • Previous cardiac surgery: CABG Aortic valve replacement • Pregnancy (usually third trimester) • Trauma • Iatrogenic: Cardiac catheterisation Intra-aortic balloon pumping (CABG = coronary artery bypass grafting) Fig. 16.73 Sagittal view of an MRI scan from a patient with long-standing aortic dissection, illustrating a biluminal aorta. There is sluggish flow in the false lumen (FL), accounting for its grey appearance. (TL = true lumen) FL TL Fig. 16.74 Images from a patient with an acute type B aortic dissection that had ruptured into the left pleural space and was repaired by deploying an endoluminal stent graft. A CT scan illustrating an intimal flap (arrow) in the descending aorta and a large pleural effusion. B Aortogram illustrating aneurysmal dilatation; a stent graft has been introduced from the right femoral artery and is about to be deployed. C CT scan after endoluminal repair. The pleural effusion has been drained but there is a haematoma around the descending aorta. D Aortogram illustrating the stent graft. E Threedimensional reconstruction of an aortic stent graft. E, Courtesy of Dr T. Lawton. A B D C E Aortic dissection is classified anatomically and for management purposes into type A and type B (see Fig. 16.72B), involving or sparing the ascending aorta, respectively. Type A dissections account for two-thirds of cases and frequently also extend into the descending aorta. Clinical features Involvement of the ascending aorta typically gives rise to anterior chest pain, and involvement of the descending aorta to intrascapular back pain. The pain is typically described as ‘tearing’ and very abrupt in onset; collapse is common. Unless there is major haemorrhage, the patient is invariably hypertensive. There may be asymmetry of the brachial, carotid or femoral pulses and signs of aortic regurgitation. Occlusion of aortic branches may cause MI (coronary), stroke (carotid), paraplegia (spinal), mesenteric infarction with an acute abdomen (coeliac and superior mesenteric), renal failure (renal) and acute limb (usually leg) ischaemia. Investigations The investigations of choice are CT or MR angiography (Figs 16.73 and 16.74), both of which are highly specific and sensitive. A chest X-ray should be performed. It characteristically shows broadening of the upper mediastinum and distortion of the aortic ‘knuckle’ but these findings are absent in 10% of cases. A left-sided pleural effusion is common. The ECG may show left ventricular hypertrophy in patients with hypertension or, rarely, changes

508 • CARDIOLOGY Fig. 16.75 Echocardiograms from a patient with a chronic aortic dissection. Colour flow Doppler shows flow from the larger false lumen (FL) into the true lumen (TL), characteristic of chronic disease. TL FL of acute MI (usually inferior). Doppler echocardiography may show aortic regurgitation, a dilated aortic root and, occasionally, the flap of the dissection. TOE is particularly helpful because transthoracic echocardiography can provide images of the first 3–4 cm of the ascending aorta only (Fig. 16.75). Management The early mortality of acute dissection is approximately 1–5% per hour and so treatment is urgently required. Initial management comprises pain control and antihypertensive treatment. Type A dissections require emergency surgery to replace the ascending aorta. Type B aneurysms are treated medically unless there is actual or impending external rupture, or vital organ (gut, kidneys) or limb ischaemia, as the morbidity and mortality associated with surgery are very high. The aim of medical management is to maintain a mean arterial pressure (MAP) of 60–75 mmHg to reduce the force of the ejection of blood from the LV. First-line therapy is with β-blockers; the additional α-blocking properties of labetalol make it especially useful. Rate-limiting calcium channel blockers, such as verapamil or diltiazem, are used if β-blockers are contraindicated. Sodium nitroprusside may be considered if these fail to control BP adequately. Percutaneous or minimal access endoluminal repair is sometimes possible and involves either ‘fenestrating’ (perforating) the intimal flap so that blood can return from the false to the true lumen (so decompressing the former), or implanting a stent graft placed from the femoral artery (see Fig. 16.74). Aortitis Syphilis is a rare cause of aortitis that characteristically produces saccular aneurysms of the ascending aorta containing calcification. Other rare conditions associated with aortitis include Takayasu’s disease (p. 1041), reactive arthritis (p. 1031), giant cell arteritis (p. 1042) and ankylosing spondylitis (p. 1028). Marfan’s syndrome Marfan’s syndrome is an inherited disorder of connective tissue that is associated with a high risk of aortic aneurysm and dissection. It is inherited in an autosomal dominant manner but some cases are due to new mutations. It is a rare disorder that is estimated to affect about 0.02% of the population. Marfan’s syndrome is caused by protein-coding mutations affecting the FBN1 gene, which encodes fibrillin, an extracellular matrix protein. The causal mutations disrupt the mechanical integrity of connective tissue, giving rise to a wide range of clinical features. Clinical features Aortic dissection and aneurysm are the most serious complications of Marfan’s syndrome but many other clinical manifestations may be observed. These include aortic and mitral valve regurgitation; skin laxity and joint hypermobility; abnormalities of body habitus, including long arms, legs and fingers (arachnodactyly), scoliosis, pectus excavatum and a high-arched palate; ocular abnormalities, such as lens dislocation and retinal detachment; and an increased risk of pneumothorax. Investigations The diagnosis is usually suspected on the basis of the characteristic clinical features and can be confirmed by genetic testing. Imaging by chest X-ray may reveal evidence of aortic dilatation but echocardiography is more sensitive and can also demonstrate valvular disease, if present. Patients with Marfan’s syndrome should undergo serial monitoring of the aortic root by echocardiography; if evidence of dilatation is observed, then elective surgery should be considered. Management Treatment with β-blockers reduces the risk of aortic dilatation and should be given in all patients with Marfan’s syndrome. Activities that are associated with increases in cardiac output are best avoided. Surgery to replace the aortic root can be performed in patients with progressive aortic dilatation. Coarctation of the aorta Coarctation of the aorta is the term used to describe a narrowing distal to the origin of the left subclavian artery. It is most commonly due to congenital heart disease (p. 531), but narrowing of the aorta leading to similar symptoms can occur in other conditions such as Takayasu’s arteritis (p. 1041) and trauma. Diagnosis and management of coarctation are discussed on page 534. Hypertension The risk of cardiovascular diseases such as stroke and CAD is closely related to levels of BP. BP follows a normal distribution in the general population and there is no specific cut-off above which the risk of cardiovascular risk suddenly increases. The diagnosis of hypertension is therefore made when systolic and diastolic values rise above a specific threshold that corresponds to the level of BP at which the risk of cardiovascular complications and benefits of treatment outweigh the treatment costs and potential sideeffects of therapy. The British Hypertension Society classification, provided in Box 16.64, defines mild hypertension as existing when the BP is above 140/90 mmHg. Similar thresholds have been published by the European Society of Hypertension and the WHO–International Society of Hypertension. The cardiovascular risks associated with high BP depend on the combination of risk factors in an individual, such as age, gender, weight, physical activity, smoking, family history, serum cholesterol, diabetes mellitus and pre-existing vascular disease.

Diseases of the aorta • 509

and cerebrovascular disease, particularly if other risk factors are present. These structural changes in the vasculature often perpetuate and aggravate hypertension by increasing peripheral vascular resistance and reducing renal blood flow, thereby activating the renin–angiotensin–aldosterone axis (p. 461). Clinical features Hypertension is usually asymptomatic until the diagnosis is made at a routine physical examination or when a complication arises. Reflecting this fact, a BP check is advisable every 5 years in adults over 40 years of age to pick up occult hypertension. Sometimes clinical features may be observed that can give a clue to the underlying cause of hypertension. These include radio-femoral delay in patients with coarctation of the aorta (see Fig. 16.93, p. 534), enlarged kidneys in patients with polycystic kidney disease (p. 405), abdominal bruits that may suggest renal artery stenosis (p. 406), and the characteristic facies and habitus of Cushing’s syndrome (Box 16.65). Examination may also reveal evidence of risk factors for hypertension, such as central obesity and hyperlipidaemia. Other signs may be observed that are due to the complications of hypertension. These include signs of left ventricular hypertrophy, accentuation of the aortic component of the second heart sound, and a fourth heart sound. AF is common and may be due to diastolic dysfunction caused by left ventricular hypertrophy or the effects of CAD. Severe hypertension can cause left ventricular failure in the absence of CAD, particularly when there is an impairment of renal function. The optic fundi are often abnormal (see Fig. 16.76 below) and there may be evidence of generalised atheroma or Pathogenesis Many factors may contribute to the regulation of BP and the development of hypertension, including renal dysfunction, peripheral resistance, vessel tone, endothelial dysfunction, autonomic tone, insulin resistance and neurohumoral factors. In more than 95% of cases, however, no specific underlying cause of hypertension can be found. Such patients are said to have essential hypertension. Hypertension is more common in some ethnic groups, particularly African Americans and Japanese, and approximately 40–60% is explained by genetic factors. Age is a strong risk factor in all ethnic groups. Important environmental factors include a high salt intake, heavy consumption of alcohol, obesity and lack of exercise. Impaired intrauterine growth and low birth weight are associated with an increased risk of hypertension later in life. In about 5% of cases, hypertension is secondary to a specific disease, as summarised in Box 16.65. Hypertension has a number of adverse effects on the cardiovascular system. In larger arteries (> 1 mm in diameter), the internal elastic lamina is thickened, smooth muscle is hypertrophied and fibrous tissue is deposited. The vessels dilate and become tortuous, and their walls become less compliant. In smaller arteries (< 1 mm), hyaline arteriosclerosis occurs in the wall, the lumen narrows and aneurysms may develop. Widespread atheroma develops and may lead to coronary 16.64 Definition of hypertension Category Systolic blood pressure (mmHg) Diastolic blood pressure (mmHg) Blood pressure Optimal < 120 < 80 Normal < 130

High normal 130–139 85–89 Hypertension Grade 1 (mild) 140–159 90–99 Grade 2 (moderate) 160–179 100–109 Grade 3 (severe) ≥ 180

110 Isolated systolic hypertension Grade 1 140–159 < 90 Grade 2 ≥ 160 < 90 16.65 Causes of secondary hypertension Alcohol Obesity Pregnancy Renal disease • Parenchymal renal disease, particularly glomerulonephritis • Renal vascular disease • Polycystic kidney disease Endocrine disease • Phaeochromocytoma • Cushing’s syndrome • Primary hyperaldosteronism (Conn’s syndrome) • Glucocorticoid-suppressible hyperaldosteronism • Hyperparathyroidism • Acromegaly • Primary hypothyroidism • Thyrotoxicosis • Congenital adrenal hyperplasia due to 11β-hydroxylase or 17α-hydroxylase deficiency • Liddle’s syndrome (p. 361) • 11β-hydroxysteroid dehydrogenase deficiency Drugs Coarctation of the aorta Fig. 16.76 Retinal changes in hypertension. A Grade 4 hypertensive retinopathy showing swollen optic disc, retinal haemorrhages and multiple cotton wool spots (infarcts). B Central retinal vein thrombosis showing swollen optic disc and widespread fundal haemorrhage, commonly associated with systemic hypertension. A and B, Courtesy of Dr B. Cullen. A B

510 • CARDIOLOGY number of clinic readings and correlate more closely with evidence of target organ damage than casual BP measurements. Treatment thresholds and targets (see Box 16.71 below) must be adjusted downwards, however, because ambulatory BP readings are systematically lower (approximately 12/7 mmHg) than clinic measurements. The average ambulatory daytime (not 24-hour or night-time) BP should be used to guide management decisions. Home blood pressure measurements Patients can measure their own BP at home using a range of commercially available semi-automatic devices. The value of such measurements is less well established and is dependent on the environment and timing of the readings measured. Home or ambulatory BP measurements are particularly helpful in patients with unusually labile BP, those with refractory hypertension, those who may have symptomatic hypotension, and those in whom white coat hypertension is suspected. Other investigations All hypertensive patients should undergo a limited number of investigations (Box 16.68) but additional investigations are appropriate in patients younger than 40 years of age or those with resistant hypertension (Box 16.69). Family history, lifestyle (exercise, salt intake, smoking habit) and other risk factors should also be recorded. A careful history will identify those patients with drug- or alcohol-induced hypertension and may elicit the symptoms of other causes of secondary hypertension, such as phaeochromocytoma (paroxysmal headache, palpitation and sweating, p. 675) or complications such as CAD. Management The objective of antihypertensive therapy is to reduce the incidence of adverse cardiovascular events, particularly CAD, stroke and heart failure. Randomised controlled trials have specific complications, such as aortic aneurysm, PAD or stroke. Examination of the optic fundi reveals a gradation of changes linked to the severity of hypertension; fundoscopy can, therefore, provide an indication of the arteriolar damage occurring elsewhere (Box 16.66). ‘Cotton wool’ exudates are associated with retinal ischaemia or infarction, and fade in a few weeks (Fig. 16.76A). ‘Hard’ exudates (small, white, dense deposits of lipid) and microaneurysms (‘dot’ haemorrhages) are more characteristic of diabetic retinopathy (see Fig. 27.8, p. 1176). Hypertension is also associated with central retinal vein thrombosis (Fig. 16.76B). Investigations A decision to embark on antihypertensive therapy effectively commits the patient to life-long treatment, so readings must be as accurate as possible. The objectives are to: • confirm the diagnosis by obtaining accurate, representative BP measurements • identify contributory factors and any underlying causes • assess other risk factors and quantify cardiovascular risk • detect any complications that are already present • identify comorbidity that may influence the choice of antihypertensive therapy. Blood pressure measurements BP measurements should be made to the nearest 2 mmHg, in the sitting position with the arm supported, and repeated after 5 minutes’ rest if the first recording is high (Box 16.67). To avoid spuriously high readings in obese subjects, the cuff should contain a bladder that encompasses at least two-thirds of the arm circumference. Exercise, anxiety, discomfort and unfamiliar surroundings can all lead to a transient rise in BP. Sphygmomanometry, particularly when performed by a doctor, can cause a transient elevation in BP, which has been termed ‘white coat’ hypertension. It has been estimated that up to 20% of patients who are found to have raised BP at outpatient clinics have a normal BP when it is recorded by automated devices used at home. The risk of cardiovascular disease in these patients is less than that in patients with sustained hypertension but greater than that in normotensive subjects. If clinic BP measurements show borderline levels of BP or if white coat hypertension is suspected, then ambulatory measurement or home-based measurements may be of value in confirming the diagnosis. Ambulatory blood pressure measurements A series of automated ambulatory BP measurements obtained over 24 hours or longer provide a better profile than a limited 16.66 Hypertensive retinopathy Grade 1 • Arteriolar thickening, tortuosity and increased reflectiveness (‘silver wiring’) Grade 2 • Grade 1 plus constriction of veins at arterial crossings (‘arteriovenous nipping’) Grade 3 • Grade 2 plus evidence of retinal ischaemia (flame-shaped or blot haemorrhages and ‘cotton wool’ exudates) Grade 4 • Grade 3 plus papilloedema 16.67 How to measure blood pressure • Use a machine that has been validated, well maintained and properly calibrated • Measure sitting BP routinely, with additional standing BP in elderly and diabetic patients and those with possible postural hypotension; rest the patient for 2 minutes • Remove tight clothing from the arm • Support the arm at the level of the heart • Use a cuff of appropriate size (the bladder must encompass more than two-thirds of the arm) • Lower the pressure slowly (2 mmHg per second) • Read the BP to the nearest 2 mmHg • Use phase V (disappearance of sounds) to measure diastolic BP • Take two measurements at each visit 16.68 Investigation of hypertension • Urinalysis for blood, protein and glucose • Blood urea, electrolytes and creatinine Hypokalaemic alkalosis may indicate primary hyperaldosteronism but is usually due to diuretic therapy • Blood glucose • Serum total and HDL cholesterol • Thyroid function tests • 12-lead ECG (left ventricular hypertrophy, coronary artery disease) (HDL = high-density lipoprotein)

Diseases of the aorta • 511

is greatest in those at highest risk. For example, to extrapolate from the Medical Research Council (MRC) Mild Hypertension Trial (1985), 566 young patients would have to be treated with bendroflumethiazide for 1 year to prevent 1 stroke, while in the MRC trial of antihypertensive treatment in the elderly (1992), 1 stroke was prevented for every 286 patients treated for 1 year. A formal estimate of absolute cardiovascular risk, which takes account of all the relevant risk factors, may help to determine whether the likely benefits of therapy will outweigh its costs and hazards. A variety of risk algorithms are available for this purpose, such as the Joint British Societies risk calculator (Fig. 16.77 and see ‘Further information’). Most of the excess morbidity and mortality associated with hypertension are attributable to CAD and many treatment guidelines are therefore based on estimates of the 10-year CAD risk. Total cardiovascular risk can be estimated by multiplying CAD risk by 4/3 (i.e. if CAD risk is 30%, cardiovascular risk is 40%). The value of this approach can be illustrated by comparing the two hypothetical cases on page 487. Intervention thresholds Systolic BP and diastolic BP are both powerful predictors of cardiovascular risk. The British Hypertension Society management 16.69 Specialised investigation of hypertension • Chest X-ray: to detect cardiomegaly, heart failure, coarctation of the aorta • Ambulatory BP recording: to assess borderline or ‘white coat’ hypertension • Echocardiogram: to detect or quantify left ventricular hypertrophy • Renal ultrasound: to detect possible renal disease • Renal angiography: to detect or confirm the presence of renal artery stenosis • Urinary catecholamines: to detect possible phaeochromocytoma (p. 675) • Urinary cortisol and dexamethasone suppression test: to detect possible Cushing’s syndrome (p. 666) • Plasma renin activity and aldosterone: to detect possible primary aldosteronism (p. 674) Fig. 16.77 Example of cardiovascular risk prediction chart for non-diabetic men. Cardiovascular risk is predicted from the patient’s age, sex, smoking habit, BP and cholesterol ratio. The ratio of total to high-density lipoprotein (HDL) cholesterol can be determined in a non-fasting blood sample. Where HDL cholesterol concentration is unknown, it should be assumed to be 1 mmol/L; the lipid scale should be used as total serum cholesterol. Current guidelines suggest initiation of primary prevention in individuals with a 10-year cardiovascular risk ≥ 20%. Patients with diabetes mellitus should be assumed to have a 10-year cardiovascular risk of ≥ 20% and receive secondary prevention therapy. Modified charts exist for women. For further details, see www.who.int/ cardiovascular_diseases/guidelines/Pocket_GL_information. • To estimate an individual’s absolute 10-year risk of developing cardiovascular disease (CVD), choose the panel for the appropriate gender, smoking status and age. Within this, define the level of risk from the point where the coordinates for systolic blood pressure (SBP) and ratio of the total to HDL-cholesterol cross. • Highest-risk individuals (red areas) are those whose 10-year CVD risk exceeds 20%, which is approximately equivalent to a 10-year coronary artery disease risk of > 15%. As a minimum, those with CVD risk > 30% (shown by the line within the red area) should be targeted and treated now. When resources allow, others with a CVD risk > 20% should be targeted progressively. • The chart also assists in identification of individuals with a moderately high 10-year CVD risk, in the range of 10–20% (orange area) and those in whom it is < 10% (green area). • Smoking status should reflect lifetime exposure to tobacco. For further information, see www.bhf.org.uk. From Joint British Societies Cardiovascular Risk Prediction Chart, reproduced with permission from the University of Manchester. Non-smoker Smoker Age under 50 years Non-diabetic men

SBP 140

3 4 5 6 7 8 9 10 TC:HDL

SBP 140

3 4 5 6 7 8 9 10 TC:HDL

SBP 140

3 4 5 6 7 8 9 10 TC:HDL

SBP 140

3 4 5 6 7 8 9 10 TC:HDL

SBP 140

3 4 5 6 7 8 9 10 TC:HDL

SBP 140

3 4 5 6 7 8 9 10 TC:HDL Age 50–59 years Age 60 years and over CVD risk < 10% over next 10 years CVD risk 10–20% over next 10 years CVD risk > 20% over next 10 years CVD risk over next 10 years 30% 10% 20% SBP = systolic blood pressure (mmHg) TC:HDL = serum total cholesterol to HDL cholesterol ratio demonstrated that antihypertensive therapy can reduce the incidence of stroke and, to a lesser extent, CAD. The relative benefits (approximately 30% reduction in risk of stroke and 20% reduction in risk of CAD) are similar in all patient groups, so the absolute benefit of treatment (total number of events prevented)

512 • CARDIOLOGY guidelines therefore utilise both readings, and treatment should be initiated if they exceed the given threshold (Fig. 16.78). Patients with diabetes or cardiovascular disease are at particularly high risk and the threshold for initiating antihypertensive therapy is therefore lower (≥ 140/90 mmHg) in these patient groups. The thresholds for treatment in the elderly are the same as for younger patients (Box 16.70). Treatment targets The optimum BP for reduction of major cardiovascular events has been found to be 139/83 mmHg, and even lower in patients with diabetes mellitus. Moreover, reducing BP below this level causes no harm. The targets suggested by the British Hypertension Society (Box 16.71) are ambitious. Primary care strategies have been devised to improve screening and detection of hypertension that, in the past, remained undetected in up to half 16.70 Hypertension in old age • Prevalence: hypertension affects more than half of all people over the age of 60 years (including isolated systolic hypertension). • Risks: hypertension is the most important risk factor for myocardial infarction, heart failure and stroke in older people. • Benefit of treatment: absolute benefit from therapy is greatest in older people (at least up to age 80 years). • Target blood pressure: targets be relaxed in older people to 150/90 mmHg. • Tolerance of treatment: antihypertensives are tolerated as well as in younger patients. • Drug of choice: low-dose thiazides but, in the presence of coexistent disease such as gout or diabetes, other agents may be more appropriate. Fig. 16.78 Management of hypertension: British Hypertension Society guidelines. 1Signs of papilloedema or retinal haemorrhage. 2Labile or postural hypotension, headache, palpitations, pallor and diaphoresis. (ABPM = ambulatory blood pressure monitoring; HBPM = home blood pressure monitoring) From NICE Clinical Guideline 127 – Hypertension in adults; August 2011. Clinic blood pressure ≥ 140/90 mmHg Offer antihypertensive drug treatment Consider alternative causes for target organ damage Clinic blood pressure ≥ 180/110 mmHg Consider starting hypertensive drug treatment immediately Offer ABPM (or HBPM if ABPM is declined or not tolerated) Offer lifestyle interventions Offer patient education and interventions to support adherence to treatment Offer annual review of care to monitor blood pressure, provide support and discuss lifestyle, symptoms and medication Offer to check blood pressure at least every 5 yrs, more often if blood pressure is close to 140/90 mmHg Offer to assess cardiovascular risk and target organ damage ABPM/HBPM ≥ 135/85 mmHg Stage 1 hypertension ABPM/HBPM ≥ 150/95 mmHg Stage 2 hypertension ABPM/HBPM < 135/85 mmHg Normotensive If accelerated hypertension1 or suspected phaeochromocytoma2 If target organ damage present or 10-yr cardiovascular risk > 20% Consider specialist referral If < 40 yrs If evidence of target organ damage Refer same day for specialist care Clinic blood pressure < 140/90 mmHg Normotensive

Diseases of the aorta • 513

Beta-blockers These are no longer used as first-line antihypertensive therapy, except in patients with another indication for the drug such as angina. Metoprolol (100–200 mg daily), atenolol (50–100 mg daily) and bisoprolol (5–10 mg daily), which preferentially block cardiac β1-adrenoceptors, should be used rather than non-selective agents that also block β2-adrenoceptors, which mediate vasodilatation and bronchodilatation. Combined β- and α-blockers Labetalol (200 mg–2.4 g daily in divided doses) and carvedilol (6.25–25 mg twice daily) are combined β- and α-adrenoceptor antagonists that are sometimes more effective than pure β-blockers. Labetalol can be used as an infusion in malignant phase hypertension (see below). Other vasodilators A variety of other vasodilators may be used. These include the α1-adrenoceptor antagonists prazosin (0.5–20 mg daily in divided doses), indoramin (25–100 mg twice daily) and doxazosin (1–16 mg daily), and drugs that act directly on vascular smooth muscle, such as hydralazine (25–100 mg twice daily) and minoxidil (10–50 mg daily). Side-effects include first-dose and postural hypotension, headache, tachycardia and fluid retention. Minoxidil also causes increased facial hair and is therefore unsuitable for female patients. Aspirin Antiplatelet therapy is a powerful means of reducing cardiovascular risk but may cause bleeding, particularly intracerebral haemorrhage, in a small number of patients. The benefits are thought to outweigh the risks in hypertensive patients aged 50 years or over who have well-controlled BP and either target organ damage or diabetes or a 10-year CAD risk of at least 15% (or 10-year cardiovascular disease risk of at least 20%). Statins Treating hyperlipidaemia can produce a substantial reduction in cardiovascular risk. These drugs are strongly indicated in patients who have established vascular disease, or hypertension with a high (at least 10% in 10 years) risk of developing cardiovascular disease (p. 376). Choice of antihypertensive drug Trials that have compared thiazides, calcium antagonists, ACE inhibitors and ARBs have not shown consistent differences in outcome, efficacy, side-effects or quality of life. Beta-blockers, which previously featured as first-line therapy in guidelines, have a weaker evidence base. The choice of antihypertensive therapy is initially dictated by the patient’s age and ethnic background, although cost and convenience will influence the exact drug and preparation used. Response to initial therapy and side-effects guide subsequent treatment. Comorbid conditions also have an influence on initial drug selection (Box 16.72); for example, a β-blocker might be the most appropriate treatment for a patient with angina. Thiazide diuretics and dihydropyridine calcium channel antagonists are the most suitable drugs for treatment in older people. Combination therapy Although some patients can be treated with a single antihypertensive drug, a combination of drugs is often required to achieve optimal control (Fig. 16.79). Combination therapy may be desirable for other reasons; for example, low-dose therapy with two drugs may produce fewer unwanted effects than treatment with the maximum dose of a single drug. Some drug combinations have complementary or synergistic actions; for example, thiazides increase activity of the renin–angiotensin system, while ACE inhibitors block it. of affected individuals. Application of new guidelines should help establish patients on appropriate treatment, and allow step-up if lifestyle modification and first-line drug therapy fail to control hypertension. Patients taking antihypertensive therapy require follow-up at regular intervals to monitor BP, minimise side-effects and reinforce lifestyle advice. Non-drug therapy Appropriate lifestyle measures may obviate the need for drug therapy in patients with borderline hypertension, reduce the dose and/or the number of drugs required in patients with established hypertension, and directly reduce cardiovascular risk. Correcting obesity, reducing alcohol intake, restricting salt intake, taking regular physical exercise and increasing consumption of fruit and vegetables can all lower BP. Moreover, stopping smoking, eating oily fish and adopting a diet that is low in saturated fat may produce further reductions in cardiovascular risk that are independent of changes in BP. Drug therapy Thiazides The mechanism of action of these drugs is incompletely understood and it may take up to a month for the maximum effect to be observed. An appropriate daily dose is 2.5 mg bendroflumethiazide or 0.5 mg cyclopenthiazide. More potent loop diuretics, such as furosemide (40 mg daily) or bumetanide (1 mg daily), have few advantages over thiazides in the treatment of hypertension, unless there is substantial renal impairment or they are used in conjunction with an ACE inhibitor. ACE inhibitors ACE inhibitors (enalapril 20 mg daily, ramipril 5–10 mg daily or lisinopril 10–40 mg daily) are effective and usually well tolerated. They should be used with care in patients with impaired renal function or renal artery stenosis because they can reduce glomerular filtration rate and precipitate renal failure. Electrolytes and creatinine should be checked before and 1–2 weeks after commencing therapy. Side-effects include first-dose hypotension, cough, rash, hyperkalaemia and renal dysfunction. Angiotensin receptor blockers ARBs (irbesartan 150–300 mg daily, valsartan 40–160 mg daily) have similar efficacy to ACE inhibitors but they do not cause cough and are better tolerated. Calcium channel antagonists Amlodipine (5–10 mg daily) and nifedipine (30–90 mg daily) are effective and usually well-tolerated antihypertensive drugs that are particularly useful in older people. Side-effects include flushing, palpitations and fluid retention. The rate-limiting calcium channel antagonists (diltiazem 200–300 mg daily, verapamil 240 mg daily) can be useful when hypertension coexists with angina but may cause bradycardia. The main side-effect of verapamil is constipation. 16.71 Optimal target blood pressures1 Age Clinic BP (mmHg) Ambulatory or home BP (mmHg)2 < 80 years < 140/90 < 135/85 ≥ 80 years < 150/90 < 140/85 1Both systolic and diastolic values should be attained. 2Average BP during waking hours.

514 • CARDIOLOGY can cause cerebral damage, including occipital blindness, and precipitate coronary or renal insufficiency. Even in the presence of cardiac failure or hypertensive encephalopathy, a controlled reduction to a level of about 150/90 mmHg over a period of 24–48 hours is ideal. In most patients, it is possible to avoid parenteral therapy and bring BP under control with bed rest and oral drug therapy. Intravenous or intramuscular labetalol (2 mg/min to a maximum of 200 mg), intravenous GTN (0.6–1.2 mg/hr), intramuscular hydralazine (5 or 10 mg aliquots repeated at half-hourly intervals) and intravenous sodium nitroprusside (0.3–1.0 μg/kg body weight/ min) are all effective but require careful supervision, preferably in a high-dependency unit. Diseases of the heart valves The heart valves allow forward movement of blood through the cardiac chambers when they are open and prevent backward flow when they are closed. Diseased valve may become narrowed, obstructing forward flow, or become leaky, causing backward flow or regurgitation. Breathlessness is a common symptom of valve disease, and acute severe breathlessness may be a presenting symptom of valve failure. The causes of this are shown in Box 16.73. Predisposition to valvular disease may be genetically determined, can arise as the result of rheumatic fever or infections, or can occur in association with dilatation of Refractory hypertension Refractory hypertension refers to the situation where multiple drug treatments do not give adequate control of BP. Although this may be due to genuine resistance to therapy in some cases, a more common cause of treatment failure is non-adherence to drug therapy. Resistant hypertension can also be caused by failure to recognise an underlying cause, such as renal artery stenosis or phaeochromocytoma. There is no easy solution to problems with adherence but simple treatment regimens, attempts to improve rapport with the patient and careful supervision can all help. Spironolactone is a particularly useful addition in patients with treatment-resistant hypertension. Accelerated hypertension Accelerated or malignant hypertension is a rare condition that can complicate hypertension of any aetiology. It is characterised by accelerated microvascular damage with necrosis in the walls of small arteries and arterioles (fibrinoid necrosis) and by intravascular thrombosis. The diagnosis is based on evidence of high BP and rapidly progressive end-organ damage, such as retinopathy (grade 3 or 4), renal dysfunction (especially proteinuria) and/or hypertensive encephalopathy (see above). Left ventricular failure may occur and, if this is untreated, death occurs within months. Management In accelerated phase hypertension, lowering BP too quickly may compromise tissue perfusion due to altered autoregulation and 16.72 The influence of comorbidity on choice of antihypertensive drug therapy Class of drug Compelling indications Possible indications Caution Compelling contraindications α-blockers Benign prostatic hypertrophy – Postural hypotension, heart failure1 Urinary incontinence ACE inhibitors Heart failure Left ventricular dysfunction, post-MI or established CAD Type 1 diabetic nephropathy Secondary stroke prevention4 Chronic renal disease2 Type 2 diabetic nephropathy Renal impairment2 PAD3 Pregnancy Renovascular disease2 Angiotensin II receptor blockers ACE inhibitor intolerance Type 2 diabetic nephropathy Hypertension with left ventricular hypertrophy Heart failure in ACE-intolerant patients, after MI Left ventricular dysfunction after MI Intolerance of other antihypertensive drugs Proteinuric or chronic renal disease2 Heart failure Renal impairment2 PAD3 Pregnancy β-blockers MI, angina Heart failure5 – Heart failure5 PAD Diabetes (except with CAD) Asthma or chronic obstructive pulmonary disease Heart block Calcium channel blockers (dihydropyridine) Older patients, isolated systolic hypertension Angina – – Calcium channel blockers (rate-limiting) Angina Older patients Combination with β-blockade Atrioventricular block, heart failure Thiazides or thiazide-like diuretics Older patients, isolated systolic hypertension, heart failure, secondary stroke prevention – – Gout6 1ln heart failure when used as monotherapy. 2ACE inhibitors or ARBs may be beneficial in chronic renal failure and renovascular disease but should be used with caution, close supervision and specialist advice when there is established and significant renal impairment. 3Caution with ACE inhibitors and ARBs in PAD because of association with renovascular disease. 4In combination with a thiazide or thiazide-like diuretic. 5β-blockers are used increasingly to treat stable heart failure but may worsen acute heart failure. 6Thiazides or thiazide-like diuretics may sometimes be necessary to control BP in people with a history of gout, ideally used in combination with allopurinol. (ACE = angiotensin-converting enzyme; ARBs = angiotensin II receptor blockers; CAD = coronary artery disease; MI = myocardial infarction; PAD = peripheral arterial disease)

Diseases of the heart valves • 515

Fig. 16.79 Antihypertensive drug combinations. Black patients are those of African or Caribbean descent and not mixed-race, Asian or Chinese patients. 1A = Angiotensin-converting enzyme (ACE) inhibitor or consider angiotensin II receptor blocker (ARB); choose a low-cost ARB. 2C = calcium channel blocker (CCB); a CCB is preferred but consider a thiazide-like diuretic if a CCB is not tolerated or the person has oedema, evidence of heart failure or a high risk of heart failure. 3D = thiazide-type diuretic. 4Consider a low dose of spironolactone or higher doses of a thiazide-like diuretic. At the time of publication by NICE (August 2011), spironolactone did not have a UK marketing authorisation for this indication. Informed consent should be obtained and documented. 5Consider an α- or β-blocker if further diuretic therapy is not tolerated, or is contraindicated or ineffective. From NICE Clinical Guideline 127 – Hypertension in adults; August 2011. Aged < 55 yrs A1 A + C C2 Step 1 Step 2 A + C + D

Step 3 Resistant hypertension A + C + D + consider further diuretic4 or α- or β-blocker5 Consider seeking expert advice Step 4 Aged > 55 yrs or black person of African or Caribbean family origin of any age 16.73 Causes of acute valve failure Aortic regurgitation • Aortic dissection • Infective endocarditis Mitral regurgitation • Papillary muscle rupture due to acute myocardial infarction • Infective endocarditis • Rupture of chordae due to myxomatous degeneration Prosthetic valve failure • Mechanical valves: fracture, jamming, thrombosis, dehiscence • Biological valves: degeneration with cusp tear the cardiac chambers in heart failure. The principal causes of valvular disease are summarised in Box 16.74. Rheumatic heart disease Acute rheumatic fever Acute rheumatic fever usually affects children and young adults between the ages of 5 and 15 years. It is now rare in high-income countries in Western Europe and North America, where the 16.74 Principal causes of valve disease Valve regurgitation • Congenital • Acute rheumatic carditis • Chronic rheumatic carditis • Infective endocarditis • Cardiac failure* • Syphilitic aortitis • Traumatic valve rupture • Senile degeneration • Damage to chordae and papillary muscles Valve stenosis • Congenital • Rheumatic carditis • Senile degeneration *Causes dilatation of the valve ring. incidence is about 0.5 cases per 100 000, but remains endemic in the Indian subcontinent, Africa and South America. Recent studies indicate that the current incidence of rheumatic heart disease in India ranges between 13 and 150 cases per 100 000 population per year and it is by far the most common cause of acquired heart disease in childhood and adolescence in that country. Pathogenesis The condition is triggered by an immune-mediated delayed response to infection with specific strains of group A streptococci, which have antigens that cross-react with cardiac myosin and sarcolemmal membrane proteins. Antibodies produced against the streptococcal antigens cause inflammation in the endocardium, myocardium and pericardium, as well as the joints and skin. Histologically, fibrinoid degeneration is seen in the collagen of connective tissues. Aschoff nodules are pathognomonic and occur only in the heart. They are composed of multinucleated giant cells surrounded by macrophages and T lymphocytes, and are not seen until the subacute or chronic phases of rheumatic carditis. Clinical features Acute rheumatic fever is a multisystem disorder that usually presents with fever, anorexia, lethargy and joint pain, 2–3 weeks after an episode of streptococcal pharyngitis. There may be no history of sore throat, however. Arthritis occurs in approximately 75% of patients. Other features include rashes, subcutaneous nodules, carditis and neurological changes (Fig. 16.80). The diagnosis, made using the revised Jones criteria (Box 16.75), is based on two or more major manifestations, or one major and two or more minor manifestations, along with evidence of preceding streptococcal infection. A presumptive diagnosis of acute rheumatic fever can be made without evidence of preceding streptococcal infection in cases of isolated chorea or pancarditis, if other causes of these have been excluded. In cases of established rheumatic heart disease or prior rheumatic fever, a diagnosis of acute rheumatic fever can be made based only on the presence of multiple minor criteria and evidence of preceding group A streptococcal pharyngitis. Carditis Rheumatic fever causes a pancarditis involving the endocardium, myocardium and pericardium to varying degrees. Its incidence declines with increasing age, ranging from 90% at 3 years to around 30% in adolescence. It may manifest as breathlessness (due to heart failure or pericardial effusion), palpitations or chest pain (usually due to pericarditis or pancarditis). Other features include tachycardia, cardiac enlargement and new or changed

516 • CARDIOLOGY murmurs. A soft systolic murmur due to mitral regurgitation is very common. A soft mid-diastolic murmur (the Carey Coombs murmur) is typically due to valvulitis, with nodules forming on the mitral valve leaflets. Aortic regurgitation occurs in 50% of cases but the tricuspid and pulmonary valves are rarely involved. Pericarditis may cause chest pain, a pericardial friction rub and precordial tenderness. Cardiac failure may be due to myocardial dysfunction or valvular regurgitation. ECG evidence commonly includes ST and T wave changes. Conduction defects, including AV block, sometimes occur and may cause syncope. Arthritis This is the most common major manifestation and occurs early when streptococcal antibody titres are high. An acute painful, Fig. 16.80 Clinical features of rheumatic fever. Bold labels indicate Jones major criteria. (CCF = congestive cardiac failure) Inset (Erythema marginatum) From Savin JA, Hunter JAA, Hepburn NC. Skin signs in clinical medicine. London: Mosby–Wolfe, Elsevier; 1997. Sydenham's chorea St Vitus dance Carditis Dyspnoea (CCF) Syncope Pericarditis (pain, rub) Carey Coombs murmur Aortic or mitral regurgitation Heart block Erythema marginatum Oedema (heart failure) Flitting polyarthritis

Diseases of the heart valves • 517

(1.0–2.0 mg/kg per day in divided doses) should be continued until the ESR is normal and then tailed off. Chronic rheumatic heart disease Chronic valvular heart disease develops in at least half of those affected by rheumatic fever with carditis. Two-thirds of cases occur in women. Some episodes of rheumatic fever pass unrecognised and it is possible to elicit a history of rheumatic fever or chorea in only about half of all patients with chronic rheumatic heart disease. The mitral valve is affected in more than 90% of cases; the aortic valve is the next most frequently involved, followed by the tricuspid and then the pulmonary valve. Isolated mitral stenosis accounts for about 25% of all cases, and an additional 40% have mixed mitral stenosis and regurgitation. Pathogenesis The main pathological process in chronic rheumatic heart disease is progressive fibrosis. The heart valves are predominantly affected but involvement of the pericardium and myocardium also occurs and may contribute to heart failure and conduction disorders. Fusion of the mitral valve commissures and shortening of the chordae tendineae may lead to mitral stenosis with or without regurgitation. Similar changes in the aortic and tricuspid valves produce distortion and rigidity of the cusps, leading to stenosis and regurgitation. Once a valve has been damaged, the altered haemodynamic stresses perpetuate and extend the damage, even in the absence of a continuing rheumatic process. Mitral valve disease Mitral stenosis Mitral stenosis is almost always rheumatic in origin, although in older people it can be caused by heavy calcification of the mitral valve. There is also a rare form of congenital mitral stenosis. Pathogenesis In rheumatic mitral stenosis, the mitral valve orifice is slowly diminished by progressive fibrosis, calcification of the valve leaflets, and fusion of the cusps and subvalvular apparatus. The mitral valve orifice is normally about 5 cm2 in diastole but can be reduced to < 1 cm2 in severe mitral stenosis. The patient is usually asymptomatic until the orifice is < 2 cm2. As stenosis progresses, left ventricular filling becomes more dependent on left atrial contraction. There is dilatation and hypertrophy of the LA and left atrial pressure rises, leading to pulmonary venous congestion and breathlessness. Any increase in heart rate shortens diastole when the mitral valve is open and produces a further rise in left atrial pressure. Situations that demand an increase in cardiac output, such as pregnancy and exercise, also increase left atrial pressure and are poorly tolerated. Atrial fibrillation is very common due to progressive dilatation of the LA. Its onset often precipitates pulmonary oedema because the accompanying tachycardia and loss of atrial contraction lead to marked haemodynamic deterioration and a rapid rise in left atrial pressure. In the absence of AF, a more gradual rise in left atrial pressure may occur. In the presence or absence of AF, pulmonary hypertension may occur, which can protect the patient from pulmonary oedema. Pulmonary hypertension leads to right ventricular hypertrophy and dilatation, tricuspid regurgitation and right heart failure. Fewer than 20% of patients does not respond to medical treatment, valve replacement may be necessary and is often associated with a dramatic decline in rheumatic activity. Occasionally, AV block may occur but is seldom progressive and usually resolves spontaneously. Rarely, pacemaker insertion may be required. Antibiotics A single dose of benzathine benzylpenicillin (1.2 million U IM) or oral phenoxymethylpenicillin (250 mg 4 times daily for 10 days) should be given on diagnosis to eliminate any residual streptococcal infection. If the patient is penicillin-allergic, erythromycin or a cephalosporin can be used. Patients are susceptible to further attacks of rheumatic fever if another streptococcal infection occurs, and long-term prophylaxis with penicillin should be given with oral phenoxymethylpenicillin (250 mg twice daily) or as benzathine benzylpenicillin (1.2 million U IM monthly), if adherence is in doubt. Sulfadiazine or erythromycin may be used if the patient is allergic to penicillin; sulphonamides prevent infection but are not effective in the eradication of group A streptococci. Further attacks of rheumatic fever are unusual after the age of 21, when antibiotic treatment can usually be stopped. The duration of prophylaxis should be extended if an attack has occurred in the last 5 years, or if the patient lives in an area of high prevalence and has an occupation (such as teaching) with a high risk of exposure to streptococcal infection. In those with residual heart disease, prophylaxis should continue until 10 years after the last episode or 40 years of age, whichever is later. While long-term antibiotic prophylaxis prevents further attacks of acute rheumatic fever, it does not protect against infective endocarditis. Aspirin This usually relieves the symptoms of arthritis rapidly and a response within 24 hours helps confirm the diagnosis. A reasonable starting dose is 60 mg/kg body weight/day, divided into six doses. In adults, 100 mg/kg per day may be needed up to the limits of tolerance or a maximum of 8 g per day. Mild toxicity includes nausea, tinnitus and deafness; vomiting, tachypnoea and acidosis are more serious. Aspirin should be continued until the ESR has fallen and then gradually tailed off. Glucocorticoids These produce more rapid symptomatic relief than aspirin and are indicated in cases with carditis or severe arthritis. There is no evidence that long-term steroids are beneficial. Prednisolone 16.76 Investigations in acute rheumatic fever Evidence of a systemic illness • Leucocytosis, raised erythrocyte sedimentation rate and C-reactive protein Evidence of preceding streptococcal infection • Throat swab culture: group A β-haemolytic streptococci (also from family members and contacts) • Antistreptolysin O antibodies (ASO titres): rising titres, or levels of

200 U (adults) or > 300 U (children) Evidence of carditis • Chest X-ray: cardiomegaly; pulmonary congestion • ECG: first- and, rarely, second-degree atrioventricular block; features of pericarditis; T-wave inversion; reduction in QRS voltages • Echocardiography: cardiac dilatation and valve abnormalities

518 • CARDIOLOGY 16.77 Clinical features of mitral stenosis Clinical feature Cause Symptoms Breathlessness Pulmonary congestion, low cardiac output Fatigue Low cardiac output Oedema, ascites Right heart failure Palpitation Atrial fibrillation Haemoptysis Pulmonary congestion, pulmonary embolism Cough Pulmonary congestion Chest pain Pulmonary hypertension Thromboembolism Atrial stasis and atrial fibrillation Signs Atrial fibrillation Atrial dilatation Mitral facies Low cardiac output Auscultation: Loud first heart sound, opening snap Mid-diastolic murmur Pressure gradient across the valve Crepitations Pulmonary oedema Pleural effusions Left heart failure Right ventricular heave, loud P2 Pulmonary hypertension Fig. 16.81 Mitral stenosis: murmur and the diastolic pressure gradient between left atrium (LA) and left ventricle (LV). (Mean gradient is reflected by the area between LA and LV in diastole.) The first heart sound is loud, and there is an opening snap (OS) and mid-diastolic murmur (MDM) with pre-systolic accentuation. A Echocardiogram showing reduced opening of the mitral valve in diastole. B Colour Doppler showing turbulent flow. Roll patient towards left to hear murmur best (low-pitched, use bell of stethoscope at apex) A B Loud Loud MDM Stenosed mitral valve Dilated left atrium Increased pulmonary artery pressure OS A2P2 Right ventricular hypertrophy Normal left ventricle Diastolic gradient across valve mmHg LV LA Systole

remain in sinus rhythm but many of these have a small fibrotic LA and severe pulmonary hypertension. Clinical features Effort-related dyspnoea is usually the dominant symptom (Box 16.77). Typically, exercise tolerance diminishes very slowly over many years until symptoms eventually occur at rest. Patients frequently do not appreciate the extent of their disability until the diagnosis is made and their valve disease is treated. Acute pulmonary oedema or pulmonary hypertension can lead to haemoptysis. Fatigue is a common symptom due to a low cardiac output. Thromboembolism is a common complication, especially in patients with AF. Prior to the advent of anticoagulant therapy, emboli caused one-quarter of all deaths. The physical signs of mitral stenosis are often found before symptoms develop and their recognition is of particular importance in pregnancy. The forces that open and close the mitral valve increase as left atrial pressure rises. The first heart sound (S1) is therefore loud and can be palpable (tapping apex beat). An opening snap may be audible and moves closer to the second sound (S2) as the stenosis becomes more severe and left atrial pressure rises. However, the first heart sound and opening snap may be inaudible if the valve is heavily calcified. Turbulent flow produces the characteristic low-pitched middiastolic murmur and sometimes a thrill (Fig. 16.81). The murmur is accentuated by exercise and during atrial systole (pre-systolic accentuation). Early in the disease, a pre-systolic murmur may be

Diseases of the heart valves • 519

the only auscultatory abnormality, but in patients with symptoms, the murmur extends from the opening snap to the first heart sound. Coexisting mitral regurgitation causes a pansystolic murmur that radiates towards the axilla. Pulmonary hypertension may ultimately lead to right ventricular hypertrophy and dilatation with secondary tricuspid regurgitation, which causes a systolic murmur and giant ‘v waves’ in the venous pulse. Investigations Doppler echocardiography is the investigation of choice for evaluation of suspected mitral stenosis (Fig. 16.81). Cardiac catheterisation may also be required if surgery or valvuloplasty is being considered, to screen for coexisting conditions such as CAD. The ECG may show either AF or bifid P waves (P mitrale) associated with left atrial hypertrophy (Box 16.78). A typical chest X-ray is shown in Figure 16.9 (p. 451). Management Patients with mild symptoms can be treated medically but intervention by balloon valvuloplasty, mitral valvotomy or mitral valve replacement should be considered if the patient remains symptomatic despite medical treatment or if pulmonary hypertension develops. Medical management This consists of anticoagulation to reduce the risk of systemic embolism, ventricular rate control with digoxin, β-blockers or rate-limiting calcium antagonists in AF, and diuretic to control pulmonary congestion. Antibiotic prophylaxis against infective endocarditis is no longer routinely recommended. Mitral balloon valvuloplasty and valve replacement Valvuloplasty is the treatment of choice if specific criteria are fulfilled (Box 16.79 and Fig. 16.82), although surgical closed or open mitral valvotomy is an acceptable alternative. Patients who have undergone mitral valvuloplasty or valvotomy should be followed up at 1–2-yearly intervals because restenosis may occur. Clinical symptoms and signs are a guide to the severity 16.78 Investigations in mitral stenosis ECG • Right ventricular hypertrophy: tall R waves in V1–V3 • P mitrale or atrial fibrillation Chest X-ray • Enlarged left atrium and appendage • Signs of pulmonary venous congestion Echo • Thickened immobile cusps • Reduced valve area • Enlarged left atrium • Reduced rate of diastolic filling of left ventricle Doppler • Pressure gradient across mitral valve • Pulmonary artery pressure • Left ventricular function Cardiac catheterisation • Coronary artery disease • Pulmonary artery pressure • Mitral stenosis and regurgitation For comprehensive guidelines on valvular heart disease, see www.acc.org. 16.79 Criteria for mitral valvuloplasty • Significant symptoms • Isolated mitral stenosis • No (or trivial) mitral regurgitation • Mobile, non-calcified valve/subvalve apparatus on echo • Left atrium free of thrombus Fig. 16.82 Mitral valvuloplasty. A guidewire is introduced into the right atrium (RA) from the femoral vein and the inferior vena cava (IVC). The inter-atrial septum is punctured, providing access to the left atrium and mitral valve. A balloon catheter is then advanced over the guidewire across the mitral valve and the balloon dilated to stretch the valve and reduce the degree of stenosis. Atrial septal puncture Balloon catheter Mitral valve IVC RA of mitral restenosis but Doppler echocardiography provides a more accurate assessment. Valve replacement is indicated if there is substantial mitral reflux or if the valve is rigid and calcified (p. 526). Mitral regurgitation Rheumatic disease is the principal cause in countries where rheumatic fever is common but elsewhere, including in the UK, other causes are more important (Box 16.80). Mitral regurgitation may also follow mitral valvotomy or valvuloplasty. Pathogenesis Chronic mitral regurgitation causes gradual dilatation of the LA with little increase in pressure and therefore relatively few symptoms. Nevertheless, the LV dilates slowly and the left ventricular diastolic and left atrial pressures gradually increase as a result of chronic volume overload of the LV. In contrast, acute mitral regurgitation causes a rapid rise in left atrial pressure (because left atrial compliance is normal) and marked symptomatic deterioration. 16.80 Causes of mitral regurgitation • Mitral valve prolapse • Dilatation of the left ventricle and mitral valve ring (e.g. coronary artery disease, cardiomyopathy) • Damage to valve cusps and chordae (e.g. rheumatic heart disease, endocarditis) • Ischaemia or infarction of the papillary muscle • Myocardial infarction

520 • CARDIOLOGY Fig. 16.83 Mitral regurgitation: murmur and systolic wave in left atrial pressure. The first sound is normal or soft and merges with a pansystolic murmur (PSM) extending to the second heart sound. A third heart sound occurs with severe regurgitation. A A transoesophageal echocardiogram shows mitral valve prolapse, with one leaflet bulging towards the left atrium (LA, arrow). B This results in a jet of mitral regurgitation on colour Doppler (arrow). Pansystolic murmur heard best at apex and left sternal edge (diaphragm), radiates to axilla LA LV A B

Systolic wave in LA Dilated left ventricle Dilated left atrium

LA LV Systole mmHg

Soft PSM A2P2 S3 Mitral valve prolapse This is also known as ‘floppy’ mitral valve and is a common cause of mild mitral regurgitation (Fig. 16.83). Some cases are thought to be due to a developmental abnormality of the mitral valve and others due to degenerative myxomatous change in a normal mitral valve. Rarely, mitral valve prolapse may occur in association with Marfan’s syndrome (p. 508). In its mildest forms, the valve remains competent but bulges back into the atrium during systole, causing a mid-systolic click but no murmur. In the presence of a regurgitant valve, the click is followed by a late systolic murmur, which lengthens as the regurgitation becomes more severe. A click is not always audible and the physical signs may vary with both posture and respiration. Progressive elongation of the chordae tendineae leads to increasing mitral regurgitation, and if chordal rupture occurs, regurgitation suddenly becomes severe. This is rare before the fifth or sixth decade of life. Mitral valve prolapse is associated with a variety of typically benign arrhythmias, atypical chest pain and a very small risk of embolic stroke or transient ischaemic attack (TIA). Nevertheless, the overall long-term prognosis is good. Other causes of mitral regurgitation Mitral valve function depends on the chordae tendineae and their papillary muscles; dilatation of the LV distorts the geometry of these and may cause mitral regurgitation (Box 16.80). Dilated cardiomyopathy and heart failure from CAD are common causes of so-called ‘functional’ mitral regurgitation. Endocarditis is an important cause of acute mitral regurgitation. Clinical features Symptoms and signs depend on the underlying cause and how suddenly the regurgitation develops (Box 16.81). Chronic mitral regurgitation produces a symptom complex that is similar to that of mitral stenosis but sudden-onset mitral regurgitation usually presents with acute pulmonary oedema. The regurgitant jet causes an apical systolic murmur (Fig. 16.83), which radiates into the axilla and may be accompanied by a thrill. Increased forward flow through the mitral valve causes a loud third heart sound and even a short mid-diastolic murmur. The apex beat feels active and rocking due to left ventricular volume overload and is usually displaced to the left as a result of left ventricular dilatation. Investigations Echocardiography is a pivotal investigation. The severity of regurgitation can be assessed by Doppler and information may also be gained on papillary muscle function and valve prolapse. An ECG should be performed and commonly shows AF, as a consequence of atrial dilatation. Cardiac catheterisation is

Diseases of the heart valves • 521

16.82 Investigations in mitral regurgitation ECG • Left atrial hypertrophy • Atrial fibrillation Chest X-ray • Enlarged left atrium • Enlarged left ventricle • Pulmonary venous congestion • Pulmonary oedema (if acute) Echo • Dilated left atrium, left ventricle • Dynamic left ventricle (unless myocardial dysfunction predominates) • Structural abnormalities of mitral valve Doppler • Detects and quantifies regurgitation Cardiac catheterisation • Dilated left atrium, dilated left ventricle, mitral regurgitation • Pulmonary hypertension • Coexisting coronary artery disease 16.83 Medical management of mitral regurgitation • Diuretics • Vasodilators if hypertension is present • Digoxin if atrial fibrillation is present • Anticoagulants if atrial fibrillation is present 16.84 Causes of aortic stenosis Infants, children, adolescents • Congenital aortic stenosis • Congenital subvalvular aortic stenosis • Congenital supravalvular aortic stenosis Young adults to middle-aged • Calcification and fibrosis of congenitally bicuspid aortic valve • Rheumatic aortic stenosis Middle-aged to elderly • Senile degenerative aortic stenosis • Calcification of bicuspid valve • Rheumatic aortic stenosis indicated when surgery is being considered (Box 16.82). During catheterisation, the severity of mitral regurgitation can be assessed by left ventriculography and by the size of the v (systolic) waves in the left atrial or pulmonary artery wedge pressure trace. Management Mitral regurgitation of moderate severity can be treated medically with diuretics and vasodilators. Digoxin and anticoagulants should be given if AF is present (Box 16.83). If systemic hypertension is present, it should be treated with vasodilators such as ACE inhibitors or ARBs, since high afterload may worsen the degree of regurgitation. All patients should be reviewed at regular intervals, both clinically and by echocardiography. Worsening symptoms, progressive cardiomegaly or echocardiographic evidence of deteriorating left ventricular function are indications for mitral valve replacement or repair. Mitral valve repair is now the treatment of choice for severe mitral regurgitation, even in asymptomatic patients, because results are excellent and early repair prevents irreversible left ventricular damage. Mitral regurgitation often accompanies left ventricular failure associated with CAD. If such patients are to undergo CABG surgery, it is common practice to repair the valve and restore mitral valve function by inserting an annuloplasty ring to overcome annular dilatation and to bring the valve leaflets closer together. Unfortunately, it can be difficult to determine whether it is the ventricular dilatation or the mitral regurgitation that is the predominant problem. If ventricular dilatation is the underlying cause of mitral regurgitation, then mitral valve repair or replacement may actually worsen ventricular function, as the ventricle can no longer empty into the low-pressure LA. Aortic valve disease Aortic stenosis There are several causes of aortic stenosis but the age at which patients present can give a clue to the most likely diagnosis (Box 16.84). In congenital aortic stenosis, obstruction is present from birth or becomes apparent during infancy. With bicuspid aortic valves, obstruction may take years to develop as the valve becomes fibrotic and calcified, and these patients present as young to middle-aged adults. Rheumatic disease of the aortic valve presents at a similar age but is usually accompanied by mitral valve disease. In older people, structurally normal aortic valves may become stenotic as the result of fibrosis and calcification. Haemodynamically significant stenosis develops slowly, typically occurring at 30–60 years in those with rheumatic disease, 50–60 years in those with bicuspid aortic valves and 70–90 years in those with calcific tricuspid disease. Pathogenesis Cardiac output is initially maintained in patients with aortic stenosis at the cost of a steadily increasing pressure gradient across the aortic valve. With progression of the stenosis the LV becomes increasingly hypertrophied and coronary blood flow may be inadequate to supply the myocardium, such that Clinical feature Cause Symptoms Breathlessness Pulmonary congestion Fatigue Low cardiac output Oedema, ascites Right heart failure Palpitation Atrial fibrillation Signs Atrial fibrillation Atrial dilatation Displaced apex beat Cardiomegaly Auscultation: Apical pansystolic murmur Regurgitation of blood from left ventricle to left atrium Soft S1 Apical S3 Valve does not close properly Rapid flow of blood into left ventricle Crepitations Pulmonary oedema Pleural effusions Left heart failure Right ventricular heave Raised jugular venous pressure Oedema Pulmonary hypertension Right heart failure Right heart failure 16.81 Clinical features of mitral regurgitation

522 • CARDIOLOGY 16.85 Clinical features of aortic stenosis Symptoms • Mild or moderate stenosis: usually asymptomatic • Exertional dyspnoea • Angina • Exertional syncope • Sudden death • Episodes of acute pulmonary oedema Signs • Ejection systolic murmur • Slow-rising carotid pulse • Thrusting apex beat (left ventricular pressure overload) • Narrow pulse pressure • Signs of pulmonary venous congestion Fig. 16.84 Aortic stenosis. Pressure traces show the systolic gradient between left ventricle (LV) and aorta. The ‘diamond-shaped’ murmur is heard best with the diaphragm in the aortic outflow and also at the apex. An ejection click (EC) may be present in young patients with a bicuspid aortic valve but not in older patients with calcified valves. Aortic stenosis may lead to left ventricular hypertrophy with a fourth sound at the apex and post-stenotic dilatation of the aortic arch. Figure 16.11 (p. 451) shows the typical Doppler signal with aortic stenosis. mmHg Peak-to-peak systolic gradient Diminished pulse pressure Systolic pressure gradient Aorta LV

Ejection systolic murmur radiates to right upper sternal edge, suprasternal notch and carotids Murmur also heard at apex Post-stenotic dilatation of aortic arch Stenosed aortic valve Left ventricular hypertrophy

EC A2 P2 Soft

EC A2 P2 angina can develop even in the absence of coexisting CAD. The fixed outflow obstruction limits the increase in cardiac output required on exercise. Eventually, the LV can no longer overcome the outflow tract obstruction and LV failure results, leading to pulmonary oedema. Clinical features Aortic stenosis is commonly picked up in asymptomatic patients at routine clinical examination but the three cardinal symptoms are angina, breathlessness and syncope (Box 16.85). Angina arises either because of the increased demands of the hypertrophied LV working against the high-pressure outflow tract obstruction, or the presence of coexisting CAD, which affects over 50% of patients. Exertional breathlessness suggests cardiac decompensation as a consequence of the excessive pressure overload placed on the LV. Syncope usually occurs on exertion when cardiac output fails to rise to meet demand, leading to a fall in BP. Sometimes patients with severe aortic stenosis do not complain of symptoms. If, on clinical evaluation, this appears to be due to a sedentary lifestyle, a careful exercise test may reveal symptoms on modest exertion. The characteristic clinical signs of severe aortic stenosis are shown in Box 16.85. A harsh ejection systolic murmur radiates to the neck, with a soft second heart sound, particularly in those with calcific valves. The murmur is often likened to a saw cutting wood and may (especially in older patients) have a musical quality like the ‘mew’ of a seagull (Fig. 16.84). The severity of aortic stenosis may be difficult to gauge clinically, as older patients with a non-compliant ‘stiff’ arterial system may have an apparently normal carotid upstroke in the presence of severe aortic stenosis. Milder degrees of stenosis may be difficult to distinguish from aortic sclerosis, in which the valve is thickened or calcified but not obstructed. A careful examination should be made for other valve lesions, particularly in rheumatic heart disease, when there is frequently concomitant mitral valve disease. In contrast to patients with mitral stenosis, which tends to progress very slowly, patients with aortic stenosis typically remain asymptomatic for many years but deteriorate rapidly when symptoms develop; if otherwise untreated, they usually die within 3–5 years of presentation. Investigations Echocardiography is a pivotal investigation in patients suspected of having aortic stenosis. It can demonstrate restricted valve opening (Fig. 16.85) and Doppler assessment permits calculation of the systolic gradient across the aortic valve, from which the severity of stenosis can be assessed (see Fig. 16.11, p. 451). In

Diseases of the heart valves • 523

Fig. 16.85 Two-dimensional echocardiogram comparing a normal individual and a patient with calcific aortic stenosis. A Normal individual in diastole; the aortic leaflets are closed and thin, and a point of coaptation is seen (arrow). B Calcific aortic stenosis in diastole; the aortic leaflets are thick and calcified (arrow). C Normal in systole; the aortic leaflets are open (arrows). D Calcific aortic stenosis in systole; the thickened leaflets have barely moved (arrows). From Newby D, Grubb N. Cardiology: an illustrated colour text. Edinburgh: Churchill Livingstone, Elsevier Ltd; 2005. A C D B patients with impaired left ventricular function, velocities across the aortic valve may be diminished because of a reduced stroke volume; this is called low-flow aortic stenosis. When marked aortic regurgitation or elevated cardiac output is present, velocities are increased because of an increased stroke volume and this may overestimate stenosis severity on Doppler echocardiography. In advanced cases, ECG features of hypertrophy (Box 16.86) are often pronounced (Fig. 16.86), and down-sloping ST segments 16.86 Investigations in aortic stenosis ECG • Left ventricular hypertrophy • Left bundle branch block Chest X-ray • May be normal; sometimes enlarged left ventricle and dilated ascending aorta on postero-anterior view, calcified valve on lateral view Echo • Calcified valve with restricted opening, hypertrophied left ventricle Doppler • Measurement of severity of stenosis • Detection of associated aortic regurgitation Cardiac catheterisation • Mainly to identify associated coronary artery disease • May be used to measure gradient between left ventricle and aorta Fig. 16.86 Left ventricular hypertrophy. QRS complexes in limb leads have increased amplitude with a very large R wave in V6 and S wave in V2. There is ST depression and T-wave inversion in leads II, III, aVF, V5 and V6: a ‘left ventricular strain’ pattern. aVR V1 V4 aVL V2 V5 III aVF V3 V6 II I

524 • CARDIOLOGY 16.87 Aortic stenosis in old age • Incidence: the most common form of valve disease affecting the very old. • Symptoms: a common cause of syncope, angina and heart failure in the very old. • Signs: because of increasing stiffening in the central arteries, low pulse pressure and a slow rising pulse may not be present. • Trans-catheter aortic valve implantation (TAVI): a good option in older individuals because less invasive than surgery. • Surgery: can be successful in those aged 80 years or more in the absence of comorbidity, but with a higher operative mortality. The prognosis without surgery is poor once symptoms have developed. • Valve replacement type: a biological valve is often preferable to a mechanical one because this obviates the need for anticoagulation, and the durability of biological valves usually exceeds the patient’s anticipated life expectancy. and T inversion (‘strain pattern’) are seen in the lateral leads, reflecting left ventricular fibrosis. Nevertheless, the ECG can be normal, despite severe stenosis. Imaging with CT and MRI may be useful in assessing the degree of valve calcification and stenosis, respectively, and may help where there is uncertainty. Management Irrespective of the severity of valve stenosis, patients with asymptomatic aortic stenosis have a good immediate prognosis and conservative management is appropriate. Such patients should be kept under review, as the development of angina, syncope, symptoms of low cardiac output or heart failure has a poor prognosis and is an indication for prompt surgery. In practice, patients with moderate or severe stenosis should be evaluated every 1–2 years with Doppler echocardiography to detect evidence of progression in severity. The intervals between reviews should be more frequent (typically 3–6-monthly) in older patients with heavily calcified valves. Patients with symptomatic severe aortic stenosis should have prompt aortic valve replacement. Delay exposes the patient to the risk of sudden death or irreversible deterioration in ventricular function. Old age is not a contraindication to valve replacement and results are very good in experienced centres, even for those in their eighties (Box 16.87). This is especially the case with transcatheter aortic valve implantation (TAVI, p. 527). Aortic balloon valvuloplasty is useful in congenital aortic stenosis but has limited value in older patients with calcific aortic stenosis. Anticoagulants are required only in patients who have AF or those who have had a valve replacement with a mechanical prosthesis. Aortic regurgitation This condition can result from either disease of the aortic valve cusps, infection, trauma or dilatation of the aortic root. The causes are summarised in Box 16.88. Pathogenesis Regurgitation of blood through the aortic value causes the LV to dilate as cardiac output increases to maintain the demands of the circulation. The stroke volume of the LV may eventually be doubled and the major arteries are then conspicuously pulsatile. As the disease progresses, left ventricular failure develops, leading to a rise in left ventricular end-diastolic pressure and pulmonary oedema. 16.88 Causes of aortic regurgitation Congenital • Bicuspid valve or disproportionate cusps Acquired • Rheumatic disease • Infective endocarditis • Trauma • Causes of aortic dilatation: Marfan’s syndrome Aneurysm Aortic dissection Syphilis Ankylosing spondylitis 16.89 Clinical features of aortic regurgitation Symptoms Mild to moderate aortic regurgitation • Often asymptomatic • Palpitations Severe aortic regurgitation • Breathlessness • Angina Signs Pulses • Large-volume or ‘collapsing’ pulse • Low diastolic and increased pulse pressure • Bounding peripheral pulses • Capillary pulsation in nail beds: Quincke’s sign • Femoral bruit (‘pistol shot’): Duroziez’s sign • Head nodding with pulse: de Musset’s sign Murmurs • Early diastolic murmur • Systolic murmur (increased stroke volume) • Austin Flint murmur (soft mid-diastolic) Other signs • Displaced, heaving apex beat (volume overload) • Pre-systolic impulse • Fourth heart sound • Crepitations (pulmonary venous congestion) Clinical features Until the onset of breathlessness, the only symptom may be an awareness of the heart beat (Box 16.89), particularly when lying on the left side, which results from the increased stroke volume. Paroxysmal nocturnal dyspnoea is sometimes the first symptom, and peripheral oedema or angina may occur. The characteristic murmur is best heard to the left of the sternum during held expiration (Fig. 16.87); a thrill is rare. A systolic murmur due to the increased stroke volume is common and does not necessarily indicate stenosis. The regurgitant jet causes fluttering of the mitral valve and, if severe, causes partial closure of the anterior mitral leaflet, leading to functional mitral stenosis and a soft mid-diastolic (Austin Flint) murmur. Acute severe regurgitation may occur as the result of perforation of an aortic cusp in endocarditis. In this circumstance, there may be no time for compensatory left ventricular hypertrophy and dilatation to develop and the features of heart failure may predominate. The classical signs of aortic regurgitation in such patients may be masked by tachycardia and an abrupt rise in

Diseases of the heart valves • 525

Fig. 16.87 Aortic regurgitation. The early diastolic murmur is best heard at the left sternal edge and may be accompanied by an ejection systolic (‘to and fro’) murmur. The aortic arch and left ventricle (LV) may become dilated. The inset shows a Doppler echocardiogram with the regurgitant jet (arrows). Inset (Colour Doppler echo) From Newby D, Grubb N. Cardiology: an illustrated colour text. Edinburgh: Churchill Livingstone, Elsevier Ltd; 2005.

A2 P2 Aorta LV

mmHg Increased pulse pressure Lean patient forward with breath held in expiration to hear early diastolic murmur best Dilated aorta Aortic valve Dilated left ventricle Colour jet of aortic regurgitation 16.90 Investigations in aortic regurgitation ECG • Initially normal, later left ventricular hypertrophy and T-wave inversion Chest X-ray • Cardiac dilatation, maybe aortic dilatation • Features of left heart failure Echo • Dilated left ventricle • Hyperdynamic left ventricle • Doppler detects reflux • Fluttering anterior mitral leaflet Cardiac catheterisation* • Dilated left ventricle • Aortic regurgitation • Dilated aortic root *Not always required. left ventricular end-diastolic pressure. The pulse pressure may also be normal or near-normal and the diastolic murmur may be short or even absent. Investigations Doppler echocardiography is the investigation of first choice for detecting regurgitation (Box 16.90). In severe acute aortic regurgitation, the rapid rise in left ventricular diastolic pressure may cause premature mitral valve closure. Cardiac catheterisation and aortography are usually performed to assess the severity of regurgitation, to determine if there is dilatation of the aorta and to screen for the presence of coexisting CAD. MRI can also be useful in assessing the degree and extent of aortic dilatation if this is suspected on chest X-ray or echocardiography. Management Treatment may be required for underlying conditions, such as endocarditis or syphilis. Aortic valve replacement is indicated if aortic regurgitation causes symptoms, and this may need to be combined with aortic root replacement and coronary bypass surgery. Those with chronic aortic regurgitation can remain asymptomatic for many years because compensatory ventricular dilatation and hypertrophy occur, but should be advised to report the development of any symptoms of breathlessness or angina. Asymptomatic patients should also be followed up annually with echocardiography for evidence of increasing ventricular size. If this occurs or if the end-systolic dimension increases to 55 mm or more, then aortic valve replacement should be undertaken. If systemic hypertension is present, vasodilators should be used to control systolic BP. There is conflicting evidence regarding the need for aortic valve replacement in asymptomatic patients with severe aortic regurgitation. When aortic root dilatation is the cause of aortic regurgitation, as can occur in Marfan’s syndrome, aortic root replacement is usually necessary. Tricuspid valve disease Tricuspid stenosis Tricuspid stenosis is usually rheumatic in origin and is rare in developed countries. Tricuspid disease occurs in fewer than 5% of patients with rheumatic heart disease and then nearly always occurs in association with mitral and aortic valve disease. Tricuspid stenosis and regurgitation may also occur in the carcinoid syndrome (p. 678). Clinical features and investigations Although the symptoms of mitral and aortic valve disease predominate, tricuspid stenosis may cause symptoms of

526 • CARDIOLOGY Pulmonary valve disease Pulmonary stenosis This can occur in the carcinoid syndrome but is usually congenital, in which case it may be isolated or associated with other abnormalities, such as Fallot’s tetralogy (p. 536). Clinical features The principal finding on examination is an ejection systolic murmur, loudest at the left upper sternum and radiating towards the left shoulder. There may be a thrill, best felt when the patient leans forwards and breathes out. The murmur is often preceded by an ejection sound (click). Delay in right ventricular ejection may cause wide splitting of the second heart sound. Severe pulmonary stenosis is characterised by a loud, harsh murmur, an inaudible pulmonary closure sound (P2), an increased right ventricular heave, and prominent a waves in the jugular pulse. Investigations Doppler echocardiography is the definitive investigation. ECG may show evidence of right ventricular hypertrophy, and poststenotic dilatation in the pulmonary artery may be observed on the chest X-ray. Management Mild to moderate isolated pulmonary stenosis is relatively common and does not usually progress or require treatment. Severe pulmonary stenosis (resting gradient > 50 mmHg with a normal cardiac output) can be treated by percutaneous pulmonary balloon valvuloplasty or, if this is not available, by surgical valvotomy. Long-term results are very good. Post-operative pulmonary regurgitation is common but benign. Pulmonary regurgitation This is rare in isolation and is usually associated with pulmonary artery dilatation due to pulmonary hypertension. It may complicate mitral stenosis, producing an early diastolic decrescendo murmur at the left sternal edge that is difficult to distinguish from aortic regurgitation (Graham Steell murmur). The pulmonary hypertension may be secondary to other disease of the left side of the heart, primary pulmonary vascular disease or Eisenmenger’s syndrome (p. 532). Trivial pulmonary regurgitation is a frequent finding in normal individuals and has no clinical significance. Prosthetic valves Diseased heart valves can be replaced with mechanical or biological prostheses. The three most commonly used types of mechanical prosthesis are the ball and cage, tilting single disc and tilting bi-leaflet valves. All generate prosthetic sounds or clicks on auscultation. Pig or allograft valves mounted on a supporting stent are the most commonly used biological valves. They generate normal heart sounds. All prosthetic valves used in the aortic position produce a systolic flow murmur. All mechanical valves require long-term anticoagulation because they can cause systemic thromboembolism or may develop valve thrombosis or obstruction (Box 16.92); the prosthetic clicks may become inaudible if the valve malfunctions. Biological valves have the advantage of not requiring anticoagulants to maintain proper function; however, many patients undergoing valve replacement surgery, especially mitral valve replacement, will have AF that right heart failure, including hepatic discomfort and peripheral oedema. The main clinical feature is a raised JVP with a prominent a wave, and a slow y descent due to the loss of normal rapid right ventricular filling (p. 443). There is also a mid-diastolic murmur, best heard at the lower left or right sternal edge. This is generally higher-pitched than the murmur of mitral stenosis and is increased by inspiration. Right heart failure causes hepatomegaly with presystolic pulsation (large a wave), ascites and peripheral oedema. The diagnosis can be confirmed by Doppler echocardiography, which shows similar appearances to those of rheumatic mitral stenosis. Management In patients who require surgery to other valves, either the tricuspid valve can also be replaced or treated with valvotomy. Balloon valvuloplasty can be used to treat rare cases of isolated tricuspid stenosis. Tricuspid regurgitation Tricuspid regurgitation is common, and is most frequently functional, occurring as a result of right ventricular dilatation due to right heart failure or biventricular failure. It may also be the result of other conditions, as summarised in Box 16.91. Clinical features Symptoms are usually non-specific, with tiredness related to reduced cardiac output, and oedema and hepatic enlargement due to venous congestion. The most prominent sign is a ‘giant’ v wave in the jugular venous pulse (a cv wave replaces the normal x descent). Other features include a pansystolic murmur at the left sternal edge and a pulsatile liver. Echocardiography may reveal dilatation of the RV. If the valve has been affected by rheumatic disease, the leaflets will appear thickened and, in endocarditis, vegetations may be seen. Management Tricuspid regurgitation due to right ventricular dilatation often improves when the cardiac failure is treated. Patients with a normal pulmonary artery pressure tolerate isolated tricuspid reflux well, and valves damaged by endocarditis do not usually need to be replaced. Patients undergoing mitral valve replacement, who have tricuspid regurgitation due to marked dilatation of the tricuspid annulus, benefit from valve repair with an annuloplasty ring to bring the leaflets closer together. Those with rheumatic damage may require tricuspid valve replacement. 16.91 Causes of tricuspid regurgitation Primary • Rheumatic heart disease • Endocarditis, particularly in intravenous drug-users • Ebstein’s congenital anomaly (see Box 16.102) Secondary • Right ventricular failure • Right ventricular infarction • Pulmonary hypertension

Diseases of the heart valves • 527

16.92 Anticoagulation targets and prosthetic heart valves Mechanical valves Target INR Ball and cage (e.g. Starr–Edwards) Tilting disc (e.g. Bjork–Shiley) 3.0–4.0 Bi-leaflet (e.g. St Jude) 2.5–3.0 Biological valves with atrial fibrillation 2.0–3.0 (INR = international normalised ratio) Infective endocarditis This is caused by microbial infection of a heart valve, the lining of a cardiac chamber or blood vessel, or by a congenital anomaly. Both native and prosthetic valves can be affected. The most common causes of infective endocarditis are streptococci and staphylococci but other organisms may also be involved. Epidemiology The incidence of infective endocarditis in community-based studies ranges from 5 to 15 cases per 100 000 per annum. More than 50% of patients are over 60 years of age (Box 16.93). In a large British study, the underlying condition was rheumatic heart disease in 24% of patients, congenital heart disease in 19%, and other cardiac abnormalities such as calcified aortic valve or floppy mitral valve in 25%. The remaining 32% were not thought to have a pre-existing cardiac abnormality. Bacterial endocarditis is a serious illness; the case fatality is approximately 20% even with treatment, and is even higher in those with prosthetic valve endocarditis and those infected with antibiotic-resistant organisms. Pathophysiology Infective endocarditis typically occurs at sites of pre-existing endocardial damage, but infection with particularly virulent or aggressive organisms such as Staphylococcus aureus can cause endocarditis in a previously normal heart. Staphylococcal endocarditis of the tricuspid valve is a common complication of intravenous drug use. Many acquired and congenital cardiac lesions are vulnerable, particularly areas of endocardial damage caused by a high-pressure jet of blood, such as ventricular septal defect, mitral regurgitation and aortic regurgitation, many of which are haemodynamically insignificant. In contrast, the risk of endocarditis at the site of haemodynamically important lowpressure lesions, such as a large atrial septal defect, is minimal. Infection tends to occur at sites of endothelial damage because they attract deposits of platelets and fibrin that are vulnerable to colonisation by blood-borne organisms. The avascular valve tissue and presence of fibrin and platelet aggregates help to protect proliferating organisms from host defence mechanisms. When the infection is established, vegetations composed of organisms, fibrin and platelets grow and may become large enough to cause obstruction or embolism. Adjacent tissues are destroyed and abscesses may form. Valve regurgitation may develop or increase if the affected valve is damaged by tissue distortion, cusp perforation or disruption of chordae. Extracardiac manifestations, such as vasculitis and skin lesions, may occur as the result of either emboli or immune complex deposition. Mycotic aneurysms may develop in arteries at the site of infected emboli. In fatal cases, infarction of the spleen and kidneys and, sometimes, an immune glomerulonephritis may be found at postmortem. requires anticoagulation anyway. Biological valves are less durable than mechanical valves and may degenerate 7 or more years after implantation, particularly when used in the mitral position. They are more durable in the aortic position and in older patients, so are particularly appropriate for patients over 65 undergoing aortic valve replacement. Transcatheter aortic valve implantation For patients being considered for aortic valve surgery, especially due to aortic stenosis, transcatheter aortic valve implantation (TAVI) is an emerging alternative to surgical aortic valve replacement. The native valve is not removed but is compressed by the new bioprosthetic valve, which is implanted within it. The bioprosthetic valve is mounted on a large stent-like structure and is implanted through a catheter inserted in the femoral artery (Fig. 16.88). TAVI has several major advantages. It avoids the need for a sternotomy, is associated with a short recovery period, can be used in high-risk and otherwise inoperable patients, and is much better tolerated by elderly patients. Complications include stroke (2%) and heart block necessitating pacemaker implantation (5–15%). Prosthetic valve dysfunction Symptoms or signs of unexplained heart failure in a patient with a prosthetic heart valve may be due to valve dysfunction, and urgent assessment is required. Metallic valves can suffer strut fracture and fail, causing catastrophic regurgitation. Alternatively, they may thrombose and cause systemic thromboembolism or valve obstruction, especially in the presence of inadequate anticoagulation. Biological valve dysfunction is usually associated with the development of a regurgitant murmur and may begin to develop 8–10 years after implantation. Fig. 16.88 Transcatheter aortic valve implantation (TAVI): bioprosthetic valve. 16.93 Endocarditis in old age • Symptoms and signs: may be non-specific, with delirium, weight loss, malaise and weakness, and the diagnosis may not be suspected. • Common causative organisms: often enterococci (from the urinary tract) and Streptococcus gallolyticus subsp. gallolyticus (from a colonic source). • Morbidity and mortality: much higher.

528 • CARDIOLOGY aphrophilus – now known as Aggregatibacter aphrophilus– Aggregatibacter actinomycetemcomitans; Cardiobacterium hominis; Eikenella corrodens; and Kingella kingae). These are slow-growing, fastidious Gram-negative organisms that are oropharyngeal commensals. The diagnosis may be revealed only after prolonged culture and the organisms may be resistant to penicillin. Brucella endocarditis is associated with a history of contact with goats or cattle and often affects the aortic valve. Yeasts and fungi, such as Candida and Aspergillus, may attack previously normal or prosthetic valves, particularly in immunocompromised patients or those with in-dwelling intravenous catheters. Abscesses and emboli are common, therapy is difficult, surgery is often required and mortality is high. Concomitant bacterial infection may be present. Clinical features Endocarditis can take either an acute or a more insidious ‘subacute’ form. There is considerable overlap, however, because the clinical pattern is influenced not only by the organism but also by the site of infection, prior antibiotic therapy and the presence of a valve or shunt prosthesis. The subacute form may abruptly develop acute life-threatening complications, such as valve disruption or emboli. The Duke criteria for diagnosis of infective endocarditis are shown in Box 16.95. Subacute endocarditis This should be suspected when a patient with congenital or valvular heart disease develops a persistent fever, complains of unusual tiredness, night sweats or weight loss, or develops new signs of valve dysfunction or heart failure. Less often, it presents as an embolic stroke or peripheral arterial embolism. Other features (Fig. 16.89) include purpura and petechial haemorrhages in the skin and mucous membranes, and splinter haemorrhages under the fingernails or toenails. Osler’s nodes are painful, tender swellings at the fingertips that are probably the product of vasculitis; they are rare. Digital clubbing is a late sign. The spleen is frequently palpable; in Coxiella infections, the spleen and the Microbiology Over three-quarters of cases are caused by streptococci or staphylococci. Viridans streptococci, such as Streptococcus mitis and Strep. sanguis, which are commensals in the oral cavity, can enter the blood stream on chewing or tooth-brushing, or at the time of dental treatment, and are common causes of subacute endocarditis (Box 16.94). Other organisms, including Enterococcus faecalis, E. faecium and Strep. gallolyticus subsp. gallolyticus (previously known as Strep. bovis), may enter the blood from the bowel or urinary tract. Patients who are found to have endocarditis caused by Strep. gallolyticus should undergo colonoscopy, since this organism is associated with large-bowel malignancy. Staph. aureus has now overtaken streptococci as the most common cause of acute endocarditis. It originates from skin infections, abscesses or vascular access sites such as intravenous and central lines, or from intravenous drug use. It is highly virulent and invasive, usually producing florid vegetations, rapid valve destruction and abscess formation. Other causes of acute endocarditis include Strep. pneumoniae and Strep. pyogenes. Post-operative endocarditis after cardiac surgery may affect native or prosthetic heart valves or other prosthetic materials. The most common organisms are coagulase-negative staphylococci such as Staph. epidermidis, which are part of the normal skin flora. There is frequently a history of wound infection with the same organism. Coagulase-negative staphylococci cause native valve endocarditis in approximately 5% of cases and this possibility should always be considered before they are dismissed as blood culture contaminants. Another coagulasenegative staphylococcus, Staph. lugdenensis, causes a rapidly destructive acute endocarditis that is associated with previously normal valves and multiple emboli. Unless accurately identified, it may also be overlooked as a contaminant. In Q fever endocarditis due to Coxiella burnetii, the patient often has a history of contact with farm animals. The aortic valve is usually affected and there may also be hepatitis, pneumonia and purpura. Life-long antibiotic therapy may be required. In about 3–4% of cases, endocarditis may be caused by Gramnegative bacteria of the so-called HACEK group (Haemophilus 16.94 Microbiology of infective endocarditis Pathogen Of native valve (n = 280) In injection drug users (n = 87) Of prosthetic valve Early (n = 15) Late (n = 72) Staphylococci 124 (44%) 60 (69%) 10 (67%) 33 (46%) Staph. aureus 106 (38%) 60 (69%) 3 (20%) 15 (21%) Coagulase-negative 18 (6%)

7 (47%) 18 (25%) Streptococci 86 (31%) 7 (8%)

25 (35%) Oral 59 (21%) 3 (3%)

19 (26%) Others (non-enterococcal) 27 (10%) 4 (5%)

6 (8%) Enterococcus spp. 21 (8%) 2 (2%) 1 (7%) 5 (7%) HACEK 12 (4%)

1 (1%) Polymicrobial 6 (2%) 8 (9%)

1 (1%) Other bacteria 12 (4%) 4 (5%)

2 (3%) Fungi 3 (1%) 2 (2%)

Negative blood culture 16 (6%) 4 (5%) 4 (27%) 5 (7%) (HACEK = Haemophilus aphrophilus – now known as Aggregatibacter aphrophilus–Aggregatibacter actinomycetemcomitans; Cardiobacterium hominis; Eikenella corrodens; and Kingella kingae) Adapted from Moreillon P, Que YA. Infective endocarditis. Lancet 2004; 363:139–149.

Diseases of the heart valves • 529

16.95 Diagnosis of infective endocarditis* Major criteria Positive blood culture • Typical organism from two cultures • Persistent positive blood cultures taken > 12 hrs apart • Three or more positive cultures taken over > 1 hr Endocardial involvement • Positive echocardiographic findings of vegetations • New valvular regurgitation Minor criteria • Predisposing valvular or cardiac abnormality • Intravenous drug misuse • Pyrexia ≥ 38°C • Embolic phenomenon • Vasculitic phenomenon • Blood cultures suggestive: organism grown but not achieving major criteria • Suggestive echocardiographic findings *Modified Duke criteria. Patients with two major, or one major and three minor, or five minor have definite endocarditis. Patients with one major and one minor, or three minor have possible endocarditis. liver may be considerably enlarged. Non-visible haematuria is common. The finding of any of these features in a patient with persistent fever or malaise is an indication for re-examination to detect hitherto unrecognised heart disease. Acute endocarditis This presents as a severe febrile illness with prominent and changing heart murmurs and petechiae. Clinical stigmata of chronic endocarditis are usually absent. Embolic events are common, and cardiac or renal failure may develop rapidly. Abscesses may be detected on echocardiography. Partially treated acute endocarditis behaves like subacute endocarditis. Post-operative endocarditis This may present as an unexplained fever in a patient who has had heart valve surgery. The infection usually involves the valve ring and may resemble subacute or acute endocarditis, depending on the virulence of the organism. Morbidity and mortality are high and revision surgery is often required. The range of organisms is similar to that seen in native valve disease, but when endocarditis occurs during the first few weeks after surgery it is usually due to infection with a coagulase-negative staphylococcus that was introduced during the perioperative period. Fig. 16.89 Clinical features that may be present in endocarditis. Insets (Petechial rash, nail-fold infarct) From Newby D, Grubb N. Cardiology: an illustrated colour text. Edinburgh: Churchill Livingstone, Elsevier Ltd; 2005. Osler's nodes (5%) Petechial rash (40–50%, may be transient) Haematuria (60–70%) Loss of pulses Subconjunctival haemorrhages (2–5%) Poor dentition Systemic emboli (7%) Nail-fold infarct Petechial haemorrhages on mucous membranes and fundi (20–30%) 'Varying' murmurs (90% new or changed murmur) Conduction disorder (10–20%) Cardiac failure (40–50%) Cerebral emboli (15%) Roth's spots in fundi (rare, < 5%) Splenomegaly (30–40%, long-standing endocarditis only) Digital clubbing (10%, long-standing endocarditis only) Splinter haemorrhages (10%)

530 • CARDIOLOGY 16.96 Antimicrobial treatment of common causative organisms in infective endocarditis Antimicrobial susceptibility Antimicrobial Dose Duration Native valve Prosthetic valve Streptococci Penicillin MIC ≤ 0.125 mg/L Benzylpenicillin IV 1.2 g 6 times daily 4 weeks1 6 weeks Penicillin MIC > 0.125, ≤ 0.5 mg/L Benzylpenicillin IV and gentamicin IV 2.4 g 6 times daily 1 mg/kg twice daily2 4 weeks 6 weeks 2 weeks 2 weeks Penicillin MIC > 0.5 mg/L Vancomycin IV and gentamicin IV 1 g twice daily3 1 mg/kg twice daily2 4 weeks 6 weeks 4 weeks 6 weeks Enterococci Amoxicillin MIC ≤ 4 mg/L and gentamicin MIC ≤ 128 mg/L Amoxicillin IV and gentamicin IV2 2 g 6 times daily 1 mg/kg twice daily2 4 weeks 6 weeks 4 weeks 6 weeks Amoxicillin MIC > 4 mg/L and gentamicin MIC ≤ 128 mg/L Vancomycin IV and gentamicin IV2 1 g twice daily3 1 mg/kg twice daily2 4 weeks 6 weeks 4 weeks 6 weeks Staphylococci – native valve Meticillin-sensitive Flucloxacillin IV 2 g 4–6 times daily4 4 weeks – Meticillin-resistant, vancomycin MIC ≤ 2 mg/L, rifampicin-sensitive Vancomycin IV 1 g twice daily3 4 weeks – Rifampicin orally 300–600 mg twice daily 4 weeks – Staphylococci – prosthetic valve Meticillin-sensitive Flucloxacillin IV 2 g 4–6 times daily – 6 weeks and gentamicin IV 1 mg/kg twice daily2 – 6 weeks and rifampicin orally 300–600 mg twice daily – 6 weeks Meticillin-resistant, vancomycin MIC ≤ 2 mg/L, rifampicin-sensitive Vancomycin IV 1 g twice daily3 – 6 weeks and rifampicin orally 300–600 mg twice daily – 6 weeks 1When conditions in Box 16.97 are met, 2 weeks of benzylpenicillin and gentamicin (1 mg/kg twice daily) may be sufficient. Ceftriaxone 2 g once daily IV/IM can be used instead of benzylpenicillin for those with non-severe penicillin allergy. 2Pre-dose gentamicin level should be ≤ 1 mg/L, post-dose 3–5 mg/L. Adjust dose according to levels and renal function. 3Pre-dose vancomycin level should be 15–20 mg/L. Adjust dose according to levels and renal function. 4Use 6 times daily if weight > 85 kg. (IV = intravenous; MIC = minimum inhibitory concentration) Adapted from Gould FK, Denning DW, Elliott TS, et al. Guidelines for the diagnosis and antibiotic treatment of endocarditis in adults: a report of the working party of the British Society for Antimicrobial Chemotherapy. J Antimicrob Chemother 2012; 67:269–289. Investigations Blood culture (see Fig. 6.6, p. 107) is the pivotal investigation to identify the organism that is the cause of the infection and to guide antibiotic therapy. Three to six sets of blood cultures should be taken prior to commencing therapy and should not wait for episodes of pyrexia. The first two specimens will detect bacteraemia in 90% of culture-positive cases. A meticulous aseptic technique is essential. Taking discrete sets of blood cultures from peripheral sites at intervals of ≥ 6 hours reduces the risk of misdiagnosis due to contamination with skin commensals. Isolation of a typical organism in more than one culture provides strong evidence in favour of the diagnosis (Box 16.95). An in-dwelling line should not be used to take cultures. Both aerobic and anaerobic cultures are required. Echocardiography is key for detecting and following the progress of vegetations, for assessing valve damage and for detecting abscess formation. Vegetations as small as 2–4 mm can be detected by transthoracic echocardiography, and even smaller ones (1–1.5 mm) can be visualised by trans-oesophageal echocardiography (TOE), which is particularly valuable for identifying abscess formation and investigating patients with prosthetic heart valves. Vegetations may be difficult to distinguish in the presence of an abnormal valve; the sensitivity of transthoracic echo is approximately 65% but that of TOE is more than 90%. Failure to detect vegetations does not exclude the diagnosis. Elevation of the ESR, a normocytic normochromic anaemia, and leucocytosis are common but not invariable. Measurement of serum CRP is more reliable than the ESR in monitoring progress. Proteinuria may occur and non-visible haematuria is usually present. The ECG may show the development of AV block (due to aortic root abscess formation) and occasionally infarction due to emboli. The chest X-ray may show evidence of cardiac failure and cardiomegaly. Management A multidisciplinary approach, with cooperation between the physician, surgeon and microbiologist, increases the chance of a successful outcome. Any source of infection should be removed as soon as possible; for example, a tooth with an apical abscess should be extracted. Empirical treatment depends on the mode of presentation, the suspected organism and the presence of a prosthetic valve or penicillin allergy. If the presentation is subacute, antibiotic treatment should ideally be withheld until the results of blood cultures are available. However, if empirical antibiotic treatment is considered necessary, amoxicillin (2 g 6 times daily IV) should be considered (with or without gentamicin). If the presentation is acute, empirical therapy should be started with vancomycin (1 g twice daily IV) and gentamicin (1 mg/kg twice daily IV), with dose adjustment based on antibiotic levels. The same regimen is used in true penicillin allergy. Patients with suspected prosthetic valve endocarditis should be treated with vancomycin and gentamicin at the above-mentioned doses, plus rifampicin orally in a dose of 300–600 mg twice daily. Following identification of the causal organism, determination of the minimum inhibitory concentration (MIC) for the organism helps guide antibiotic therapy. Recommended regimens for some of the most common scenarios are shown in Box 16.96. More detailed information

Congenital heart disease • 531

16.100 Presentation of congenital heart disease throughout life Birth and neonatal period • Cyanosis • Heart failure Infancy and childhood • Cyanosis • Heart failure • Arrhythmia • Murmur • Failure to thrive Adolescence and adulthood • Heart failure • Murmur • Arrhythmia • Eisenmenger’s syndrome • Hypertension (coarctation) • Complications of previous cardiac surgery: Arrhythmia related to scarring Heart failure secondary to scarring can be found in the 2012 British Society for Antimicrobial Chemotherapy guidelines (see ‘Further reading’). A 2-week treatment regimen may be sufficient for fully sensitive strains of streptococci, provided specific conditions are met (Box 16.97). Cardiac surgery with débridement of infected material and valve replacement may be required in a substantial proportion of patients, particularly those with Staph. aureus and fungal infections (Box 16.98). Antimicrobial therapy must be started before surgery. Prevention Until recently, antibiotic prophylaxis was routinely given to people at risk of infective endocarditis undergoing interventional procedures. However, as this has not been proven to be effective and the link between episodes of infective endocarditis and interventional procedures has not been demonstrated, antibiotic prophylaxis is no longer offered routinely. Congenital heart disease Congenital heart disease can be the result of defects in the formation of the heart or great vessels or can arise because the anatomical changes that occur during transition between the fetus and the newborn child fail to proceed normally. Congenital heart disease usually presents in childhood but some patients do not present until adult life. It has been estimated that the incidence of haemodynamically significant congenital cardiac abnormalities is about 0.8% of live births (Box 16.99). Defects that are well tolerated, such as atrial septal defect, may cause no symptoms until adult life or may be detected incidentally on routine examination or chest X-ray. Congenital defects that were previously fatal in childhood can now be corrected, or at least partially, so that survival to adult life is the norm. Such patients remain well for many years but subsequently re-present in later life with related problems such as arrhythmia or heart failure (Box 16.100). Pathophysiology Understanding the fetal circulation helps clarify how some forms of congenital heart disease occur. Figure 16.90 shows the fetal circulation and the changes that normally occur immediately after birth. In the fetus there is little blood flow through the lungs, which are collapsed because they are not required for gas exchange. Instead, oxygenated blood from the placenta passes directly from the right atrium to the left side of the heart through the foramen ovale without having to flow through the lungs, and also from the pulmonary artery into the aorta via the ductus arteriosus. During early embryonic life, the heart develops as a single tube that folds back on itself and then divides into two separate circulations. Failure of septation can cause some forms of atrial and ventricular septal defect, whereas failure of alignment of the great vessels with the ventricles contributes to transposition of the great arteries, tetralogy of Fallot and truncus arteriosus. Atrial septal defects occur because the foramen ovale fails to close at birth, as is normal. Similarly, a persistent ductus arteriosus will remain persistent if it fails to close after birth. Failure of the aorta to develop at the point of the aortic isthmus and where the ductus arteriosus attaches can lead to coarctation of the aorta. Maternal infection and exposure to drugs or toxins are important causes of congenital heart disease. Maternal rubella infection is associated with persistent ductus arteriosus, pulmonary valvular 16.97 Conditions for the short-course treatment of endocarditis caused by fully sensitive streptococci • Native valve infection • Minimum inhibitory concentration (MIC) ≤ 0.125 mg/L • No adverse prognostic factors (heart failure, aortic regurgitation, conduction defect) • No evidence of thromboembolic disease • No vegetations > 5 mm diameter • Clinical response within 7 days 16.98 Indications for cardiac surgery in infective endocarditis* • Heart failure due to valve damage • Failure of antibiotic therapy (persistent/uncontrolled infection) • Large vegetations on left-sided heart valves with echo appearance suggesting high risk of emboli • Previous evidence of systemic emboli • Abscess formation *Patients with prosthetic valve endocarditis or fungal endocarditis often require cardiac surgery. 16.99 Incidence and relative frequency of congenital cardiac malformations Lesion % of all congenital heart defects Ventricular septal defect

Atrial septal defect

Persistent ductus arteriosus

Pulmonary stenosis

Coarctation of aorta

Aortic stenosis

Tetralogy of Fallot

Complete transposition of great arteries

Others

532 • CARDIOLOGY Fig. 16.90 Changes in the circulation at birth. A In the fetus, oxygenated blood comes through the umbilical vein where it enters the inferior vena cava (IVC) via the ductus venosus (red). The oxygenated blood streams from the right atrium (RA) through the open foramen ovale to the left atrium (LA) and via the left ventricle (LV) into the aorta. Venous blood from the superior vena cava (SVC, blue) crosses under the main blood stream into the RA and then, partly mixed with oxygenated blood (purple), into the right ventricle (RV) and pulmonary artery (PA). The pulmonary vasculature has a high resistance and so little blood passes to the lungs; most blood passes through the ductus arteriosus to the descending aorta. The aortic isthmus is a constriction in the aorta that lies in the aortic arch before the junction with the ductus arteriosus and limits the flow of oxygen-rich blood to the descending aorta. This configuration means that less oxygen-rich blood is supplied to organ systems that take up their function mainly after birth, e.g. the kidneys and intestinal tract. B At birth, the lungs expand with air and pulmonary vascular resistance falls, so that blood now flows to the lungs and back to the LA. The left atrial pressure rises above right atrial pressure and the flap valve of the foramen ovale closes. The umbilical arteries and the ductus venosus close. In the next few days, the ductus arteriosus closes under the influence of hormonal changes (particularly prostaglandins) and the aortic isthmus expands. (PV = pulmonary vein) Adapted from Drews U. Colour atlas of embryology. Stuttgart: Georg Thieme; 1995. Ascending aorta LA SVC Open foramen ovale RA IVC Ductus venosus Umbilical vein Umbilical arteries RV Head and neck vessels Aortic isthmus Ductus arteriosus Main pulmonary artery Descending aorta LV Renal artery Iliac artery Umbilical arteries close Intestinal arteries Involution of isthmus Ductus venosus closes Closed ductus arteriosus PA PV Closed foramen ovale A B and/or artery stenosis, and atrial septal defect. Maternal alcohol misuse is associated with septal defects, and maternal lupus erythematosus with congenital complete heart block. Genetic or chromosomal abnormalities, such as Down’s syndrome, may cause septal defects, and gene defects have also been identified as leading to specific abnormalities, such as Marfan’s syndrome (p. 508) and DiGeorge’s syndrome (deletion in chromosome 22q). Clinical features Symptoms may be absent, or the child may be breathless or fail to attain normal growth and development. Some defects are not compatible with extrauterine life and lead to neonatal death. Clinical signs vary with the anatomical lesion. Murmurs, thrills or signs of cardiomegaly may be present. In coarctation of the aorta, radio-femoral delay may be noted (Fig. 16.91) and some female patients have the features of Turner’s syndrome (p. 659). Features of other congenital conditions, such as Marfan’s syndrome or Down’s syndrome, may also be apparent. Cerebrovascular events and cerebral abscesses may complicate severe cyanotic congenital disease. Early diagnosis is important because many types of congenital heart disease are amenable to surgery, but this opportunity is lost if secondary changes, such as irreversible pulmonary hypertension, occur. Fig. 16.91 Radio-femoral delay. The difference in pulse pressures is shown. Radial Femoral Central cyanosis and digital clubbing Central cyanosis of cardiac origin occurs when desaturated blood enters the systemic circulation without passing through the lungs (right-to-left shunting). In the neonate, the most common cause is transposition of the great arteries, in which the aorta arises from the RV and the pulmonary artery from the LV in association with a ventricular septal defect. In older children, cyanosis is usually the consequence of a ventricular septal defect combined with severe pulmonary stenosis (as in tetralogy of Fallot) or with pulmonary vascular disease (Eisenmenger’s syndrome). Prolonged cyanosis is associated with finger and toe clubbing (p. 442).

Congenital heart disease • 533

Persistent ductus arteriosus Normally, the ductus arteriosus closes soon after birth but in this anomaly it fails to do so. Persistence of the ductus is often associated with other abnormalities and is more common in females. Pathophysiology During fetal life, before the lungs begin to function, most of the blood from the pulmonary artery passes through the ductus arteriosus into the aorta (see Fig. 16.90). Persistence of the ductus causes a continuous AV shunt from the aorta to the pulmonary artery since pressure in the aorta is higher than that in the pulmonary circulation. The volume of the shunt depends on the size of the ductus but as much as 50% of the left ventricular output may be recirculated through the lungs, with a consequent increase in the work of the heart (Fig. 16.92). A large left-to-right shunt in infancy may cause a considerable rise in pulmonary artery pressure and sometimes this leads to progressive pulmonary vascular damage. Clinical features With small shunts there may be no symptoms for years, but when the ductus is large, growth and development may be retarded. Usually, there is no disability in infancy but cardiac failure may eventually ensue, dyspnoea being the first symptom. A continuous ‘machinery’ murmur is heard with late systolic accentuation, maximal in the second left intercostal space below the clavicle (Fig. 16.92). It is frequently accompanied by a thrill. Pulses are increased in volume. Enlargement of the pulmonary artery may be detected radiologically. The ECG is usually normal. If pulmonary vascular resistance increases, pulmonary artery pressure may rise until it equals or exceeds aortic pressure. The shunt through the defect Growth retardation and learning difficulties These may occur with large left-to-right shunts at ventricular or great arterial level, and also with other defects, especially if they form part of a genetic syndrome. Major intellectual impairment is uncommon in children with isolated congenital heart disease; minor learning difficulties can occur, however. Cerebral function can also be affected after cardiac surgery if cerebral perfusion is compromised. Syncope In the presence of increased pulmonary vascular resistance or severe left or right ventricular outflow obstruction, exercise may provoke syncope as systemic vascular resistance falls but pulmonary vascular resistance rises, worsening right-to-left shunting and cerebral oxygenation. Syncope can also occur because of associated arrhythmias. Pulmonary hypertension Persistently raised pulmonary flow with a left-to-right shunt causes increased pulmonary vascular resistance followed by pulmonary hypertension. Progressive changes, including obliteration of distal arterioles, take place and are irreversible. At this stage, central cyanosis occurs and digital clubbing develops. The chest X-ray shows enlarged central pulmonary arteries and peripheral ‘pruning’ of the pulmonary vessels. The ECG shows features of right ventricular hypertrophy. Eisenmenger’s syndrome In patients with severe and prolonged pulmonary hypertension the left-to-right shunt may reverse, resulting in right-to-left shunt and marked cyanosis. This is termed Eisenmenger’s syndrome. The cyanosis in Eisenmenger’s syndrome may be more apparent in the feet and toes than in the upper part of the body, resulting in so-called differential cyanosis. Eisenmenger’s syndrome is more common with large ventricular septal defects or persistent ductus arteriosus than with atrial septal defects. Patients with Eisenmenger’s syndrome are at particular risk from abrupt changes in afterload that exacerbate right-to-left shunting, such as vasodilatation, anaesthesia and pregnancy. Congenital heart disease in pregnancy During pregnancy, there is a 50% increase in plasma volume, a 40% increase in whole blood volume and a similar increase in cardiac output, so problems may arise in women with congenital heart disease (Box 16.101). Many with palliated or untreated disease will tolerate pregnancy well, however. Pregnancy is particularly hazardous in the presence of conditions associated with cyanosis or severe pulmonary hypertension; maternal mortality in patients with Eisenmenger’s syndrome is more than 50%. 16.101 Pregnancy in women with congenital heart disease • Obstructive lesions: poorly tolerated and associated with significant maternal morbidity and mortality. • Cyanotic conditions: especially poorly tolerated. Specialised pre-conception counselling should explain the increased risks. • Surgically corrected disease: patients often tolerate pregnancy well. • Children of patients with congenital heart disease: 2–5% will be born with cardiac abnormalities, especially if the mother is affected. The risk may be up to 20% in babies born of women with left-sided lesions. Fig. 16.92 Persistent ductus arteriosus. There is a connection between the aorta and the pulmonary artery with left-to-right shunting. (LA = left atrium; LV = left ventricle; PA = pulmonary artery; RA = right atrium; RV = right ventricle) RA RV LV (dilated) LA (dilated) Ductus arteriosus PA (dilated) Aorta

534 • CARDIOLOGY Management In untreated cases, death may occur from left ventricular failure, dissection of the aorta or cerebral haemorrhage. Surgical correction is advisable in all but the mildest cases. If this is carried out sufficiently early in childhood, persistent hypertension can be avoided. Patients repaired in late childhood or adult life often remain hypertensive or develop recurrent hypertension later on. Recurrence of stenosis may occur as the child grows and this may be managed by balloon dilatation and sometimes stenting. The latter may be used as the primary treatment. Coexistent bicuspid aortic valve, which occurs in over 50% of cases, may lead to progressive aortic stenosis or regurgitation, and also requires long-term follow-up. Atrial septal defect Atrial septal defect is one of the most common congenital heart defects and occurs twice as frequently in females. Most are ‘ostium secundum’ defects, involving the fossa ovalis that, in utero, was the foramen ovale (see Fig. 16.90). ‘Ostium primum’ defects result from a defect in the atrioventricular septum and are associated with a ‘cleft mitral valve’ (split anterior leaflet). Pathogenesis Since the normal RV is more compliant than the LV, a patent foramen ovale is associated with shunting of blood from the LA to the RA, and then to the RV and pulmonary arteries (Fig. 16.94). As a result, there is gradual enlargement of the right side of the heart and of the pulmonary arteries. Pulmonary hypertension and shunt reversal sometimes complicate atrial septal defect, but are less common and tend to occur later in life than with other types of left-to-right shunt. Clinical features Most children are asymptomatic for many years and the condition is often detected at routine clinical examination or following a chest X-ray. Symptoms that can occur include dyspnoea, chest infections, may then reverse, causing Eisenmenger’s syndrome. The murmur becomes quieter, may be confined to systole or may disappear. Investigations Echocardiography is the investigation of choice although the persistent ductus requires specific echocardiographic views, such as from the suprasternal notch, to reveal it. The ECG shows evidence of right ventricular hypertrophy Management A persistent ductus can be closed at cardiac catheterisation with an implantable occlusive device. Closure should be undertaken in infancy if the shunt is significant and pulmonary resistance not elevated, but this may be delayed until later childhood in those with smaller shunts, for whom closure remains advisable to reduce the risk of endocarditis. When the ductus is structurally intact, a prostaglandin synthetase inhibitor (indometacin or ibuprofen) may be used in the first week of life to induce closure. However, in the presence of a congenital defect with impaired lung perfusion, such as occurs in severe pulmonary stenosis and left-to-right shunt through the ductus, it may be advisable to improve oxygenation by keeping the ductus open with prostaglandin treatment. Unfortunately, these treatments do not work if the ductus is intrinsically abnormal. Coarctation of the aorta This condition is twice as common in males and occurs in 1 in 4000 children. It is associated with other abnormalities, most frequently bicuspid aortic valve and ‘berry’ aneurysms of the cerebral circulation (p. 1160). Acquired coarctation of the aorta is rare but may follow trauma or occur as a complication of a progressive arteritis (Takayasu’s disease, p. 1041). Pathogenesis Narrowing of the aorta occurs in the region where the ductus arteriosus joins the aorta, at the isthmus just below the origin of the left subclavian artery (see Fig. 16.90). This causes raised BP affecting vessels of the head and neck proximal to the coarctation, and reduced BP and impaired circulation distally. Clinical features Aortic coarctation is an important cause of cardiac failure in the newborn but symptoms are often absent in older children or adults. Headaches may occur from hypertension proximal to the coarctation, and occasionally weakness or cramps in the legs may result from decreased circulation in the lower part of the body. The BP is raised in the upper body but normal or low in the legs. The femoral pulses are weak and delayed in comparison with the radial pulse (see Fig. 16.91). A systolic murmur is usually heard posteriorly, over the coarctation. There may also be an ejection click and systolic murmur in the aortic area due to a bicuspid aortic valve. As a result of the aortic narrowing, collaterals form; they mainly involve the periscapular, internal mammary and intercostal arteries, and may result in localised bruits. Investigations Imaging by MRI is the investigation of choice (Fig. 16.93). The chest X-ray in early childhood is often normal but later may show changes in the contour of the aorta (indentation of the descending aorta, ‘3 sign’) and notching of the under-surfaces of the ribs from collaterals. The ECG may show evidence of left ventricular hypertrophy, which can be confirmed by echocardiography. Fig. 16.93 MRI scan of coarctation of the aorta. The aorta is severely narrowed just beyond the arch at the start of the descending aorta (arrow A). Extensive collaterals have developed; a large internal mammary artery (arrow B) and several intercostal arteries (arrows C) are shown. Unusually, in this case, there is also a coarctation of the abdominal aorta (arrow D). A B C D

Congenital heart disease • 535

Severe pulmonary hypertension and shunt reversal are both contraindications to surgery. Ventricular septal defect Ventricular septal defect is the most common congenital cardiac defect, occurring once in 500 live births. The defect may be isolated or part of complex congenital heart disease. Pathogenesis Congenital ventricular septal defect occurs as a result of incomplete septation of the ventricles. Embryologically, the interventricular septum has a membranous and a muscular portion, and the latter is further divided into inflow, trabecular and outflow portions. Most congenital defects are ‘perimembranous’, occurring at the junction of the membranous and muscular portions of the septum. Clinical features Flow from the high-pressure LV to the low-pressure RV during systole produces a pansystolic murmur, usually heard best at the left sternal edge but radiating all over the precordium (Fig. 16.97). A small defect often produces a loud murmur (maladie de Roger) in the absence of other haemodynamic disturbance. Conversely, a large defect produces a softer murmur, cardiac failure and arrhythmias, especially AF. The characteristic physical signs are the result of the volume overload of the RV: • wide, fixed splitting of the second heart sound: wide because of delay in right ventricular ejection (increased stroke volume and RBBB), and fixed because the septal defect equalises left and right atrial pressures throughout the respiratory cycle • a systolic flow murmur over the pulmonary valve. In children with a large shunt, there may be a diastolic flow murmur over the tricuspid valve. Unlike a mitral flow murmur, this is usually high-pitched. Investigations Echocardiography is diagnostic. It directly demonstrates the defect and typically shows right ventricular dilatation, right ventricular hypertrophy and pulmonary artery dilatation. The precise size and location of the defect are best defined by TOE (Fig. 16.95). The chest X-ray typically shows enlargement of the heart and the pulmonary artery, as well as pulmonary plethora. The ECG usually demonstrates incomplete RBBB because right ventricular depolarisation is delayed as a result of ventricular dilatation (with a ‘primum’ defect, there is also left axis deviation). Management Atrial septal defects in which pulmonary flow is increased 50% above systemic flow (i.e. a flow ratio of 1.5 : 1) are often large enough to be clinically recognisable and should be closed surgically. (Smaller defects may be managed conservatively and patients are monitored with echocardiography.) Closure can also be accomplished at cardiac catheterisation using implantable closure devices (Fig. 16.96). The long-term prognosis thereafter is excellent, unless pulmonary hypertension has developed. Fig. 16.94 Atrial septal defect. Blood flows across the atrial septum (arrow) from left to right. The murmur is produced by increased flow velocity across the pulmonary valve, as a result of left-to-right shunting and a large stroke volume. The density of shading is proportional to velocity of blood flow. (LV = left ventricle; PA = pulmonary artery; RA = right atrium; RV = right ventricle) PA (dilated) RV (dilated) LV RA Aorta Fig. 16.95 Transoesophageal echocardiogram of an atrial septal defect. The defect is clearly seen (arrow) between the left atrium above and right atrium below. Doppler colour-flow imaging shows flow (blue) across the defect. Fig. 16.96 Percutaneous closure of atrial septal defect. The closure device is delivered across the interatrial septum and a disc deployed on either side to seal the defect. (IVC = inferior vena cava; LV = left ventricle; PA = pulmonary artery; RA = right atrium; RV = right ventricle) LV RV RA Percutaneous sheath across atrial septal defect IVC

536 • CARDIOLOGY syndrome, in which case heart–lung transplantation is the only effective treatment. The long-term prognosis is generally very good. An exception is in Eisenmenger’s syndrome, when death normally occurs in the second or third decade of life, but a few individuals survive to the fifth decade without transplantation. Tetralogy of Fallot This is complex defect consisting of right ventricular outflow tract obstruction and right ventricular hypertrophy, a large ventricular septal defect and an over-riding aorta that, when combined with the septal defect, allows blood to be pumped directly from the RV into the aorta. It occurs in about 1 in 2000 births and is the most common cause of cyanosis in infancy after the first year of life. Pathogenesis Tetralogy of Fallot occurs as the result of abnormal development of the bulbar septum that separates the ascending aorta from the pulmonary artery, and which normally aligns and fuses with the outflow part of the interventricular septum. The right ventricular outflow obstruction is most often subvalvular (infundibular) but may be valvular, supravalvular or a combination of these (Fig. 16.98). The subvalvular component of the right ventricular outflow obstruction is dynamic and may increase suddenly under adrenergic stimulation. The ventricular septal defect is usually large and similar in aperture to the aortic orifice. The combination results in elevated right ventricular pressure and right-to-left shunting of cyanotic blood across the ventricular septal defect into the aorta. particularly if pressure in the RV is elevated. This may be found immediately after birth, while pulmonary vascular resistance remains high, or when the shunt is reversed in Eisenmenger’s syndrome. Congenital ventricular septal defect may present as cardiac failure in infants, as a murmur with only minor haemodynamic disturbance in older children or adults, or, rarely, as Eisenmenger’s syndrome. In a proportion of infants, the murmur becomes quieter or disappears due to spontaneous closure of the defect. If cardiac failure complicates a large defect, it is usually absent in the immediate postnatal period and becomes apparent only in the first 4–6 weeks of life. In addition to the murmur, there is prominent parasternal pulsation, tachypnoea and indrawing of the lower ribs on inspiration. Investigations Doppler echocardiography should be performed since it helps to identify the small septal defects that are not haemodynamically significant and are likely to close spontaneously. Patients with larger defects should be monitored by serial ECG and echocardiography to screen for signs of pulmonary hypertension. With larger defects, the chest X-ray shows pulmonary congestion and the ECG shows bilateral ventricular hypertrophy. Management Small ventricular septal defects require no specific treatment. If there is cardiac failure in infancy, this should initially be treated medically with digoxin and diuretics. Persisting failure is an indication for surgical repair of the defect. Percutaneous closure devices are under development. If serial ECG and echocardiography suggest that pulmonary hypertension is developing, surgical repair should be performed. Surgical closure is contraindicated in fully developed Eisenmenger’s Fig. 16.97 Ventricular septal defect. In this example, a large left-to-right shunt (arrows) has resulted in chamber enlargement. (LA = left atrium; LV = left ventricle; PA = pulmonary artery; RA = right atrium) Aorta PA (dilated) LA (dilated) LV (dilated) RA Fig. 16.98 Tetralogy of Fallot. The tetralogy comprises (1) pulmonary stenosis, (2) overriding of the ventricular septal defect by the aorta, (3) a ventricular septal defect and (4) right ventricular hypertrophy. (LA = left atrium; LV = left ventricle; PA = pulmonary artery; RA = right atrium; RV = right ventricle) (4) Right ventricular hypertrophy (3) Ventricular septal defect (1) Pulmonary stenosis (valvular) (2) Overriding aorta Aorta RA PA LA LV RV Pulmonary stenosis (infundibular)

Congenital heart disease • 537

Clinical features Children are usually cyanosed but this may not be the case in the neonate because it is only when right ventricular pressure rises to equal or exceed left ventricular pressure that a large right-to-left shunt develops. The affected child may suddenly become increasingly cyanosed, often after feeding or a crying attack, and may become apnoeic and unconscious. These attacks are called ‘Fallot’s spells’. In older children, Fallot’s spells are uncommon but cyanosis becomes increasingly apparent, with stunting of growth, digital clubbing and polycythaemia. Some children characteristically obtain relief by squatting after exertion, which increases the afterload of the left heart and reduces the right-to-left shunting. This is called Fallot’s sign. The natural history before the development of surgical correction was variable but most patients died in infancy or childhood. On examination, the most characteristic feature is the combination of cyanosis with a loud ejection systolic murmur in the pulmonary area (as for pulmonary stenosis). Cyanosis may be absent in the newborn or in patients with only mild right ventricular outflow obstruction, however. This is called acyanotic tetralogy of Fallot. Investigations Echocardiography is diagnostic and demonstrates that the aorta is not continuous with the anterior ventricular septum. The ECG shows right ventricular hypertrophy and the chest X-ray shows an abnormally small pulmonary artery and a ‘boot-shaped’ heart. Management The definitive management is total correction of the defect by surgical relief of the pulmonary stenosis and closure of the ventricular septal defect. Primary surgical correction may be undertaken prior to the age of 5 years. If the pulmonary arteries are too hypoplastic, then palliation in the form of a Blalock–Taussig shunt may be performed, with an anastomosis created between the pulmonary artery and subclavian artery. This improves pulmonary blood flow and pulmonary artery development, and may facilitate later definitive correction. The prognosis after total correction is good, especially if the operation is performed in childhood. Follow-up is needed to identify residual shunting, recurrent pulmonary stenosis and arrhythmias. An implantable defibrillator is sometimes recommended in adulthood. Other causes of cyanotic congenital heart disease There are other causes of cyanotic congenital heart disease, as summarised in Box 16.102. Echocardiography is usually the definitive diagnostic procedure, supplemented, if necessary, by cardiac catheterisation. Adult congenital heart disease There are increasing numbers of children who have had surgical correction of congenital defects and who may have further problems as adults. The transition period between paediatric and adult care needs to be managed in a carefully planned manner, addressing many diverse aspects of care (Box 16.103). Those who have undergone correction of coarctation of the aorta may develop hypertension in adult life. Those with transposition of the great arteries who have had a ‘Mustard’ repair, in which 16.102 Other causes of cyanotic congenital heart disease Defect Features Tricuspid atresia Absent tricuspid orifice, hypoplastic RV, RA-to-LA shunt, ventricular septal defect shunt, other anomalies Surgical correction may be possible Transposition of the great vessels Aorta arises from the morphological RV, pulmonary artery from LV Shunt via atria, ductus and possibly ventricular septal defect Palliation by balloon atrial septostomy/ enlargement Surgical correction possible Pulmonary atresia Pulmonary valve atretic and pulmonary artery hypoplastic RA-to-LA shunt, pulmonary flow via ductus Palliation by balloon atrial septostomy Surgical correction may be possible Ebstein’s anomaly Tricuspid valve is dysplastic and displaced into RV, RV ‘atrialised’ Tricuspid regurgitation and RA-to-LA shunt Wide spectrum of severity Arrhythmias Surgical repair possible but significant risk (LA = left atrium; LV = left ventricle; RA = right atrium; RV = right ventricle) 16.103 Congenital heart disease in adolescence • Patients: a heterogeneous population with residual disease and sequelae that vary according to the underlying lesion and in severity; each patient must be assessed individually. • Management plan: should be agreed with the patient and include short- and long-term goals and timing of transition to adult care. • Risks of surgery: non-cardiac surgery for associated congenital abnormalities carries increased risks and needs to be planned, with careful pre-operative assessment. Risks include thrombosis, embolism from synthetic shunts or patches, and volume overload from fluid shifts. Operative approaches should address cosmetic concerns, such as site of implantation of abdominal generator. • Exercise: patients with mild or repaired defects can undertake moderately vigorous exercise but those with complex defects, cyanosis, ventricular dysfunction or arrhythmias require specialist evaluation and individualised advice regarding exercise. • Genetics: Between 10% and 15% have a genetic basis and this should be assessed to understand the impact it may have for the patient’s own future children. A family history, genetic evaluation of syndromic versus non-syndromic disorders and, sometimes, cytogenetics are required. • Education and employment: may be adversely affected and occupational activity levels need to be assessed. • End of life: some adolescents with complex disorders may misperceive and think they have been cured; transition to adult services may be the first time they receive information about mortality. Expectations on life expectancy need to be managed and adolescents are often willing to engage with this and play a role in decision-making. blood is redirected at atrial level leaving the RV connected to the aorta, may develop right ventricular failure in adult life. This is because the RV is unsuited for function at systemic pressures and may begin to dilate and fail when patients are in their twenties or thirties.

538 • CARDIOLOGY myocardium. Other drugs, including penicillins and sulphonamides, and poisons such as lead and carbon monoxide may cause a hypersensitivity reaction and associated myocarditis. Occasionally, autoimmune conditions, such as systemic lupus erythematosus and rheumatoid arthritis, are associated with myocarditis. Clinical features Myocarditis may present in one of four ways: • Fulminant myocarditis follows a viral prodrome or influenza-like illness and results in severe heart failure or cardiogenic shock. • Acute myocarditis presents over a longer period with heart failure; it can lead to dilated cardiomyopathy. • Chronic active myocarditis is rare and associated with chronic myocardial inflammation. • Chronic persistent myocarditis is characterised by focal myocardial infiltrates and can cause chest pain and arrhythmia without necessarily causing ventricular dysfunction. Myocarditis is self-limiting in most patients and the immediate prognosis is good. Death may, however, occur due to a ventricular arrhythmia or rapidly progressive heart failure. Myocarditis has been reported as a cause of sudden and unexpected death in young athletes. Some forms of myocarditis may lead to chronic low-grade myocarditis or dilated cardiomyopathy (see below). For example, in Chagas’ disease (p. 279), the patient frequently recovers from the acute infection but goes on to develop a chronic dilated cardiomyopathy 10 or 20 years later. Investigations The diagnosis of myocarditis is often made after other more common causes of cardiac dysfunction have been excluded. Echocardiography should be performed and may reveal left ventricular dysfunction that is sometimes regional (due to focal myocarditis). Cardiac MRI is also useful since it may show diagnostic patterns of myocardial inflammation or infiltration. The ECG is frequently abnormal but the changes are non-specific. Blood should be taken for analysis of troponin I and T, and creatine kinase. Levels may be elevated in the early phases. Occasionally, endomyocardial biopsy may be required to confirm the diagnosis. Management Treatment of myocarditis is primarily supportive. Treatment for cardiac failure or arrhythmias should be given and patients should be advised to avoid intense physical exertion because there is some evidence that this can induce potentially fatal ventricular arrhythmias. There is no evidence of benefit from treatment with glucocorticoids and immunosuppressive agents. Specific antimicrobial therapy may be used if a causative organism has been identified but this is rare. Patients who do not respond adequately to medical treatment may temporarily require circulatory support with a mechanical ventricular assist device. Rarely, cardiac transplantation may be required. Cardiomyopathy Cardiomyopathies are primary diseases of the myocardium, which are classified according to their effects on cardiac structure and function (Fig. 16.99). They can be inherited or be caused by infections or exposure to toxins. In some cases no cause is identified. 16.104 Some causes of myocarditis Infections Viral • Coxsackie • Adenovirus • Influenza A • Human immunodeficiency virus (HIV) • Influenza B Bacterial • Borrelia burgdorferi (Lyme disease) • Mycoplasma pneumoniae Protozoal • Trypanosoma cruzi (Chagas’ disease) • Toxoplasma gondii Fungal • Aspergillus Parasitic • Shistosoma Drugs/Toxins • Alcohol • Anthracyclines • Clozapine • Cocaine • Lithium Autoimmune • Systemic lupus erythematosus • Systemic sclerosis • Rheumatoid arthritis • Sarcoidosis • Hypersensitivity reaction to penicillins, sulphonamides, lead, carbon monoxide Those who have had surgery involving the atria may develop atrial arrhythmias, and those who have ventricular scars may develop ventricular arrhythmias and need consideration for placement of an ICD. Such patients require careful follow-up from the teenage years throughout adult life, so that problems can be identified early and appropriate medical or surgical treatment instituted. The management of patients with grown-up congenital heart disease (GUCH) is complex and has developed as a cardiological subspecialty. Diseases of the myocardium Although the myocardium is involved as the result of ischaemia in CAD and in valvular heart disease, this section focus on conditions that primarily affect the heart muscle. Myocarditis This is an acute inflammatory condition that can have an infectious, toxic or autoimmune aetiology (Box 16.104). Myocarditis can complicate many infections in which inflammation may be due directly to infection of the myocardium or the effects of circulating toxins. Viral infections are the most common causes, such as Coxsackie (35 cases per 1000 infections) and influenza A and B (25 cases per 1000 infections) viruses. Myocarditis may occur several weeks after the initial viral symptoms, and susceptibility is increased by glucocorticoid treatment, immunosuppression, radiation, previous myocardial damage and exercise. Some bacterial and protozoal infections may be complicated by myocarditis; for example, approximately 5% of patients with Lyme disease (Borrelia burgdorferi, p. 255) develop myopericarditis, which is often associated with AV block. Toxins such as alcohol and drugs such as cocaine, lithium and doxorubicin may directly injure the

Diseases of the myocardium • 539

sporadic chest pain is a surprisingly frequent symptom. The differential diagnosis includes ventricular dysfunction due to CAD, and a diagnosis of dilated cardiomyopathy should be made only when this has been excluded. Investigations Echocardiography and cardiac MRI are the most useful investigations. Although ECG changes are common, they are non-specific. Genetic testing is indicated if more than one family member is diagnosed with the condition. Management The focus of management is to control heart failure using the strategies described earlier in this chapter (p. 464). Although some patients remain well for many years, the prognosis is variable and cardiac transplantation may be indicated. Patients with dilated cardiomyopathy and moderate or severe heart failure are at risk of sudden arrhythmic death and this can be reduced by rigorous medical therapy with β-blockers and either ACE inhibitors or ARBs. Some patients may be considered for implantation of a cardiac defibrillator and/or cardiac resynchronisation therapy (pp. 483 and 484). Hypertrophic cardiomyopathy This is the most common form of cardiomyopathy, with a prevalence of approximately 100 per 100 000. It is characterised by inappropriate and elaborate left ventricular hypertrophy with malalignment of the myocardial fibres and myocardial fibrosis. The hypertrophy may be generalised or confined largely to the interventricular septum (asymmetric septal hypertrophy, Fig. 16.99) or other regions of the heart. A specific variant termed apical hypertrophic cardiomyopathy is common in the Far East. Dilated cardiomyopathy In North America and Europe, symptomatic dilated cardiomyopathy has an incidence of 20 per 100 000 and a prevalence of 38 per 100 000. Men are affected more than twice as often as women. Pathogenesis Cardiomyopathy is characterised by dilatation and impaired contraction of the LV and often the RV. Left ventricular mass is increased but wall thickness is normal or reduced (Fig. 16.99). Dilatation of the valve rings can lead to functional mitral and tricuspid incompetence. Histological changes are variable but include myofibrillary loss, interstitial fibrosis and T-cell infiltrates. The term ‘dilated cardiomyopathy’ encompasses a heterogeneous group of conditions. Alcohol may be an important cause in some patients. At least 25% of cases are inherited as an autosomal dominant trait and a variety of single-gene mutations have been identified. Most of these mutations affect proteins in the cytoskeleton of the myocytes, such as dystrophin, lamin A and C, emerin and metavinculin. Many are also associated with abnormalities of skeletal muscle Conversely, most of the X-linked inherited skeletal muscular dystrophies, such as Becker and Duchenne (p. 1143), are associated with cardiomyopathy. Finally, a late autoimmune reaction to viral myocarditis is thought to be the cause in a substantial subgroup of patients with dilated cardiomyopathy; a similar mechanism is believed to be responsible for the myocardial involvement that occurs in up to 10% of patients with advanced human immunodeficiency virus (HIV) infection. Clinical features Most patients present with heart failure or are found to have the condition during routine investigation. Arrhythmia, thromboembolism and sudden death may occur at any stage; Fig. 16.99 Types of cardiomyopathy. A Normal heart. B Hypertrophic cardiomyopathy: asymmetric septal hypertrophy (ASH) with systolic anterior motion of the mitral valve (SAM), causing mitral reflux and dynamic left ventricular outflow tract obstruction. C Hypertrophic cardiomyopathy: concentric hypertrophy. D Hypertrophic cardiomyopathy: apical hypertrophy. E Dilated cardiomyopathy. F Arrhythmogenic right ventricular cardiomyopathy. G Obliterative cardiomyopathy. H Restrictive cardiomyopathy. SAM ASH A B C D E F G H

540 • CARDIOLOGY Investigations Echocardiography is the investigation of choice and is usually diagnostic. Sometimes the diagnosis is more difficult when another cause of left ventricular hypertrophy is present but the degree of hypertrophy in hypertrophic cardiomyopathy is usually greater than in physiological hypertrophy and the pattern is asymmetrical. The ECG is abnormal and shows features of left ventricular hypertrophy with a wide variety of often bizarre abnormalities, including deep T-wave inversion. Genetic testing can be performed and is helpful in screening relatives of affected individuals. Management Beta-blockers, rate-limiting calcium antagonists and disopyramide can help to relieve symptoms and prevent syncopal attacks. Arrhythmias often respond to treatment with amiodarone. No pharmacological treatment has been identified that can improve prognosis, however. Outflow tract obstruction can be improved by partial surgical resection (myectomy) or by iatrogenic infarction of the basal septum (septal ablation) using a catheter-delivered alcohol solution. An ICD should be considered in patients with clinical risk factors for sudden death (Box 16.106). Digoxin and vasodilators may increase outflow tract obstruction and should be avoided. Arrhythmogenic ventricular cardiomyopathy Arrhythmogenic ventricular cardiomyopathy (AVC) predominantly affects the myocardium of the right ventricle. It is inherited in an autosomal dominant manner and has a prevalence of approximately 10 per 100 000. The genetic defect involves desmosomal protein genes, most commonly plakophilin 2 (PKP-2), although current genetic testing protocols will not identify the culprit gene in many cases. It is characterised by replacement of patches of the right ventricular myocardium with fibrous and fatty tissue (see Fig. 16.99). In some cases, the LV is also involved and this is associated with a poorer prognosis. The diagnosis is based on a complex set of criteria that take account of the ECG, structural assessment, genetics and arrhythmias. The dominant clinical problems are ventricular arrhythmias, sudden death and right-sided cardiac failure. The ECG typically shows a slightly broadened QRS complex and inverted T waves in the right precordial leads. MRI is a helpful diagnostic tool and is used, along with the 12-lead ECG and ambulatory ECG monitoring, to screen the first-degree relatives of affected individuals. Management is based on treating right-sided cardiac failure with diuretics and cardiac arrhythmias with β-blockers or, in patients at high risk of sudden death, an implantable defibrillator can be offered. Restrictive cardiomyopathy In this rare condition, ventricular filling is impaired because the ventricles are ‘stiff’ (see Fig. 16.99). This leads to high atrial pressures with atrial hypertrophy, dilatation and, later, AF. Amyloidosis is the most common cause in the UK, although other forms of infiltration due to glycogen storage diseases, idiopathic perimyocyte fibrosis and a familial form of restrictive cardiomyopathy can also occur. The diagnosis can be difficult and requires assessment with Doppler echocardiography, CT or MRI, and endomyocardial biopsy. Treatment is symptomatic but the prognosis is usually poor and transplantation may be indicated. Pathogenesis Hypertrophic cardiomyopathy is a genetic disorder, usually with autosomal dominant transmission, a high degree of penetrance and variable expression. In most patients, it is due to a single-point mutation in one of the genes that encode sarcomeric contractile proteins. There are three common groups of mutation with different phenotypes. Beta-myosin heavy-chain mutations are associated with elaborate ventricular hypertrophy. Troponin mutations are associated with little, and sometimes even no, hypertrophy but marked myocardial fibre disarray, exercise-induced hypotension and a high risk of sudden death. Myosin-binding protein C mutations tend to present late in life and are often associated with hypertension and arrhythmia. In all subtypes, heart failure may develop because the stiff, non-compliant LV impedes diastolic filling. Septal hypertrophy may also cause dynamic left ventricular outflow tract obstruction (hypertrophic obstructive cardiomyopathy, HOCM) and mitral regurgitation due to abnormal systolic anterior motion of the anterior mitral valve leaflet. Clinical features Effort-related symptoms, such as angina, breathlessness, arrhythmia and sudden death, are the dominant clinical presentations. The symptoms and signs are similar to those of aortic stenosis, except that, in hypertrophic cardiomyopathy, the character of the arterial pulse is jerky (Box 16.105). The annual mortality from sudden death is 2–3% among adults and 4–6% in children and adolescents (Box 16.106). Sudden death typically occurs during or just after vigorous physical activity and is thought to be due to ventricular arrhythmias. Hypertrophic cardiomyopathy is the most common cause of sudden death in young athletes. In patients who do not suffer fatal arrhythmias, the natural history is variable but clinical deterioration is often slow. 16.105 Clinical features of hypertrophic cardiomyopathy Symptoms • Angina on effort • Dyspnoea on effort • Syncope on effort • Sudden death Signs • Jerky pulse* • Palpable left ventricular hypertrophy • Double impulse at the apex (palpable fourth heart sound due to left atrial hypertrophy) • Mid-systolic murmur at the base* • Pansystolic murmur (due to mitral regurgitation) at the apex *Signs of left ventricular outflow tract obstruction may be augmented by standing up (reduced venous return), inotropes and vasodilators (e.g. sublingual nitrate). 16.106 Risk factors for sudden death in hypertrophic cardiomyopathy • A history of previous cardiac arrest or sustained ventricular tachycardia • Recurrent syncope • An adverse genotype and/or family history • Exercise-induced hypotension • Non-sustained ventricular tachycardia on ambulatory ECG monitoring • Marked increase in left ventricular wall thickness

Diseases of the myocardium • 541

Obliterative cardiomyopathy This is a rare form of restrictive cardiomyopathy, involving the endocardium of one or both ventricles; it is characterised by thrombosis and fibrosis, with gradual obliteration of the ventricular cavities by fibrous tissue (see Fig. 16.99). The mitral and tricuspid valves become regurgitant. Heart failure and pulmonary and systemic embolism are prominent features. It can sometimes be associated with eosinophilia and can occur in eosinophilic leukaemia and eosinophilic granulomatosis with polyangiitis (formerly known as Churg–Strauss syndrome, p. 1043). In tropical countries, the disease can be responsible for up to 10% of cardiac deaths. Mortality is high: 50% at 2 years. Anticoagulation and antiplatelet therapy are used, and diuretics may help symptoms of heart failure. Surgery (tricuspid and/or mitral valve replacement with decortication of the endocardium) may be helpful in selected cases. Takotsubo cardiomyopathy Takotsubo cardiomyopathy (Takotsubo syndrome) is a form of acute left ventricular dysfunction characterised by dilatation of the left ventricular apex and adjacent myocardium, with associated left ventricular impairment. The mechanism is poorly understood but may involve noradrenergic coronary vasoconstriction and acute left ventricular outflow obstruction. It is often associated with acute environmental or emotional stress (such as a bereavement) and presents with chest pain, breathlessness and sometimes cardiac failure. It occurs more frequently in women than in men. In terms of both symptoms and the ECG, the condition mimics acute ST elevation acute coronary syndrome. The diagnosis is usually made at coronary angiography, when CAD is found to be absent or minimal. Echocardiography then shows characteristic ‘apical ballooning’ of the LV. The dilated apex and narrow outflow of the LV resemble a Japanese octopus trap, or takotsubo (Fig. 16.100). 16.107 Specific diseases of heart muscle Infections Viral • Coxsackie A and B • Influenza • HIV Bacterial • Diphtheria • Borrelia burgdorferi Protozoal • Trypanosomiasis • Toxoplasma gondii Endocrine and metabolic disorders • Diabetes • Hypo- and hyperthyroidism • Acromegaly • Carcinoid syndrome • Phaeochromocytoma • Inherited storage diseases Connective tissue diseases • Systemic sclerosis • Systemic lupus erythematosus • Polyarteritis nodosa Infiltrative disorders • Haemochromatosis • Haemosiderosis • Sarcoidosis • Amyloidosis Toxins • Doxorubicin • Alcohol • Cocaine • Irradiation Neuromuscular disorders • Dystrophia myotonica • Friedreich’s ataxia Fig. 16.100 Takotsubo cardiomyopathy. Left ventriculogram following injection of contrast in a patient with Takotsubo cardiomyopathy. The outline of the dilated left ventricle is indicated by arrows. Left ventricular dysfunction usually recovers within 4–5 days, although this can take weeks in some cases. Treatment is with a β-blocker, to prevent arrhythmia, and an ACE inhibitor, to treat left ventricular dysfunction. These drugs are continued only until cardiac function has recovered. Secondary causes of cardiomyopathy Many systemic conditions can produce a picture that is indistinguishable from dilated cardiomyopathy, including connective tissue disorders, sarcoidosis, haemochromatosis and alcoholic heart muscle disease (Box 16.107). In contrast, amyloidosis and eosinophilic heart disease produce symptoms and signs similar to those found in restrictive or obliterative cardiomyopathy, whereas the heart disease associated with Friedreich’s ataxia (p. 1116) can mimic hypertrophic cardiomyopathy. Treatment and prognosis are determined by the underlying disorder. Abstention from alcohol may lead to a dramatic improvement in patients with alcoholic heart muscle disease. Cardiac tumours Primary cardiac tumours are rare (< 0.2% of autopsies) but the heart and mediastinum may be the sites of metastases. Most primary tumours are benign (75%) and, of these, the majority are myxomas. The remainder are fibromas, lipomas, fibroelastomas and haemangiomas. Atrial myxoma Myxomas most commonly arise in the LA as single or multiple polypoid tumours, attached by a pedicle to the interatrial septum.

542 • CARDIOLOGY friction rub is a high-pitched, superficial scratching or crunching noise, produced by movement of the inflamed pericardium, and is diagnostic of pericarditis; it is usually heard in systole but may also be audible in diastole and frequently has a ‘to-and-fro’ quality. Investigations The diagnosis can often be made on the basis of clinical features and the ECG; the latter shows ST elevation with upward concavity (Fig. 16.101) over the affected area, which may be widespread. PR interval depression is a very specific indicator of acute pericarditis. Later, there may be T-wave inversion, particularly if there is a degree of myocarditis. Echocardiography may be normal or may reveal pericardial effusion, in which case regular echocardiographic monitoring is recommended. Management The pain usually responds to aspirin (600 mg 6 times daily) but a more potent anti-inflammatory agent, such as indometacin (50 mg 3 times daily), may be required. Colchicine or glucocorticoids can also suppress symptoms but there is no evidence that they accelerate cure. In viral pericarditis, recovery usually occurs within a few days or weeks but there may be recurrences (chronic relapsing pericarditis). Purulent pericarditis requires treatment with antimicrobial therapy, pericardiocentesis and, if necessary, surgical drainage. They are usually gelatinous but may be solid and even calcified, with superimposed thrombus. On examination, the first heart sound is usually loud, and there may be a murmur of mitral regurgitation with a variable diastolic sound (tumour ‘plop’) due to prolapse of the mass through the mitral valve. The tumour can be detected incidentally on echocardiography, or following investigation of pyrexia, syncope, arrhythmias or emboli. Occasionally, the condition presents with malaise and features suggestive of a connective tissue disorder, including a raised ESR. Treatment is by surgical excision. If the pedicle is removed, fewer than 5% of tumours recur. Diseases of the pericardium The normal pericardial sac contains about 50 mL of fluid, similar to lymph, which lubricates the surface of the heart. The pericardium limits distension of the heart, contributes to the haemodynamic interdependence of the ventricles, and acts as a barrier to infection. Nevertheless, congenital absence of the pericardium does not result in significant clinical or functional limitations. Acute pericarditis This is due to an acute inflammatory process affecting the pericardium, which may coexist with myocarditis. Pathogenesis A number of causes are recognised (Box 16.108), but in some cases the cause is unclear. All forms of pericarditis may produce a pericardial effusion that, depending on the aetiology, may be fibrinous, serous, haemorrhagic or purulent. A fibrinous exudate may eventually lead to varying degrees of adhesion formation, whereas serous pericarditis often produces a large effusion of turbid, straw-coloured fluid with a high protein content. A haemorrhagic effusion is often due to malignant disease, particularly carcinoma of the breast or bronchus, and lymphoma. Purulent pericarditis is rare and may occur as a complication of sepsis, by direct spread from an intrathoracic infection, or from a penetrating injury. Clinical features The typical presentation is with chest pain that is retrosternal, radiates to the shoulders and neck, and is typically aggravated by deep breathing, movement, a change of position, exercise and swallowing. A low-grade fever is common. A pericardial 16.108 Causes of acute pericarditis and pericardial effusion Infection • Viral • Bacterial • Tuberculosis Inflammatory • Rheumatoid arthritis • Systemic lupus erythematosus • Rheumatic fever Other • Post-myocardial infarction • Uraemia • Malignancy • Trauma Fig. 16.101 ECG in viral pericarditis. Widespread ST elevation (leads I, II, aVL and V1–V6) is shown. The upward concave shape of the ST segments (see leads II and V6) and the unusual distribution of changes (involving anterior and inferior leads) help to distinguish pericarditis from acute myocardial infarction. aVR V1 V4 aVL V2 V5 III aVF V3 V6 II I

Diseases of the pericardium • 543

the operator, the shape of the patient and the position of the effusion. A pericardial drain may be placed to provide symptomatic relief. Complications of pericardiocentesis include arrhythmias, damage to a coronary artery and bleeding, with exacerbation of tamponade as a result of injury to the RV. When tamponade is due to cardiac rupture or aortic dissection, pericardial aspiration may precipitate further potentially fatal bleeding and, in these situations, emergency surgery is the treatment of choice. A viscous, loculated or recurrent effusion may also require formal surgical drainage. Tuberculous pericarditis Tuberculous pericarditis may complicate pulmonary tuberculosis but may also be the first manifestation of the infection. In Africa, a tuberculous pericardial effusion is a common feature of AIDS (p. 322). The condition typically presents with chronic malaise, weight loss and a low-grade fever. An effusion usually develops and the pericardium may become thick and unyielding, leading to pericardial constriction or tamponade. An associated pleural effusion is often present. The diagnosis may be confirmed by aspiration of the fluid and direct examination or culture for tubercle bacilli. Treatment requires specific antituberculous chemotherapy (p. 592); in addition, a 3-month course of prednisolone (initial dose 60 mg a day, tapering down rapidly) improves outcome. Chronic constrictive pericarditis Constrictive pericarditis is due to progressive thickening, fibrosis and calcification of the pericardium. In effect, the heart is encased in a solid shell and cannot fill properly. The calcification may extend into the myocardium, so there may also be impaired myocardial contraction. The condition often follows an attack of tuberculous pericarditis but can also complicate haemopericardium, viral pericarditis, rheumatoid arthritis and purulent pericarditis. It is often impossible to identify the original insult. Clinical features The symptoms and signs of systemic venous congestion are the hallmarks of constrictive pericarditis. AF is common and there is often dramatic ascites and hepatomegaly (Box 16.109). Breathlessness is not a prominent symptom because the lungs are seldom congested. The condition is sometimes overlooked but should be suspected in any patient with unexplained right heart failure and a small heart. Investigations A chest X-ray, which may show pericardial calcification (Fig. 16.103), and echocardiography often help to establish the diagnosis. CT scanning is useful for imaging the pericardial calcification. Constrictive pericarditis is often difficult to distinguish Pericardial effusion Pericardial effusion often accompanies pericarditis and can have a number of causes, as shown in Box 16.108. Clinical features With the onset of an effusion the heart sounds may become quieter, and a friction rub, if present, may diminish in intensity but is not always abolished. Larger effusions may be accompanied by a sensation of retrosternal oppression. While most effusions do not have significant haemodynamic effects, large or rapidly developing effusions may cause cardiac tamponade. This term is used to describe acute heart failure due to compression of the heart and is described in detail below. Typical physical findings are a markedly raised JVP, hypotension, pulsus paradoxus (p. 448) and oliguria. Atypical presentations may occur when the effusion is loculated as a result of previous pericarditis or cardiac surgery. Investigations Echocardiography is the definitive investigation and is helpful in monitoring the size of the effusion and its effect on cardiac function (Fig. 16.102). The QRS voltages on the ECG are often reduced in the presence of a large effusion. The QRS complexes may alternate in amplitude due to a to-and-fro motion of the heart within the fluid-filled pericardial sac (electrical alternans). The chest X-ray may show an increase in the size of the cardiac silhouette and, when there is a large effusion, this has a globular appearance. Aspiration of the effusion may be required for diagnostic purposes and, if necessary, for treatment of large effusions, as described below. Management Patients with large effusions that are causing haemodynamic compromise or cardiac tamponade should undergo aspiration of the effusion. This involves inserting a needle under echocardiographic guidance medial to the cardiac apex or below the xiphoid process, directed upwards towards the left shoulder. The route of choice will depend on the experience of Fig. 16.102 Pericardial effusion: echocardiogram (apical view). Short-axis view of the heart showing a large circumferential pericardial effusion (arrows). (LV = left ventricle) LV 16.109 Clinical features of constrictive pericarditis • Fatigue • Rapid, low-volume pulse • Elevated JVP with a rapid y descent • Loud early third heart sound or ‘pericardial knock’ • Kussmaul’s sign • Hepatomegaly • Ascites • Peripheral oedema • Pulsus paradoxus (JVP = jugular venous pressure)

544 • CARDIOLOGY aspiration of the fluid. The ECG may show features of the underlying disease, such as pericarditis or acute MI. When there is a large pericardial effusion, the ECG complexes are small and there may be electrical alternans: a changing axis with alternate beats caused by the heart swinging from side to side in the pericardial fluid. A chest X-ray shows an enlarged globular heart but can look normal. Management Cardiac tamponade is a medical emergency. When the diagnosis is confirmed, percutaneous pericardiocentesis should be performed as soon as possible, which usually results in a dramatic improvement. In some cases, surgical drainage may be required. Further information Websites acc.org American College of Cardiology (ACC): free access to guidelines for the evaluation and management of many cardiac conditions. americanheart.org American Heart Association (AHA): free access to all the ACC/AHA/ESC guidelines, AHA scientific statements and fact sheets for patients. escardio.org European Society of Cardiology (ESC): free access to guidelines for the diagnosis and management of many cardiac conditions, and to educational modules. jbs3risk.com Joint British Societies for the Prevention of Cardiovascular Disease: risk calculator. Journal articles Gould FK, Denning DW, Elliott TS, et al. Guidelines for the diagnosis and antibiotic treatment of endocarditis in adults: a report of the working party of the British Society for Antimicrobial Chemotherapy. J Antimicrob Chemother 2012; 67:269–289. Fig. 16.103 Lateral chest X-ray from a patient with severe heart failure due to chronic constrictive pericarditis. There is heavy calcification of the pericardium. 16.110 Clinical features of cardiac tamponade • Dyspnoea • Collapse • Tachycardia • Hypotension • Gross elevation of the JVP • Soft heart sounds with an early third heart sound • Pulsus paradoxus (a large fall in BP during inspiration, when the pulse may be impalpable) • Kussmaul’s sign (a paradoxical rise in JVP during inspiration) (JVP = jugular venous pressure) from restrictive cardiomyopathy and in such cases complex echo–Doppler studies and cardiac catheterisation may be required. Management The resulting diastolic heart failure is treated using loop diuretics and aldosterone antagonists, such as spironolactone. Surgical resection of the diseased pericardium can lead to a dramatic improvement but carries a high morbidity, with disappointing results in up to 50% of patients. Cardiac tamponade This term is used to describe acute heart failure due to compression of the heart as the result of a large pericardial effusion. Tamponade may complicate any form of pericarditis but can be caused by malignant disease, by blood in the pericardial space following trauma, or by rupture of the free wall of the myocardium following MI. Clinical features Patients with tamponade are unwell, with hypotension, tachycardia and a markedly raised JVP. Other clinical features are summarised in Box 16.110. Investigations The pivotal investigation is echocardiography, which can confirm the diagnosis and also helps to identify the optimum site for

Ch04-3 Clinical Medicine

07-17 Respiratory medicine

17 Respiratory medicine

Respiratory medicine PT Reid JA Innes Clinical examination of the respiratory system 546 Functional anatomy and physiology 548 Investigation of respiratory disease 550 Imaging 551 Endoscopic examination 553 Immunological and serological tests 554 Microbiological investigations 554 Respiratory function testing 554 Presenting problems in respiratory disease 556 Cough 556 Breathlessness 557 Chest pain 558 Finger clubbing 559 Haemoptysis 559 The incidental pulmonary nodule 560 Pleural effusion 562 Respiratory failure 565 Obstructive pulmonary diseases 567 Asthma 567 Chronic obstructive pulmonary disease 573 Bronchiectasis 578 Cystic fibrosis 580 Infections of the respiratory system 581 Upper respiratory tract infection 581 Pneumonia 582 Tuberculosis 588 Respiratory diseases caused by fungi 596 Tumours of the bronchus and lung 598 Primary tumours of the lung 599 Secondary tumours of the lung 603 Tumours of the mediastinum 603 Interstitial and infiltrative pulmonary diseases 605 Diffuse parenchymal lung disease 605 Lung diseases due to systemic inflammatory disease 610 Pulmonary eosinophilia and vasculitides 611 Lung diseases due to irradiation and drugs 612 Rare interstitial lung diseases 613 Occupational and environmental lung disease 613 Occupational airway disease 613 Pneumoconiosis 614 Lung diseases due to organic dusts 616 Asbestos-related lung and pleural diseases 617 Occupational lung cancer 618 Occupational pneumonia 618 Pulmonary vascular disease 619 Pulmonary embolism 619 Pulmonary hypertension 621 Diseases of the upper airway 622 Diseases of the nasopharynx 622 Sleep-disordered breathing 622 Laryngeal disorders 624 Tracheal disorders 625 Pleural disease 625 Diseases of the diaphragm and chest wall 627 Disorders of the diaphragm 627 Deformities of the chest wall 628

546 • RESPIRATORY MEDICINE Insets (idiopathic kyphoscoliosis) Courtesy of Dr I. Smith, Papworth Hospital, Cambridge; (serous, mucopurulent and purulent sputum) Courtesy of Dr J. Foweraker, Papworth Hospital, Cambridge. Hands Digital clubbing Tar staining Peripheral cyanosis Signs of occupation CO2 retention flap Radial pulse Rate Rhythm Jugular venous pulse Elevated Pulsatile Face, mouth and eyes Pursed lips Central cyanosis Anaemia Horner’s syndrome (Ch. 25) Thorax (see opposite) – Palpation From the front: Trachea central Cricosternal distance Cardiac apex displaced Expansion From behind: Cervical lymphadenopathy Expansion Leg oedema Salt and water retention Cor pulmonale Venous thrombosis • Respiratory rate • Cachexia, fever, rash • Sputum (see below) • Fetor Observation Finger clubbing Blood pressure Arterial paradox Auscultation Breath sounds: normal, bronchial, louder or softer Added sounds: wheezes, crackles, rubs Spoken voice (vocal resonance): absent (effusion), increased (consolidation) Whispered voice: whispering pectoriloquy Percussion Resonant or dull ‘Stony dull’ (effusion) Idiopathic kyphoscoliosis • Locale: Oxygen delivery (mask, cannulae) Nebulisers Inhalers Serous/frothy/pink Pulmonary oedema Mucopurulent Bronchial or pneumonic infection Purulent Bronchial or pneumonic infection Blood-stained Cancer, tuberculosis, bronchiectasis, pulmonary embolism Sputum

Inspection Deformity (e.g. pectus excavatum) Scars Intercostal indrawing Symmetry of expansion Hyperinflation Paradoxical rib movement (low flat diaphragm)

Clinical examination of the respiratory system

Clinical examination of the respiratory system • 547

Insets (upper lobe collapse) From http://3.bp.blogspot.com; (pneumothorax) http://chestatlas.com; (pleural effusion) www.ispub.com. Chronic obstructive pulmonary disease Use of accessory muscles Hyperinflated ‘barrel’ chest Auscultation Reduced breath sounds – wheeze Pursed lip breathing Central cyanosis Prolonged expiration Reduced cricosternal distance Intercostal indrawing during inspiration Cardiac apex not palpable Loss of cardiac dullness on percussion Inward movement of lower ribs on inspiration (low flat diaphragm) Also: raised jugular venous pressure (JVP), peripheral oedema from salt and water retention and/or cor pulmonale Heart sounds loudest in epigastrium Pulmonary fibrosis Small lungs Reduced expansion Dull percussion at bases (high diaphragm) Central cyanosis Tachypnoea Auscultation Fine inspiratory crackles at bases See also Fig. 17.56 Also: finger clubbing common in idiopathic pulmonary fibrosis; raised JVP and peripheral oedema if cor pulmonale Right middle lobe pneumonia Right upper lobe collapse Right pneumothorax Large right pleural effusion Inspection Tachypnoea Central cyanosis (if severe) Palpation ↓Expansion on R Percussion Dull R mid-zone and axilla Auscultation Bronchial breath sounds and ↑vocal resonance over consolidation and whispering pectoriloquy Pleural rub if pleurisy Inspection ↓Volume R upper zone Palpation Trachea deviated to R ↓Expansion R upper zone Percussion Dull R upper zone Auscultation ↓Breath sounds with central obstruction Inspection Tachypnoea (pain, deflation reflex) Palpation ↓Expansion R side Percussion Resonant or hyper-resonant on R Auscultation Absent breath sounds on R Tension pneumothorax also causes

Deviation of trachea to

opposite side Tachycardia and

hypotension Inspection Tachypnoea Palpation ↓Expansion on R Trachea and apex may be moved to L Percussion Stony dull R mid- and lower zones Auscultation Absent breath sounds and vocal resonance R base Bronchial breathing or crackles above effusion Obscures R heart border on X-ray X-ray Deviated trachea (to R) Elevated horizontal fissure ↓Volume R hemithorax Central (hilar) mass may be seen

548 • RESPIRATORY MEDICINE outward movement of the ribs on the costovertebral joints, caused by contraction of the external intercostal muscles (innervated by intercostal nerves originating from the thoracic spinal cord). Expiration is largely passive, driven by elastic recoil of the lungs. The conducting airways from the nose to the alveoli connect the external environment with the extensive, thin and vulnerable alveolar surface. As air is inhaled through the upper airways, it is filtered in the nose, heated to body temperature and fully saturated with water vapour; partial recovery of this heat and moisture occurs on expiration. Total airway cross-section is smallest in the glottis and trachea, making the central airway particularly vulnerable to obstruction by foreign bodies and tumours. Normal breath sounds originate mainly from the rapid turbulent airflow in the larynx, trachea and main bronchi. The multitude of small airways within the lung parenchyma has a very large combined cross-sectional area (over 300 cm2 in the third-generation respiratory bronchioles), resulting in very slow flow rates. Airflow is virtually silent here and gas transport occurs largely by diffusion in the final generations. Major bronchial and pulmonary divisions are shown in Figure 17.1. The acinus (Fig. 17.2) is the gas exchange unit of the lung and comprises branching respiratory bronchioles and clusters of alveoli. Here the air makes close contact with the blood in the pulmonary capillaries (gas-to-blood distance < 0.4 μm), and oxygen uptake and CO2 excretion occur. The alveoli are lined with flattened epithelial cells (type I pneumocytes) and a few, more cuboidal, type II pneumocytes. The latter produce surfactant, which is a mixture of phospholipids that reduces surface tension and counteracts the tendency of alveoli to collapse under surface Respiratory disease is responsible for a major burden of morbidity and untimely death, with conditions such as tuberculosis, pandemic influenza and pneumonia the most important in world health terms. The increasing prevalence of allergy, asthma and chronic obstructive pulmonary disease (COPD) contributes to the overall burden of chronic disease in the community. By 2025, the number of cigarette smokers worldwide is anticipated to increase to 1.5 billion, ensuring a growing burden of tobacco-related respiratory conditions. Respiratory disease covers a breadth of pathologies, including infectious, inflammatory, neoplastic and degenerative processes. The practice of respiratory medicine thus requires collaboration with a range of disciplines. Recent advances have improved the lives of many patients with obstructive lung disease, cystic fibrosis, obstructive sleep apnoea and pulmonary hypertension, but the outlook remains poor for lung and other respiratory cancers and for some of the fibrosing lung conditions. Functional anatomy and physiology The lungs occupy the upper two-thirds of the bony thorax, bounded medially by the spine, the heart and the mediastinum and inferiorly by the diaphragm. During breathing, free movement of the lung surface relative to the chest wall is facilitated by sliding contact between the parietal and visceral pleura, which cover the inner surface of the chest wall and the lung, respectively, and are normally in close apposition. Inspiration involves downward contraction of the dome-shaped diaphragm (innervated by the phrenic nerves originating from C3, 4 and 5) and upward, Fig. 17.1 The major bronchial divisions and the fissures, lobes and segments of the lungs. The angle of the oblique fissure means that the left upper lobe is largely anterior to the lower lobe. On the right, the transverse fissure separates the upper from the anteriorly placed middle lobe, which is matched by the lingular segment on the left side. The site of a lobe determines whether physical signs are mainly anterior or posterior. Each lobe is composed of two or more bronchopulmonary segments that are supplied by the main branches of each lobar bronchus. Bronchopulmonary segments: Right Upper lobe: (1) Anterior, (2) Posterior, (3) Apical. Middle lobe: (1) Lateral, (2) Medial. Lower lobe: (1) Apical, (2) Posterior basal, (3) Lateral basal, (4) Anterior basal, (5) Medial basal. Left Upper lobe: (1) Anterior, (2) Apical, (3) Posterior, (4) Lingular. Lower lobe: (1) Apical, (2) Posterior basal, (3) Lateral basal, (4) Anterior basal. Upper lobe Middle lobe

Lower lobe Upper lobe Lower lobe Middle lobe

T r a ns ver se fi ssure RIGHT LEFT Upper lobe Lower lobe

O bli que fissure Upper lobe

Lower lobe

Anterior

Lateral aspects of lungs Spine Spine Major bronchial subdivisions

Functional anatomy and physiology • 549

the small airways unsupported, and their collapse on expiration causes air trapping and limits expiration at a high end-expiratory volume (p. 575). Control of breathing The respiratory motor neurons in the posterior medulla oblongata are the origin of the respiratory cycle. Their activity is modulated by multiple external inputs in health and in disease (see Fig. 17.9): • Central chemoreceptors in the ventrolateral medulla sense the pH of the cerebrospinal fluid (CSF) and are indirectly stimulated by a rise in arterial PCO2. • The carotid bodies sense hypoxaemia but are mainly activated by arterial PO2 values below 8 kPa (60 mmHg). They are also sensitised to hypoxia by raised arterial PCO2. • Muscle spindles in the respiratory muscles sense changes in mechanical load. • Vagal sensory fibres in the lung may be stimulated by stretch, by inhaled toxins or by disease processes in the interstitium. • Cortical (volitional) and limbic (emotional) influences can override the automatic control of breathing. Ventilation/perfusion matching and the pulmonary circulation To achieve optimal gas exchange within the lungs, the regional distribution of ventilation and perfusion must be matched. At tension. Type II pneumocytes can divide to reconstitute type I pneumocytes after lung injury. Lung mechanics Healthy alveolar walls contain a fine network of elastin and collagen fibres (Fig. 17.2). The volume of the lungs at the end of a tidal (‘normal’) breath out is called the functional residual capacity (FRC). At this volume, the inward elastic recoil of the lungs (resulting from elastin fibres and surface tension in the alveolar lining fluid) is balanced by the resistance of the chest wall to inward distortion from its resting shape, causing negative pressure in the pleural space. Elastin fibres allow the lung to be easily distended at physiological lung volumes, but collagen fibres cause increasing stiffness as full inflation is approached, so that, in health, the maximum inspiratory volume is limited by the lung (rather than the chest wall). Within the lung, the weight of tissue compresses the dependent regions and distends the uppermost parts, so a greater portion of an inhaled breath passes to the basal regions, which also receive the greatest blood flow as a result of gravity. Elastin fibres in alveolar walls maintain small airway patency by radial traction on the airway walls. Even in health, however, these small airways narrow during expiration because they are surrounded by alveoli at higher pressure, but are prevented from collapsing by radial elastic traction. The volume that can be exhaled is thus limited purely by the capacity of the expiratory muscles to distort the chest wall inwards. In emphysema, loss of alveolar walls leaves Fig. 17.2 Functional anatomy of the lung. A The tapering, branching bronchus is armoured against compression by plates of cartilage. The more distal bronchioles are collapsible, but held patent by surrounding elastic tissue. B The unit of lung supplied by a terminal bronchiole is called an acinus. The bronchiolar wall contains smooth muscle and elastin fibres. The latter also run through the alveolar walls. Gas exchange occurs in the alveoli, which are connected to each other by the pores of Kohn. C Vascular anatomy of an acinus. Both the pulmonary artery (carrying desaturated blood) and the bronchial artery (systemic supply to airway tissue) run along the bronchus. The venous drainage to the left atrium follows the interlobular septa. From www.Netter.com: Illustrations 155 (bronchus, acinus) and 191 (circulation), Elsevier. Cartilage plates Smooth muscle Terminal bronchiole Bronchial artery Pulmonary artery Pulmonary vein Interlobular septum Alveolar capillaries Respiratory bronchiole Alveoli Pores of Kohn Elastin fibres Bronchus Bronchiole Terminal bronchiole Respiratory bronchiole Alveoli A B C

550 • RESPIRATORY MEDICINE as a sphincter, closing to protect the airway during swallowing and vomiting. Lower airway defences The sterility, structure and function of the lower airways are maintained by close cooperation between the innate and adaptive immune responses (pp. 62 and 67). The innate response in the lungs is characterised by a number of non-specific defence mechanisms. Inhaled particulate matter is trapped in airway mucus and cleared by the mucociliary escalator. Cigarette smoke increases mucus secretion but reduces mucociliary clearance and predisposes towards lower respiratory tract infections, including pneumonia. Defective mucociliary transport is also a feature of several rare diseases, including Kartagener’s syndrome, Young’s syndrome and ciliary dysmotility syndrome, which are characterised by repeated sino-pulmonary infections and bronchiectasis. Airway secretions contain an array of antimicrobial peptides (such as defensins, immunoglobulin A (IgA) and lysozyme), antiproteinases and antioxidants. Many assist with the opsonisation and killing of bacteria and the regulation of the powerful proteolytic enzymes secreted by inflammatory cells. In particular, α1-antitrypsin regulates neutrophil elastase, and deficiency of this may be associated with premature emphysema. Macrophages engulf microbes, organic dusts and other particulate matter. They are unable to digest inorganic agents, such as asbestos or silica, which cause their death and lead to the release of powerful proteolytic enzymes that damage the lung. Neutrophil numbers in the airway are low but the pulmonary circulation contains a marginated pool that may be recruited rapidly in response to bacterial infection. This may explain the prominence of lung injury in sepsis syndromes and trauma. Adaptive immunity is characterised by the specificity of the response and the development of memory. Lung dendritic cells facilitate antigen presentation to T and B lymphocytes. Investigation of respiratory disease A detailed history, thorough examination and basic haematological and biochemical tests usually indicate the likely diagnosis and Fig. 17.3 The mucociliary escalator. Scanning electron micrograph of the respiratory epithelium showing large numbers of cilia (C) overlaid by the mucus ‘raft’ (M). M C 17.1 Respiratory function in old age • Reserve capacity: a significant reduction in function can occur with ageing with only minimal effect on normal breathing, but the ability to combat acute disease is reduced. • Decline in FEV1: the FEV1/FVC (forced expiratory volume/forced vital capacity, p. 55) ratio falls by around 0.2% per year from 70% at the age of 40–45 years, due to a decline in elastic recoil in the small airways with age. Smoking accelerates this decline threefold on average. Symptoms usually occur only when FEV1 drops below 50% of predicted. • Increasing ventilation–perfusion mismatch: the reduction in elastic recoil causes a tendency for the small airways to collapse during expiration, particularly in dependent areas of the lungs, thus reducing ventilation. • Reduced ventilatory responses to hypoxia and hypercapnia: older people may be less tachypnoeic for any given fall in PaO2 or rise in PaCO2. • Impaired defences against infection: due to reduced numbers of glandular epithelial cells, which lead to a reduction in protective mucus. • Decline in maximum oxygen uptake: due to a combination of impairments in muscle, and the respiratory and cardiovascular systems. This leads to a reduction in cardiorespiratory reserve and exercise capacity. • Loss of chest wall compliance: due to reduced intervertebral disc spaces and ossification of the costal cartilages; respiratory muscle strength and endurance also decline. These changes become important only in the presence of other respiratory disease. segmental and subsegmental level, hypoxia constricts pulmonary arterioles and airway CO2 dilates bronchi, helping to maintain good regional matching of ventilation and perfusion. Lung disease may create regions of relative under-ventilation or under-perfusion, which disturb this regional matching, causing respiratory failure (p. 565). In addition to causing ventilation–perfusion mismatch, diseases that destroy capillaries or thicken the alveolar capillary membrane (e.g. emphysema or fibrosis) can impair gas diffusion directly. The pulmonary circulation in health operates at low pressure (approximately 24/9 mmHg) and can accommodate large increases in flow with minimal rise in pressure, e.g. during exercise. Pulmonary hypertension occurs when vessels are destroyed by emphysema, obstructed by thrombus, involved in interstitial inflammation or thickened by pulmonary vascular disease. The right ventricle responds by hypertrophy, with right axis deviation and P pulmonale (tall, peaked p waves) on the electrocardiogram (ECG), and clinical features of right heart failure; the term ‘cor pulmonale’ is often used for these findings. Lung defences Upper airway defences Large airborne particles are trapped by nasal hairs, and smaller particles settling on the mucosa are cleared towards the oropharynx by the columnar ciliated epithelium that covers the turbinates and septum (Fig. 17.3). During cough, expiratory muscle effort against a closed glottis results in high intrathoracic pressure, which is then released explosively. The flexible posterior tracheal wall is pushed inwards by the high surrounding pressure, which reduces tracheal cross-section and thus maximises the airspeed to achieve effective expectoration. The larynx also acts

Investigation of respiratory disease • 551

Fig. 17.4 The normal chest X-ray. The lung markings consist of branching and tapering lines radiating out from the hila. Where airways and vessels turn towards the film, they can appear as open or filled circles (see upper pole of right hilum). The scapulae may overlie the lung fields; trace the edge of bony structures to avoid mistaking them for pleural or pulmonary shadows. To check for hyperinflation, count the ribs; if more than 10 are visible posteriorly above the diaphragm, the lungs are hyperinflated. From Innes JA. Davidson’s Essentials of medicine. Edinburgh: Churchill Livingstone, Elsevier Ltd; 2009. Lung apex Right hilum Right atrial border Right costophrenic angle Right hemidiaphragm Right cardiophrenic angle Gastric air bubble Left hemidiaphragm (normally lower than right) Medial border of scapula Aortic arch Left hilum Left ventricular border Cardiac apex Trachea Clavicular heads symmetrical either side of spine – no rotation 17.2 How to interpret a chest X-ray Name, date, orientation Films are posteroanterior (PA) unless marked AP to denote that they are anteroposterior Lung fields Equal translucency? Check horizontal fissure from right hilum to sixth rib at the anterior axillary line Masses? Consolidation? Cavitation? Lung apices Check behind the clavicles. Masses? Consolidation? Cavitation? Trachea Central (midway between the clavicular heads)? Paratracheal mass? Goitre? Heart Normal shape? Cardiothoracic ratio (should be < half the intrathoracic diameter) Retrocardiac mass? Hila Left should be higher than right Shape (should be concave laterally; if convex, consider mass or lymphadenopathy)? Density? Diaphragm Right should be higher than left Hyperinflation (no more than 10 ribs should be visible posteriorly above the diaphragm)? Costophrenic angles Acute and well defined (pleural fluid or thickening, if not)? Soft tissues Breast shadows in females Chest wall for masses or subcutaneous emphysema Bones Ribs, vertebrae, scapulae and clavicles Any fracture visible at bone margins or lucencies? differential. A number of other investigations are normally required to confirm the diagnosis and/or monitor disease activity. Imaging The ‘plain’ chest X-ray This is performed on the majority of patients suspected of having chest disease. A posteroanterior (PA) film provides information on the lung fields, heart, mediastinum, vascular structures and thoracic cage (Fig. 17.4). Additional information may be obtained from a lateral film, particularly if pathology is suspected behind the heart shadow or deep in the diaphragmatic sulci. An approach to interpreting the chest X-ray is given in Box 17.2 and common abnormalities are listed in Box 17.3. Increased shadowing may represent accumulation of fluid, lobar collapse or consolidation. Uncomplicated consolidation should not change the position of the mediastinum and the presence of an air bronchogram means that proximal bronchi are patent. Collapse (implying obstruction of the lobar bronchus) is accompanied by loss of volume and displacement of the mediastinum towards the affected side (Fig. 17.5). The presence of ring shadows (thickened bronchi seen end-on), tramline shadows (thickened bronchi side-on) or tubular shadows (bronchi filled with secretions) suggests bronchiectasis, but computed tomography is a much more sensitive test than plain X-ray in bronchiectasis. The presence of pleural fluid is suggested by a dense basal shadow, which, in the erect patient, ascends towards the axilla (p. 547). In large pulmonary embolism, relative oligaemia may cause a lung field to appear abnormally dark.

552 • RESPIRATORY MEDICINE Computed tomography Computed tomography (CT) provides detailed images of the pulmonary parenchyma, mediastinum, pleura and bony structures. The displayed range of densities can be adjusted to highlight different structures, such as the lung parenchyma, the mediastinal vascular structures or bone. Cross-sectional formatting allows recognition of the axial distribution of the disease, while coronal reformation displays the craniocaudal distribution. In cases of suspected lung cancer, CT is central to both diagnosis and staging, and facilitates percutaneous needle biopsy. CT identifies the extent and appearance of pleural thickening (see Fig. 17.65) and reliably differentiates pleural and pericardial fat from other pathologies. High-resolution thin-section scanning provides detailed images of the pulmonary parenchyma and is particularly useful in assessing diffuse parenchymal lung disease (see Fig. 17.56), identifying airway thickening, bronchiectasis (see Fig. 17.29) and emphysema (see Fig. 17.27). The relative contribution of competing pathologies to a breathless patient may be assessed. Prone imaging may be used to differentiate the gravity-induced posterobasal attenuation seen in supine scans. CT pulmonary angiography (CTPA) has become the investigation of choice in the diagnosis of pulmonary thromboembolism (see Fig. 17.68), when it may either confirm the suspected embolism or highlight an alternative diagnosis. It has largely replaced the radioisotope-based ventilation–perfusion scan, although the latter continues to provide useful information in the pre-operative assessment of patients being considered for lung resection and in the assessment of pulmonary hypertension. CT may assist in identifying the cavitation of tuberculosis, fungal infection (p. 300) and other signs of infection (halo – air crescent). Finally, CT may be used to assess disease progression, thereby predicting prognosis, and in screening to detect the earliest signs of disease. Fig. 17.5 Radiological features of lobar collapse caused by bronchial obstruction. The dotted line in the drawings represents the normal position of the diaphragm. The dark pink area represents the extent of shadowing seen on the X-ray. 3LM[ \WWLY SVIL 3PUN\SH 3LM[ SV^LY SVIL 9PNO[ \WWLY SVIL 9PNO[ TPKKSL SVIL 9PNO[ SV^LY SVIL 17.3 Common chest X-ray abnormalities Pulmonary and pleural shadowing • Consolidation: infection, infarction, inflammation and, rarely, bronchoalveolar cell carcinoma • Lobar collapse: mucus plugging, tumour, compression by lymph nodes • Solitary nodule: see page 560 • Multiple nodules: miliary tuberculosis (TB), dust inhalation, metastatic malignancy, healed varicella pneumonia, rheumatoid disease • Ring shadows, tramlines and tubular shadows: bronchiectasis • Cavitating lesions: tumour, abscess, infarct, pneumonia (Staphylococcus/Klebsiella), granulomatosis with polyangiitis (formerly known as Wegener’s granulomatosis) • Reticular, nodular and reticulonodular shadows: diffuse parenchymal lung disease, infection • Pleural abnormalities: fluid, plaques, tumour Increased translucency • Bullae • Pneumothorax • Oligaemia Hilar abnormalities • Unilateral hilar enlargement: TB, lung cancer, lymphoma • Bilateral hilar enlargement: sarcoid, lymphoma, TB, silicosis Other abnormalities • Hiatus hernia • Surgical emphysema

Investigation of respiratory disease • 553

when paradoxical movement of the vocal cords may mimic asthma. Left-sided lung tumours may involve the left recurrent laryngeal nerve, paralysing the left vocal cord and leading to a hoarse voice and a ‘bovine’ cough. Continuous laryngoscopy during exercise tests allows the identification of exercise-induced laryngeal obstruction. Bronchoscopy The trachea and the first 3–4 generations of bronchi may be inspected using a flexible bronchoscope. Flexible bronchoscopy is usually performed under local anaesthesia with sedation, on an outpatient basis. Abnormal tissue in the bronchial lumen or wall can be biopsied, and bronchial brushings, washings or aspirates can be taken for cytological or bacteriological examination. Small biopsy specimens of lung tissue, taken by forceps passed through the bronchial wall (transbronchial biopsies), may be helpful in the diagnosis of bronchocentric disorders such as sarcoidosis and diffuse malignancy but are generally too small to be of diagnostic value in other diffuse parenchymal pulmonary disease (p. 605). Rigid bronchoscopy requires general anaesthesia and is reserved for specific situations, such as massive haemoptysis or removal of a foreign body (see Fig. 10.2, p. 179), and can facilitate endobronchial laser therapy and stenting. Endobronchial ultrasound Endobronchial ultrasound (EBUS) allows directed needle aspiration from peribronchial nodes and is used increasingly to stage lung cancer. It may also be useful in non-malignant conditions, such as tuberculosis of the mediastinal lymph nodes or sarcoid. Lymph nodes down to the main carina can also be sampled using a mediastinoscope passed through a small incision at the suprasternal notch under general anaesthetic. Lymph nodes in the lower mediastinum may be biopsied via the oesophagus using endoscopic ultrasound (EUS), an oesophageal endoscope equipped with an ultrasound transducer and biopsy needle. Thoracoscopy Thoracoscopy, which involves the insertion of an endoscope through the chest wall, facilitates biopsy under direct vision and is performed by surgeons and an increasing number of physicians. This modality is the gold standard for the evaluation of the pleural interface, characterisation of complex pleural effusion, and identification of exudate and haemorrhage, as well as the analysis of superior sulcus tumours, as it enables more accurate staging. Positron emission tomography Positron emission tomography (PET) scanners employ the radiotracer 18F-fluorodeoxyglucose (FDG) to quantify the rate of glucose metabolism by cells. The 18FDG is rapidly taken up by metabolically active tissue, where it is phosphorylated and ‘trapped’ in the cell. The assessment of 18FDG uptake may be qualitative (visual analysis) or semi-quantitative, using the standardised uptake value (SUV) (Fig. 17.6). PET is useful in the staging of mediastinal lymph nodes and distal metastatic disease in patients with lung cancer and in the investigation of pulmonary nodules. Co-registration of PET and CT (PET-CT) enhances localisation and characterisation of metabolically active deposits (Fig. 17.6). PET may also differentiate benign from malignant pleural disease and can be used to assess the extent of extrapulmonary disease in sarcoidosis. However, 18FDG uptake by a lesion is affected by a large number of parameters, including equipment used, the physics, and biological factors such as amount of body fat and brown fat uptake and the level of fasting blood glucose. Magnetic resonance imaging Conventional magnetic resonance imaging (MRI) of the lung parenchyma is seldom useful, although the technique is increasingly finding a role in the differentiation of benign from malignant pleural disease, and in delineating invasion of the chest wall or diaphragm by tumour. Ultrasound Transthoracic ultrasound has evolved into a point-of-care investigation to assess the pleural space (see Fig. 17.15). In the hands of an experienced operator it can distinguish pleural fluid from pleural thickening, identify a pneumothorax and, by directly visualising the diaphragm and solid organs such as the liver, spleen and kidneys, may be used to guide pleural aspiration, biopsy and intercostal chest drain insertion safely. It is also used to guide needle biopsy of superficial lymph node or chest wall masses and provides useful information on the shape and movement of the diaphragm. Endoscopic examination Laryngoscopy The larynx may be inspected directly with a fibreoptic laryngoscope and this is useful in cases of suspected vocal cord dysfunction, Fig. 17.6 Computed tomography and positron emission tomography combined to reveal intrathoracic metastases. A In a patient with lung cancer, CT shows some posterior pleural thickening. B PET scanning reveals FDG uptake in two pleural lesions (arrows). C The lesions are highlighted in yellow in the combined PET/CT image. A–C, From http://radiology.rsnajnls.org. A B C

554 • RESPIRATORY MEDICINE bronchoscopy. Molecular tests are increasingly being used to provide rapid and accurate identification of many infective organisms. Nucleic acid amplification tests (NAATs) identify common respiratory viruses, such as influenza, adenovirus and respiratory syncytial virus, and have largely replaced paired serology for Mycoplasma, Legionella and other organisms. NAATs are increasingly adopted as the first-line investigation for identification of tuberculosis and rapid identification of drug resistance. Cytology and histopathology Cytological examination of exfoliated cells in pleural fluid or bronchial brushings and washings, or of fine needle aspirates from lymph nodes or pulmonary lesions, can support a diagnosis of malignancy but a larger tissue biopsy is often necessary, particularly as this allows immunohistochemistry using a panel of antibodies to characterise the tumour. Histopathology may also allow identification of infective agents such as Mycobacterium tuberculosis, Pneumocystis jirovecii or fungi. Differential cell counts in bronchial lavage fluid may help to distinguish pulmonary changes due to sarcoidosis (p. 608) from those caused by idiopathic pulmonary fibrosis (p. 605) or hypersensitivity pneumonitis (p. 616). Respiratory function testing Respiratory function tests are used to aid diagnosis, quantify functional impairment, and monitor treatment or progression of disease. Airway narrowing, lung volume and gas exchange capacity are quantified and compared with normal values Immunological and serological tests The diagnosis of asthma may be supported by demonstrating an elevated level of immunoglobulin E (IgE), and the measurement of IgE directed against specific antigens can be useful in assessing the contribution of specific allergens to the presentation. Many autoimmune diseases present with pulmonary involvement and autoantibodies may be identified in the serum. Serum precipitins are antibodies that form visible lines of precipitated glycoprotein when they encounter their specific antigen in an agarose gel or on an acetate cellulose sheet. They may identify a reaction to fungi such as Aspergillus (p. 596) or to antigens involved in hypersensitivity pneumonitis, such as farmer’s lung (p. 616). IgG enzyme immunoassay may be used interchangeably. The presence of pneumococcal antigen in sputum, blood or urine may be of diagnostic importance in pneumonia. Respiratory viruses can be detected in nose/throat swabs by immunofluorescence and Legionella infection may diagnosed by detection of the urinary antigen. The detection of galactomannan, a component of the cell wall of Aspergillus, may assist in the diagnosis of invasive aspergillosis, and interferon-gamma release assays are useful in the detection of latent tuberculosis. Microbiological investigations Sputum, pleural fluid, throat swabs, blood, and bronchial washings and aspirates can be examined for bacteria, fungi and viruses. The use of hypertonic saline to induce expectoration of sputum may obviate the need for more invasive procedures, such as Fig. 17.7 Respiratory function tests in health and disease. A Volume/time traces from forced expiration in health, chronic obstructive pulmonary disease (COPD) and fibrosis. COPD causes slow, prolonged and limited exhalation. In fibrosis, forced expiration results in rapid expulsion of a reduced forced vital capacity (FVC). Forced expiratory volume (FEV1) is reduced in both diseases but disproportionately so, compared to FVC, in COPD. B The same data plotted as flow/volume loops. In COPD, collapse of intrathoracic airways limits flow, particularly during mid- and late expiration. The blue trace illustrates large airway obstruction, which particularly limits peak flow rates. C Lung volume measurement. Volume/time graphs during quiet breathing with a single maximal breath in and out. COPD causes hyperinflation with increased residual volume. Fibrosis causes a proportional reduction in all lung volumes. A B C Volume Inspiratory capacity Functional residual capacity Residual volume Time Total lung capacity Volume Time 1 sec Expiration Inspiration Volume

Normal COPD Fibrosis Tracheal obstruction Flow FEV1 Vital capacity

FVC

Investigation of respiratory disease • 555

Arterial blood gases and oximetry The measurement of hydrogen ion concentration, PaO2 and PaCO2, and derived bicarbonate concentration in an arterial blood sample is essential for assessing the degree and type of respiratory failure and for measuring acid–base status. This is discussed in detail on pages 363 and 565. Interpretation of results is made easier by blood gas diagrams (Fig. 17.8), which indicate whether any acidosis or alkalosis is due to acute or chronic respiratory derangements of PaCO2 or to metabolic causes. Pulse oximeters with finger or ear probes measure the difference in absorbance of light by oxygenated and deoxygenated blood and calculate the percentage of haemoglobin that is oxygenated (the oxygen saturation). This allows non-invasive continuous adjusted for age, gender, height and ethnic origin. In diseases characterised by airway narrowing (e.g. asthma, bronchitis and emphysema), maximum expiratory flow is limited by dynamic compression of small intrathoracic airways, some of which may close completely during expiration, limiting the volume that can be expired (‘obstructive’ defect). Hyperinflation of the chest results and can become extreme if elastic recoil is also lost due to parenchymal destruction, as in emphysema. In contrast, diseases that cause interstitial inflammation and/or fibrosis lead to progressive loss of lung volume (‘restrictive’ defect) with normal expiratory flow rates. Typical laboratory traces are illustrated in Figure 17.7. Measurement of airway obstruction Airway narrowing is assessed by asking patients to breathe in fully, then blow out as hard and fast as they can into a peak flow meter or a spirometer. Peak flow meters are cheap and convenient for home monitoring of peak expiratory flow (PEF) in the detection and monitoring of asthma but results are effort-dependent. More accurate and reproducible measures are obtained by maximum forced expiration into a spirometer. The forced expired volume in 1 second (FEV1) is the volume exhaled in the first second, and the forced vital capacity (FVC) is the total volume exhaled. FEV1 is disproportionately reduced in airflow obstruction, resulting in FEV1/FVC ratios of less than 70%. In this situation, spirometry should be repeated following inhaled short-acting β2-adrenoceptor agonists (e.g. salbutamol); an increase of > 12% and > 200 mL in FEV1 or FVC indicates significant reversibility. A large improvement in FEV1 (> 400 mL) and variability in peak flow over time are features of asthma (p. 567). To distinguish large airway narrowing (e.g. tracheal stenosis or compression; see Fig. 18.12, p. 648) from small airway narrowing, spirometry data are plotted as flow/volume loops. These display flow in relation to lung volume (rather than time) during maximum expiration and inspiration, and the pattern of flow reveals the site of airflow obstruction (Fig. 17.7B). Lung volumes Spirometry can measure only the volume of gas that can be exhaled; it cannot measure the gas remaining in the lungs after a maximal expiration. All the gas in the lungs can be measured by rebreathing an inert non-absorbed gas (usually helium) and recording how much the test gas is diluted by lung gas at equilibrium. This measures the volume of intrathoracic gas that mixes freely with tidal breaths. Alternatively, lung volume may be measured by body plethysmography (p. 175), which determines the pressure/volume relationship of the thorax. This method measures total intrathoracic gas volume, including poorly ventilated areas such as bullae. The terms used to describe lung volume are shown in Figure 17.7C. Transfer factor To measure the capacity of the lungs to exchange gas, patients inhale a test mixture of 0.3% carbon monoxide, which is taken up avidly by haemoglobin in pulmonary capillaries. After a short breath-hold, the rate of disappearance of CO into the circulation is calculated from a sample of expirate, and expressed as the TLCO or carbon monoxide transfer factor. Helium is also included in the test breath to allow calculation of the volume of lung examined by the test breath. Transfer factor expressed per unit lung volume is termed KCO. Common respiratory function abnormalities are summarised in Box 17.4. 17.4 How to interpret respiratory function abnormalities Asthma Chronic bronchitis Emphysema Pulmonary fibrosis FEV1 ↓↓ ↓↓ ↓↓ ↓ FVC ↓ ↓ ↓ ↓↓ FEV1/FVC ↓ ↓ ↓ →/↑ TLCO → → ↓↓ ↓↓ KCO →/↑ → ↓ →/↓ TLC →/↑ ↑ ↑↑ ↓ RV →/↑ ↑ ↑↑ ↓ (RV = residual volume; TLC = total lung capacity; see text for other abbreviations) Fig. 17.8 Changes in blood [H+], PaCO2 and plasma [HCO3 −] in acid–base disorders. The rectangle indicates normal limits for [H+] and PaCO2. The bands represent 95% confidence limits of single disturbances in human blood. To determine the likely cause of an acid–base disorder, plot the values of [H+] and PaCO2 from an arterial blood gas measurement.. The diagram indicates whether any acidosis or alkalosis results primarily from a respiratory disorder of PaCO2 or from a metabolic derangement. Reprinted with permission from Elsevier (Flenley D. Lancet 1971; 1:1921). Arterial PaCO2 Reference range 95% Confidence limits Acute respiratory acidosis

Resp. alkalosis pH [HCO3 – ] mmol/L

7.0 7.1 7.2 7.3 7.4

7.5 7.6 [H+] nmol/L kPa mmHg Metabolic acidosis Chronic respiratory acidosis Metabolic alkalosis

556 • RESPIRATORY MEDICINE an inspiratory noise (stridor) indicates partial obstruction of a major airway (e.g. laryngeal oedema, tracheal tumour, scarring, compression or inhaled foreign body) and requires urgent investigation and treatment. Sputum production is common in patients with acute or chronic cough, and its nature and appearance can provide clues to the aetiology (p. 546). Aetiology Acute transient cough is most commonly caused by viral lower respiratory tract infection, post-nasal drip resulting from rhinitis or sinusitis, aspiration of a foreign body, or throat-clearing secondary to laryngitis or pharyngitis. When cough occurs in the context of more serious diseases, such as pneumonia, aspiration, congestive heart failure or pulmonary embolism, it is usually easy to diagnose from other clinical features. Patients with chronic cough present more of a challenge, especially when physical examination, chest X-ray and lung function studies are normal. In this context, it is most often explained by cough-variant asthma (where cough may be the principal or exclusive clinical manifestation), post-nasal drip secondary to nasal or sinus disease, or gastro-oesophageal reflux disease (GORD) with aspiration. Diagnosis of the latter may require oesophageal pH monitoring or a prolonged trial of anti-reflux therapy (p. 793). Between 10% and 15% of patients (particularly women) taking angiotensin-converting enzyme (ACE) inhibitors develop a drug-induced chronic cough. Bordetella pertussis infection in adults (p. 582) can result in cough lasting up to 3 months. While most patients with lung cancer have an abnormal chest X-ray on presentation, fibreoptic bronchoscopy or thoracic CT is advisable in most adults (especially smokers) with otherwise unexplained cough of recent onset, as this may reveal a small endobronchial tumour or unexpected foreign body (see Fig. 10.2, p. 179). In a small percentage of patients, dry cough may be the presenting feature of interstitial lung disease. Adapted from Munro JF, Campbell IW. Macleod’s Clinical examination, 10th edn. Edinburgh: Churchill Livingstone, Elsevier Ltd; 2000. 17.5 Cough Origin Common causes Clinical features Pharynx Post-nasal drip History of chronic rhinitis Larynx Laryngitis, tumour, whooping cough, croup Voice or swallowing altered, harsh or painful cough Paroxysms of cough, often associated with stridor Trachea Tracheitis Raw retrosternal pain with cough Bronchi Bronchitis (acute) and chronic obstructive pulmonary disease (COPD) Dry or productive, worse in mornings Asthma Usually dry, worse at night Eosinophilic bronchitis Features similar to asthma but airway hyper-reactivity absent Lung cancer Persistent (often with haemoptysis) Lung parenchyma Tuberculosis Productive (often with haemoptysis) Pneumonia Dry initially, productive later Bronchiectasis Productive, changes in posture induce sputum production Pulmonary oedema Often at night (may be productive of pink, frothy sputum) Interstitial fibrosis Dry and distressing Drug side-effect Angiotensin-converting enzyme (ACE) inhibitors Dry cough Aspiration Gastro-oesophageal reflux disease (GORD) History of acid reflux, heartburn, hiatus hernia Obesity assessment of oxygen saturation in patients and its response to oxygen therapy. Exercise tests Resting measurements may be unhelpful in early disease or in patients complaining only of exercise-induced symptoms. Exercise testing with spirometry before and after can help to reveal exercise-induced asthma. Walk tests include the self-paced 6-minute walk and the externally paced incremental ‘shuttle’ test, where patients walk at increasing pace between two cones 10 m apart. These provide simple, repeatable assessments of disability and response to treatment. Cardiopulmonary bicycle exercise testing, with measurement of metabolic gas exchange, ventilation and ECG changes, is useful for quantifying exercise limitation and detecting occult cardiovascular or respiratory limitation in a breathless patient. Presenting problems in respiratory disease Cough Cough is the most frequent symptom of respiratory disease and is caused by stimulation of sensory nerves in the mucosa of the pharynx, larynx, trachea and bronchi. Acute sensitisation of the normal cough reflex occurs in a number of conditions and it is typically induced by changes in air temperature or exposure to irritants, such as cigarette smoke or perfumes. Distinguishing characteristics of various causes of cough are detailed in Box 17.5. The explosive quality of a normal cough is lost in patients with respiratory muscle paralysis or vocal cord palsy. Paralysis of a single vocal cord gives rise to a prolonged, low-pitched, inefficient ‘bovine’ cough accompanied by hoarseness. Coexistence of

Presenting problems in respiratory disease • 557

Individual patients differ greatly in the intensity of breathlessness reported for a given set of circumstances, but breathlessness scores during exercise within individuals are reproducible and can be used to monitor the effects of therapy. Differential diagnosis Patients with breathlessness present either with chronic exertional symptoms or as an emergency with acute breathlessness, when symptoms are prominent even at rest. The causes can be classified accordingly (Box 17.6). Chronic exertional breathlessness The cause of breathlessness is often apparent from a careful clinical history. Key questions are detailed below. How is your breathing at rest and overnight? In COPD, there is a fixed, structural limit to maximum ventilation, and a tendency for progressive hyperinflation during exercise. Breathlessness is apparent mainly when walking and patients usually report minimal symptoms at rest and overnight. In contrast, patients with significant asthma are often woken from their sleep by breathlessness with chest tightness and wheeze. Orthopnoea is common in COPD, as well as in heart disease, because airflow obstruction is made worse by cranial displacement of the diaphragm by the abdominal contents when recumbent, so many patients choose to sleep propped up. Thus it is not a useful differentiating symptom unless there is a clear history of previous angina or infarction to suggest cardiac disease. Breathlessness Breathlessness or dyspnoea can be defined as the feeling of an uncomfortable need to breathe. It is unusual among sensations, as it has no defined receptors, no localised representation in the brain, and multiple causes both in health (e.g. exercise) and in diseases of the lungs, heart or muscles. Pathophysiology Stimuli to breathing resulting from disease processes are shown in Figure 17.9. Respiratory diseases can stimulate breathing and dyspnoea by: • stimulating intrapulmonary sensory nerves (e.g. pneumothorax, interstitial inflammation and pulmonary embolus) • increasing the mechanical load on the respiratory muscles (e.g. airflow obstruction or pulmonary fibrosis) • causing hypoxia, hypercapnia or acidosis, which stimulate chemoreceptors. In cardiac failure, pulmonary congestion reduces lung compliance and can also obstruct the small airways. Reduced cardiac output also limits oxygen supply to the skeletal muscles during exercise, causing early lactic acidaemia and further stimulating breathing via the central chemoreceptors. Breathlessness and the effects of treatment can be quantified using a symptom scale. Patients tend to report breathlessness in proportion to the sum of the above stimuli to breathing. Fig. 17.9 Respiratory stimuli contributing to breathlessness. Mechanisms by which disease can stimulate the respiratory motor neurons in the medulla. Breathlessness is usually felt in proportion to the sum of these stimuli. Further explanation is given on page 179. (CSF = cerebrospinal fluid; Vࡆ/Qࡆ = ventilation/perfusion match) Breathlessness Limbic drives (emotion) Cortical drive Carotid body (↓PaO2, ↑PaCO2) IX Central chemoreceptors (↓CSF pH) Spinal afferents Vagal lung afferents Type II respiratory failure, ↑PaCO2 + acidosis Airway obstruction • Asthma • Emphysema Pulmonary fibrosis Increased mechanical load Altered V/Q Hypoxaemia Pulmonary embolus Interstitial disease • Inflammation • Infection • Fibrosis Deflation • Pneumothorax • Collapse • Effusion

558 • RESPIRATORY MEDICINE questionnaire can be used to score some of the typical symptoms of hyperventilation (Box 17.7). Arterial blood gases show normal PO2, low PCO2 and alkalosis. Pleuritic chest pain in a patient with chronic breathlessness, particularly if it occurs in more than one site over time, should raise suspicion of thromboembolic disease. Thromboembolism may occasionally present as chronic breathlessness with no other specific features and should always be considered before a diagnosis of psychogenic hyperventilation is made. Morning headache is an important symptom in patients with breathlessness, as it may signal the onset of carbon dioxide retention and respiratory failure. This is particularly significant in patients with musculoskeletal disease impairing respiratory function (e.g. kyphoscoliosis or muscular dystrophy). Acute severe breathlessness This is one of the most common and dramatic medical emergencies. Although respiratory causes are common, it can result from cardiac disease, metabolic disease or poisoning causing acidosis, or from psychogenic causes. The approach to patients with acute severe breathlessness is covered on page 179. Chest pain Chest pain can result from cardiac, respiratory, oesophageal or musculoskeletal disorders. The approach to this common symptom is covered on page 176. How much can you do on a good day? Noting ‘breathless on exertion’ is not enough; the approximate distance the patient can walk on the level should be documented, along with capacity to climb inclines or stairs. Variability within and between days is a hallmark of asthma; in mild asthma, the patient may be free of symptoms and signs when well. Gradual, progressive loss of exercise capacity over months and years, with consistent disability over days, is typical of COPD. When asthma is suspected, the degree of variability is best documented by home peak flow monitoring. Relentless, progressive breathlessness that is also present at rest, often accompanied by a dry cough, suggests interstitial fibrosis. Impaired left ventricular function can also cause chronic exertional breathlessness, cough and wheeze. A history of angina, hypertension or myocardial infarction raises the possibility of a cardiac cause. This may be confirmed by a displaced apex beat, a raised JVP and cardiac murmurs (although these signs can occur in severe hypoxic lung disease with fluid retention). The chest X-ray may show cardiomegaly and an ECG and echocardiogram may provide evidence of left ventricular disease. Measurement of arterial blood gases may help, as, in the absence of an intracardiac shunt or pulmonary oedema, the PaO2 in cardiac disease is normal and the PaCO2 is low or normal. Did you have breathing problems in childhood or at school? When present, a history of childhood wheeze increases the likelihood of asthma, although this history may be absent in late-onset asthma. A history of atopic allergy also increases the likelihood of asthma. Do you have other symptoms along with your breathlessness? Digital or perioral paraesthesiae and a feeling that ‘I cannot get a deep enough breath in’ are typical features of psychogenic hyperventilation but this cannot be diagnosed until investigations have excluded other potential causes. Additional symptoms include lightheadedness, central chest discomfort or even carpopedal spasm due to acute respiratory alkalosis. These alarming symptoms may provoke further anxiety and exacerbate hyperventilation. Psychogenic breathlessness rarely disturbs sleep, frequently occurs at rest, may be provoked by stressful situations and may even be relieved by exercise. The Nijmegen 17.7 Factors suggesting psychogenic hyperventilation • ‘Inability to take a deep breath’ • Frequent sighing/erratic ventilation at rest • Short breath-holding time in the absence of severe respiratory disease • Difficulty in performing and/or inconsistent spirometry measures • High score (over 26) on Nijmegen questionnaire • Induction of symptoms during submaximal hyperventilation • Resting end-tidal CO2 < 4.5% • Associated digital and/or perioral paraesthesiae 17.6 Causes of breathlessness System Acute dyspnoea Chronic exertional dyspnoea Cardiovascular *Acute pulmonary oedema (p. 463) Chronic heart failure (p. 463) Myocardial ischaemia (angina equivalent) (p. 180) Respiratory *Acute severe asthma *Acute exacerbation of COPD *Pneumothorax *Pneumonia *Pulmonary embolus ARDS Inhaled foreign body (especially in children) Lobar collapse Laryngeal oedema (e.g. anaphylaxis) *COPD *Chronic asthma Lung cancer Interstitial lung disease (sarcoidosis, fibrosing alveolitis, extrinsic allergic alveolitis, pneumoconiosis) Chronic pulmonary thromboembolism Lymphangitis carcinomatosis (may cause intolerable breathlessness) Large pleural effusion(s) Others Metabolic acidosis (e.g. diabetic ketoacidosis, lactic acidosis, uraemia, overdose of salicylates, ethylene glycol poisoning) Psychogenic hyperventilation (anxiety- or panic-related) Severe anaemia Obesity Deconditioning *Denotes a common cause. (ARDS = acute respiratory distress syndrome; COPD = chronic obstructive pulmonary disease)

Presenting problems in respiratory disease • 559

vascular condition, e.g. arteriovenous shunts for dialysis. It is sometimes congenital but in over 90% of patients it indicates a serious underlying disorder. The most common underlying causes are suppurative or malignant lung disease but a variety of other conditions can cause clubbing (Box 17.8). Clubbing may recede if the underlying condition resolves, e.g. following lung transplantation for cystic fibrosis. Haemoptysis Coughing up blood, irrespective of the amount, is an alarming symptom and patients nearly always seek medical advice. Care should be taken to establish that it is true haemoptysis and not haematemesis, or gum or nose bleeding. Haemoptysis must always be assumed to have a serious cause until this is excluded (Box 17.9). Many episodes of haemoptysis remain unexplained, even after full investigation, and are likely to be due to simple bronchial infection. A history of repeated small haemoptysis, or bloodstreaking of sputum, is highly suggestive of lung cancer. Fever, night sweats and weight loss suggest tuberculosis. Pneumococcal pneumonia often causes ‘rusty’-coloured sputum but can cause frank haemoptysis, as can all suppurative pneumonic infections, including lung abscess (p. 586). Bronchiectasis (p. 578) and intracavitary mycetoma (p. 597) can cause catastrophic bronchial haemorrhage, and in these patients there may be a history of previous tuberculosis or pneumonia in early life. Finally, pulmonary thromboembolism is a common cause of haemoptysis and should always be considered. Physical examination may reveal additional clues. Finger clubbing suggests lung cancer or bronchiectasis; other signs of malignancy, such as cachexia, hepatomegaly and lymphadenopathy, should also be sought. Fever, pleural rub and signs of consolidation occur in pneumonia or pulmonary infarction; a minority of patients with pulmonary infarction also have unilateral leg swelling or pain suggestive of deep venous Finger clubbing Finger clubbing describes painless swelling of the soft tissues of the terminal phalanges, causing increased longitudinal and lateral convexity of the nail (Fig. 17.10). Upward displacement of the proximal nail margin causes the anteroposterior diameter of the finger at that point to exceed that at the distal interphalangeal joint. It also removes the normal hyponychial angle between the proximal part of the nail and the adjoining skin. Clubbing usually affects the fingers symmetrically and commonly also involves the toes, but can be unilateral if caused by a proximal Fig. 17.10 Finger clubbing. A Anterior view. B Lateral view. From Douglas G, Nicol F, Robertson C. Macleod’s Clinical examination, 13th edn. Edinburgh: Churchill Livingstone, Elsevier Ltd; 2013. A B 17.8 Differential diagnosis of finger clubbing Congenital or familial (5–10%) Acquired Thoracic (~80%) • Chronic suppurative conditions: Pulmonary tuberculosis Bronchiectasis Lung abscess Empyema Cystic fibrosis • Tumours: Lung cancer Mesothelioma Fibroma • Pulmonary fibrosis Cardiovascular • Cyanotic congenital heart disease • Infective endocarditis • Arteriovenous shunts and aneurysms Gastrointestinal • Cirrhosis • Inflammatory bowel disease • Coeliac disease Others • Thyrotoxicosis (thyroid acropachy) • Primary hypertrophic osteoarthropathy 17.9 Causes of haemoptysis Bronchial disease • Cancer* • Bronchiectasis* • Acute bronchitis* • Bronchial adenoma • Foreign body Parenchymal disease • Tuberculosis* • Suppurative pneumonia • Parasites (e.g. hydatid disease, flukes) • Lung abscess • Trauma • Actinomycosis • Mycetoma Lung vascular disease • Pulmonary infarction* • Goodpasture’s syndrome (p. 612) • Polyarteritis nodosa • Idiopathic pulmonary haemosiderosis Cardiovascular disease • Acute left ventricular failure* • Mitral stenosis • Aortic aneurysm Blood disorders • Leukaemia • Haemophilia • Anticoagulants *More common causes.

560 • RESPIRATORY MEDICINE The ‘incidental’ pulmonary nodule A pulmonary nodule may be defined as a well or poorly circumscribed, approximately rounded structure that appears on imaging as a focal opacity less than 3 cm in diameter that is surrounded by aerated lung. The increased use of helical multi-detector CT (Fig 17.12) has been accompanied by an epidemic of ‘incidental’ pulmonary nodules. Nodules must not be dismissed as ‘incidental’, however, until an important and treatable infective or malignant condition in its earliest stage is excluded or stability over at least 2 years has been demonstrated. The list of potential causes of pulmonary nodules is extensive and most are benign (Box 17.10). Features on a CT scan consistent with a benign lesion include being less than 5 mm in diameter or less than 80 mm3 in volume; diffuse, central, laminated or popcorn calcification; or the presence of macroscopic fat. In addition, perifissural lymph nodes and subpleural nodules with a lentiform or triangular shape do not require any further investigation. In cases where a benign lesion cannot be confidently assumed, further assessment depends on both the appearance of the nodule and the clinical context. These assessments may be aided by the use of computer prediction models (Box 17.11). thrombosis. Rashes, haematuria and digital infarcts point to an underlying systemic disease, such as a vasculitis, which may be associated with haemoptysis. Management In severe acute haemoptysis, the patient should be nursed upright (or on the side of the bleeding, if this is known), given high-flow oxygen and resuscitated as required. Bronchoscopy in the acute phase is difficult and often merely shows blood throughout the bronchial tree. Infusions of the antifibrinolytic agent tranexamic acid or the vasopressin precursor terlipressin may help to limit bleeding but evidence of efficacy is limited. If radiology shows an obvious central cause, then rigid bronchoscopy under general anaesthesia may allow intervention to stop bleeding; however, the source often cannot be visualised. Intubation with a divided endotracheal tube may allow protected ventilation of the unaffected lung to stabilise the patient. Bronchial arteriography and embolisation (Fig. 17.11), or even emergency surgery, can be life-saving in the acute situation. In the vast majority of cases, however, the haemoptysis itself is not life-threatening and a logical sequence of investigations can be followed: • chest X-ray, which may provide evidence of a localised lesion, including tumour (malignant or benign), pneumonia, mycetoma or tuberculosis • full blood count (FBC) and clotting screen • bronchoscopy after acute bleeding has settled, which may reveal a central lung cancer (not visible on the chest X-ray) and permit biopsy and tissue diagnosis • CTPA, which may show underlying pulmonary thromboembolic disease or alternative causes not seen on the chest X-ray (e.g. pulmonary arteriovenous malformation or small or hidden tumours). Fig. 17.11 Bronchial artery angiography. An angiography catheter has been passed via the femoral artery and aorta into an abnormally dilated right bronchial artery (arrows). Contrast is seen flowing into the lung. This patient had post-tuberculous bronchiectasis and presented with massive haemoptysis. Bronchial artery embolisation was successfully performed. Fig. 17.12 Thoracic CT scan showing a solitary pulmonary nodule identified in the right upper lobe (arrow). 17.10 Causes of pulmonary nodules Common causes • Lung cancer • Single metastasis • Localised pneumonia • Lung abscess • Tuberculoma • Pulmonary infarct Uncommon causes • Benign tumour • Lymphoma • Arteriovenous malformation • Hydatid cyst (p. 298) • Bronchogenic cyst • Rheumatoid nodule • Granulomatosis with polyangiitis (Wegener’s granulomatosis) • Pulmonary sequestration • Pulmonary haematoma • ‘Pseudotumour’ – fluid collection in a fissure • Aspergilloma (usually surrounded by air crescent) • Cryptococcus • Aspergillus nodule

Presenting problems in respiratory disease • 561

17.11 Clinical and radiographic features distinguishing benign from malignant nodules* Feature Risk of malignancy Feature Risk of malignancy Characteristics of nodule Characteristics of patient Size Nearly all > 3 cm but fewer than 1% < 4 mm are malignant Age Increases with age and is uncommon below age of 40 Margin Usually smooth in benign lesions Smoking history Increases in proportion to duration and amount smoked Spiculated suggests malignancy Other Increased by history of lung cancer in first-degree relative and by exposure to asbestos, silica, uranium and radon Calcification or fat Laminated or central deposition of calcification suggests granuloma ‘Popcorn’ pattern suggests hamartoma Fat may suggest hamartoma or lipoid granuloma Location 70% of lung cancers occur in upper lobes Benign lesions are equally distributed throughout upper and lower lobes *Linear or sheet-like lung opacities are unlikely to represent neoplasms and do not require follow-up. Some nodular opacities may be sufficiently typical of scarring for follow-up not to be warranted. Adapted from MacMahon H, Austin JH, Gamsu G, et al. Guidelines for management of small pulmonary nodules detected on CT scans: a statement from the Fleischner Society. Radiology 2005; 237:395–400. Fig. 17.13 Recommendations on the assessment of a solid pulmonary nodule. A Initial approach to solid pulmonary nodules. The Brock model is an online calculator that can also be downloaded as an app (https://brocku.ca/lung-cancer-risk-calculator). The model integrates data on age, sex, family history of cancer, the presence of emphysema, nodule size, nodule type, nodule position, nodule count and speculation, and calculates the probability that a nodule will become malignant within a 2- to 4-year follow-up period. Herder is a similar model. Consider positron emission tomography–computed tomography (PET-CT) for larger nodules in young patients with low risk by Brock score, as this score was developed in a screening cohort (50–75 years) and so performance in younger patients is unproven. Continues overleaf. Solid non-calcified nodule(s) on CT Previous imaging? <10% risk of malignancy ≥10% risk of malignancy 10–70% risk of malignancy <10% risk of malignancy

70% risk of malignancy Consider excision or non-surgical treatment (± image-guided biopsy) CT surveillance ( Fig. 17.13B) Discharge Yes Assess risk of lung cancer according to Fig. 17.13B Yes Yes No Nodule <8mm diameter or <300mm3 volume? No Assess risk using Brock model No Clear features of benign disease (e.g. hamartoma, typical perifissural nodule), or nodule <5mm diameter (or <80mm3) or patient unfit for any treatment PET-CT with risk assessment using Herder model (provided size is greater than local PET-CT threshold) Consider image-guided biopsy; other options are excision biopsy or CT surveillance guided by individual risk and patient preference A

562 • RESPIRATORY MEDICINE Baseline volumetric analysis (or diameter measurement if volumetry not available/technically impossible) ≥80mm3 volume or ≥6mm diameter 5–6mm diameter CT 1 year after baseline CT 3 months after baseline VDT ≤400 days or clear evidence of growth? VDT ≤400 days or clear evidence of growth Stable on basis of 2D non-automated diameter value Stable on basis of volumetry VDT

600 days VDT 400–600 days Further workup and consideration of definitive management CT 2 years after baseline VDT assessment and manage as per VDT categories at 1 year Discharge if stable Discharge Consider discharge (only if based on volumetry) or ongoing surveillance depending on patient preference Consider biopsy or further CT surveillance depending on patient preference Yes No B B Solid pulmonary nodule surveillance algorithm. (VDT = volume doubling time) From Callister ME, Baldwin DR, Akram AR, et al. British Thoracic Society Guidelines on the investigation and management of pulmonary nodules. Thorax 2015; Suppl. 2:ii1–ii54. Fig. 17.13, cont’d A variety of diagnostic approaches may be considered, including bronchoscopy, percutaneous needle biopsy, PET, interval CT scanning or even surgical resection of the lesion. Pulmonary nodules are invariably beyond the vision of the bronchoscope and, with the notable exception of pulmonary infection (e.g. tuberculosis), the yield from blind washings is low, although this may improve as advances in endobronchial imaging are adopted. If the nodule is favourably located and of sufficient size, percutaneous needle biopsy under ultrasound or CT guidance may be employed. The risk of pneumothorax is approximately 15% and around 7% require intercostal drainage, so this should be contemplated only in individuals with an FEV1 of more than 35% predicted. Haemorrhage into the lung or pleural space, air embolism and tumour seeding are rare but recognised complications. Where clinical suspicion remains high despite a benign or indeterminate biopsy or where a nodule is considered to be of sufficiently high risk for malignancy to merit proceeding straight to surgery, then surgical resection may be the best management, as surgery remains the best chance of curing lung cancer. It is important for the logic underlying this approach to be discussed with the patient and the consequences of resection of a benign lesion explained. PET scanning provides useful information about nodules of at least 1 cm in diameter. The presence of high metabolic activity is strongly suggestive of malignancy, while an inactive ‘cold’ nodule is consistent with benign disease. However, a high SUV is a marker of glucose metabolism, not malignancy, and PET has significant limitations in regions with high endemic rates of infectious or granulomatous disease. False-negative results may occur with neuro-endocrine tumours and minimally invasive lepidic adenocarcinoma. Detection of neuro-endocrine tumours may be improved by the use of 68Ga-Dotatoc in place of FDG. If the nodule is small and inaccessible, interval CT scanning may be employed. A repeat CT scan at 3 months will reliably detect growth in larger nodules and may also demonstrate resolution. Further interval scans may be arranged, depending on the clinical context (Fig. 17.13). Particular care must be taken with subsolid nodules, particularly if further imaging demonstrates the development of a new solid component, as these may represent a pre-malignant or an early invasive form of adenocarcinoma. In cases where the probability of cancer is low, the potential risk of further scanning must be considered. Subsequent scans often detect further nodules, increase the risk of false-positive findings and lead to unnecessary patient anxiety while exposing the individual to increased radiation. Pleural effusion The accumulation of serous fluid within the pleural space is termed pleural effusion. The accumulation of frank pus is termed empyema (p. 564), that of blood is haemothorax, and that of chyle is a chylothorax. In general, pleural fluid accumulates as a result of either increased hydrostatic pressure or decreased osmotic pressure (‘transudative’ effusion, as seen in cardiac, liver or renal failure), or from increased microvascular pressure due to disease of the pleura or injury in the adjacent lung (‘exudative’

Presenting problems in respiratory disease • 563

17.13 Pleural effusion: main causes and features Cause Appearance of fluid Type of fluid Predominant cells in fluid Other diagnostic features Tuberculosis Serous, usually amber-coloured Exudate Lymphocytes (occasionally polymorphs) Positive tuberculin test Isolation of Mycobacterium tuberculosis from pleural fluid (20%) Positive pleural biopsy (80%) Raised adenosine deaminase Malignant disease Serous, often blood-stained Exudate Serosal cells and lymphocytes Often clumps of malignant cells Positive pleural biopsy (40%) Evidence of malignancy elsewhere Cardiac failure Serous, strawcoloured Transudate Few serosal cells Other signs of cardiac failure Response to diuretics Pulmonary infarction Serous or blood-stained Exudate (rarely transudate) Red blood cells Eosinophils Evidence of pulmonary infarction Obvious source of embolism Factors predisposing to venous thrombosis Rheumatoid disease Serous Turbid if chronic Exudate Lymphocytes (occasionally polymorphs) Rheumatoid arthritis: rheumatoid factor and anti-cyclic citrullinated peptide (anti-CCP) antibodies Cholesterol in chronic effusion; very low glucose in pleural fluid Systemic lupus erythematosus (SLE) Serous Exudate Lymphocytes and serosal cells Other signs of SLE Antinuclear factor or anti-DNA positive Acute pancreatitis Serous or blood-stained Exudate No cells predominate Higher amylase in pleural fluid than in serum Obstruction of thoracic duct Milky Chyle None Chylomicrons May cause bilateral effusions. 17.12 Causes of pleural effusion Common causes • Pneumonia (‘parapneumonic effusion’) • Tuberculosis • Pulmonary infarction • Malignant disease • Cardiac failure* • Subdiaphragmatic disorders (subphrenic abscess, pancreatitis etc.) Uncommon causes • Hypoproteinaemia* (nephrotic syndrome, liver failure, malnutrition) • Connective tissue diseases* (particularly systemic lupus erythematosus and rheumatoid arthritis) • Post-myocardial infarction syndrome • Acute rheumatic fever • Meigs’ syndrome (ovarian tumour plus pleural effusion) • Myxoedema* • Uraemia* • Asbestos-related benign pleural effusion effusion). The causes of the majority of pleural effusions (Boxes 17.12 and 17.13) are identified by a thorough history, examination and relevant investigations. Clinical assessment Symptoms (pain on inspiration and coughing) and signs of pleurisy (a pleural rub) often precede the development of an effusion, especially in patients with underlying pneumonia, pulmonary infarction or connective tissue disease. When breathlessness is the only symptom, however, the onset may be insidious, depending on the size and rate of accumulation. The physical signs are detailed on page 547. Investigations Radiological investigations The classical appearance of pleural fluid on the erect PA chest film is of a curved shadow at the lung base, blunting the costophrenic angle and ascending towards the axilla (p. 547). Fluid appears to track up the lateral chest wall. In fact, fluid surrounds the whole lung at this level but casts a radiological shadow only where the X-ray beam passes tangentially across the fluid against the lateral chest wall. Around 200 mL of fluid is required in order for it to be detectable on a PA chest X-ray. Previous scarring or adhesions in the pleural space can cause localised effusions. Pleural fluid localised below the lower lobe (‘subpulmonary effusion’) simulates an elevated hemidiaphragm. Pleural fluid localised within an oblique fissure may produce a rounded opacity that may be mistaken for a tumour. Ultrasound is more accurate than plain chest X-ray for determining the presence of fluid. A clear hypoechoic space is consistent with a transudate and the presence of moving, floating densities suggests an exudate. The presence of septation most likely indicates an evolving empyema or resolving haemothorax. CT scanning is indicated where malignant disease i s suspected. Pleural aspiration and biopsy In some conditions (e.g. left ventricular failure), it should not be necessary to sample fluid unless atypical features are present; appropriate treatment should be administered and the effusion re-evaluated. In most other circumstances, however, diagnostic sampling is required. Simple aspiration provides information on the colour and texture of fluid and these alone may immediately suggest an empyema or chylothorax. The presence of blood is consistent with pulmonary infarction or malignancy but may result from a traumatic tap. Biochemical analysis allows classification into

564 • RESPIRATORY MEDICINE Fig. 17.14 Chest X-ray showing a ‘D’-shaped shadow in the left mid-zone, consistent with an empyema. In this case, an intercostal chest drain has been inserted but the loculated collection of pus remains. 17.15 Clinical features of empyema Systemic features • Pyrexia, usually high and remittent • Rigors, sweating, malaise and weight loss • Polymorphonuclear leucocytosis, high C-reactive protein Local features • Pleural pain; breathlessness; cough and sputum, usually because of underlying lung disease; copious purulent sputum if empyema ruptures into a bronchus (bronchopleural fistula) • Clinical signs of pleural effusion 17.14 Light’s criteria for distinguishing pleural transudate from exudate Exudate is likely if one or more of the following criteria are met: • Pleural fluid protein:serum protein ratio > 0.5 • Pleural fluid LDH:serum LDH ratio > 0.6 • Pleural fluid LDH > two-thirds of the upper limit of normal serum LDH (LDH = lactate dehydrogenase) transudate and exudate (Box 17.14) and Gram stain may suggest parapneumonic effusion. The predominant cell type provides useful information and cytological examination is essential. A low pH suggests infection but may also be seen in rheumatoid arthritis, ruptured oesophagus or advanced malignancy. Ultrasound- or CT-guided pleural biopsy provides tissue for pathological and microbiological analysis. Where necessary, video-assisted thoracoscopy allows visualisation of the pleura and direct guidance of a biopsy. Management Therapeutic aspiration may be required to palliate breathlessness but removing more than 1.5 L at a time is associated with a small risk of re-expansion pulmonary oedema. An effusion should never be drained to dryness before establishing a diagnosis, as biopsy may be precluded until further fluid accumulates. Treatment of the underlying cause – e.g. heart failure, pneumonia, pulmonary embolism or subphrenic abscess – will often be followed by resolution of the effusion. The management of pleural effusion in pneumonia, tuberculosis and malignancy is dealt with below. Empyema This is a collection of pus in the pleural space, which may be as thin as serous fluid or so thick that it is impossible to aspirate, even through a wide-bore needle. Microscopically, neutrophil leucocytes are present in large numbers. An empyema may involve the whole pleural space or only part of it (‘loculated’ or ‘encysted’ empyema) and is usually unilateral. It is always secondary to infection in a neighbouring structure, usually the lung, most commonly due to the bacterial pneumonias and tuberculosis. Over 40% of patients with community-acquired pneumonia develop an associated pleural effusion (‘parapneumonic’ effusion) and about 15% of these become secondarily infected. Other causes are infection of a haemothorax following trauma or surgery, oesophageal rupture, and rupture of a subphrenic abscess through the diaphragm. Both pleural surfaces are covered with a thick, shaggy, inflammatory exudate. The pus in the pleural space is often under considerable pressure, and if the condition is not adequately treated, pus may rupture into a bronchus, causing a bronchopleural fistula and pyopneumothorax, or track through the chest wall with the formation of a subcutaneous abscess or sinus, so-called empyema necessitans. Clinical assessment An empyema should be suspected in patients with pulmonary infection if there is severe pleuritic chest pain or persisting or recurrent pyrexia, despite appropriate antibiotic treatment. In other cases, the primary infection may be so mild that it passes unrecognised and the first definite clinical features are due to the empyema itself. Once an empyema has developed, systemic features are prominent (Box 17.15). Investigations Chest X-ray appearances may be indistinguishable from those of pleural effusion, although pleural adhesions may confine the empyema to form a ‘D’-shaped shadow against the inside of the chest wall (Fig. 17.14). When air is present as well as pus (pyopneumothorax), a horizontal ‘fluid level’ marks the air/liquid interface. Ultrasound shows the position of the fluid, the extent of pleural thickening and whether fluid is in a single collection or multiloculated, containing fibrin and debris (Fig. 17.15). CT provides information on the pleura, underlying lung parenchyma and patency of the major bronchi. Ultrasound or CT is used to identify the optimal site for aspiration, which is best performed using a wide-bore needle. If the fluid is thick and turbid pus, empyema is confirmed. Other features suggesting empyema are a fluid glucose of less than 3.3 mmol/L (60 mg/dL), lactate dehydrogenase (LDH) of more than 1000 IU/L, or a fluid pH of less than 7.0 (H+ > 100 nmol/L). However, pH measurement should be avoided if pus is thick, as it damages blood gas machines. The pus is frequently sterile on culture if antibiotics have already been given. The distinction between tuberculous and non-tuberculous disease can be difficult and may require pleural biopsy, histology, culture and/or a NAAT.

Presenting problems in respiratory disease • 565

preventing re-expansion of the lung. Surgery is also necessary if a bronchopleural fistula develops. Despite the widespread availability of antibiotics that are effective against pneumonia, empyema remains a significant cause of morbidity and mortality. Respiratory failure The term ‘respiratory failure’ is used when pulmonary gas exchange fails to maintain normal arterial oxygen and carbon dioxide levels. Its classification into types I and II is defined by the absence or presence of hypercapnia (raised PaCO2). Pathophysiology When disease impairs ventilation of part of a lung (e.g. in asthma or pneumonia), perfusion of that region results in hypoxic and CO2laden blood entering the pulmonary veins. Increased ventilation of neighbouring regions of normal lung can increase CO2 excretion, correcting arterial CO2 to normal, but cannot augment oxygen uptake because the haemoglobin flowing through these normal regions is already fully saturated. Admixture of blood from the under-ventilated and normal regions thus results in hypoxia with normocapnia, which is called ‘type I respiratory failure’. Diseases causing this include all those that impair ventilation locally with sparing of other regions (Box 17.16). Arterial hypoxia with hypercapnia (type II respiratory failure) is seen in conditions that cause generalised, severe ventilation– perfusion mismatch, leaving insufficient normal lung to correct PaCO2, or any disease that reduces total ventilation. The latter includes not just diseases of the lung but also disorders affecting any part of the neuromuscular mechanism of ventilation (Box 17.16). Management of acute respiratory failure Prompt diagnosis and management of the underlying cause is crucial. In type I respiratory failure, high concentrations of oxygen (40–60% by mask) will usually relieve hypoxia by increasing the alveolar PO2 in poorly ventilated lung units. Occasionally, however (e.g. severe pneumonia affecting several lobes), mechanical ventilation may be needed to relieve hypoxia. Patients who need high concentrations of oxygen for more than a few hours should receive humidified oxygen. Management An empyema will heal only if infection is eradicated and the empyema space is obliterated, allowing apposition of the visceral and parietal pleural layers. This can only occur if re-expansion of the compressed lung is secured at an early stage by removal of all the pus from the pleural space. When the pus is sufficiently thin, this is most easily achieved by the insertion of a wide-bore intercostal tube into the most dependent part of the empyema space. If the initial aspirate reveals turbid fluid or frank pus, or if loculations are seen on ultrasound, the tube should be put on suction (−5 to −10 cmH2O) and flushed regularly with 20 mL normal saline. If the organism causing the empyema can be identified, the appropriate antibiotic should be given for 2–4 weeks. Empirical antibiotic treatment (e.g. intravenous co-amoxiclav or cefuroxime with metronidazole) should be used if the organism is unknown. Intrapleural fibrinolytic therapy is of no benefit. An empyema can often be aborted if these measures are started early, but if the intercostal tube is not providing adequate drainage – e.g. when the pus is thick or loculated – surgical intervention is required to clear the empyema cavity of pus and break down any adhesions. Surgical ‘decortication’ of the lung may also be required if gross thickening of the visceral pleura is Fig. 17.15 Pleural ultrasound showing septation. Courtesy of Dr P. Sivasothy, Department of Respiratory Medicine, Addenbrooke’s Hospital, Cambridge. 17.16 How to interpret blood gas abnormalities in respiratory failure Type I Type II Hypoxia (PaO2 < 8.0 kPa (60 mmHg)) Normal or low PaCO2 (≤ 6 kPa (45 mmHg)) Hypoxia (PaO2 < 8.0 kPa (60 mmHg)) Raised PaCO2 (> 6 kPa (45 mmHg)) Acute Chronic Acute Chronic H+ → → ↑ → or ↑ Bicarbonate → → → ↑ Causes Acute asthma Pulmonary oedema Pneumonia Lobar collapse Pneumothorax Pulmonary embolus ARDS COPD Lung fibrosis Lymphangitic carcinomatosis Right-to-left shunts Acute severe asthma Acute exacerbation of COPD Upper airway obstruction Acute neuropathies/paralysis Narcotic drugs Primary alveolar hypoventilation Flail chest injury COPD Sleep apnoea Kyphoscoliosis Myopathies/muscular dystrophy Ankylosing spondylitis (ARDS = acute respiratory distress syndrome; COPD = chronic obstructive pulmonary disease)

566 • RESPIRATORY MEDICINE due to COPD may not appear distressed, despite being critically ill with severe hypoxaemia, hypercapnia and acidaemia. While the physical signs of CO2 retention (delirium, flapping tremor, bounding pulses and so on) can be helpful if present, they may not be, so measurement of arterial blood gases is mandatory in the assessment of initial severity and response to treatment. Management The principal aims of treatment in acute on chronic type II respiratory failure are to achieve a safe PaO2 (> 7.0 kPa (52 mmHg)) without increasing PaCO2 and acidosis, while identifying and treating the precipitating condition. In these patients, it is not necessary to achieve a normal PaO2; even a small increase will greatly improve tissue oxygen delivery, since their PaO2 values are often on the steep part of the oxygen dissociation curve (see Fig. 10.9, p. 191). The risks of worsening hypercapnia and coma must be balanced against those of severe hypoxaemia, which include potentially fatal arrhythmias and hypoxic brain damage. Immediate treatment is shown in Box 17.17. Patients who are conscious and have adequate respiratory drive may benefit from non-invasive ventilation (NIV), which has been shown to reduce the need for intubation and shorten hospital stay in acidotic exacerbations of COPD. Patients who are drowsy and have low respiratory drive require an urgent decision regarding intubation and ventilation, as this is likely to be the only effective treatment, even though weaning off the ventilator may be difficult in severe disease. The decision is challenging, and important factors to consider include patient and family wishes, presence of a potentially remediable precipitating condition, prior functional Acute type II respiratory failure is an emergency requiring immediate intervention. It is useful to distinguish between patients with high ventilatory drive (rapid respiratory rate and accessory muscle recruitment) who cannot move sufficient air, and those with reduced or inadequate respiratory effort. In the former, particularly if inspiratory stridor is present, acute upper airway obstruction from foreign body inhalation or laryngeal obstruction (angioedema, carcinoma or vocal cord paralysis) must be considered, as the Heimlich manœuvre (p. 625), immediate intubation or emergency tracheostomy may be life-saving. More commonly, the problem is in the lungs, with severe generalised bronchial obstruction from COPD or asthma, acute respiratory distress syndrome (ARDS) arising from a variety of insults (p. 198), or occasionally tension pneumothorax (p. 625). In all such cases, high-concentration (e.g. 60%) oxygen should be administered, pending a rapid examination of the respiratory system and measurement of arterial blood gases. Patients with the trachea deviated away from a silent and resonant hemithorax are likely to have tension pneumothorax, and air should be aspirated from the pleural space and a chest drain inserted as soon as possible. Patients with generalised wheeze, scanty breath sounds bilaterally or a history of asthma or COPD should be treated with salbutamol 2.5 mg nebulised with oxygen, repeated until bronchospasm is relieved. Failure to respond to initial treatment, declining conscious level and worsening respiratory acidosis (H+ > 50 nmol/L (pH < 7.3), PaCO2 > 6.6 kPa (50 mmHg)) on blood gases are all indications that supported ventilation is required (p. 202). A small percentage of patients with severe chronic COPD and type II respiratory failure develop abnormal tolerance to raised PaCO2 and may become dependent on hypoxic drive to breathe. In these patients only, lower concentrations of oxygen (24–28% by Venturi mask) should be used to avoid precipitating worsening respiratory depression (see below). In all cases, regular monitoring of arterial blood gases is important to assess progress. Patients with acute type II respiratory failure who have reduced drive or conscious level may be suffering from sedative poisoning, CO2 narcosis or a primary failure of neurological drive (e.g. following intracerebral haemorrhage or head injury). History from a witness may be invaluable, and reversal of specific drugs with (for example) opiate antagonists is occasionally successful, but should not delay intubation and supported mechanical ventilation in appropriate cases. Chronic and ‘acute on chronic’ type II respiratory failure The most common cause of chronic type II respiratory failure is severe COPD. Although PaCO2 may be persistently raised, there is no persisting acidaemia because the kidneys retain bicarbonate, correcting arterial pH to normal. This ‘compensated’ pattern, which may also occur in chronic neuromuscular disease or kyphoscoliosis, is maintained until there is a further acute illness (Box 17.16), such as an exacerbation of COPD that precipitates an episode of ‘acute on chronic’ respiratory failure, with acidaemia and initial respiratory distress followed by drowsiness and eventually coma. These patients have lost their chemosensitivity to elevated PaCO2, and so they may paradoxically depend on hypoxia for respiratory drive and are at risk of respiratory depression if given high concentrations of oxygen, e.g. during ambulance transfers or in emergency departments. Moreover, in contrast to acute severe asthma, some patients with ‘acute on chronic’ type II respiratory failure 17.17 Assessment and management of ‘acute on chronic’ type II respiratory failure Initial assessment Patient may not appear distressed, despite being critically ill • Conscious level (response to commands, ability to cough) • CO2 retention (warm periphery, bounding pulses, flapping tremor) • Airways obstruction (wheeze, prolonged expiration, hyperinflation, intercostal indrawing, pursed lips) • Cor pulmonale (peripheral oedema, raised jugular venous pressure, hepatomegaly, ascites) • Background functional status and quality of life • Signs of precipitating cause (see Box 17.15) Investigations • Arterial blood gases (severity of hypoxaemia, hypercapnia, acidaemia, bicarbonate) • Chest X-ray Management • Maintenance of airway • Treatment of specific precipitating cause • Frequent physiotherapy ± pharyngeal suction • Nebulised bronchodilators • Controlled oxygen therapy: Start with 24% Venturi mask Aim for a PaO2 > 7 kPa (52 mmHg) (a PaO2 < 5 (37 mmHg) is dangerous) • Antibiotics if evidence of infection • Diuretics if evidence of fluid overload Progress • If PaCO2 continues to rise or a safe PaO2 cannot be achieved without severe hypercapnia and acidaemia, mechanical ventilatory support may be required

Obstructive pulmonary diseases • 567

irradiation are employed to treat obliterative bronchiolitis but late organ failure remains a significant problem. The major factor limiting the availability of lung transplantation is the shortage of donor lungs. To improve organ availability, techniques to recondition the lungs in vitro after removal from the donor are being developed. Obstructive pulmonary diseases Asthma Asthma is a chronic inflammatory disorder of the airways, in which many cells and cellular elements play a role. Chronic inflammation is associated with airway hyper-responsiveness that leads to recurrent episodes of wheezing, breathlessness, chest tightness and coughing, particularly at night and in the early morning. These episodes are usually associated with widespread but variable airflow obstruction within the lung that is often reversible, either spontaneously or with treatment. The prevalence of asthma increased steadily over the latter part of last century. As asthma affects all age groups, it is one of the most common and important long-term respiratory conditions in terms of global years lived with disability (Fig. 17.16). The development and course of asthma and the response to treatment are influenced by genetic determinants, while the rapid rise in prevalence implies that environmental factors are critically important in the development and expression of the disease. The potential role of indoor and outdoor allergens, microbial exposure, diet, vitamins, breastfeeding, tobacco smoke, air pollution and obesity have been explored but no clear consensus has emerged. capacity and quality of life. The various types of non-invasive (via a face or nasal mask) or invasive (via an endotracheal tube) ventilation are detailed on page 202. Respiratory stimulant drugs, such as doxapram, have been superseded by intubation and mechanical ventilation in patients with CO2 narcosis. Home ventilation for chronic respiratory failure NIV is of great value in the long-term treatment of respiratory failure due to spinal deformity, neuromuscular disease and central alveolar hypoventilation. Some patients with advanced lung disease, e.g. cystic fibrosis, also benefit from NIV for respiratory failure. In these conditions, type II respiratory failure can develop slowly and insidiously. Morning headache (due to elevated PaCO2) and fatigue are common symptoms but, in many cases, the diagnosis is revealed only by sleep studies or morning blood gas analysis. In the initial stages, ventilation is insufficient for metabolic needs only during sleep, when there is a physiological decline in ventilatory drive. Over time, however, CO2 retention becomes chronic, with renal compensation of acidosis. Treatment by home-based NIV overnight is often sufficient to restore the daytime PCO2 to normal, and to relieve fatigue and headache. In advanced disease (e.g. muscular dystrophies or cystic fibrosis), daytime NIV may also be required. Lung transplantation Lung transplantation is an established treatment for carefully selected patients with advanced lung disease unresponsive to medical treatment (Box 17.18). Single-lung transplantation may be used for selected patients with advanced emphysema or lung fibrosis. This is contraindicated in patients with chronic bilateral pulmonary infection, such as cystic fibrosis and bronchiectasis, because the transplanted lung is vulnerable to cross-infection in the context of post-transplant immunosuppression, and for these individuals bilateral lung transplantation is the standard procedure. Combined heart–lung transplantation is still occasionally needed for patients with advanced congenital heart disease, such as Eisenmenger’s syndrome, and is preferred by some surgeons for the treatment of primary pulmonary hypertension unresponsive to medical therapy. The prognosis following lung transplantation is improving steadily with modern immunosuppressive drugs: over 50% 10-year survival in some UK centres. Chronic rejection with obliterative bronchiolitis continues to afflict some recipients, however. Glucocorticoids are used to manage acute rejection, but drugs that inhibit cell-mediated immunity specifically, such as ciclosporin, mycophenolate and tacrolimus (p. 89), are used to prevent chronic rejection. Azithromycin, statins and total lymphoid 17.18 Indications for lung transplantation Parenchymal lung disease • Cystic fibrosis • Emphysema • Pulmonary fibrosis • Obliterative bronchiolitis • Langerhans cell histiocytosis (p. 613) • Lymphangioleiomyomatosis (p. 613) Pulmonary vascular disease • Primary pulmonary hypertension • Thromboembolic pulmonary hypertension • Veno-occlusive disease • Eisenmenger’s syndrome (p. 532) Fig. 17.16 The burden of asthma, measured by disability life years (DALYs) per 100 000 population. The burden of asthma is greatest in children approaching adolescence and the elderly. The burden is similar in males and females at ages below 30–34 but at older ages the burden is higher in males. From The Global Asthma Report 2014. Copyright 2014 The Global Asthma Network. 80+ 70–74 75–79 65–69 60–64 55–59 50–54 45–49 40–44 35–39 30–34 25–29 20–24 15–19 10–14 5–9 1–4 DALYs (per 100000)

Females Males Years

568 • RESPIRATORY MEDICINE With increasing severity and chronicity of the disease, remodelling of the airway may occur, leading to fibrosis of the airway wall, fixed narrowing of the airway and a reduced response to bronchodilator medication. Clinical features Typical symptoms include recurrent episodes of wheezing, chest tightness, breathlessness and cough. Asthma is commonly mistaken for a cold or a persistent chest infection (e.g. longer than 10 days). Classical precipitants include exercise, particularly in cold weather, exposure to airborne allergens or pollutants, and viral upper respiratory tract infections. Wheeze apart, there is often very little to find on examination. An inspection for nasal polyps and eczema should be performed. Rarely, a vasculitic rash may suggest eosinophilic granulomatosis with polyangiitis (formerly known as Churg–Strauss syndrome; p. 1043). Patients with mild intermittent asthma are usually asymptomatic between exacerbations. Individuals with persistent asthma report ongoing breathlessness and wheeze but these are variable, with symptoms fluctuating over the course of one day, or from day to day or month to month. Asthma characteristically displays a diurnal pattern, with symptoms and lung function being worse in the early morning. Particularly when poorly controlled, symptoms such as cough and wheeze disturb sleep. Cough may be the dominant symptom in some patients, and the lack of wheeze or breathlessness may lead to a delay in reaching the diagnosis of so-called ‘cough-variant asthma’. Some patients with asthma have a similar inflammatory response in the upper airway. Careful enquiry should be made as to a history of sinusitis, sinus headache, a blocked or runny nose and loss of sense of smell. Although the aetiology of asthma is often elusive, an attempt should be made to identify any agents that may contribute to the appearance or aggravation of the condition. Particular enquiry should be made about potential allergens, such as exposure to a pet cat, guinea pig, rabbit or horse, pest infestation, exposure to moulds following water damage to a home or building, and any potential occupational agents (p. 613). In some circumstances, the appearance of asthma is triggered by medications. Beta-blockers, even when administered topically Pathophysiology Airway hyper-reactivity (AHR) – the tendency for airways to narrow excessively in response to triggers that have little or no effect in normal individuals – is integral to the diagnosis of asthma and appears to be related, although not exclusively, to airway inflammation (Fig. 17.17). Other factors likely to be important in the behaviour of airway smooth muscle include the degree of airway narrowing and neurogenic mechanisms. The relationship between atopy (the propensity to produce IgE) and asthma is well established and in many individuals there is a clear relationship between sensitisation and allergen exposure, as demonstrated by skin-prick reactivity or elevated serum-specific IgE. Common examples of allergens include house dust mites, pets such as cats and dogs, pests such as cockroaches, and fungi. Inhalation of an allergen into the airway is followed by an early and late-phase bronchoconstrictor response (Fig. 17.18). Allergic mechanisms are also implicated in some cases of occupational asthma (p. 613). In cases of aspirin-sensitive asthma, the ingestion of salicylates results in inhibition of the cyclo-oxygenase enzymes, preferentially shunting the metabolism of arachidonic acid through the lipoxygenase pathway with resultant production of the asthmogenic cysteinyl leukotrienes. In exercise-induced asthma, hyperventilation results in water loss from the pericellular lining fluid of the respiratory mucosa, which, in turn, triggers mediator release. Heat loss from the respiratory mucosa may also be important. In persistent asthma, a chronic and complex inflammatory response ensues, characterised by an influx of numerous inflammatory cells, the transformation and participation of airway structural cells, and the secretion of an array of cytokines, chemokines and growth factors. Examination of the inflammatory cell profile in induced sputum samples demonstrates that, although asthma is predominantly characterised by airway eosinophilia, neutrophilic inflammation predominates in some patients while in others scant inflammation is observed: so-called ‘paucigranulocytic’ asthma. Fig. 17.17 Airway hyper-reactivity in asthma. This is demonstrated by bronchial challenge tests with sequentially increasing concentrations of either histamine, or methacholine or mannitol. The reactivity of the airways is expressed as the concentration or dose of either chemical required to produce a specific decrease (usually 20%) in the forced expired volume in 1 second (FEV1) (PC20 or PD20, respectively).

Reduction in FEV1 (%) Increasing concentration of histamine Severe asthma Moderate asthma Mild asthma Normal Fig. 17.18 Changes in peak flow following allergen challenge. A similar biphasic response is observed following a variety of different challenges. Occasionally, an isolated late response is seen with no early reaction. Time (hours) Peak flow (L/min)

Early reaction (type I) Pre-formed mediator release Late reaction (type Il) Inflammatory cell recruitment and activation

Challenge, e.g. allergen

Obstructive pulmonary diseases • 569

available, a peak flow meter may be used. Symptomatic patients should be instructed to record peak flow readings after rising in the morning and before retiring in the evening. A diurnal variation in PEF of more than 20% (the lowest values typically being recorded in the morning) is considered diagnostic, and the magnitude of variability provides some indication of disease severity (Fig. 17.20). A trial of glucocorticoids (e.g. 30 mg daily for 2 weeks) may be useful in establishing the diagnosis, by demonstrating an improvement in either FEV1 or PEF. It is not uncommon for patients whose symptoms are suggestive of asthma to have normal lung function. In these circumstances, the demonstration of AHR by challenge tests may be useful to confirm the diagnosis (see Fig. 17.17). AHR has a high negative predictive value but positive results may be seen in other conditions, such as COPD, bronchiectasis and cystic fibrosis. The use of exercise tests is useful when symptoms are predominantly related to exercise (Fig. 17.21). The diagnosis may be supported by the presence of atopy demonstrated by skin-prick tests or measurement of total and allergen-specific IgE, an FENO (a surrogate of eosinophilic airway inflammation) of ≥ 40 parts per billion in a glucocorticoid-naïve adult, or a peripheral blood eosinophilia. Chest X-ray appearances are often normal but lobar collapse may be seen if mucus occludes a large bronchus and, if accompanied by the presence of flitting infiltrates, may suggest that asthma has been complicated by allergic bronchopulmonary aspergillosis (p. 596). A high-resolution CT scan (HRCT) may be useful to detect bronchiectasis. Management Setting goals Asthma is a chronic condition but may be controlled with appropriate treatment in the majority of patients. The goal of treatment should be to obtain and maintain complete control (Box 17.20) but aims may be modified according to the circumstances as eye drops, may induce bronchospasm, as may aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs). The classical aspirin-sensitive patient is female and presents in middle age with asthma, rhinosinusitis and nasal polyps. Aspirin-sensitive patients may also report symptoms following alcohol and foods containing salicylates. Other medications implicated include the oral contraceptive pill, cholinergic agents and prostaglandin F2α. Betel nuts contain arecoline, which is structurally similar to methacholine and can aggravate asthma. An important minority of patients develop a particularly severe form of asthma and this appears to be more common in women. Allergic triggers are less important and airway neutrophilia predominates. Diagnosis The diagnosis of asthma is predominantly clinical and is based on the combination of the history, lung function and ‘other’ tests, which allows high, intermediate or low probability of asthma to emerge. The approach may vary from patient to patient and may need to be re-evaluated following the introduction of treatment. Supportive evidence is provided by the demonstration of variable airflow obstruction, preferably by using spirometry (Box 17.19) to measure FEV1 and FVC. This identifies the obstructive defect, defines its severity, and provides a baseline for bronchodilator reversibility (Fig. 17.19). If spirometry is not 17.19 How to make a diagnosis of asthma Compatible clinical history plus either/or: • FEV1 ≥ 12% (and 200 mL) increase following administration of a bronchodilator/trial of glucocorticoids. Greater confidence is gained if the increase is > 15% and > 400 mL • > 20% diurnal variation on ≥ 3 days in a week for 2 weeks on PEF diary • FEV1 ≥ 15% decrease after 6 mins of exercise (FEV1 = forced expiratory volume in 1 sec; PEF = peak expiratory flow) Fig. 17.19 Reversibility test. Forced expiratory manœuvres before and 20 minutes after inhalation of a β2-adrenoceptor agonist. Note the increase in forced expiratory volume in 1 second (FEV1) from 1.0 to 2.5 L.

Time (seconds)

Volume expired (L) FEV1 FEV1 20 mins after bronchodilator drug administered 2.5

Before bronchodilator drug administered Fig. 17.20 Serial recordings of peak expiratory flow (PEF) in a patient with asthma. Note the sharp overnight fall (morning dip) and subsequent rise during the day. Following the introduction of glucocorticoids, there is an improvement in PEF rate and reduction of morning dipping.

am am Peak flow (L/min)

pm pm am am pm pm am am pm

Time (days)

Glucocorticoids commenced

570 • RESPIRATORY MEDICINE pet, may effect improvement. House dust mite exposure may be minimised by replacing carpets with floorboards and using miteimpermeable bedding. So far, improvements in asthma control following such measures have been difficult to demonstrate. Many patients are sensitised to several ubiquitous aeroallergens, making avoidance strategies largely impractical. Measures to reduce fungal exposure may be applicable in specific circumstances and medications known to precipitate or aggravate asthma should be avoided. Smoking cessation (p. 94) is particularly important, as smoking not only encourages sensitisation but also induces a relative glucocorticoid resistance in the airway. The stepwise approach to the management of asthma See Figure 17.22. Step 1: Occasional use of inhaled short-acting β2-adrenoreceptor agonist bronchodilators A variety of different inhaled devices are available and the choice of device should be guided by patient preference and competence Fig. 17.21 Exercise-induced asthma. Serial recordings of forced expiratory volume in 1 second (FEV1) in a patient with bronchial asthma before and after 6 minutes of strenuous exercise. Note initial rise on completion of exercise, followed by sudden fall and gradual recovery. Adequate warm-up exercise or pre-treatment with a β2-adrenoceptor agonist, nedocromil sodium or a leukotriene antagonist can protect against exercise-induced symptoms. 3.5 Time (minutes)

FEV1 (L) 3.0 2.5 2.0 Exercise and the patient. Unfortunately, surveys consistently demonstrate that the majority of individuals with asthma report suboptimal control, perhaps reflecting the poor expectations of patients and their clinicians. Whenever possible, patients should be encouraged to take responsibility for managing their own disease. A full explanation of the nature of the condition, the relationship between symptoms and inflammation, the importance of key symptoms such as nocturnal waking, the different types of medication and, if appropriate, the use of PEF to guide management decisions should be given. A variety of tools/questionnaires have been validated to assist in assessing asthma control. Written action plans can be helpful in developing self-management skills. Avoidance of aggravating factors This is particularly important in the management of occupational asthma (p. 613) but may also be relevant in atopic patients, when removing or reducing exposure to relevant antigens, such as a 17.21 Asthma in pregnancy • Clinical course: women with well-controlled asthma usually have good pregnancy outcomes. Pregnancy in women with more severe asthma can precipitate worsening control and lead to increased maternal and neonatal morbidity. • Labour and delivery: 90% have no symptoms. • Safety data: good for β2-agonists, inhaled glucocorticoids, theophyllines, oral prednisolone, and chromones. • Oral leukotriene receptor antagonists: no evidence that these harm the fetus and they should not be stopped in women who have previously demonstrated significant improvement in asthma control prior to pregnancy. • Glucocorticoids: women on maintenance prednisolone > 7.5 mg/ day should receive hydrocortisone 100 mg 3–4 times daily during labour. • Prostaglandin F2α: may induce bronchospasm and should be used with extreme caution. • Breastfeeding: use medications as normal. • Uncontrolled asthma: associated with maternal (hyperemesis, hypertension, pre-eclampsia, vaginal haemorrhage, complicated labour) and fetal (intrauterine growth restriction and low birth weight, preterm birth, increased perinatal mortality, neonatal hypoxia) complications. Characteristic Controlled Partly controlled (any present in any week) Uncontrolled Daytime symptoms None (≤ twice/week)

twice/week ≥ 3 features of partly controlled asthma present in any week Limitations of activities None Any Nocturnal symptoms/awakening None Any Need for rescue/‘reliever’ treatment None (≤ twice/week) twice/week Lung function (PEF or FEV1) Normal < 80% predicted or personal best (if known) on any day Exacerbation None ≥ 1/year 1 in any week (FEV1 = forced expiratory volume in 1 sec; PEF = peak expiratory flow) } 17.20 Levels of asthma control

Obstructive pulmonary diseases • 571

Fig. 17.22 Management approach in adults based on asthma control. (ICS = inhaled corticosteroids (glucocorticoids); LABA = long-acting β2-agonist; LAMA = long-acting muscarinic antagonist; LTRA = leukotriene receptor antagonist; SR = sustained-release) From British Thoracic Society and SIGN guideline 153: British guideline on the management of asthma (2016). Move down to find and maintain lowest controlling therapy Move up to improve control as needed Consider monitored initiation of treatment with low-dose ICS Infrequent, short-lived wheeze Low-dose ICS Short-acting β2 agonists as required – consider moving up if using three doses a week or more Evaluation: • assess symptoms, measure lung function, check inhaler technique and adherence • adjust dose • update self-management plan • move up and down as appropriate Asthma – suspected Asthma – diagnosed Diagnosis and assessment Consider trials of: Increasing ICS up to high dose Addition of a fourth drug, eg LTRA, SR theophylline, beta agonist tablet, LAMA Use daily steroid tablet in the lowest dose providing adequate control Maintain high-dose ICS Consider other treatments to minimize use of steroid tablets Regular preventer Initial add-on therapy Additional add-on therapies High-dose therapies Continuous frequent use of oral steroids Add inhaled LABA to low-dose ICS (normally as a combination inhaler) No response to LABA – stop LABA and consider increased dose of ICS If benefit from LABA but control still inadequate – continue LABA and increase ICS to medium dose If benefit from LABA but control still inadequate – continue LABA and ICS and consider trial of other therapy – LTRA, SR theophylline, LAMA Refer patient for specialist care Refer patient for specialist care Fig. 17.23 How to use a metered-dose inhaler. • Remove the cap and shake the inhaler • Breathe out gently and place the mouthpiece into the mouth • Incline the head backwards to minimise oropharyngeal deposition • Simultaneously, begin a slow deep inspiration, depress the canister and continue to inhale • Hold the breath for 10 seconds (BUD), fluticasone, mometasone or ciclesonide) should be started in addition to inhaled β2-agonists taken on an as-required basis for any patient who: • has experienced an exacerbation of asthma in the last 2 years • uses inhaled β2-agonists three times a week or more • reports symptoms three times a week or more • is awakened by asthma one night per week. For adults, a reasonable starting dose is 400 μg beclometasone dipropionate (BDP) or equivalent per day in adults, although higher doses may be required in smokers. Alternative but much less effective preventive agents include chromones, leukotriene receptor antagonists and theophyllines. Step 3: Add-on therapy If a patient remains poorly controlled despite regular use of an inhaled glucocorticoid, a thorough review should be undertaken of adherence, inhaler technique and ongoing exposure to modifiable aggravating factors. A further increase in the dose of inhaled glucocorticoid may benefit some patients but, in general, add-on therapy should be considered in adults taking 800 μg/day BDP (or equivalent). The addition of a long-acting β2-agonist (LABA) to an inhaled glucocorticoid provides more effective asthma control compared with increasing the dose of inhaled glucocorticoid alone. Fixedcombination inhalers of glucocorticoids and LABAs have been developed; these are more convenient, increase adherence and prevent patients using a LABA as monotherapy – the latter may be accompanied by an increased risk of life-threatening attacks in its use. The metered-dose inhaler remains the most widely prescribed (Fig. 17.23). For patients with mild intermittent asthma (symptoms less than once a week for 3 months and fewer than two nocturnal episodes per month), it is usually sufficient to prescribe an inhaled short-acting β2-agonist, such as salbutamol or terbutaline, to be used as required. However, many patients (and their physicians) under-estimate the severity of asthma. A history of a severe exacerbation should lead to a step-up in treatment. Step 2: Introduction of regular preventer therapy Regular anti-inflammatory therapy (preferably inhaled glucocorticoids (ICS), such as beclometasone, budesonide

572 • RESPIRATORY MEDICINE not necessary, unless glucocorticoid has been given for more than 3 weeks. Indications for ‘rescue’ courses include: • symptoms and PEF progressively worsening day by day, with a fall of PEF below 60% of the patient’s personal best recording • onset or worsening of sleep disturbance by asthma • persistence of morning symptoms until midday • progressively diminishing response to an inhaled bronchodilator • symptoms that are sufficiently severe to require treatment with nebulised or injected bronchodilators. Management of acute severe asthma Box 17.22 highlights the immediate assessment requirements in acute asthma. Measurement of PEF is mandatory, unless the patient is too ill to cooperate, and is most easily interpreted when expressed as a percentage of the predicted normal or of the previous best value obtained on optimal treatment (Fig. 17.24). Arterial blood gas analysis is essential to determine the PaCO2, a normal or elevated level being particularly dangerous. A chest X-ray is not immediately necessary, unless pneumothorax is suspected. Treatment includes the following measures: • Oxygen. High concentrations (humidified if possible) should be administered to maintain the oxygen saturation above 92% in adults. The presence of a high PaCO2 should not be taken as an indication to reduce oxygen concentration but as a warning sign of a severe or life-threatening attack. Failure to achieve appropriate oxygenation is an indication for assisted ventilation. • High doses of inhaled bronchodilators. Short-acting β2-agonists are the agent of choice. In hospital, they are most conveniently given via a nebuliser driven by oxygen, but delivery of multiple doses of salbutamol via a metered-dose inhaler through a spacer device provides equivalent bronchodilatation and can be used in primary care. Ipratropium bromide provides further bronchodilator therapy and should be added to salbutamol in acute severe or life-threatening attacks. or asthma death. The onset of action of formoterol is similar to that of salbutamol such that, in carefully selected patients, a fixed combination of budesonide and formoterol may be used as both rescue and maintenance therapy. Oral leukotriene receptor antagonists (e.g. montelukast 10 mg daily) are generally less effective than LABAs as add-on therapy but may facilitate a reduction in the dose of inhaled glucocorticoid and control exacerbations. Step 4: Poor control on moderate dose of inhaled glucocorticoid and add-on therapy: addition of a fourth drug In adults, the dose of inhaled glucocorticoid may be increased to 2000 μg BDP/BUD (or equivalent) daily. A nasal glucocorticoid preparation should be used in patients with prominent upper airway symptoms. Leukotriene receptor antagonists, long-acting antimuscarinic agents, theophyllines or a slow-release β2-agonist may be considered. If the trial of add-on therapy is ineffective, it should be discontinued. Step 5: Continuous or frequent use of oral glucocorticoids At this stage, prednisolone therapy (usually administered as a single daily dose in the morning) should be prescribed in the lowest amount necessary to control symptoms. Patients who are on long-term glucocorticoid tablets (> 3 months) or are receiving more than three or four courses per year will be at risk of systemic side-effects (p. 670). The risk of osteoporosis in this group can be reduced by giving bisphosphonates (p. 1047). In patients who continue to experience symptoms and asthma exacerbation and demonstrate impaired lung function despite step 5 treatment, omalizumab, a monoclonal antibody directed against IgE, should be considered for those with a prominent atopic phenotype, and mepolizumab, a monoclonal antibody that blocks the binding of IL-5 to its receptor on eosinophils, should be considered in those with eosinophilic-mediated disease. The use of immunosuppressants, such as methotrexate, ciclosporin or oral gold, is less common nowadays, as the response is variable and the limited benefits may be easily offset by side-effects. Step-down therapy Once asthma control is established, the dose of inhaled (or oral) glucocorticoid should be titrated to the lowest dose at which effective control of asthma is maintained. Decreasing the dose of glucocorticoid by around 25–50% every 3 months is a reasonable strategy for most patients. Exacerbations of asthma The course of asthma may be punctuated by exacerbations with increased symptoms, deterioration in lung function, and an increase in airway inflammation. Exacerbations are most commonly precipitated by viral infections but moulds (Alternaria and Cladosporium), pollens (particularly following thunderstorms) and air pollution are also implicated. Most attacks are characterised by a gradual deterioration over several hours to days but some appear to occur with little or no warning: so-called brittle asthma. An important minority of patients appear to have a blunted perception of airway narrowing and fail to appreciate the early signs of deterioration. Management of mild to moderate exacerbations Doubling the dose of inhaled glucocorticoids does not prevent an impending exacerbation. Short courses of ‘rescue’ glucocorticoids (prednisolone 30–60 mg daily) are therefore often required to regain control. Tapering of the dose to withdraw treatment is 17.22 Immediate assessment of acute severe asthma Acute severe asthma • PEF 33–50% predicted (< 200 L/min) • Heart rate ≥ 110 beats/min • Respiratory rate ≥ 25 breaths/min • Inability to complete sentences in 1 breath Life-threatening features • PEF < 33% predicted (< 100 L/min) • SpO2 < 92% or PaO2 < 8 kPa (60 mmHg) (especially if being treated with oxygen) • Normal or raised PaCO2 • Silent chest • Cyanosis • Feeble respiratory effort • Bradycardia or arrhythmias • Hypotension • Exhaustion • Delirium • Coma Near-fatal asthma • Raised PaCO2 and/or requiring mechanical ventilation with raised inflation pressures (PEF = peak expiratory flow)

Obstructive pulmonary diseases • 573

patient, contributes to delay in delivering appropriate therapy and to under-treatment. Prior to discharge, patients should be stable on discharge medication (nebulised therapy should have been discontinued for at least 24 hours) and the PEF should have reached 75% of predicted or personal best. The acute attack should prompt a look for and avoidance of any trigger factors, the delivery of asthma education and the provision of a written self-management plan. The patient should be offered an appointment with a GP or asthma nurse within 2 working days of discharge, and follow-up at a specialist hospital clinic within a month. Chronic obstructive pulmonary disease Chronic obstructive pulmonary disease (COPD) is defined as a preventable and treatable disease characterised by persistent airflow limitation that is usually progressive and associated with an enhanced chronic inflammatory response in the airways • Systemic glucocorticoids. These reduce the inflammatory response and hasten the resolution of an exacerbation. They should be administered to all patients with an acute severe attack. They can usually be administered orally as prednisolone but intravenous hydrocortisone may be used in patients who are vomiting or unable to swallow. There is no evidence base for the use of intravenous fluids but many patients are dehydrated due to high insensible water loss and will probably benefit. Potassium supplements may be necessary, as repeated doses of salbutamol can lower serum potassium. If patients fail to improve, a number of further options may be considered. Intravenous magnesium may provide additional bronchodilatation in patients whose presenting PEF is below 30% predicted. Some patients appear to benefit from the use of intravenous aminophylline but cardiac monitoring is recommended. PEF should be recorded every 15–30 minutes and then every 4–6 hours. Pulse oximetry should ensure that SaO2 remains above 92%, but repeat arterial blood gases are necessary if the initial PaCO2 measurements were normal or raised, the PaO2 was below 8 kPa (60 mmHg) or the patient deteriorates. Box 17.23 lists the indications for endotracheal intubation and intermittent positive pressure ventilation (IPPV). Prognosis The outcome from acute severe asthma is generally good but a considerable number of deaths occur in young people and many are preventable. Failure to recognise the severity of an attack, on the part of either the assessing physician or the Fig. 17.24 Immediate treatment of patients with acute severe asthma. • Check with senior medical staff • Prednisolone 40 mg daily for 5 days • Start or double inhaled glucocorticoids • Return immediately if worse • Appointment with GP within 48 hours • Usual treatment • Return immediately if worse • Appointment with GP within 48 hours Usual inhaled bronchodilator Wait 60 mins Wait 30 mins • Administer repeat salbutamol 5 mg + ipratropium bromide 500 μg by oxygen-driven nebuliser • Consider continuous salbutamol nebuliser 5–10 mg/hr • Consider intravenous magnesium sulphate 1.2–2.0 g over 20 mins, or aminophylline 5 mg/kg loading dose over 20 mins followed by a continuous infusion at 1 mg/kg/hr • Correct fluid and electrolytes (especially K+) Arterial blood gas Nebulised salbutamol 5 mg or terbutaline 2.5 mg Oxygen–high-flow/60% Prednisolone 40 mg orally PEF < 60% predicted PEF > 60% predicted Life-threatening/acute severe MEASURE PEAK EXPIRATORY FLOW Convert PEF to % best or % predicted 0% 50% 51% 75% 76% 100% Mild Moderate Measure PEF Home Admit Home Intravenous access, chest X-ray, plasma theophylline level, plasma K+ Arterial blood gas Nebulised salbutamol 5 mg or terbutaline 2.5 mg 6–12 times daily or as required Oxygen–high-flow/60% Prednisolone 40 mg orally (or hydrocortisone 200 mg IV) Did patient receive nebulised therapy before PEF recorded? Yes No 17.23 Indications for assisted ventilation in acute severe asthma • Coma • Respiratory arrest • Deterioration of arterial blood gas tensions despite optimal therapy: PaO2 < 8 kPa (60 mmHg) and falling PaCO2 > 6 kPa (45 mmHg) and rising pH low and falling (H+ high and rising) • Exhaustion, delirium, drowsiness

574 • RESPIRATORY MEDICINE affecting pulmonary and chest wall compliance. Pulmonary hyperinflation also results, which flattens the diaphragmatic muscles and leads to an increasingly horizontal alignment of the intercostal muscles, placing the respiratory muscles at a mechanical disadvantage. The work of breathing is therefore markedly increased – first on exercise, when the time for expiration is further shortened, but then, as the disease advances, at rest. and the lung to noxious particles or gases. Exacerbations and co-morbidities contribute to the overall severity in individual patients. Related diagnoses include chronic bronchitis (cough and sputum for at least 3 consecutive months in each of 2 consecutive years) and emphysema (abnormal permanent enlargement of the airspaces distal to the terminal bronchioles, accompanied by destruction of their walls and without obvious fibrosis). Extrapulmonary effects include weight loss and skeletal muscle dysfunction (Fig. 17.25). Commonly associated co-morbid conditions include cardiovascular disease, cerebrovascular disease, the metabolic syndrome (p. 730), osteoporosis, depression and lung cancer. The prevalence of COPD is directly related to the prevalence of risk factors in the community, such as tobacco smoking, coal dust exposure or the use of biomass fuels, and to the age of the population being studied. Those with the most severe disease bear the greatest personal impact of the condition and contribute to its significant social and economic consequences on society. It is predicted that, by 2030, COPD will represent the seventh leading cause of disability and fourth most common cause of death worldwide. Risk factors are shown in Box 17.24. Cigarette smoking represents the most significant risk factor for COPD and the risk of developing the condition relates to both the amount and duration of smoking. It is unusual to develop COPD with less than 10 pack years (1 pack year = 20 cigarettes/day/year) and not all smokers develop the condition, suggesting that individual susceptibility factors are important. Pathophysiology COPD has both pulmonary and systemic components (Fig. 17.25). The presence of airflow limitation combined with premature airway closure leads to gas trapping and hyperinflation, adversely Fig. 17.25 The pulmonary and systemic features of chronic obstructive pulmonary disease. Altered fat metabolism contributing to weight loss Enlargement of mucus-secreting glands and increase in number of goblet cells, accompanied by an inflammatory cell infiltrate, result in increased sputum production leading to chronic bronchitis Loss of elastic tissue, inflammation and fibrosis in airway wall result in premature airway closure, gas trapping and dynamic hyperinflation leading to changes in pulmonary and chest wall compliance Unopposed action of proteases and oxidants leading to destruction of alveoli and appearance of emphysema Pulmonary vascular remodelling and impaired cardiac performance Muscular weakness reflecting deconditioning and cellular changes in skeletal muscles Impaired salt and water excretion leading to peripheral oedema ↑ Prevalence of osteoporosis Increased circulating inflammatory markers Pulmonary Systemic 17.24 Risk factors for development of chronic obstructive pulmonary disease Environmental factors • Tobacco smoke: accounts for 95% of cases in the UK • Indoor air pollution: cooking with biomass fuels in confined areas in developing countries • Occupational exposures, such as coal dust, silica and cadmium • Low birth weight: may reduce maximally attained lung function in young adult life • Lung growth: childhood infections or maternal smoking may affect growth of lung during childhood, resulting in a lower maximally attained lung function in adult life • Infections: recurrent infection may accelerate decline in FEV1; persistence of adenovirus in lung tissue may alter local inflammatory response, predisposing to lung damage; HIV infection is associated with emphysema • Low socioeconomic status • Cannabis smoking Host factors • Genetic factors: α1-antitrypsin deficiency; other COPD susceptibility genes are likely to be identified • Airway hyper-reactivity (FEV1 = forced expiratory volume in 1 sec)

Obstructive pulmonary diseases • 575

particularly if there is coexisting sleep apnoea or thromboembolic disease (‘cor pulmonale’). However, even in the absence of heart failure, COPD patients often have pitting oedema from salt and water retention caused by renal hypoxia and hypercapnia. The term ‘cor pulmonale’ is a misnomer in such patients, as they do not have heart failure. Fatigue, anorexia and weight loss may point to the development of lung cancer or tuberculosis, but are common in patients with severe COPD and the body mass index (BMI) is of prognostic significance. Depression and anxiety are also common and contribute to morbidity. Two classical phenotypes have been described: ‘pink puffers’ and ‘blue bloaters’. The former are typically thin and breathless, and maintain a normal PaCO2 until the late stage of disease. The latter develop (or tolerate) hypercapnia earlier and may develop oedema and secondary polycythaemia. In practice, these phenotypes often overlap. Investigations Although there are no reliable radiographic signs that correlate with the severity of airflow limitation, a chest X-ray is essential to identify alternative diagnoses such as cardiac failure, other complications of smoking such as lung cancer, and the presence of bullae. A blood count is useful to exclude anaemia or document polycythaemia, and in younger patients with predominantly basal emphysema α1-antitrypsin should be assayed. The diagnosis requires objective demonstration of airflow obstruction by spirometry and is established when the postbronchodilator FEV1/FVC is < 70%. The severity of COPD may be defined in relation to the post-bronchodilator FEV1 (Box 17.26). Measurement of lung volumes provides an assessment of hyperinflation. This is generally performed by helium dilution technique (p. 515); however, in patients with severe COPD, and in particular large bullae, body plethysmography is preferred because the use of helium may under-estimate lung volumes. The presence of emphysema is suggested by a low gas transfer (p. 515). Exercise tests provide an objective assessment of exercise tolerance and provide a baseline on which to judge the response to bronchodilator therapy or rehabilitation programmes; they may also be valuable when assessing prognosis. Pulse oximetry may prompt referral for a domiciliary oxygen assessment if less than 93%. The assessment of health status by the St George’s Respiratory Questionnaire (SGRQ) is commonly used for research. In practice, the COPD Assessment Test and the COPD Control Questionnaire are easier to administer. HRCT is likely to play an increasing role in the assessment of COPD, as it allows the detection, Fig. 17.26 The pathology of emphysema. A Normal lung. B Emphysematous lung, showing gross loss of the normal surface area available for gas exchange. B, Courtesy of the British Lung Foundation. A B Emphysema (Fig. 17.26) may be classified by the pattern of the enlarged airspaces: centriacinar, panacinar and paraseptal. Bullae form in some individuals. This results in impaired gas exchange and respiratory failure. Clinical features COPD should be suspected in any patient over the age of 40 years who presents with symptoms of chronic bronchitis and/or breathlessness. Depending on the presentation, important differential diagnoses include chronic asthma, tuberculosis, bronchiectasis and congestive cardiac failure. Cough and associated sputum production are usually the first symptoms, and are often referred to as a ‘smoker’s cough’. Haemoptysis may complicate exacerbations of COPD but should not be attributed to COPD without thorough investigation. Breathlessness usually prompts presentation to a health professional. The level should be quantified for future reference, often by documenting what the patient can manage before stopping; scales such as the modified Medical Research Council (MRC) dyspnoea scale may be useful (Box 17.25). In advanced disease, enquiry should be made as to the presence of oedema (which may be seen for the first time during an exacerbation) and morning headaches (which may suggest hypercapnia). Physical signs (p. 546) are non-specific, correlate poorly with lung function, and are seldom obvious until the disease is advanced. Breath sounds are typically quiet; crackles may accompany infection but, if persistent, raise the possibility of bronchiectasis. Finger clubbing is not a feature of COPD and should trigger further investigation for lung cancer or fibrosis. Right heart failure may develop in patients with advanced COPD, 17.25 Modified Medical Research Council (MRC) dyspnoea scale Grade Degree of breathlessness related to activities

No breathlessness, except with strenuous exercise

Breathlessness when hurrying on the level or walking up a slight hill

Walks slower than contemporaries on level ground because of breathlessness or has to stop for breath when walking at own pace

Stops for breath after walking about 100 m or after a few minutes on level ground

Too breathless to leave the house, or breathless when dressing or undressing

576 • RESPIRATORY MEDICINE smokers, and cessation (p. 94) remains the only strategy that impacts favourably on the natural history of COPD. Complete cessation is accompanied by an improvement in lung function and deceleration in the rate of FEV1 decline (Fig. 17.28). In regions where the indoor burning of biomass fuels is important, the introduction of non-smoking cooking devices or alternative fuels should be encouraged. Bronchodilators Bronchodilator therapy is central to the management of breathlessness. The inhaled route is preferred and a number of different agents delivered by a variety of devices are available. Choice should be informed by patient preference and inhaler assessment. Short-acting bronchodilators may be used for patients with mild disease but longer-acting bronchodilators are usually more appropriate for those with moderate to severe disease. Significant improvements in breathlessness may be reported despite minimal changes in FEV1, probably reflecting improvements in lung emptying that reduce dynamic hyperinflation and ease the work of breathing. Oral bronchodilator therapy, such as theophylline preparations, may be contemplated in patients who cannot use inhaled devices efficiently but their use may be limited by side-effects, unpredictable metabolism and drug interactions; hence the requirement to monitor plasma levels. Orally active, highly selective phosphodiesterase inhibitors remain under appraisal. Combined inhaled glucocorticoids and bronchodilators The fixed combination of an inhaled glucocorticoid and a LABA improves lung function, reduces the frequency and severity of exacerbations and improves quality of life. These advantages may be accompanied by an increased risk of pneumonia, particularly in the elderly. LABA/inhaled glucocorticoid combinations are frequently given with a long-acting muscarinic antagonist (LAMA). LAMAs should be used with caution in patients with significant heart disease or a history of urinary retention. Oral glucocorticoids Oral glucocorticoids are useful during exacerbations but maintenance therapy contributes to osteoporosis and impaired skeletal muscle function, and should be avoided. Oral characterisation and quantification of emphysema (Fig. 17.27) and is more sensitive than the chest X-ray at detecting bullae. It is also used to guide lung volume reduction surgery. Assessment of severity The severity of COPD has traditionally been defined in relation to the FEV% predicted. However, assessing the impact of COPD on individual patients in terms of the symptoms and limitations in activity that they experience and whether they suffer frequent or significant exacerbations may provide a more clinically relevant assessment and help guide management. Management The management of COPD focuses on improving breathlessness, reducing the frequency and severity of exacerbations, and improving health status and prognosis. Reducing exposure to noxious particles and gases Sustained smoking cessation in mild to moderate COPD is accompanied by a reduced decline in FEV1 compared to persistent Fig. 17.27 Gross emphysema. High-resolution computed tomogram showing emphysema, most evident in the right lower lobe. R L 17.26 Spirometric classification of COPD severity based on post-bronchodilator FEV1 PD FEV1/ FVC FEV1% predicted Severity of airflow obstruction post-bronchodilator ATS/ERS (2004) GOLD (2008) NICE Clinical Guideline 101 (2010) < 0.7 ≥ 80% Mild Stage I – mild Stage I – mild1 < 0.7 50–79% Moderate Stage II – moderate Stage II – moderate < 0.7 30–49% Severe Stage III – severe Stage III – severe < 0.7 < 30% Very severe Stage IV – very severe2 Stage IV – very severe2 1Mild COPD should not be diagnosed on lung function alone if the patient is asymptomatic. 2Or FEV1 < 50% with respiratory failure. (ATS/ERS = American Thoracic Society/European Respiratory Journal; FEV1 = forced expiratory volume in 1 sec; GOLD = Global Initiative for Chronic Obstructive Lung Disease; PD = post-bronchodilator) Adapted from National Institute for Health and Care Excellence (NICE) CG101 – Chronic obstructive pulmonary disease in over 16s: diagnosis and management; 2010. Fig. 17.28 Model of annual decline in FEV1 with accelerated decline in susceptible smokers. When smoking is stopped, subsequent loss is similar to that in healthy non-smokers. (FEV1 = forced expiratory volume in 1 second)

Age (years) Smoked regularly and susceptible to its effects Stopped smoking at 45 Stopped smoking at 65 Never smoked or not susceptible to smoke FEV1 (% of value at age 25) Disability Death

Obstructive pulmonary diseases • 577

Prognosis COPD has a variable natural history but is usually progressive. The prognosis is inversely related to age and directly related to the post-bronchodilator FEV1. Additional poor prognostic indicators include weight loss and pulmonary hypertension. A composite score (BODE), comprising the body mass index (B), the degree of airflow obstruction (O), a measurement of dyspnoea (D) and exercise capacity (E) may assist in predicting death from respiratory and other causes (Box 17.28). Respiratory failure, cardiac disease and lung cancer represent common modes of death. Acute exacerbations of COPD Acute exacerbations of COPD are characterised by an increase in symptoms and deterioration in lung function and health status. They become more frequent as the disease progresses and are usually triggered by bacteria, viruses or a change in air quality. They may be accompanied by the development of respiratory failure and/or fluid retention and represent an important cause of death. Many patients can be managed at home with the use of increased bronchodilator therapy, a short course of oral glucocorticoids and, if appropriate, antibiotics. The presence of cyanosis, peripheral oedema or an alteration in consciousness should prompt referral to hospital. In other patients, consideration of comorbidity and social circumstances may influence decisions regarding hospital admission. Oxygen therapy In patients with an exacerbation of severe COPD, high concentrations of oxygen may cause respiratory depression and worsening acidosis (p. 566). Controlled oxygen at 24% or 28% should be used with the aim of maintaining a PaO2 of more than 8 kPa (60 mmHg) (or an SaO2 of more than 90%) without worsening acidosis. Bronchodilators Nebulised short-acting β2-agonists combined with an anticholinergic agent (e.g. salbutamol and ipratropium) should be administered. With careful supervision it is usually safe to drive nebulisers with oxygen, but if concern exists regarding oxygen sensitivity, they may be driven by compressed air and supplemental oxygen delivered by nasal cannula. glucocorticoid trials assist in the diagnosis of asthma but do not predict response to inhaled glucocorticoids in COPD. Pulmonary rehabilitation Exercise should be encouraged at all stages and patients reassured that breathlessness, while distressing, is not dangerous. Multidisciplinary programmes that incorporate physical training, disease education and nutritional counselling reduce symptoms, improve health status and enhance confidence. Most programmes include two to three sessions per week, last between 6 and 12 weeks, and are accompanied by demonstrable and sustained improvements in exercise tolerance and health status. Oxygen therapy Long-term domiciliary oxygen therapy (LTOT) improves survival in selected patients with COPD complicated by severe hypoxaemia (arterial PaO2 < 7.3 kPa (55 mmHg); Box 17.27). It is most conveniently provided by an oxygen concentrator and patients should be instructed to use oxygen for a minimum of 15 hours/ day; greater benefits are seen in those who use it for more than 20 hours/day. The aim of therapy is to increase the PaO2 to at least 8 kPa (60 mmHg) or SaO2 to at least 90%. Ambulatory oxygen therapy should be considered in patients who desaturate on exercise and show objective improvement in exercise capacity and/or dyspnoea with oxygen. Oxygen flow rates should be adjusted to maintain SaO2 above 90%. Surgical intervention Bullectomy may be considered when large bullae compress surrounding normal lung tissue. Patients with predominantly upper lobe emphysema, preserved gas transfer and no evidence of pulmonary hypertension may benefit from lung volume reduction surgery (LVRS), in which peripheral emphysematous lung tissue is resected with the aim of reducing hyperinflation and decreasing the work of breathing. Both bullectomy and LVRS can be performed thorascopically, minimising morbidity. Lung transplantation may benefit carefully selected patients with advanced disease (p. 567). Other measures Patients with COPD should be offered an annual influenza vaccination and, as appropriate, pneumococcal vaccination. Obesity, poor nutrition, depression and social isolation should be identified and, if possible, improved. Mucolytic agents are occasionally used but evidence of benefit is limited. Palliative care Addressing end-of-life needs is an important, yet often ignored, aspect of care in advanced disease. Morphine preparations may be used for palliation of breathlessness in advanced disease and benzodiazepines in low dose may reduce anxiety. Decisions regarding resuscitation should be addressed in advance of critical illness. 17.27 Prescription of long-term oxygen therapy in COPD Arterial blood gases are measured in clinically stable patients on optimal medical therapy on at least two occasions 3 weeks apart: • PaO2 < 7.3 kPa (55 mmHg) irrespective of PaCO2 and FEV1 < 1.5 L • PaO2 7.3–8 kPa (55–60 mmHg) plus pulmonary hypertension, peripheral oedema or nocturnal hypoxaemia • the patient has stopped smoking Use at least 15 hrs/day at 2–4 L/min to achieve a PaO2 > 8 kPa (60 mmHg) without unacceptable rise in PaCO2 17.28 Calculation of the BODE index Variable Points on BODE index

FEV1 ≥ 65 50–64 36–49 ≤ 35 Distance walked in 6 mins (m) ≥ 350 250–349 150–249 ≤ 149 MRC dyspnoea scale* 0–1

Body mass index

21 ≤ 21 A patient with a BODE score of 0–2 has a mortality rate of around 10% at 52 months, whereas a patient with a BODE score of 7–10 has a mortality rate of around 80% at 52 months. *See Box 17.25. (BODE – see text; FEV1 = forced expiratory volume in 1 sec)

578 • RESPIRATORY MEDICINE Discharge Discharge from hospital may be contemplated once patients are clinically stable on their usual maintenance medication. Hospital at-home teams may provide short-term nebuliser loan, improving discharge rates and providing additional support for the patient. Bronchiectasis Bronchiectasis means abnormal dilatation of the bronchi. Chronic suppurative airway infection with sputum production, progressive scarring and lung damage occur, whatever the cause. Aetiology and pathology Bronchiectasis may result from a congenital defect affecting airway ion transport or ciliary function, such as cystic fibrosis (see below), or may be acquired secondary to damage to the airways by a destructive infection, inhaled toxin or foreign body. The result is chronic inflammation and infection in the airways. Box 17.30 shows the common causes, of which tuberculosis is the most common worldwide. Localised bronchiectasis may occur due to the accumulation of pus beyond an obstructing bronchial lesion, such as enlarged tuberculous hilar lymph nodes, a bronchial tumour or an inhaled foreign body (e.g. an aspirated peanut). The bronchiectatic cavities may be lined by granulation tissue, squamous epithelium or normal ciliated epithelium. There may also be inflammatory changes in the deeper layers of the bronchial wall and hypertrophy of the bronchial arteries. Chronic inflammatory and fibrotic changes are usually found in the surrounding lung tissue, resulting in progressive destruction of the normal lung architecture in advanced cases. Clinical features The symptoms are shown in Box 17.31. Physical signs in the chest may be unilateral or bilateral. If the bronchiectatic airways do not contain secretions and there is no associated lobar collapse, there are no abnormal physical signs. When there are large amounts of sputum in the bronchiectatic spaces, numerous coarse crackles may be heard over the affected areas. Collapse with retained secretions blocking a proximal bronchus may lead to locally diminished breath sounds, while advanced disease may cause scarring and overlying bronchial Glucocorticoids Oral prednisolone reduces symptoms and improves lung function. Doses of 30 mg for 10 days are currently recommended but shorter courses may be acceptable. Prophylaxis against osteoporosis should be considered in patients who receive repeated courses of glucocorticoids (p. 670). Antibiotic therapy The role of bacteria in exacerbations remains controversial and there is little evidence for the routine administration of antibiotics. They are currently recommended for patients reporting an increase in sputum purulence, sputum volume or breathlessness. In most cases simple regimens are advised, such as an aminopenicillin, a tetracycline or a macrolide. Co-amoxiclav is only required in regions where β-lactamase-producing organisms are known to be common. Non-invasive ventilation Non-invasive ventilation is safe and effective in patients with an acute exacerbation of COPD complicated by mild to moderate respiratory acidosis (H+ ≥ 45 nmol/L, pH < 7.35), and should be considered early in the course of respiratory failure to reduce the need for endotracheal intubation, treatment failure and mortality. It is not useful in patients who cannot protect their airway. Mechanical ventilation may be contemplated when there is a reversible cause for deterioration (e.g. pneumonia) or when no prior history of respiratory failure has been noted. Additional therapy Exacerbations may be accompanied by the development of peripheral oedema; this usually responds to diuretics. There has been a vogue for using an infusion of intravenous aminophylline but evidence for benefit is limited and attention must be paid to the risk of inducing arrhythmias and drug interactions. The use of the respiratory stimulant doxapram has been largely superseded by the development of NIV but it may be useful for a limited period in selected patients with a low respiratory rate. 17.29 Obstructive pulmonary disease in old age • Asthma: may appear de novo in old age, so airflow obstruction should not always be assumed to be due to COPD. • Peak expiratory flow recordings: older people with poor vision have difficulty reading PEF meters. • Perception of bronchoconstriction: impaired by age, so an older patient’s description of symptoms may not be a reliable indicator of severity. • Stopping smoking: the benefits on the rate of loss of lung function decline with age but remain valuable up to the age of 80. • Metered-dose inhalers: many older people cannot use these because of difficulty coordinating and triggering the device. Even mild cognitive impairment virtually precludes their use. Frequent demonstration and re-instruction in the use of all devices are required. • Mortality rates for acute asthma: higher in old age, partly because patients under-estimate the severity of bronchoconstriction and also develop a lower degree of tachycardia and pulsus paradoxus for the same degree of bronchoconstriction. • Treatment decisions: advanced age in itself is not a barrier to intensive care or mechanical ventilation in an acute episode of asthma or COPD, but this decision may be difficult and should be shared with the patient (if possible), the relatives and the GP. 17.30 Causes of bronchiectasis Congenital • Cystic fibrosis • Ciliary dysfunction syndromes: Primary ciliary dyskinesia (immotile cilia syndrome) Kartagener’s syndrome (sinusitis and transposition of the viscera) • Primary hypogammaglobulinaemia (p. 79) Acquired: children • Severe infections in infancy (especially whooping cough, measles) • Primary tuberculosis • Inhaled foreign body Acquired: adults • Suppurative pneumonia • Pulmonary tuberculosis • Allergic bronchopulmonary aspergillosis complicating asthma (p. 596) • Bronchial tumours

Obstructive pulmonary diseases • 579

Management In patients with airflow obstruction, inhaled bronchodilators and glucocorticoids should be used to enhance airway patency. Physiotherapy Patients should be shown how to perform regular daily physiotherapy to assist the drainage of excess bronchial secretions. Efficiently executed, this is of great value both in reducing the amount of cough and sputum, and in preventing recurrent episodes of bronchopulmonary infection. Patients should lie in a position in which the lobe to be drained is uppermost. Deep breathing, followed by forced expiratory manœuvres (the ‘active cycle of breathing’ technique), helps to move secretions in the dilated bronchi towards the trachea, from which they can be cleared by vigorous coughing. Devices that increase airway pressure either by a constant amount (positive expiratory pressure mask) or in an oscillatory manner (flutter valve) aid sputum clearance in some patients and a variety of techniques should be tried to find the one that suits the individual. The optimum duration and frequency of physiotherapy depend on the amount of sputum but 5–10 minutes twice daily is a minimum for most patients. Antibiotic therapy For most patients with bronchiectasis, the appropriate antibiotics are the same as those used in COPD (p. 578) but larger doses and longer courses are required, and resolution of symptoms is often incomplete. When secondary infection occurs with staphylococci and Gram-negative bacilli, in particular Pseudomonas species, antibiotic therapy becomes more challenging and should be guided by the microbiological sensitivities. For Pseudomonas, oral ciprofloxacin (500–750 mg twice daily) or an intravenous anti-pseudomonal β-lactam (e.g. piperacillin–tazobactam or ceftazidime) will be required. Haemoptysis in bronchiectasis often responds to treatment of the underlying infection, although percutaneous embolisation of the bronchial circulation by an interventional radiologist may be necessary in severe cases. Surgical treatment Excision of bronchiectatic areas is indicated in only a small proportion of cases. These are usually patients in whom the bronchiectasis is confined to a single lobe or segment on CT. Unfortunately, many of those in whom medical treatment proves unsuccessful are also unsuitable for surgery because of either extensive bilateral bronchiectasis or coexisting severe airflow obstruction. In progressive forms of bronchiectasis, resection of destroyed areas of lung that are acting as a reservoir of infection should be considered only as a last resort. Prognosis The disease is progressive when associated with ciliary dysfunction and cystic fibrosis, and eventually causes respiratory failure. In other patients, the prognosis can be relatively good if physiotherapy is performed regularly and antibiotics are used aggressively. Prevention As bronchiectasis commonly starts in childhood following measles, whooping cough or a primary tuberculous infection, adequate prophylaxis for and treatment of these conditions are essential. Early recognition and treatment of bronchial obstruction are also important. Fig. 17.29 Computed tomogram of bronchiectasis. Extensive dilatation of the bronchi, with thickened walls (arrows) in both lower lobes. R L 17.31 Symptoms of bronchiectasis • Cough: chronic, daily, persistent • Sputum: copious, continuously purulent • Pleuritic pain: when infection spreads to involve pleura, or with segmental collapse due to retained secretions • Haemoptysis: Streaks of blood common, larger volumes with exacerbations of infection Massive haemoptysis requiring bronchial artery embolisation sometimes occurs • Infective exacerbation: increased sputum volume with fever, malaise, anorexia • Halitosis: frequently accompanies purulent sputum • General debility: difficulty maintaining weight, anorexia, exertional breathlessness breathing. Acute haemoptysis is an important complication of bronchiectasis; management is described on page 560. Investigations In addition to common respiratory pathogens, sputum culture may reveal Pseudomonas aeruginosa and Staphylococcus aureus, fungi such as Aspergillus and various mycobacteria. Frequent cultures are necessary to ensure appropriate treatment of resistant organisms. Bronchiectasis, unless very gross, is not usually apparent on a chest X-ray. In advanced disease, thickened airway walls, cystic bronchiectatic spaces and associated areas of pneumonic consolidation or collapse may be visible. CT is much more sensitive and shows thickened, dilated airways (Fig. 17.29). A screening test can be performed in patients suspected of having a ciliary dysfunction syndrome by measuring the time taken for a small pellet of saccharin placed in the anterior chamber of the nose to reach the pharynx, at which point the patient can taste it. This time should not exceed 20 minutes but is greatly prolonged in patients with ciliary dysfunction. Ciliary beat frequency may also be assessed from biopsies taken from the nose. Structural abnormalities of cilia can be detected by electron microscopy.

580 • RESPIRATORY MEDICINE Clinical features The lungs are macroscopically normal at birth, but bronchiolar inflammation and infections usually lead to bronchiectasis in childhood. At this stage, the lungs are most commonly infected with Staph. aureus; however, in adulthood, many patients become colonised with P. aeruginosa, Stenotrophomonas maltophilia or other Gram-negative bacilli. Recurrent exacerbations of bronchiectasis, initially in the upper lobes but subsequently throughout both lungs, cause progressive lung damage, resulting ultimately in death from respiratory failure. Other clinical manifestations are shown in Box 17.32. Most men with CF are infertile due to failure of development of the vas deferens, but microsurgical sperm aspiration and in vitro fertilisation are possible. Genotype is a poor predictor of disease severity in individuals; even siblings with matching genotypes may have different phenotypes. This suggests that other ‘modifier genes’, as yet unidentified, influence clinical outcome. Management Treatment of CF lung disease The management of CF lung disease is that of severe bronchiectasis. All patients with CF who produce sputum should perform chest physiotherapy daily, and more frequently during exacerbations. While infections with Staph. aureus can often be managed with oral antibiotics, intravenous treatment (frequently self-administered at home through an implanted subcutaneous vascular access device) is usually needed for Pseudomonas infections. Unfortunately, the bronchi of many patients with CF eventually become colonised with pathogens that are resistant to most antibiotics. Resistant strains of P. aeruginosa, Stenotrophomonas maltophilia and Burkholderia cepacia are the main culprits and may require prolonged treatment with unusual combinations of antibiotics. Aspergillus and non-tuberculous mycobacteria are also frequently found in the sputum of patients with CF but in most cases these behave as benign ‘colonisers’ of the bronchiectatic airways and do not require specific therapy. An Cystic fibrosis Genetics, pathogenesis and epidemiology Cystic fibrosis (CF) is the most common fatal genetic disease in Caucasians, with autosomal recessive inheritance, a carrier rate of 1 in 25, and an incidence of about 1 in 2500 live births (pp. 40 and 48). It is much less common in people of African descent and rarer still in Asians. CF is the result of mutations affecting a gene on the long arm of chromosome 7, which codes for a chloride channel known as cystic fibrosis transmembrane conductance regulator (CFTR); this influences salt and water movement across epithelial cell membranes. The most common CFTR mutation in northern European and American populations is ΔF508 but over 2000 mutations of this gene have now been identified. The genetic defect causes increased sodium and chloride content in sweat and increased resorption of sodium and water from respiratory epithelium (Fig. 17.30). Relative dehydration of the airway epithelium is thought to predispose to chronic bacterial infection and ciliary dysfunction, leading to bronchiectasis. The gene defect also causes disorders in the gut epithelium, pancreas, liver and reproductive tract (see below). In the 1960s, few patients with CF survived childhood, yet with aggressive treatment of airway infection and nutritional support, life expectancy has improved dramatically, so that there are now more adults than children with CF in many developed countries. Until recently, the diagnosis was most commonly made from the clinical picture (bowel obstruction, failure to thrive, steatorrhoea and/or chest symptoms in a young child), supported by sweat electrolyte testing and genotyping. Patients with unusual phenotypes were commonly missed, however, and late diagnosis led to poorer outcomes. Neonatal screening for CF using immunoreactive trypsin and genetic testing of newborn blood samples is now routine in the UK and should reduce delayed diagnosis and improve outcomes. Pre-implantation and/or prenatal testing may be offered to those known to be at high risk (p. 56). Fig. 17.30 Cystic fibrosis: basic defect in the pulmonary epithelium. A The cystic fibrosis gene (CFTR) codes for a chloride channel (1) in the apical (luminal) membrane of epithelial cells in the conducting airways. This is normally controlled by cyclic adenosine monophosphate (cAMP) and indirectly by β-adrenoceptor stimulation, and is one of several apical ion channels that control the quantity and solute content of airway-lining fluid. Normal channels appear to inhibit the adjacent epithelial sodium channels (2). B In cystic fibrosis, one of many cystic fibrosis gene defects causes absence or defective function of this chloride channel (3). This leads to reduced chloride secretion and loss of inhibition of sodium channels, with excessive sodium resorption (4) and dehydration of the airway lining. The resulting abnormal airway-lining fluid predisposes to infection by mechanisms still to be fully explained. cAMP Chloride ion Sodium ion Chloride ion Sodium ion Water cAMP Chloride ion Sodium ion Chloride ion Sodium ion Water Basal surface

Airway lumen Apical surface EPITHELIAL CELL β2-adrenoceptor Cystic fibrosis Normal A B

Infections of the respiratory system • 581

eventually develops in over 25% of patients and often requires insulin therapy. Osteoporosis secondary to malabsorption and chronic ill health should be sought and treated. Novel therapies for cystic fibrosis Small molecules designed to correct the function of particular CFTR defects are being developed. One such drug, ivacaftor (a CFTR ‘potentiator’), is now an established oral treatment for the 5% of patients with the G551D mutation, causing sustained improvements in FEV1 and weight, and normalising the sweat test. The combination of ivacaftor and lumacaftor (a CFTR ‘corrector’) has been found to have modest short-term benefit in patients with DF508 mutations. Improved versions of these treatments may soon offer similar benefits for these patients. Somatic gene therapy for CF is also under development. Manufactured normal copies of the CF gene are ‘packaged’ in liposomes or virus vectors and administered to the airways by aerosol inhalation. Trials are under way but more efficient gene delivery methods are needed to make this practical. Infections of the respiratory system Infections of the upper and lower respiratory tract are a major cause of morbidity and mortality, particularly in patients at the extremes of age and those with pre-existing lung disease or immune suppression. Upper respiratory tract infection Upper respiratory tract infections (URTIs), such as coryza (the common cold), acute pharyngitis and acute tracheobronchitis, are the most common of all communicable diseases and represent the most frequent cause of short-term absenteeism from work and school. The vast majority are caused by viruses (p. 249) and, in adults, are usually short-lived and rarely serious. Acute coryza is the most common URTI and is usually the result of rhinovirus infection. In addition to general malaise, acute coryza typically causes nasal discharge, sneezing and cough. Involvement of the pharynx results in a sore throat, and that of exception is Mycobacterium abscessus, which is multi-resistant, may be transmissible between patients with CF and can cause progressive lung destruction that is hard to treat. Some patients have coexistent asthma, which is treated with inhaled bronchodilators and glucocorticoids; allergic bronchopulmonary aspergillosis (p. 596) also occurs occasionally in CF. Four maintenance treatments have been shown to cause modest rises in lung function and/or to reduce the frequency of chest exacerbations in patients with CF (Box 17.33). Individual responses are variable and should be carefully monitored to avoid burdening patients with treatments that prove ineffective. For advanced CF lung disease, home oxygen and NIV may be necessary to treat respiratory failure. Ultimately, lung transplantation can produce dramatic improvements but is limited by donor organ availability. Treatment of non-respiratory manifestations of CF There is a clear link between good nutrition and prognosis in CF. Malabsorption occurs in 85% of patients due to exocrine pancreatic failure and is treated with oral pancreatic enzymes and vitamin supplements. The increased calorie requirements of patients with CF are met by supplemental feeding, including nasogastric or gastrostomy tube feeding if required. Diabetes 17.33 Treatments that reduce chest exacerbations and/or improve lung function in cystic fibrosis Therapy Patients treated Nebulised recombinant human DNase 2.5 mg daily Age ≥ 5, FVC > 40% predicted Nebulised tobramycin 300 mg twice daily, given in alternate months Patients colonised with Pseudomonas aeruginosa Regular oral azithromycin 500 mg 3 times a week Patients colonised with P. aeruginosa Nebulised hypertonic saline 4 mL 7%, twice daily Age ≥ 6, FEV1 > 40% predicted (FEV1 = forced expiratory volume in 1 sec; FVC = forced vital capacity) 17.32 Complications of cystic fibrosis Respiratory • Progressive airway obstruction • Infective exacerbations of bronchiectasis • Respiratory failure • Spontaneous pneumothorax • Haemoptysis • Lobar collapse due to secretions • Pulmonary hypertension • Nasal polyps Gastrointestinal and hepatic • Malabsorption and steatorrhoea • Distal intestinal obstruction syndrome • Biliary cirrhosis • Portal hypertension, varices and splenomegaly • Gallstones Others • Diabetes (25% of adults) • Delayed puberty • Male infertility • Stress incontinence due to repeated forced cough • Psychosocial problems • Osteoporosis • Arthropathy • Cutaneous vasculitis 17.34 Cystic fibrosis in adolescence Issues for the patient • Move to adult CF centre – loss of trusted paediatric team • Feelings of being different from peers due to chronic illness • Demanding treatments that conflict with social and school life • Pressure to take responsibility for self-care • Relationship/fertility concerns Issues for the patient’s parents • Loss of control over patient’s treatment – feeling excluded • Loss of trusted paediatric team • Need to develop trust in adult team • Feelings of helplessness when adolescent rebels or will not take treatment Issues for the CF team • Reluctance or refusal by patient to engage with transition • Management of deterioration due to non-adherence • Motivation of adolescents to self-care • Provision of adolescent-friendly health-care environment

582 • RESPIRATORY MEDICINE most common infecting agent, and thereafter the likelihood that other organisms may be involved depends on the age of the patient and the clinical context. Viral infections are recognised as important causes of CAP in children and their contribution to adult CAP is increasingly recognised. The common causative organisms are shown in Box 17.36. Clinical features Pneumonia, particularly lobar pneumonia, usually presents as an acute illness. Systemic features, such as fever, rigors, shivering and malaise, predominate and delirium may be present. The appetite is invariably lost and headache frequently reported. Pulmonary symptoms include cough, which at first is characteristically short, painful and dry, but later is accompanied by the expectoration of mucopurulent sputum. Rust-coloured sputum may be produced by patients with Strep. pneumoniae infection and the occasional patient may report haemoptysis. the larynx a hoarse or lost voice. If complicated by a tracheitis or bronchitis, chest tightness and wheeze typical of asthma occur. Specific investigation is rarely warranted and treatment with simple analgesics, antipyretics and decongestants is all that is required. Symptoms usually resolve quickly, but if repeated URTIs ‘go to the chest’, a more formal diagnosis of asthma ought to be considered. A variety of viruses causing URTI may also trigger exacerbations of asthma or COPD and aggravate other lung diseases. Bordetella pertussis, the cause of whooping cough, is an important source of URTI. It is highly contagious and is notifiable in the UK. Vaccination confers protection and is usually offered in infancy, but its efficacy wanes in adult life and the infection is easily spread. Adults usually experience a mild illness similar to acute coryza but some individuals develop paroxysms of coughing that can persist for weeks to months, earning whooping cough the designation of ‘the cough of 100 days’. The diagnosis may be confirmed by bacterial culture, polymerase chain reaction (PCR) from a nasopharyngeal swab or serological testing. If the illness is recognised early in the clinical course, macrolide antibiotics may ameliorate the course. Rhinosinusitis typically causes a combination of nasal congestion, blockage or discharge and may be accompanied by facial pain/pressure or loss of smell. Examination usually confirms erythematous swollen nasal mucosa and pus may be evident. Nasal polyps should be sought and dental infection excluded. Treatment with topical glucocorticoids, nasal decongestants and regular nasal douching is usually sufficient and, although bacterial infection is often present, antibiotics are indicated only if symptoms persist for more than 5 days. Persistent symptoms or recurrent episodes should prompt a referral to an ear, nose and throat specialist. Influenza is discussed on page 240. Pneumonia Pneumonia is as an acute respiratory illness associated with recently developed radiological pulmonary shadowing that may be segmental, lobar or multilobar. The context in which pneumonia develops is highly suggestive of the likely organism(s) involved; therefore, pneumonias are usually classified as community- or hospital-acquired, or those occurring in immunocompromised hosts. ‘Lobar pneumonia’ is a radiological and pathological term referring to homogeneous consolidation of one or more lung lobes, often with associated pleural inflammation; bronchopneumonia refers to more patchy alveolar consolidation associated with bronchial and bronchiolar inflammation, often affecting both lower lobes. Community-acquired pneumonia Figures from the UK suggest that an estimated 5–11/1000 adults suffer from community-acquired pneumonia (CAP) each year, accounting for around 5–12% of all lower respiratory tract infections. CAP may affect all age groups but is particularly common at the extremes of age; for example, worldwide, CAP continues to kill more children than any other illness and the propensity to ease the passing of the debilitated and the elderly led to designation of pneumonia as the ‘old man’s friend’. Most cases are spread by droplet infection, and while CAP may occur in previously healthy individuals, several factors may impair the effectiveness of local defences and predispose to CAP (Box 17.35). Streptococcus pneumoniae (Fig. 17.31) remains the Fig. 17.31 Gram stain of sputum showing Gram-positive diplococci characteristic of Streptococcus pneumoniae (arrows). 17.36 Organisms causing community-acquired pneumonia Bacteria • Streptococcus pneumoniae • Mycoplasma pneumoniae • Legionella pneumophila • Chlamydia pneumoniae • Haemophilus influenzae • Staphylococcus aureus • Chlamydia psittaci • Coxiella burnetii (Q fever) • Klebsiella pneumoniae (Freidländer’s bacillus) Viruses • Influenza, parainfluenza • Measles • Herpes simplex • Varicella • Adenovirus • Cytomegalovirus • Coronaviruses (SARS-CoV and MERS-CoV) (MERS = Middle East respiratory syndrome; SARS = severe acute respiratory syndrome) 17.35 Factors that predispose to pneumonia • Cigarette smoking • Upper respiratory tract infections • Alcohol • Glucocorticoid therapy • Old age • Recent influenza infection • Pre-existing lung disease • HIV • Indoor air pollution

Infections of the respiratory system • 583

identify the development of complications. While many cases of mild to moderate CAP can be successfully managed without identification of the organism, a range of microbiological tests should be performed on patients with severe CAP. Management The most important aspects of management include oxygenation, fluid balance and antibiotic therapy. In severe or prolonged illness, nutritional support may be required. Oxygen Oxygen should be administered to all patients with tachypnoea, hypoxaemia, hypotension or acidosis with the aim of maintaining the PaO2 ≥ 8 kPa (60 mmHg) or SaO2 ≥ 92%. High concentrations (≥ 35%), preferably humidified, should be used in all patients who do not have hypercapnia associated with COPD. Continuous positive airway pressure (CPAP) should be considered in those who remain hypoxic despite high-concentration oxygen therapy, and these patients should be managed in a high-dependency or intensive care environment where mechanical ventilation may be rapidly employed. Indications for ITU referral are summarised in Box 17.39. Fluid balance Intravenous fluids should be considered in those with severe illness, in older patients and those with vomiting. It may be appropriate to discontinue hypertensive agents temporarily. Otherwise, an adequate oral intake of fluid should be encouraged. Inotropic support may be required in patients with shock (p. 204). Pleuritic chest pain may be a presenting feature and on occasion may be referred to the shoulder or anterior abdominal wall. Upper abdominal tenderness is sometimes apparent in patients with lower lobe pneumonia or those with associated hepatitis. Less typical presentations may be seen in the very young and the elderly. While different organisms often give rise to a similar clinical and radiological picture, it may be possible to infer the likely agent from the clinical context. Mycoplasma pneumoniae is more common in young people and rare in the elderly, whereas Haemophilus influenzae is more common in the elderly, particularly if underlying lung disease is present. Legionella pneumophila occurs in local outbreaks centred on contaminated cooling towers in hotels, hospitals and other industries. Staph. aureus is more common following an episode of influenza. Klebsiella pneumonia has a specific association with alcohol abuse and often presents with a particularly severe bacteraemic illness. Recent foreign travel raises the possibility of infections that may otherwise be unusual in the UK, e.g. MERS-coronavirus (Middle East; p. 249), melioidosis caused by Burkholderia pseudomallei (South-east Asia and northern Australia; p. 261) and endemic fungal infection (North, Central or South America; p. 301). Certain occupations may be associated with exposure to specific bacteria (p. 618). Clinical examination should first focus on the respiratory and pulse rates, blood pressure and an assessment of the mental state, as these are important in forming a judgement as to severity of the illness (Fig. 17.32). Chest signs (p. 547) vary, depending on the inflammatory response, which proceeds through stages of acute exudation, red and then grey hepatisation, and finally resolution. When consolidated, the lung is typically dull to percussion and, as conduction of sound is enhanced, auscultation reveals bronchial breathing and whispering pectoriloquy; crackles are heard throughout. An assessment of the state of nutrition is important, particularly in the elderly. The presence of herpes labialis may point to streptococcal infection, as may the finding of ‘rusty’ sputum. The differential diagnosis of pneumonia is shown in Box 17.37. Investigations The object of investigations, which are summarised in Box 17.38, is to confirm the diagnosis, assess the severity and Fig. 17.32 Hospital CURB-65. Defined as a mental test score of 8 or less, or new disorientation in person, place or time. (ICU = intensive care unit; urea of 7 mmol/L ≅ 20 mg/dL) Consider hospital-supervised treatment Options may include • Short-stay inpatient • Hospital-supervised outpatient Likely to be suitable for home treatment Manage in hospital as severe pneumonia Assess for ICU admission, especially if CURB-65 score = 4 or 5 3 or more 0 or 1 Any of: • Confusion • Urea > 7 mmol/L • Respiratory rate > 30/min • Blood pressure (systolic < 90 mmHg or diastolic < 60 mmHg) • Age > 65 years CURB-65 score

Score 1 point for each feature present 17.37 Differential diagnosis of pneumonia • Pulmonary infarction • Pulmonary/pleural tuberculosis • Pulmonary oedema (can be unilateral) • Pulmonary eosinophilia (p. 611) • Malignancy: bronchoalveolar cell carcinoma • Cryptogenic organising pneumonia/bronchiolitis obliterans organising pneumonia (COP/BOOP) (p. 606)

584 • RESPIRATORY MEDICINE Treatment of pleural pain It is important to relieve pleural pain in order to allow the patient to breathe normally and cough efficiently. For the majority, simple analgesia with paracetamol, co-codamol or NSAIDs is sufficient. In some patients, opiates may be required but must be used with extreme caution in individuals with poor respiratory function. Physiotherapy Physiotherapy is not usually indicated in patients with CAP, although it may be helpful to assist expectoration in patients who suppress cough because of pleural pain. Antibiotic treatment Prompt administration of antibiotics improves the outcome. The initial choice of antibiotic is guided by clinical context, severity assessment, local knowledge of antibiotic resistance patterns and, at times, epidemiological information. Current regimens are detailed in Box 17.40. In most patients with uncomplicated pneumonia a 5-day course is adequate, although treatment is usually required for longer in patients with Legionella, staphylococcal or Klebsiella pneumonia. Oral antibiotics are usually adequate unless the patient has a severe illness, impaired consciousness, loss of swallowing reflex or functional or anatomical reasons for malabsorption. Fig. 17.33 Pneumonia of the right middle lobe. A Posteroanterior view: consolidation in the right middle lobe with characteristic opacification beneath the horizontal fissure and loss of normal contrast between the right heart border and lung. B Lateral view: consolidation confined to the anteriorly situated middle lobe. A B 17.39 Indications for referral to ITU • CURB score of 4–5 (see Fig. 17.32), failing to respond rapidly to initial management • Persisting hypoxia (PaO2 < 8 kPa (60 mmHg)), despite high concentrations of oxygen • Progressive hypercapnia • Severe acidosis • Circulatory shock • Reduced conscious level 17.38 Investigations in community-acquired pneumonia Blood Full blood count • Very high (> 20 × 109/L) or low (< 4 × 109/L) white cell count: marker of severity • Neutrophil leucocytosis > 15 × 109/L: suggests bacterial aetiology • Haemolytic anaemia: occasional complication of Mycoplasma Urea and electrolytes • Urea > 7 mmol/L (~20 mg/dL): marker of severity • Hyponatraemia: marker of severity Liver function tests • Abnormal if basal pneumonia inflames liver • Hypoalbuminaemia: marker of severity Erythrocyte sedimentation rate/C-reactive protein • Non-specifically elevated Blood culture • Bacteraemia: marker of severity Cold agglutinins • Positive in 50% of patients with Mycoplasma Arterial blood gases • Measure when SaO2 < 93% or when clinical features are severe, to assess ventilatory failure or acidosis Sputum Sputum samples • Gram stain (see Fig. 17.31), culture and antimicrobial sensitivity testing Oropharynx swab • Polymerase chain reaction for Mycoplasma pneumoniae and other atypical pathogens Urine • Pneumococcal and/or Legionella antigen Chest X-ray Lobar pneumonia • Patchy opacification evolves into homogeneous consolidation of affected lobe • Air bronchogram (air-filled bronchi appear lucent against consolidated lung tissue) may be present (Fig. 17.33) Bronchopneumonia • Typically patchy and segmental shadowing Complications • Para-pneumonic effusion, intrapulmonary abscess or empyema Staphylococcus aureus • Suggested by multilobar shadowing, cavitation, pneumatoceles and abscesses Pleural fluid • Always aspirate and culture when present in more than trivial amounts, preferably with ultrasound guidance

Infections of the respiratory system • 585

Prevention Current smokers should be advised to stop. Influenza and pneumococcal vaccination should be considered in patients at highest risk of pneumonia (e.g. those over 65 or with chronic lung, heart, liver or kidney disease, diabetes or immunosuppression). Because of the mode of spread, Legionella pneumophila has important public health implications and usually requires notification to the appropriate health authority for investigation of potential sources. In resource-poor settings, tackling malnourishment and indoor air pollution, and encouraging immunisation against measles, pertussis and Haemophilus influenzae type b are particularly important in children. Hospital-acquired pneumonia Hospital-acquired pneumonia (HAP) or nosocomial pneumonia refers to a new episode of pneumonia occurring at least 2 days after admission to hospital. It is the second most common hospital-acquired infection (HAI) and the leading cause of HAIassociated death. The elderly are particularly at risk, as are patients in intensive care units, especially when mechanically ventilated; here, the term ventilator-associated pneumonia (VAP) is applied. Health-care-associated pneumonia (HCAP) refers to the development of pneumonia in a person who has spent at least 2 days in hospital within the last 90 days, or has attended a haemodialysis unit, or received intravenous antibiotics, or been resident in a nursing home or other long-term care facility. The factors predisposing to the development of pneumonia in a hospitalised patient are listed in Box 17.42. Clinical features and investigation The diagnosis should be considered in any hospitalised or ventilated patient who develops purulent sputum (or endotracheal secretions), new radiological infiltrates, an otherwise unexplained increase in oxygen requirement, a core temperature > 38.3°C, and a leucocytosis or leucopenia. The clinical features and radiographic signs are variable and non-specific, however, raising a broad differential diagnosis that includes pulmonary embolism, ARDS, pulmonary oedema, pulmonary haemorrhage and drug toxicity. Therefore, in contrast to CAP, microbiological confirmation should Prognosis Most patients respond promptly to antibiotic therapy. Fever may persist for several days, however, and the chest X-ray often takes several weeks or even months to resolve, especially in old age. Delayed recovery suggests either that a complication has occurred (Box 17.41) or that the diagnosis is incorrect (see Box 17.37). Alternatively, the pneumonia may be secondary to a proximal bronchial obstruction or recurrent aspiration. The mortality rate of adults with non-severe pneumonia is very low (< 1%); hospital death rates are typically between 5% and 10% but may be as high as 50% in severe illness. Discharge and follow-up The decision to discharge a hospitalised patient depends on the home circumstances and the likelihood of complications. A chest X-ray need not be repeated before discharge in patients making a satisfactory clinical recovery. Clinical review by GP or hospital should be arranged around 6 weeks later and a chest X-ray obtained if there are persistent symptoms, physical signs or reasons to suspect underlying malignancy. 17.42 Factors predisposing to hospital-acquired pneumonia Reduced host defences against bacteria • Reduced immune defences (e.g. glucocorticoid treatment, diabetes, malignancy) • Reduced cough reflex (e.g. post-operative) • Disordered mucociliary clearance (e.g. anaesthetic agents) • Bulbar or vocal cord palsy Aspiration of nasopharyngeal or gastric secretions • Immobility or reduced conscious level • Vomiting, dysphagia (N.B. stroke disease), achalasia or severe reflux • Nasogastric intubation Bacteria introduced into lower respiratory tract • Endotracheal intubation/tracheostomy • Infected ventilators/nebulisers/bronchoscopes • Dental or sinus infection Bacteraemia • Abdominal sepsis • Intravenous cannula infection • Infected emboli 17.41 Complications of pneumonia • Para-pneumonic effusion – common • Empyema (p. 564) • Retention of sputum causing lobar collapse • Deep vein thrombosis and pulmonary embolism • Pneumothorax, particularly with Staphylococcus aureus • Suppurative pneumonia/lung abscess • ARDS, renal failure, multi-organ failure (p. 198) • Ectopic abscess formation (Staph. aureus) • Hepatitis, pericarditis, myocarditis, meningoencephalitis • Arrhythmias (e.g. atrial fibrillation) • Pyrexia due to drug hypersensitivity (ARDS = acute respiratory distress syndrome) Antibiotic use in individual patients should take into account local guidance and antibiotic sensitivity patterns. 17.40 Antibiotic treatment for community-acquired pneumonia Uncomplicated CAP • Amoxicillin 500 mg 3 times daily orally If patient is allergic to penicillin • Clarithromycin 500 mg twice daily orally or Erythromycin 500 mg 4 times daily orally If Staphylococcus is cultured or suspected • Flucloxacillin 1–2 g 4 times daily IV plus • Clarithromycin 500 mg twice daily IV If Mycoplasma or Legionella is suspected • Clarithromycin 500 mg twice daily orally or IV or Erythromycin 500 mg 4 times daily orally IV plus • Rifampicin 600 mg twice daily IV in severe cases Severe CAP • Clarithromycin 500 mg twice daily IV or Erythromycin 500 mg 4 times daily IV plus • Co-amoxiclav 1.2 g 3 times daily IV or Ceftriaxone 1–2 g daily IV or Cefuroxime 1.5 g 3 times daily IV or • Amoxicillin 1 g 4 times daily IV plus flucloxacillin 2 g 4 times daily IV Adapted from British Thoracic Society Guidelines.

586 • RESPIRATORY MEDICINE aid expectoration in the immobile and elderly, and adequate nutritional support is often required. Prevention Despite appropriate management, the mortality from HAP is high (approximately 30%), mandating prevention whenever possible. Good hygiene is paramount, particularly with regard to hand-washing and any equipment used. Steps should be taken to minimise the chances of aspiration and to limit the use of stress ulcer prophylaxis with proton pump inhibitors. Oral antiseptic (chlorhexidine 2%) may be used to decontaminate the upper airway and some intensive care units employ selective decontamination of the digestive tract when the anticipated requirement for ventilation will exceed 48 hours. Suppurative pneumonia, aspiration pneumonia and pulmonary abscess These conditions are considered together, as their aetiology and clinical features overlap. Suppurative pneumonia is characterised by destruction of the lung parenchyma by the inflammatory process. Although microabscess formation is a characteristic histological feature, ‘pulmonary abscess’ is usually taken to refer to lesions in which there is a large localised collection of pus, or a cavity lined by chronic inflammatory tissue, from which pus has escaped by rupture into a bronchus. Suppurative pneumonia and pulmonary abscess often develop after the inhalation of septic material during operations on the nose, mouth or throat, under general anaesthesia, or of vomitus during anaesthesia or coma, particularly if oral hygiene is poor. Additional risk factors for aspiration pneumonia include bulbar or vocal cord palsy, achalasia or oesophageal reflux, and alcoholism. Aspiration tends to localise to dependent areas of the lung, such as the apical segment of the lower lobe in a supine patient. These conditions may also complicate local bronchial obstruction from a neoplasm or foreign body. Infections are usually due to a mixture of anaerobes and aerobes in common with the typical flora encountered in the mouth and upper respiratory tract. Isolates of Prevotella melaninogenica, Fusobacterium necrophorum, anaerobic or microaerophilic cocci, and Bacteroides fragilis may be identified. When suppurative pneumonia or a pulmonary abscess occurs in a previously healthy lung, the most likely infecting organisms are Staph. aureus or K. pneumoniae. Actinomyces infections (mostly A. israelii) cause chronic suppurative pulmonary infections, which may be associated with poor dental hygiene. Actinomycosis presents a particular diagnostic challenge because of the slow growth of actinomycetes. Bacterial infection of a pulmonary infarct or a collapsed lobe may also produce a suppurative pneumonia or lung abscess. The organism(s) isolated from the sputum include Strep. pneumoniae, Staph. aureus, Streptococcus pyogenes, H. influenzae and, in some cases, anaerobic bacteria. In many cases, however, no pathogen can be isolated, particularly when antibiotics have been given. Some strains of community-acquired MRSA (CA-MRSA) produce the cytotoxin Panton–Valentine leukocidin. The organism is mainly responsible for suppurative skin infection but may be associated with rapidly progressive severe necrotising pneumonia. Lemierre’s syndrome is a rare cause of pulmonary abscesses. The usual causative agent is the anaerobe Fusobacterium necrophorum. The illness typically commences as a sore throat, be sought whenever possible. Adequate sputum samples may be difficult to obtain in the frail elderly person and physiotherapy should be considered to aid expectoration. In patients who are mechanically ventilated, bronchoscopy-directed protected brush specimens, bronchoalveolar lavage (BAL) or endotracheal aspirates may be obtained. Management The principles of management are similar to those of CAP, focusing on adequate oxygenation, appropriate fluid balance and antibiotics. The choice of empirical antibiotic therapy is considerably more challenging, however, given the diversity of pathogens and the potential for drug resistance. The organisms implicated in early-onset HAP (occurring within 4–5 days of admission) are similar to those involved in CAP. In patients who have received no previous antibiotics, co-amoxiclav or cefuroxime represents a sensible choice. If the patient has received a course of recent antibiotics, then piperacillin/tazobactam or a third-generation cephalosporin should be considered. Late-onset HAP is more often attributable to Gram-negative bacteria (e.g. Escherichia coli, Pseudomonas aeruginosa, Klebsiella spp. and Acinetobacter baumannii), Staph. aureus (including meticillin-resistant Staph. aureus (MRSA)) and anaerobes, and the choice of antibiotics ought to cover these possibilities. Antipseudomonal cover may be provided by a carbapenem (meropenem), an anti-pseudomonal cephalosporin or piperacillin–tazobactam. MRSA cover may be provided by glycopeptides such as vancomycin or linezolid. A. baumannii is usually sensitive to carbapenems but resistant cases may require nebulised and/or intravenous colistin. The choice of agents is most appropriately guided by knowledge of local patterns of microbiology and antibiotic resistance. It is sensible to commence broad-based cover, discontinuing less appropriate antibiotics as culture results become available. In the absence of good evidence, the duration of antibiotic therapy remains a matter for clinical judgement. Physiotherapy is important to 17.43 Respiratory infection in old age • Increased risk of and from respiratory infection: because of reduced immune responses, increased closing volumes, reduced respiratory muscle strength and endurance, altered mucus layer, poor nutritional status and the increased prevalence of chronic lung disease. • Predisposing factors: other medical conditions may predispose to infection, e.g. swallowing difficulties due to stroke increase the risk of aspiration pneumonia. • Atypical presentation: older patients often present with delirium, rather than breathlessness or cough. • Mortality: the vast majority of deaths from pneumonia in developed countries occur in older people. • Influenza: has a much higher complication rate, and morbidity and mortality. Vaccination significantly reduces morbidity and mortality in old age but uptake is poor. • Tuberculosis: most cases in old age represent reactivation of previous, often unrecognised, disease and may be precipitated by glucocorticoid therapy, diabetes mellitus and the factors above. Cryptic miliary tuberculosis is an occasional alternative presentation. Older people more commonly suffer adverse effects from antituberculous chemotherapy and require close monitoring.

Infections of the respiratory system • 587

Pneumonia in the immunocompromised patient Patients immunocompromised by drugs or disease (particularly human immunodeficiency virus (HIV) infection; p. 318) are at increased risk of pulmonary infection and pneumonia is the most common cause of death in this group. The majority of infections are caused by the same pathogens that cause pneumonia in immunocompetent individuals, but in patients with more profound immunosuppression less common organisms, or those normally considered to be of low virulence or non-pathogenic, may become ‘opportunistic’ pathogens. Depending on the clinical context, clinicians should consider the possibility of Gram-negative bacteria, especially P. aeruginosa, viruses, fungi, mycobacteria, and less common organisms such as Nocardia spp. Infection is often due to more than one organism. Clinical features These typically include fever, cough and breathlessness but are influenced by the degree of immunosuppression, and the presentation may be less specific in the more profoundly immunosuppressed. The onset of symptoms tends to be swift in those with a bacterial infection but more gradual in patients with opportunistic organisms such as Pneumocystis jirovecii and mycobacterial infections (p. 318). In P. jirovecii pneumonia, symptoms of cough and breathlessness can be present several days or weeks before the onset of systemic symptoms or the appearance of radiographic abnormality. The clinical features of invasive pulmonary aspergillosis are dealt with on page 597. Investigations The approach is informed by the clinical context and severity of the illness. Invasive investigations, such as bronchoscopy, BAL, transbronchial biopsy or surgical lung biopsy, are often impractical, as many patients are too ill to undergo these safely; however, ‘induced sputum’ (p. 554) offers a relatively safe method of obtaining microbiological samples. HRCT can be helpful: • focal unilateral airspace opacification favours bacterial infection, mycobacteria or Nocardia • bilateral opacification favours P. jirovecii pneumonia, fungi, viruses and unusual bacteria, e.g. Nocardia • cavitation may be seen with N. asteroides, mycobacteria and fungi • the presence of a ‘halo sign’ (a zone of intermediate attenuation between the nodule and the lung parenchyma) may suggest aspergillosis (p. 596) • pleural effusions suggest pyogenic bacterial infections and are uncommon in P. jirovecii pneumonia. Management In theory, treatment should be based on an established aetiological diagnosis; in practice, however, the causative agent is frequently unknown. Factors that favour a bacterial aetiology include neutropenia, rapid onset and deterioration. In these circumstances, broad-spectrum antibiotic therapy should be commenced immediately, e.g. a third-generation cephalosporin, or a quinolone, plus an antistaphylococcal antibiotic, or an antipseudomonal penicillin plus an aminoglycoside. Thereafter, treatment may be tailored according to the results of investigations and the clinical response. Depending on the clinical context and response to treatment, antifungal or antiviral therapies may be added. The management of P. jirovecii infection is detailed on page 318 and that of invasive aspergillosis on page 596. painful swollen neck, fever, rigor, haemoptysis and dyspnoea; spread into the jugular veins leads to thrombosis and metastatic dispersal of the organisms. Injecting drug-users are at particular risk of developing haematogenous lung abscess, often in association with endocarditis affecting the pulmonary and tricuspid valves. A non-infective form of aspiration pneumonia – exogenous lipid pneumonia – may follow the aspiration of animal, vegetable or mineral oils. The clinical features of suppurative pneumonia are summarised in Box 17.44. Investigations Radiological features of suppurative pneumonia include homogeneous lobar or segmental opacity consistent with consolidation or collapse. Abscesses are characterised by cavitation and a fluid level. Occasionally, a pre-existing emphysematous bulla becomes infected and appears as a cavity containing an air–fluid level. Management Aspiration pneumonia can usually be treated with amoxicillin and metronidazole. Co-amoxiclav also has a suitable antibiotic spectrum but increases the risk of Clostridium difficile infection. Further modification of antibiotics should be informed by clinical response and microbiological results. CA-MRSA is usually susceptible to a variety of oral non-β-lactam antibiotics, such as trimethoprim/sulfamethoxazole, clindamycin, tetracyclines and linezolid. Parenteral therapy with vancomycin or linezolid can also be considered. Fusobacterium necrophorum is highly susceptible to β-lactam antibiotics and to metronidazole, clindamycin and third-generation cephalosporins. Prolonged treatment for 4–6 weeks may be required in some patients with lung abscess. Established pulmonary actinomycosis requires 6–12 months’ treatment with intravenous or oral penicillin, or with a tetracycline in penicillin-allergic patients. Physiotherapy is of great value, especially when suppuration is present in the lower lobes or when a large abscess cavity has formed. In most patients there is a good response to treatment, and although residual fibrosis and bronchiectasis are common sequelae, these seldom give rise to serious morbidity. Surgery should be contemplated if no improvement occurs despite optimal medical therapy. Removal or treatment of any obstructing endobronchial lesion is essential. 17.44 Clinical features of suppurative pneumonia Symptoms • Cough with large amounts of sputum, sometimes fetid and blood-stained • Pleural pain common • Sudden expectoration of copious amounts of foul sputum if abscess ruptures into a bronchus Clinical signs • High remittent pyrexia • Profound systemic upset • Digital clubbing may develop quickly (10–14 days) • Consolidation on chest examination; signs of cavitation rarely found • Pleural rub common • Rapid deterioration in general health, with marked weight loss if not adequately treated

588 • RESPIRATORY MEDICINE (p. 594). If these reparative processes fail, primary progressive disease ensues (Fig. 17.36). The estimated lifetime risk of developing disease after primary infection is 10%, with roughly half of this risk occurring in the first 2 years after infection. Factors predisposing to TB are summarised in Box 17.45 and the natural history of infection with TB is summarised in Box 17.46. Clinical features: pulmonary disease Primary pulmonary TB Primary TB refers to the infection of a previously uninfected (tuberculin-negative) individual. A few patients develop a selflimiting febrile illness but clinical disease occurs only if there is a hypersensitivity reaction or progressive infection (Box 17.47). Progressive primary disease may appear during the course of the initial illness or after a latent period of weeks or months. Miliary TB Blood-borne dissemination gives rise to miliary TB, which may present acutely but more frequently is characterised by 2–3 weeks of fever, night sweats, anorexia, weight loss and a Fig. 17.34 Worldwide incidence of tuberculosis (2014). Estimated new cases (all forms) per 100 000 population. From World Health Organisation. Global tuberculosis report, 20th edn. Geneva: WHO; 2015. 0–9.9 10–19 20–49 50–124 125–299 300–499 ≥500 No data Not applicable Fig. 17.35 Tuberculous granuloma. Normal lung tissue is lost and replaced by a mass of fibrous tissue with granulomatous inflammation characterised by large numbers of macrophages and multinucleate giant cells (white arrow). The central area of this focus shows caseous degeneration (black arrow). Courtesy of Dr William Wallace, Department of Pathology, Royal Infirmary of Edinburgh. Tuberculosis Epidemiology Tuberculosis (TB) is caused by infection with Mycobacterium tuberculosis (MTB), which is part of a complex of organisms including M. bovis (reservoir cattle) and M. africanum (reservoir humans). The resurgence in TB in the UK observed over the latter part of the last century has finally halted and notification of TB has fallen by around 1.5% per year since 2000. None the less, its impact on world health remains significant. An estimated 9.6 million new cases were recorded in 2014, with the majority presenting in the world’s poorest nations, which struggle to cover the costs associated with management and control programmes (Fig. 17.34). In the same year, 1.5 million men, women and children died of TB, and TB continues to rank alongside HIV as a leading cause of death worldwide. Pathology and pathogenesis M. bovis infection arises mainly drinking non-sterilised milk from infected cows. M. tuberculosis is spread by the inhalation of aerosolised droplet nuclei from other infected patients. Once inhaled, the organisms lodge in the alveoli and initiate the recruitment of macrophages and lymphocytes. Macrophages undergo transformation into epithelioid and Langhans cells, which aggregate with the lymphocytes to form the classical tuberculous granuloma (Fig. 17.35). Numerous granulomas aggregate to form a primary lesion or ‘Ghon focus’ (a pale yellow, caseous nodule, usually a few millimetres to 1–2 cm in diameter), which is characteristically situated in the periphery of the lung. Spread of organisms to the hilar lymph nodes is followed by a similar pathological reaction, and the combination of the primary lesion and regional lymph nodes is referred to as the ‘primary complex of Ranke’. Reparative processes encase the primary complex in a fibrous capsule, limiting the spread of bacilli. If no further complications ensue, this lesion eventually calcifies and is clearly seen on a chest X-ray. Lymphatic or haematogenous spread may occur before immunity is established, however, seeding secondary foci in other organs, including lymph nodes, serous membranes, meninges, bones, liver, kidneys and lungs, which may lie dormant for years. The only clue that infection has occurred may be the appearance of a cell-mediated, delayed-type hypersensitivity reaction to tuberculin, demonstrated by tuberculin skin testing or an interferon gamma release assay (IGRA): so-called latent TB

Infections of the respiratory system • 589

Fig. 17.36 Primary pulmonary tuberculosis. (1) Spread from the primary focus to hilar and mediastinal lymph glands to form the ‘primary complex’, which heals spontaneously in most cases. (2) Direct extension of the primary focus – progressive pulmonary tuberculosis. (3) Spread to the pleura – tuberculous pleurisy and pleural effusion. (4) Blood-borne spread: few bacilli – pulmonary, skeletal, renal, genitourinary infection, often months or years later; massive spread – miliary pulmonary tuberculosis and meningitis.

dry cough. Hepatosplenomegaly may develop and the presence of a headache may indicate coexistent tuberculous meningitis. Auscultation of the chest is frequently normal but in more advanced disease widespread crackles are evident. Fundoscopy may show choroidal tubercles. The classical appearances on chest X-ray are of fine 1–2 mm lesions (‘millet seed’) distributed throughout the lung fields, although occasionally the appearances are coarser. Anaemia and leucopenia reflect bone marrow involvement. ‘Cryptic’ miliary TB is an unusual presentation sometimes seen in old age (Box 17.48). Post-primary pulmonary TB Post-primary disease refers to exogenous (‘new’ infection) or endogenous (reactivation of a dormant primary lesion) infection in a person who has been sensitised by earlier exposure. It is most frequently pulmonary and characteristically occurs in the apex of an upper lobe, where the oxygen tension favours survival of the strictly aerobic organism. The onset is usually insidious, developing slowly over several weeks. Systemic symptoms include fever, night sweats, malaise and loss of appetite and weight, and are accompanied by progressive pulmonary symptoms (Box 17.49). Very occasionally, this form of TB may present with one of the complications listed in Box 17.50. Radiological changes include ill-defined opacification in one or both of the upper lobes, and as progression occurs, consolidation, collapse and cavitation develop to varying degrees (Fig. 17.37). It is often difficult to distinguish active from quiescent disease on radiological criteria alone but the presence of a miliary pattern or cavitation favours active disease. In extensive disease, collapse may be marked and results in significant displacement of the trachea and mediastinum. Occasionally, a caseous lymph node may drain into an adjoining bronchus, leading to tuberculous pneumonia. 17.46 Natural history of untreated primary tuberculosis Time from infection Manifestations 3–8 weeks Primary complex, positive tuberculin skin test 3–6 months Meningeal, miliary and pleural disease Up to 3 years Gastrointestinal, bone and joint, and lymph node disease Around 8 years Renal tract disease From 3 years onwards Post-primary disease due to reactivation or re-infection Adapted from Davies PDO, ed. Clinical tuberculosis. London: Hodder Arnold; 1998. 17.45 Factors increasing the risk of tuberculosis Patient-related • Age (children > young adults < elderly) • First-generation immigrants from high-prevalence countries • Close contacts of patients with smear-positive pulmonary TB • Overcrowding (prisons, collective dormitories); homelessness (doss houses and hostels) • Chest X-ray evidence of self-healed TB • Primary infection < 1 year previously • Smoking: cigarettes, bidis (Indian cigarettes made of tobacco wrapped in temburini leaves) and cannabis Associated diseases • Immunosuppression: HIV, anti-tumour necrosis factor (TNF) and other biologic therapies, high-dose glucocorticoids, cytotoxic agents • Malignancy (especially lymphoma and leukaemia) • Diabetes mellitus • Chronic kidney disease • Silicosis • Gastrointestinal disease associated with malnutrition (gastrectomy, jejuno-ileal bypass, cancer of the pancreas, malabsorption) • Deficiency of vitamin D or A • Recent measles in children 17.47 Features of primary tuberculosis Infection (4–8 weeks) • Influenza-like illness • Skin test conversion • Primary complex Disease • Lymphadenopathy: hilar (often unilateral), paratracheal or mediastinal • Collapse (especially right middle lobe) • Consolidation (especially right middle lobe) • Obstructive emphysema • Cavitation (rare) • Pleural effusion • Miliary • Meningitis • Pericarditis Hypersensitivity • Erythema nodosum • Phlyctenular conjunctivitis • Dactylitis 17.48 Cryptic tuberculosis • Age over 60 years • Intermittent low-grade pyrexia of unknown origin • Unexplained weight loss, general debility (hepatosplenomegaly in 25–50%) • Normal chest X-ray • Blood dyscrasias; leukaemoid reaction, pancytopenia • Negative tuberculin skin test • Confirmation by biopsy with granulomas and/or acid-fast bacilli in liver or bone marrow

590 • RESPIRATORY MEDICINE distortion of the bowel, with caecal involvement predominating. Diagnosis rests on obtaining histology by either colonoscopy or mini-laparotomy. The main differential diagnosis is Crohn’s disease (p. 813). Tuberculous peritonitis is characterised by abdominal distension, pain and constitutional symptoms. The ascitic fluid is exudative and cellular, with a predominance of lymphocytes. Laparoscopy reveals multiple white ‘tubercles’ over the peritoneal and omental surfaces. Low-grade hepatic dysfunction is common in miliary disease, in which biopsy reveals granulomas. Occasionally, patients may be frankly icteric, with a mixed hepatic/cholestatic picture. Pericardial disease Disease occurs in two forms (see Fig. 17.38 and p. 542): pericardial effusion and constrictive pericarditis. Fever and night sweats are rarely prominent and the presentation is usually insidious, with breathlessness and abdominal swelling. Coexistent pulmonary disease is very rare, with the exception of pleural effusion. Pulsus paradoxus, a raised JVP, hepatomegaly, prominent ascites and peripheral oedema are common to both types. Pericardial effusion is associated with increased pericardial dullness and a globular enlarged heart on chest X-ray, and pericardial calcification occurs in around 25% of cases. Constriction is associated with an early third heart sound and, occasionally, atrial fibrillation. Diagnosis is based on the clinical, radiological and echocardiographic findings (p. 542). The effusion is frequently blood-stained. Open pericardial biopsy can be performed where there is diagnostic uncertainty. The addition of glucocorticoids to antituberculosis treatment has been shown to help both forms of pericardial disease. Fig. 17.37 Chest X-ray: major manifestations and differential diagnosis of pulmonary tuberculosis. Less common manifestations include pneumothorax, acute respiratory distress syndrome (ARDS; p. 198), cor pulmonale and localised emphysema. ‘Miliary’ diffuse shadowing Differential diagnosis • Sarcoidosis • Malignancy • Pneumoconiosis • Infection (e.g. histoplasmosis) Pleural effusion/empyema Differential diagnosis • Bacterial pneumonia • Pulmonary infarction • Carcinoma • Connective tissue disorder Cavitation Differential diagnosis • Pneumonia/lung abscess • Lung cancer • Pulmonary infarct • Granulomatosis with polyangiitis (Wegener’s granulomatosis) • Progressive massive fibrosis Consolidation/collapse Differential diagnosis • Pneumonia • Bronchial carcinoma • Pulmonary infarct From swallowed sputum. 17.50 Complications of chronic pulmonary tuberculosis Pulmonary • Massive haemoptysis • Cor pulmonale • Fibrosis/emphysema • Atypical mycobacterial infection • Lung/pleural calcification • Aspergilloma/chronic aspergillosis • Obstructive airways disease • Bronchiectasis • Bronchopleural fistula Non-pulmonary • Empyema necessitans • Laryngitis • Enteritis • Anorectal disease* • Amyloidosis • Poncet’s polyarthritis 17.49 Clinical presentations of pulmonary tuberculosis • Chronic cough, often with haemoptysis • Pyrexia of unknown origin • Unresolved pneumonia • Exudative pleural effusion • Asymptomatic (diagnosis on chest X-ray) • Weight loss, general debility • Spontaneous pneumothorax Clinical features: extrapulmonary disease Extrapulmonary TB accounts for 20% of cases in those who are HIV-negative but is more common in HIV-positive patients. Lymphadenitis Lymph nodes are the most common extrapulmonary site of disease. Cervical and mediastinal glands are affected most frequently, followed by axillary and inguinal, and more than one region may be involved. Disease may represent primary infection, spread from contiguous sites or reactivation. Supraclavicular lymphadenopathy is often the result of spread from mediastinal disease. The nodes are usually painless and initially mobile but become matted together with time. When caseation and liquefaction occur, the swelling becomes fluctuant and may discharge through the skin with the formation of a ‘collar-stud’ abscess and sinus formation. Approximately half of cases fail to show any constitutional features, such as fevers or night sweats. The tuberculin test is usually strongly positive. During or after treatment, paradoxical enlargement, development of new nodes and suppuration may all occur but without evidence of continued infection; surgical excision is rarely necessary. In non-immigrant children in the UK, most mycobacterial lymphadenitis is caused by opportunistic mycobacteria, especially of the M. avium complex. Gastrointestinal tuberculosis TB can affect any part of the bowel and patients may present with a wide range of symptoms and signs (Fig. 17.38). Upper gastrointestinal tract involvement is rare and is usually an unexpected histological finding in an endoscopic or laparotomy specimen. Ileocaecal disease accounts for approximately half of abdominal TB cases. Fever, night sweats, anorexia and weight loss are usually prominent and a right iliac fossa mass may be palpable. Up to 30% of cases present with an acute abdomen. Ultrasound or CT may reveal thickened bowel wall, abdominal lymphadenopathy, mesenteric thickening or ascites. Barium enema and small bowel enema reveal narrowing, shortening and

Infections of the respiratory system • 591

immunologically mediated polyarthritis that usually resolves within 2 months of starting treatment. Genitourinary disease Fever and night sweats are rare with renal tract TB and patients are often only mildly symptomatic for many years. Haematuria, frequency and dysuria are often present, with sterile pyuria found on urine microscopy and culture. In women, infertility from endometritis, or pelvic pain and swelling from salpingitis or a tubo-ovarian abscess occurs occasionally. In men, genitourinary TB may present as epididymitis or prostatitis. Investigations The presence of an otherwise unexplained cough for more than 2–3 weeks, particularly in regions where TB is prevalent, or typical chest X-ray or CT changes (Fig. 17.39) should prompt further investigation (Box 17.51). Direct microscopy of a sputum smear remains the most important first step. At least two sputum samples (including at least one obtained in the early morning) from a spontaneously produced deep cough should be obtained. Induced sputum may be used in those unable to expectorate. In selected cases, bronchoscopy and lavage or aspiration of a lymph node by EBUS may be used. Light-emitting diode fluorescent microscopy with auramine staining is increasingly replacing the more traditional standard light microscopy and Ziehl–Neelsen stain (Fig. 17.40) or the use of mercury-vapour fluorescent microscopy. A positive smear is sufficient for the presumptive diagnosis of TB but definitive Central nervous system disease Meningeal disease represents the most important form of central nervous system TB. Unrecognised and untreated, it is rapidly fatal. Even when appropriate treatment is prescribed, mortality rates of 30% have been reported, while survivors may be left with neurological sequelae. Clinical features, investigations and management are described on page 1120. Bone and joint disease The spine is the most common site for bony TB (Pott’s disease), which usually presents with chronic back pain and typically involves the lower thoracic and lumbar spine (see Fig. 17.38). The infection starts as a discitis and then spreads along the spinal ligaments to involve the adjacent anterior vertebral bodies, causing angulation of the vertebrae with subsequent kyphosis. Paravertebral and psoas abscess formation is common and the disease may present with a large (cold) abscess in the inguinal region. CT or MRI is valuable in gauging the extent of disease, the amount of cord compression, and the site for needle biopsy or open exploration, if required. The major differential diagnosis is malignancy, which tends to affect the vertebral body and leave the disc intact. Important complications include spinal instability or cord compression. TB can affect any joint but most frequently involves the hip or knee. Presentation is usually insidious, with pain and swelling; fever and night sweats are uncommon. Radiological changes are often non-specific but, as disease progresses, reduction in joint space and erosions appear. Poncet’s arthropathy is an Fig. 17.38 Systemic presentations of extrapulmonary tuberculosis. Exudative ascites Mesenteric adenitis Intestinal obstruction Cranial nerve palsy Lymph node enlargement Pericardial effusion Constrictive pericarditis Monoarthritis Haematuria/dysuria Infertility in women Epididymitis Anorectal ulceration Headache, vomiting, seizures, delirium Lymphocytic meningitis Hydrocephalus Space-occupying lesion (tuberculoma) Kyphosis Cord compression Abdominal mass Psoas abscess General observation

Weight loss

Fever

Night sweats Chronic back pain

592 • RESPIRATORY MEDICINE of rapid NAATs (p. 106). For example, Xpert MTB/RIF (a DNA detection-based NAAT) has the capacity to detect MTB (and rifampicin resistance) in less than 2 hours. However, while it is specific to MTB, it is not sufficiently sensitive to have replaced culture. The diagnosis of extrapulmonary TB can be more challenging. There are generally fewer organisms (particularly in meningeal or pleural fluid), so culture, histopathological examination of tissue and/or NAAT may be required. Stimulation of T cells by mycobacterial antigens leads to increased levels of adenosine deaminase in pleural, pericardial, cerebrospinal and ascitic fluid, and so may assist in confirming suspected TB. In the presence of HIV, examination of sputum may still be useful, as subclinical pulmonary disease is common. Lateral flow urinary lipoarabinomannan assay (LF-LAM) may be useful in the severely ill patient with a CD4 count of 100 cells/μL or less. Drug sensitivity testing The rapid detection of drug resistance is central both to the management of the individual with TB and to control of the disease in the population. The gold standard remains culture, in either solid or liquid media, but the use of other phenotypic tests, such as microscopically observed drug susceptibility (MODS), colorimetric redox indicator (CRI) methods and nitrate reductase assay, offer low-cost alternatives, depending on the resource and expertise available. The potential for molecular tests to provide rapid drug sensitivity testing (DST) is improving, particularly with regard to the detection of rifampicin resistance, which is important because rifampicin forms the cornerstone of 6-month chemotherapy. Rapid identification of rifampicin resistance is provided by Xpert MTB/RIF. Line probe assays (LPAs) use PCR and reverse hybridisation to detect genetic sequences linked to resistance to both rifampicin and isoniazid, and increasingly to resistance to pyrazinamide, ethambutol and other second-line agents. Management Chemotherapy The treatment of TB is based on the principle of an initial intensive phase to reduce the bacterial population rapidly, followed by a continuation phase to destroy any remaining bacteria (Box 17.52). Standard treatment involves 6 months’ treatment with isoniazid and rifampicin, supplemented in the first 2 months with diagnosis requires culture. The probability of detecting acid-fast bacilli is proportional to the bacillary burden in the sputum. Smear-negative sputum should also be cultured, as only 10–100 viable organisms are required for sputum to be culture-positive. A diagnosis of smear-negative TB may be made in advance of culture if the chest X-ray appearances are typical of TB. The slow growth of MTB on solid (typically between 4 and 6 weeks) and automated and semi-automated liquid (typically around 2 weeks) culture media has prompted the development Fig. 17.39 Typical changes of tuberculosis. The chest X-ray shows bilateral upper lobe airspace shadowing with cavitation. Fig. 17.40 Positive Ziehl–Neelsen stain. Mycobacteria (arrow) retain the red carbol fuchsin stain, despite washing with acid and alcohol. Courtesy of Adam Hill. 17.51 Diagnosis of tuberculosis Specimens required Pulmonary • Sputum* (induced with nebulised hypertonic saline if patient not expectorating) • Bronchoscopy with washings or BAL • Gastric washing* (mainly used for children) Extrapulmonary • Fluid examination (cerebrospinal, ascitic, pleural, pericardial, joint): yield classically very low • Tissue biopsy (from affected site): bone marrow/liver may be diagnostic in disseminated disease Diagnostic tests • Tuberculin skin test: low sensitivity/specificity; useful only in primary or deep-seated infection • Stain Ziehl–Neelsen Auramine fluorescence • Nucleic acid amplification • Culture Solid media (Löwenstein–Jensen, Middlebrook) Liquid media (e.g. MGIT) • Pleural fluid: adenosine deaminase • Response to empirical antituberculous drugs (usually seen after 5–10 days) Baseline blood tests • Full blood count, C-reactive protein, erythrocyte sedimentation rate, urea and electrolytes, liver function tests (BAL = bronchoalveolar lavage; MGIT = mycobacteria growth indicator tube) *At least two but preferably three, including an early morning sample.

Infections of the respiratory system • 593

17.52 Treatment of new tuberculosis patients (World Health Organisation recommendations) Intensive phase Continuation phase Comments Standard regimen 2 months of HRZE 4 months of HR 2 months of HRZE 4 months of HRE Applies only in countries with high levels of isoniazid resistance in new TB patients, and where isoniazid drug susceptibility testing in new patients is not done (or results are unavailable) before the continuation phase begins Dosing frequency Daily* Daily Optimal Daily* 3 times/week Acceptable alternative for any new patient receiving directly observed therapy 3 times/week 3 times/week Acceptable alternative, provided that the patient is receiving directly observed therapy and is NOT living with HIV or living in an HIV-prevalent setting *Daily (rather than 3 times weekly) intensive-phase dosing may help to prevent acquired drug resistance in TB patients starting treatment with isoniazid resistance. (H = isoniazid; R = rifampicin; Z = pyrazinamide; E = ethambutol) Adapted from World Health Organisation. Treatment of tuberculosis guidelines, 4th edn; 2010. 17.53 Main adverse reactions of first-line antituberculous drugs Isoniazid Rifampicin Pyrazinamide Streptomycin Ethambutol Mode of action Cell wall synthesis DNA transcription Unknown Protein synthesis Cell wall synthesis Major adverse reactions Peripheral neuropathy1 Hepatitis2 Rash Febrile reactions Hepatitis Rash Gastrointestinal disturbance Hepatitis Gastrointestinal disturbance Hyperuricaemia 8th nerve damage Rash Retrobulbar neuritis3 Arthralgia Less common adverse reactions Lupoid reactions Seizures Psychoses Interstitial nephritis Thrombocytopenia Haemolytic anaemia Rash Photosensitisation Gout Nephrotoxicity Agranulocytosis Peripheral neuropathy Rash 1The risk may be reduced by prescribing pyridoxine. 2More common in patients with a slow acetylator status and in alcoholics. 3Reduced visual acuity and colour vision may be reported with higher doses and are usually reversible. pyrazinamide and ethambutol. Fixed-dose tablets combining two or three drugs are preferred. Treatment should be commenced immediately in any patient who is smear-positive, and in those who are smear-negative but with typical chest X-ray changes and no response to standard antibiotics. Six months of therapy is appropriate for all patients with new-onset pulmonary TB and most cases of extrapulmonary TB. However, 12 months of therapy is recommended for meningeal TB, including involvement of the spinal cord in cases of spinal TB; in these cases, ethambutol may be replaced by streptomycin. Pyridoxine should be prescribed in pregnant women and malnourished patients to reduce the risk of peripheral neuropathy with isoniazid. Where drug resistance is not anticipated, patients can be assumed to be non-infectious after 2 weeks of appropriate therapy. Most patients can be treated at home. Admission to a hospital unit with appropriate isolation facilities should be considered where there is uncertainty about the diagnosis, intolerance of medication, questionable treatment adherence, adverse social conditions or a significant risk of multidrug-resistant TB (culturepositive after 2 months on treatment, or contact with known multidrug-resistant TB). Patients treated with rifampicin should be advised that their urine, tears and other secretions will develop a bright, orange/ red coloration, and women taking the oral contraceptive pill must be warned that its efficacy will be reduced and alternative contraception may be necessary. Ethambutol and streptomycin should be used with caution in renal impairment, with appropriate dose reduction and monitoring of drug levels. Adverse drug reactions occur in about 10% of patients but are significantly more common with HIV co-infection (Box 17.53). Baseline liver function and regular monitoring are important for patients treated with standard therapy. Rifampicin may cause asymptomatic hyperbilirubinaemia but, along with isoniazid and pyrazinamide, may also cause hepatitis. Mild asymptomatic increases in transaminases are common but significant hepatotoxicity only occurs in 2–5%. It is appropriate to stop treatment and allow any symptoms to subside and the liver function tests to recover before commencing a stepwise re-introduction of the individual drugs. Less hepatotoxic regimens may be considered, including streptomycin, ethambutol and fluoroquinolones. Glucocorticoids reduce inflammation and limit tissue damage; they are currently recommended when treating pericardial or meningeal disease, and in children with endobronchial disease. They may confer benefit in TB of the ureter, pleural effusions and extensive pulmonary disease, and can suppress hypersensitivity drug reactions. Surgery should be considered in cases complicated by massive haemoptysis, loculated empyema, constrictive pericarditis, lymph node suppuration, and spinal disease with cord compression, but usually only after a full course of antituberculosis treatment. The effectiveness of therapy for pulmonary TB is assessed by further sputum smear at 2 months and at 5 months. Treatment failure is defined as a positive sputum smear or culture at 5 months or any patient with a multidrug-resistant strain, regardless of

594 • RESPIRATORY MEDICINE asymptomatic contact who tests positive but has a normal chest X-ray may be treated with chemoprophylaxis to prevent infection from progressing to clinical disease. Chemoprophylaxis should be offered to adults up to the age of 65 (although age-specific cut-off varies by country). It should also be considered for HIV-infected close contacts of a patient with smear-positive disease. A course of rifampicin and isoniazid for 3 months or isoniazid for 6 months is effective. Tuberculin skin testing may be associated with false-positive reactions in those who have had a BCG vaccination and in areas where exposure to non-tuberculous mycobacteria is high. The skin tests may also be falsely negative in the setting of immunosuppression or overwhelming TB infection. IGRAs detect the release of interferon-gamma (IFN-γ) from sensitised T cells in response to antigens, such as early secretory antigenic target (ESAT)-6 or culture filtrate protein (CFP)-10, which are encoded by genes specific to Mycobacterium tuberculosis and are not shared with BCG or opportunistic mycobacteria (Fig. 17.42). IGRAs are more specific than skin testing and logistically more convenient, as they require a single blood test rather than two clinic visits. In the UK, a dual strategy of TST followed by IGRA is recommended. TST remains the first choice in children, while IGRA represents the first choice for individuals with HIV. Directly observed therapy Poor adherence to therapy is a major factor in prolonged illness, risk of relapse, and the emergence of drug resistance. Directly observed therapy (DOT) involves the supervised administration of therapy 3 times weekly to improve adherence. DOT has become an important control strategy in resource-poor nations. In the UK, it is currently recommended for patients thought unlikely to be adherent to therapy: homeless people and drifters, alcohol or Fig. 17.41 The tuberculin skin test. A The reaction to the intradermal injection of tuberculin purified protein derivative (PPD) on the inner surface of the forearm is read between 48 and 72 hours. B The diameter of the indurated area should be measured across the forearm and is positive when ≥ 5 mm. A B Fig. 17.42 The principles of interferon-gamma release assays (IGRAs). A sample of either (A) purified T cells (T-SPOT.TB test) or (B) whole blood (QuantiFERON–TB Gold test) is incubated in the presence of antigens specific to Mycobacterium tuberculosis (MTB). The release of interferon-gamma (IFN-γ) by the cells is measured by enzyme-linked immunosorbent assay (ELISA). (ELISPOT = enzyme-linked immunosorbent spot assay) Incubate in the presence of antigens specific to MTB Incubate in the presence of antigens specific to MTB Purified T lymphocytes IFN-γ released IFN-γ binds to antibody on base of ELISPOT wells Spots counted A Whole blood IFN-γ released Supernatant removed and IFN-γ measured by ELISA B whether they are smear-positive or negative. Extrapulmonary TB must be assessed clinically or radiographically, as appropriate. Control and prevention TB is preventable, particularly so in those with latent TB. Supporting the development of laboratory and health-care services to improve detection and treatment of active and latent TB is an important component of this goal. Detection of latent TB The majority of individuals exposed to MTB harbour the bacteria, which remain dormant. They do not develop any signs of active disease and are non-infectious. They are however, at risk of developing active TB disease and becoming infectious. The lifetime risk of TB disease for a person with documented latent TB infection is estimated at 5–15%, with the majority of cases occurring within the first 5 years after initial infection. Latent TB may be identified by the presence of immune responses to M. tuberculosis antigens. Contact tracing is a legal requirement in many countries. It has the potential to identify the probable index case, other cases infected by the same index patient (with or without evidence of disease), and close contacts who should receive BCG vaccination (see below) or chemotherapy. Approximately 10–20% of close contacts of patients with smear-positive pulmonary TB and 2–5% of those with smear-negative, culture-positive disease have evidence of TB infection. Cases are commonly identified using the tuberculin skin test (TST; Fig. 17.41) or an IGRA (Fig. 17.42). An otherwise

Infections of the respiratory system • 595

5 months and usually have the same drug susceptibility. In the absence of treatment, a patient with smear-positive TB will remain infectious for an average of 2 years; in 1 year, 25% of untreated cases will die. Death is more likely in those who are smear-positive and those who smoke. A few patients die unexpectedly soon after commencing therapy and it is possible that some have subclinical hypoadrenalism that is unmasked by a rifampicin-induced increase in glucocorticoid metabolism. HIV-positive patients have higher mortality rates and a modestly increased risk of relapse. Opportunistic mycobacterial infection Other species of environmental mycobacteria (often termed ‘atypical’) may cause human disease (Box 17.55). The sites commonly involved are the lungs, lymph nodes, skin and soft tissues. The most widely recognised of these mycobacteria, M. avium complex (MAC), is well described in severe HIV disease (CD4 count < 50 cells/mL – p. 324). However, several others (including MAC) colonise and/or infect apparently immunocompetent patients with chronic lung diseases such as COPD, bronchiectasis, pneumoconiosis, old TB, or cystic fibrosis. The clinical presentation varies from a relatively indolent course in some to an aggressive course characterised by cavitatory or nodular disease in others. Radiological appearances may be similar to classical TB, but in patients with bronchiectasis, opportunistic infection may present with lower-zone nodules. The most commonly reported organisms include M. kansasii, M. malmoense, M. xenopi and M. abscessus but geographical variation is marked. M. abscessus and M. fortuitum grow rapidly but the majority grow slowly. More rapid diagnostic systems are under development, including DNA probes, high-performance liquid chromatography (HPLC), PCR restriction enzyme analysis (PRA) and 16S rRNA gene sequence analysis. With the exception of M. kansasii, drug sensitivity testing is usually unhelpful in predicting treatment response. In the UK, these organisms are not notifiable to local public health departments as they are not normally communicable, although there is some evidence of patient-to-patient transmission of M. abscessus in cystic fibrosis. drug users, patients with serious mental illness and those with a history of non-adherence. TB and HIV/AIDS The close links between HIV and TB, particularly in sub-Saharan Africa, and the potential for both diseases to overwhelm healthcare funding in resource-poor nations have been recognised, with the promotion of programmes that link detection and treatment of TB with detection and treatment of HIV. It is recommended that all patients with TB should be tested for HIV infection. Mortality is high and TB is a leading cause of death in HIV patients. Full discussion of its presentation and management is given on page 318. Drug-resistant TB Drug-resistant TB is defined by the presence of resistance to any first-line agent. Multidrug-resistant tuberculosis (MDR-TB) is defined by resistance to at least rifampicin and isoniazid, with or without other drug resistance. Globally, an estimated 3.3% of new TB cases and 20% of previously treated cases have MDR-TB. In 2014, an estimated 190 000 people died of MDR-TB. Extensively drug-resistant tuberculosis (XDR-TB) is defined as resistance to at least rifampicin and isoniazid, in addition to any quinolone and at least one injectable second-line agent. An estimated 9.7% of people with MDR-TB have XDR-TB. The prevalence of MDR-TB is rising, particularly in the former Soviet Union, Central Asia and Africa. It is more common in individuals with a prior history of TB, particularly if treatment has been inadequate, and those with HIV infection. Box 17.54 lists the factors contributing to the emergence of drug-resistant TB. Diagnosis is challenging, especially in resource-poor settings, and although cure may be possible, it requires prolonged treatment with less effective, more toxic and more expensive therapies. The mortality rate from MDR-TB is high and that from XDR-TB higher still. Vaccines BCG (the Calmette–Guérin bacillus), a live attenuated vaccine derived from M. bovis, is the most established TB vaccine. It is administered by intradermal injection and is highly immunogenic. BCG appears to be effective in preventing disseminated disease, including tuberculous meningitis, in children, but its efficacy in adults is inconsistent and new vaccines are urgently needed. Current vaccination policies vary worldwide according to incidence and health-care resources, but usually target children and other high-risk individuals. BCG is very safe, with the occasional complication of local abscess formation. It should not be administered to those who are immunocompromised (e.g. by HIV) or pregnant. Prognosis Following successful completion of chemotherapy, cure should be anticipated in the majority of patients. There is a small (< 5%) and unavoidable risk of relapse. Most relapses occur within 17.55 Site-specific opportunistic mycobacterial disease Pulmonary • M. xenopi • M. kansasii • M. malmoense • MAC • M. abscessus (in cystic fibrosis) Lymph node • MAC • M. malmoense • M. fortuitum • M. chelonei Soft tissue/skin • M. leprae • M. ulcerans (prevalent in Africa, northern Australia and South-east Asia) • M. marinum • M. fortuitum • M. chelonae Disseminated • MAC (HIV-associated) • M. haemophilum • M. genavense • M. fortuitum • M. chelonae • BCG (BCG = bacille Calmette–Guérin; MAC = Mycobacterium avium complex – M. scrofulaceum, M. intracellulare and M. avium) 17.54 Factors contributing to the emergence of drug-resistant tuberculosis • Drug shortages • Poor-quality drugs • Lack of appropriate supervision • Transmission of drug-resistant strains • Prior antituberculosis treatment • Treatment failure (smear-positive at 5 months)

596 • RESPIRATORY MEDICINE glucocorticoids; a 4-month trial is usually recommended to assess its efficacy. The use of specific anti-IgE monoclonal antibodies is under consideration. Exacerbations, particularly when associated with new chest X-ray changes, should be treated promptly with prednisolone (40–60 mg daily) and physiotherapy. If persistent lobar collapse occurs, bronchoscopy (usually under general anaesthetic) should be performed to remove impacted mucus and ensure prompt re-inflation. Chronic pulmonary aspergillosis The term chronic pulmonary aspergillosis (CPA) encompasses simple aspergilloma, chronic cavitary pulmonary aspergillosis, chronic fibrosing pulmonary aspergillosis, Aspergillus nodule and semi-invasive aspergillosis. They are uncommon conditions and challenging to diagnose and treat. Simple aspergilloma Cavities left by diseases such as TB or by damaged bronchi provide favourable conditions in which inhaled Aspergillus may lodge and germinate. At the earliest stage, CT scanning may identify an irregular mucosal wall and, as fungal growth progresses, this finally collapses into the cavity, forming a fungal ball that may be identified on imaging (Fig. 17.44). Simple aspergillomas are often asymptomatic. They can, however, give rise to a variety of non-specific symptoms, such as lethargy and weight loss, and may cause recurrent haemoptysis, which may be life-threatening. Fig. 17.43 Branching Aspergillus hyphae seen in allergic bronchopulmonary aspergillosis. The figure shows the use of calcofluor white, a non-specific fluorochrome stain that binds to fungi and fluoresces when exposed to light of the appropriate wavelength. Aspergillus fumigatus was subsequently grown on culture. Courtesy of Mr T. Russell and Dr M. Hanson, Department of Microbiology, NHS Lothian. 17.58 Features of allergic bronchopulmonary aspergillosis • Asthma (in the majority of cases) • Proximal bronchiectasis (inner two-thirds of chest CT field) • Positive skin test to an extract of Aspergillus fumigatus • Elevated total serum immunoglobulin E (IgE) > 417 kU/L (1000 ng/mL) • Elevated A. fumigatus-specific IgE or IgG • Peripheral blood eosinophilia > 0.5 × 109/L • Presence or history of chest X-ray abnormalities • Fungal hyphae of A. fumigatus on microscopic examination of sputum 17.57 Classification of bronchopulmonary aspergillosis • Allergic bronchopulmonary aspergillosis (asthmatic pulmonary eosinophilia) • Extrinsic allergic alveolitis (Aspergillus clavatus) • Intracavitary aspergilloma • Invasive pulmonary aspergillosis • Chronic and subacute pulmonary aspergillosis 17.56 Factors predisposing to pulmonary fungal disease Systemic factors • Haematological malignancy • HIV • Diabetes mellitus • Chronic alcoholism • Radiotherapy • Glucocorticoids, cytotoxic chemotherapy, biologic therapies and other immunosuppressant medication Local factors • Tissue damage by suppuration or necrosis • Alteration of normal bacterial flora by antibiotic therapy Respiratory diseases caused by fungi The majority of fungi encountered by humans are harmless saprophytes but in certain circumstances (Box 17.56) some species may cause disease by infecting human tissue, promoting damaging allergic reactions or producing toxins. ‘Mycosis’ is the term applied to disease caused by fungal infection. The conditions associated with Aspergillus species are listed in Box 17.57. Allergic bronchopulmonary aspergillosis Allergic bronchopulmonary aspergillosis (ABPA) occurs as a result of a hypersensitivity reaction to germinating fungal spores in the airway wall. The condition may complicate the course of asthma and cystic fibrosis, and is a recognised cause of pulmonary eosinophilia (p. 611). The prevalence of ABPA is approximately 1–2% in asthma and 5–10% in CF. A variety of human leucocyte antigens (HLAs) convey both an increased and a decreased risk of developing the condition, suggesting that genetic susceptibility is important. Clinical features Clinical features depend on the stage of the disease. Common manifestations in the early phases include fever, breathlessness, cough productive of bronchial casts and worsening of asthmatic symptoms. The appearance of radiographic infiltrates may cause ABPA to be mistaken for pneumonia but the diagnosis may also be suggested by segmental or lobar collapse on chest X-rays of patients whose asthma symptoms are stable. Diagnostic features are shown in Box 17.58 and the typical Aspergillus hyphae in Figure 17.43. If bronchiectasis develops, the symptoms and complications of that disease often overshadow those of asthma. Management ABPA is generally considered an indication for regular therapy with low-dose oral glucocorticoids (prednisolone 7.5–10 mg daily) with the aim of suppressing the immunopathological responses and preventing progressive tissue damage. In some patients, itraconazole (400 mg/day) facilitates a reduction in oral

Infections of the respiratory system • 597

The clinical and radiological picture is similar to CCPA but lung biopsy demonstrates invasion of lung tissue by hyphae. The development of SIA is favoured by mild immunocompromise and should be suspected in patients with diabetes mellitus, malnutrition or alcoholism, or with advanced age and in prolonged glucocorticoid use. It is also seen in the presence of COPD, non-tuberculous mycobacteria or HIV infection. SIA should be treated in a similar manner to invasive pulmonary aspergillosis. Invasive pulmonary aspergillosis Invasive pulmonary aspergillosis (IPA) is most commonly a complication of profound neutropenia caused by drugs (especially immunosuppressive agents) and/or disease (Box 17.59). Clinical features Acute IPA causes a severe necrotising pneumonia and must be considered in any immunocompromised patient who develops fever, new respiratory symptoms (particularly pleural pain or haemoptysis) or a pleural rub. Invasion of pulmonary vessels causes thrombosis and infarction, and systemic spread may occur Fig. 17.44 Computed tomogram of aspergilloma in the left upper lobe. The rounded fungal ball is separated from the wall of the cavity by an ‘air crescent’ (arrow). Fig. 17.45 Chronic pulmonary aspergillosis. A The chest X-ray shows pleural thickening with loss of lung volume at the left apex (arrow). B High-resolution computed tomography reveals multiple small cavities and pleural thickening with an aspergilloma and surrounding air crescent (arrow) in one of the cavities. Courtesy of Professor David Denning, National Aspergillosis Centre, Manchester, UK. A B The typical radiological picture is invariably accompanied by elevated serum precipitins/IgG to A. fumigatus. Sputum microscopy typically demonstrates scanty hyphal fragments and is usually positive on culture. Less than half exhibit skin hypersensitivity to extracts of A. fumigatus. Rarely, other filamentous fungi can cause intracavity mycetoma and are identified by culture. Asymptomatic cases do not require treatment but haemoptysis should be controlled by surgery. Tranexamic acid or bronchial artery embolisation may provide a bridge to surgery or palliate haemoptysis when surgery is not possible. Instillation of antifungal agents, such as amphotericin B, via a catheter placed into the cavity has been reported but is rarely used in the UK. Chronic cavitary pulmonary aspergillosis and chronic fibrosing pulmonary aspergillosis The features of chronic cavitary pulmonary aspergillosis (CCPA) include cough (with or without haemoptysis), weight loss, anorexia and fatigue over months or years, with associated fever, night sweats and elevated inflammatory markers. Radiological features include thick-walled cavities (predominantly apical), pulmonary infiltrates and pleural thickening (Fig. 17.45). Once again, diagnosis rests on a combination of radiological examination, histopathology, isolation of fungus from the respiratory tract and detection of Aspergillus IgG in serum. Treatment usually involves prolonged courses of itraconazole or voriconazole. Cure is unusual and the most frequent pattern is chronic relapse/remission with gradual deterioration. Surgical intervention is fraught with complications and should be avoided. Many patients are malnourished and require nutritional support. Glucocorticoids should be avoided. As CCPA progresses, fibrotic destruction of the lung results and the condition may then be referred to as chronic fibrosing pulmonary aspergillosis (CFPA). Aspergillus nodule The formation of one or more nodules is a less common manifestation of Aspergillus infection. In addition to lung cancer, the Aspergillus nodule may mimic TB but cavitation is unusual. Cryptococcosis or coccidioidomycosis should be considered in areas where these conditions are endemic. Subacute invasive aspergillosis Subacute invasive aspergillosis (SIA) was previously referred to as chronic necrotising or semi-invasive pulmonary aspergillosis.

598 • RESPIRATORY MEDICINE but the majority of patients are too ill for invasive tests, such as bronchoscopy or lung biopsy. Other investigations include detection of Aspergillus cell-wall components (galactomannan and β-1,3-glucan) in blood or BAL fluid and Aspergillus DNA by PCR. Diagnosis is often inferred from a combination of features (Box 17.60). Management and prevention IPA carries a high mortality rate, especially if treatment is delayed. The drug of choice is voriconazole. Second-line agents include liposomal amphotericin, caspofungin, posaconazole and isavuconazole. Response may be assessed clinically, radiologically and serologically (by estimation of the circulating galactomannan level). Recovery is dependent on immune reconstitution, which may be accompanied by enlargement and/or cavitation of pulmonary nodules. Patients at risk of Aspergillus (and other fungal infections) should be managed in rooms with high-efficiency particulate air (HEPA) filters and laminar airflow. In areas with high spore counts, patients are advised to wear a mask if venturing outside their hospital room. Posaconazole (200 mg 3 times daily) or itraconazole (200 mg/ day) may be prescribed for primary prophylaxis, and patients with a history of definite or probable IPA should be considered for secondary prophylaxis before further immunosuppression. Other fungal infections Mucormycosis (p. 303) may present with a pulmonary syndrome that is clinically indistinguishable from acute IPA. Diagnosis relies on histopathology (where available) and/or culture of the organism from diseased tissue. The principles of treatment are as for other forms of mucormycosis: correction of predisposing factors, antifungal therapy with high-dose lipid amphotericin B or posaconazole (second line), and surgical débridement. The endemic mycoses (histoplasmosis, coccidioidomycosis, blastomycosis and Emergomyces infection) and cryptococcosis are discussed on pages 302–304. Pneumocystis jirovecii pneumonia is described on page 318. Tumours of the bronchus and lung Lung cancer is the most common cause of death from cancer worldwide, causing 1.59 million deaths per year (Box 17.61). Tobacco use is the major preventable cause. Just as tobacco use and cancer rates are falling in some developed countries, both smoking and lung cancer are rising in Eastern Europe and in many developing countries. The great majority of tumours in the lung are primary lung cancers and, in contrast to many other tumours, the prognosis remains poor, with fewer than 30% of patients surviving at 1 year and 6–8% at 5 years. to the brain, heart, kidneys and others organs. Tracheobronchial aspergillosis involvement is characterised by the formation of fungal plaques and ulceration. HRCT characteristically shows macronodules (usually ≥ 1 cm), which may be surrounded by a ‘halo’ of intermediate attenuation if captured early (< 5 days). Culture or histopathological evidence of Aspergillus in diseased tissues provides a definitive diagnosis 17.59 Risk factors for invasive aspergillosis • Neutropenia: risk related to duration and degree • Solid organ or allogeneic stem cell transplantation • Prolonged high-dose glucocorticoid therapy • Leukaemia and other haematological malignancies • Cytotoxic chemotherapy • Advanced HIV disease • Severe chronic obstructive pulmonary disease • Critically ill patients on intensive care units • Chronic granulomatous disease 17.61 The burden of lung cancer • 1.8 million new cases worldwide each year • Most common cancer in men • Rates rising in women: Female lung cancer deaths outnumber male in some Nordic countries Has overtaken breast cancer in several countries • More than a threefold increase in deaths since 1950 • More than 50% of cases have metastatic disease at diagnosis 17.60 Criteria for the diagnosis of probable invasive pulmonary aspergillosis Host factors • Recent history of neutropenia (< 0.5 × 109/L for ≥ 10 days) temporally related to the onset of fungal disease • Recipient of allogeneic stem cell transplant • Prolonged use of glucocorticoids (average minimum 0.3 mg/kg/day prednisolone or equivalent) for > 3 weeks (excludes allergic bronchopulmonary aspergillosis) • Treatment with other recognised T-cell immune suppressants, such as ciclosporin, tumour necrosis factor, alpha-blockers, specific monoclonal antibodies (e.g. alemtuzumab) or nucleoside analogues during the last 90 days • Inherited severe immune deficiency, e.g. chronic granulomatous disease or severe combined immune deficiency (p. 79) Clinical criteria1 • The presence of one of the following on CT: Dense, well-circumscribed lesion(s) with or without a halo sign Air crescent sign Cavity Tracheobronchitis • Tracheobronchial ulceration, nodule, pseudomembrane, plaque or eschar seen on bronchoscopy Mycological criteria • Mould in sputum, BAL fluid or bronchial brush, indicated by one of the following: Recovery of fungal elements indicating a mould of Aspergillus Recovery by culture of a mould of Aspergillus • Indirect tests (detection of antigen or cell wall constituents) Galactomannan antigen in plasma, serum or BAL fluid β-1,3-glucan detected in serum (detects other species of fungi, as well as Aspergillus)2 (BAL = bronchoalveolar lavage) Adapted from De Pauw B, Walsh TJ, Donnelly JP, et al. Revised definitions of invasive fungal disease from the European Organisation for Research and Treatment of Cancer/Mycoses Study Group. Clin Infect Dis 2008; 46:1813–1821. 1Must be consistent with the mycological findings and temporally related to current episode. 2May be useful as a preliminary screening tool for invasive aspergillosis.

Tumours of the bronchus and lung • 599

In women, smoking prevalence and deaths from lung cancer continue to increase, and more women now die of lung cancer than breast cancer in the USA and the UK. Pathology Lung cancers arise from the bronchial epithelium or mucous glands. The common cell types are listed in Box 17.62. When the tumour occurs in a large bronchus, symptoms arise early but tumours originating in a peripheral bronchus can grow very large without producing symptoms, resulting in delayed diagnosis. Peripheral squamous tumours may undergo central necrosis and cavitation and may resemble a lung abscess on X-ray (Fig. 17.47). Lung cancer may involve the pleura directly or by lymphatic spread and may extend into the chest wall, invading the intercostal nerves or the brachial plexus and causing pain. Lymphatic spread to mediastinal and supraclavicular lymph nodes often occurs before diagnosis. Blood-borne metastases occur most commonly in liver, bone, brain, adrenals and skin. Even a small primary tumour may cause widespread metastatic deposits and this is a particular characteristic of small-cell lung cancers. Clinical features Lung cancer presents in many different ways, reflecting local, metastatic or paraneoplastic tumour effects. Cough This is the most common early symptom. It is often dry but secondary infection may cause purulent sputum. A change in the character of a smoker’s cough, particularly if associated with other new symptoms, should always raise suspicion of lung cancer. Haemoptysis Haemoptysis is common, especially with central bronchial tumours. Although it may be caused by bronchitic Fig. 17.46 Mortality trends from lung cancer in UK, 1979–2013, by age and year of death. A Males. B Females. Note the decline in mortality from lung cancer in men and increase in mortality in older women towards the end of this period, reflecting changes in smoking habits. From Cancer Research UK: http://www.cancerresearchuk.org/health-professional/ cancer-statistics/statistics-by-cancer-type/lung-cancer/mortality. Accessed January 2017. 25–49 50–59 60–69 70–79 80+

Year of diagnosis

Rate per 100000 1979–81 1980–82 1981–83 1982–84 1983–85 1984–86 1985–87 1986–88 1987–89 1988–90 1989–91 1990–92 1991–93 1992–94 1993–95 1994–96 1995–97 1996–98 1997–99 1998–00 1999–01 2000–02 2001–03 2002–04 2003–05 2004–06 2005–07 2006–08 2007–09 2008–10 2009–11 2010–12 2011–13 A

25–49 50–59 60–69 70–79 80+

Year of diagnosis

Rate per 100000 1979–81 1980–82 1981–83 1982–84 1983–85 1984–86 1985–87 1986–88 1987–89 1988–90 1989–91 1990–92 1991–93 1992–94 1993–95 1994–96 1995–97 1996–98 1997–99 1998–00 1999–01 2000–02 2001–03 2002–04 2003–05 2004–06 2005–07 2006–08 2007–09 2008–10 2009–11 2010–12 2011–13 B 17.62 Common cell types in lung cancer Cell type % Adenocarcinoma 35–40 Squamous 25–30 Small-cell

Large-cell 10–15 Primary tumours of the lung Aetiology Cigarette smoking is by far the most important cause of lung cancer. It is thought to be directly responsible for at least 90% of cases, the risk being proportional to the amount smoked and to the tar content of cigarettes. The death rate from the disease in heavy smokers is 40 times that in non-smokers. Risk falls slowly after smoking cessation but remains above that in non-smokers for many years. It is estimated that 1 in 2 smokers dies from a smoking-related disease, about half in middle age. The effect of ‘passive’ smoking is more difficult to quantify but is currently thought to be a factor in 5% of all lung cancer deaths. Exposure to naturally occurring radon is another risk. The incidence of lung cancer is slightly higher in urban than in rural dwellers, which may reflect differences in atmospheric pollution (including tobacco smoke) or occupation, since a number of industrial materials are associated with lung cancer (p. 1320). In recent years, the strong link between smoking and ill health has led many governments to legislate against smoking in public places, and smoking prevalence and some smoking-related diseases are already declining in these countries (p. 94). Lung cancer The incidence of lung cancer increased dramatically during the 20th century as a direct result of the tobacco epidemic (Fig. 17.46). Fig. 17.47 Large cavitated lung cancer in left lower lobe.

600 • RESPIRATORY MEDICINE Breathlessness Breathlessness may be caused by collapse or pneumonia, or by tumour causing a large pleural effusion or compressing a phrenic nerve and leading to diaphragmatic paralysis. Pain and nerve entrapment Pleural pain may indicate malignant pleural invasion, although it can occur with distal infection. Intercostal nerve involvement causes pain in the distribution of a thoracic dermatome. Cancer in the lung apex may cause Horner’s syndrome (ipsilateral partial ptosis, enophthalmos, miosis and hypohidrosis of the face; p. 1091) due to involvement of the sympathetic nerves to the eye at or above the stellate ganglion. Pancoast’s syndrome (pain in the inner aspect of the arm, sometimes with small muscle wasting in the hand) indicates malignant destruction of the T1 and C8 roots in the lower part of the brachial plexus by an apical lung tumour. Mediastinal spread Involvement of the oesophagus may cause dysphagia. If the pericardium is invaded, arrhythmia or pericardial effusion may occur. Superior vena cava obstruction by malignant nodes causes suffusion and swelling of the neck and face, conjunctival oedema, headache and dilated veins on the chest wall and is most commonly due to lung cancer. Involvement of the left recurrent laryngeal nerve by tumours at the left hilum causes vocal cord paralysis, voice alteration and a ‘bovine’ cough (lacking the normal explosive character). Supraclavicular lymph nodes may be palpably enlarged or identified using ultrasound; if so, a needle aspirate may provide a simple means of cytological diagnosis. Metastatic spread This may lead to focal neurological defects, epileptic seizures, personality change, jaundice, bone pain or skin nodules. Lassitude, anorexia and weight loss usually indicate metastatic spread. Finger clubbing Overgrowth of the soft tissue of the terminal phalanx, leading to increased nail curvature and nail bed fluctuation, is often seen (p. 546). Hypertrophic pulmonary osteoarthropathy (HPOA) This is a painful periostitis of the distal tibia, fibula, radius and ulna, with local tenderness and sometimes pitting oedema over the anterior shin. X-rays reveal subperiosteal new bone formation. While Fig. 17.48 Collapse of the right lung: effects on neighbouring structures. A Chest X-ray. B The typical abnormalities are highlighted. A B Compensatory emphysema of left lung Site of obstruction of right main bronchus Displacement of trachea, heart and other mediastinal structures to the right Position of elevated right hemidiaphragm (not seen on chest X-ray) 17.63 Causes of large bronchus obstruction Common • Lung cancer or adenoma • Enlarged tracheobronchial lymph nodes (malignant or tuberculous) • Inhaled foreign bodies (especially right lung) • Bronchial casts or plugs consisting of inspissated mucus or blood clot (especially asthma, cystic fibrosis, haemoptysis, debility) • Collections of mucus or mucopus retained in the bronchi as a result of ineffective expectoration (especially postoperative following abdominal surgery) Rare • Aortic aneurysm • Giant left atrium • Pericardial effusion • Congenital bronchial atresia • Fibrous bronchial stricture (e.g. following tuberculosis or bronchial surgery/lung transplant) infection, haemoptysis in a smoker should always be investigated to exclude a lung cancer. Occasionally, central tumours invade large vessels, causing sudden massive haemoptysis that may be fatal. Bronchial obstruction This is another common presentation. The clinical and radiological manifestations (Figs 17.48 and 17.5, p. 552; Box 17.63) depend on the site and extent of the obstruction, any secondary infection and the extent of coexisting lung disease. Complete obstruction causes collapse of a lobe or lung, with breathlessness, mediastinal displacement and dullness to percussion with reduced breath sounds. Partial bronchial obstruction may cause a monophonic, unilateral wheeze that fails to clear with coughing, and may also impair the drainage of secretions to cause pneumonia or lung abscess as a presenting problem. Pneumonia that recurs at the same site or responds slowly to treatment, particularly in a smoker, should always suggest an underlying lung cancer. Stridor (a harsh inspiratory noise) occurs when the larynx, trachea or a main bronchus is narrowed by the primary tumour or by compression from malignant enlargement of the subcarinal and paratracheal lymph nodes.

Tumours of the bronchus and lung • 601

for invasive investigation, sputum cytology may reveal malignant cells, although the yield is low. In patients with pleural effusions, pleural aspiration and biopsy is the preferred investigation. Where facilities exist, thoracoscopy increases yield by allowing targeted biopsies under direct vision. In patients with metastatic disease, the diagnosis can often be confirmed by needle aspiration or biopsy of affected lymph nodes, skin lesions, liver or bone marrow. most frequently associated with lung cancer, HPOA can occur with other tumours. Non-metastatic extrapulmonary effects (Box 17.64) The syndrome of inappropriate antidiuretic hormone secretion (SIADH, p. 357) and ectopic adrenocorticotrophic hormone secretion (p. 670) are usually associated with small-cell lung cancer. Hypercalcaemia may indicate malignant bone destruction or production of hormone-like peptides by a tumour. Associated neurological syndromes may occur with any type of lung cancer. Investigations The main aims of investigation are to confirm the diagnosis, establish the histological cell type and define the extent of the disease. Imaging Lung cancer produces a range of appearances on chest X-ray, from lobar collapse (see Fig. 17.5, p. 552) to mass lesions, effusion or malignant rib destruction (Fig. 17.49). CT should be performed early, as it may reveal mediastinal or metastatic spread and is helpful for planning biopsy procedures, e.g. in establishing whether a tumour is accessible by bronchoscopy or percutaneous CT-guided biopsy. Biopsy and histopathology Over half of primary lung tumours can be visualised and sampled directly by biopsy and brushing using a flexible bronchoscope. Bronchoscopy also allows an assessment of operability, from the proximity of central tumours to the main carina (Fig. 17.50). For tumours that are too peripheral to be accessible by bronchoscope, the yield of ‘blind’ bronchoscopic washings and brushings from the radiologically affected area is low and percutaneous needle biopsy under CT or ultrasound guidance is a more reliable way to obtain a histological diagnosis. There is a small risk of iatrogenic pneumothorax, which may preclude the procedure if there is extensive coexisting COPD. In patients with a peripheral tumour and enlarged hilar or paratracheal lymph nodes on CT, bronchoscopy with EBUS-guided node sampling may allow both diagnosis and staging. In those who are unfit Fig. 17.49 Common radiological presentations of lung cancer. (1) Unilateral hilar enlargement suggests a central tumour or hilar glandular involvement. However, a peripheral tumour in the apex of a lower lobe can look like an enlarged hilar shadow on the posteroanterior X-ray. (2) Peripheral pulmonary opacity (p. 560) is usually irregular but well circumscribed, and may contain irregular cavitation. It can be very large. (3) Lung, lobe or segmental collapse is usually caused by tumour occluding a proximal bronchus. Collapse may also be due to compression of a bronchus by enlarged lymph glands. (4) Pleural effusion usually indicates tumour invasion of the pleural space or, very rarely, infection in collapsed lung tissue distal to a lung cancer. (5) Paratracheal lymphadenopathy may cause widening of the upper mediastinum. (6) A malignant pericardial effusion may cause enlargement of the cardiac shadow. (7) A raised hemidiaphragm may be caused by phrenic nerve palsy. Screening will show paradoxical upward movement when the patient sniffs. (8) Osteolytic rib destruction indicates direct invasion of the chest wall or metastatic spread.

17.64 Non-metastatic extrapulmonary manifestations of lung cancer Endocrine (Ch. 18) • Inappropriate antidiuretic hormone (ADH, vasopressin) secretion, causing hyponatraemia • Ectopic adrenocorticotrophic hormone secretion • Hypercalcaemia due to secretion of parathyroid hormone-related peptides • Carcinoid syndrome (p. 678) • Gynaecomastia Neurological (Ch. 25) • Polyneuropathy • Myelopathy • Cerebellar degeneration • Myasthenia (Lambert–Eaton syndrome, p. 1142) Other • Digital clubbing • Hypertrophic pulmonary osteoarthropathy • Nephrotic syndrome • Polymyositis and dermatomyositis • Eosinophilia Fig. 17.50 Bronchoscopic view of a lung cancer. There is distortion of mucosal folds, partial occlusion of the airway lumen and abnormal tumour tissue.

602 • RESPIRATORY MEDICINE Radiotherapy While much less effective than surgery, radical radiotherapy can offer long-term survival in selected patients with localised disease in whom comorbidity precludes surgery. Radical radiotherapy is usually combined with chemotherapy when lymph nodes are involved (stage III). Highly targeted (stereotactic) radiotherapy may be given in 3–5 treatments for small lesions. The greatest value of radiotherapy, however, is in the palliation of distressing complications, such as superior vena cava obstruction, recurrent haemoptysis, and pain caused by chest wall invasion or by skeletal metastatic deposits. Obstruction of the trachea and main bronchi can also be relieved temporarily. Radiotherapy can be used in conjunction with chemotherapy in the treatment of small-cell carcinoma and is particularly efficient at preventing the development of brain metastases in patients who have had a complete response to chemotherapy (p. 1331). Chemotherapy The treatment of small-cell carcinoma with combinations of cytotoxic drugs, sometimes with radiotherapy, can increase median survival from 3 months to well over a year. The use of combinations of chemotherapeutic drugs requires considerable skill and should be overseen by multidisciplinary teams of clinical oncologists and specialist nurses. Combination chemotherapy leads to better outcomes than single-agent treatment. Regular cycles of therapy, including combinations of intravenous cyclophosphamide, doxorubicin and vincristine or intravenous cisplatin and etoposide, are commonly used. In NSCLC chemotherapy is less effective, though platinumbased chemotherapy regimens offer 30% response rates and a modest increase in survival, and are widely used. Some non-small-cell lung tumours, particularly adenocarcinomas in non-smokers, carry detectable mutations, e.g. in the epidermal growth factor receptor (EGFR) gene. Tyrosine kinase inhibitors, such as erlotinib and monoclonal antibodies to EGFR (e.g. bevacizumab), show improved treatment responses in metastatic Staging to guide treatment The propensity of small-cell lung cancer to metastasise early means these patients are usually not suitable for surgical intervention. In non-small-cell lung cancer (NSCLC), treatment and prognosis are determined by disease extent, so careful staging is required. CT is used early to detect obvious local or distant spread. Enlarged upper mediastinal nodes may be sampled using an EBUSequipped bronchoscope or by mediastinoscopy. Nodes in the lower mediastinum can be sampled through the oesophageal wall using endoscopic ultrasound. Combined CT and whole-body PET (see Fig. 17.6, p. 553) is commonly used to detect occult but metabolically active metastases. Head CT, radionuclide bone scanning, liver ultrasound and bone marrow biopsy are generally reserved for patients with clinical, haematological or biochemical evidence of tumour spread to these sites. Information on tumour size and nodal and metastatic spread is then collated to assign the patient to one of seven staging groups that determine optimal management and prognosis (Fig. 17.51). Detailed physiological testing is required to assess whether respiratory and cardiac function is sufficient to allow aggressive treatment. Management Surgical resection carries the best hope of long-term survival but some patients treated with radical radiotherapy and chemotherapy also achieve prolonged remission or cure. In over 75% of cases, treatment with the aim of cure is not possible or is inappropriate due to extensive spread or comorbidity. Such patients are offered palliative therapy and best supportive care. Radiotherapy and, in some cases, chemotherapy can relieve symptoms. Surgical treatment Accurate pre-operative staging, coupled with improvements in surgical and post-operative care, now offers 5-year survival rates of over 75% in stage I disease (N0, tumour confined within visceral pleura) and 55% in stage II disease, which includes resection in patients with ipsilateral peribronchial or hilar node involvement. Fig. 17.51 Tumour stage and 5-year survival in non-small-cell lung cancer. The figure shows the relationship between tumour extent (size, lymph node status and metastases) and prognosis (% survival at 5 years for each clinical stage). Based on data from Detterbeck FC, Boffa DJ, Kim AW, Tanoue T. The eighth edition lung cancer stage classification. Chest 2017; 151:193–203. N2 (Ipsilateral mediastinal or subcarinal) N1 (Ipsilateral hilar) N0 (None) T1a (≤1 cm) T1b (>1 to ≤2 cm) T1c (>2 to ≤3 cm) T2a (>3 to ≤4 cm) T2b (>4 cm to ≤5 cm) T3 (>5 cm) M1a Lung metastasis/effusion M1b Single extrathoracic metastasis M1c Multiple extrathoracic metastases T4 (>7 cm or invading heart, vessels, oesophagus, carina etc.) IA1 (92%) IIB (53%) IIIA (36%) IVA (10%) IVB (0%) IIIB (26%) IIIB (26%) IIIC (13%) IIIA (36%) IA2 (83%) IA3 (77%) IB (68%) IIA (60%) IIB (53%) N3 (Contralateral or supraclavicular) Lymph node spread Tumour stage

Tumours of the bronchus and lung • 603

other sarcomas. These secondary deposits are usually multiple and bilateral. Often there are no respiratory symptoms and the diagnosis is incidental on X-ray. Breathlessness may occur if a considerable amount of lung tissue has been replaced by metastatic tumour. Endobronchial deposits are uncommon but can cause haemoptysis and lobar collapse. Lymphatic infiltration may develop in carcinoma of the breast, stomach, bowel, pancreas or bronchus. ‘Lymphangitic carcinomatosis’ causes severe, rapidly progressive breathlessness with marked hypoxaemia. The chest X-ray shows diffuse pulmonary shadowing radiating from the hilar regions, often with septal lines, and CT shows characteristic polygonal thickened interlobular septa. Palliation of breathlessness with opiates may help (p. 1353). Tumours of the mediastinum Figure 17.52 shows the major compartments of the mediastinum and Box 17.66 lists likely causes of a mediastinal mass. NSCLC and EGFR mutations, and similar approaches are being developed to target other known genetic abnormalities. In NSCLC there is some evidence that chemotherapy given before surgery may increase survival and can effectively ‘down-stage’ disease with limited nodal spread. Post-operative chemotherapy is now proven to enhance survival rates when operative samples show nodal involvement by tumour. Nausea and vomiting are common side-effects of chemotherapy and are best treated with 5-HT3 receptor antagonists (p. 1353). Laser therapy and stenting Palliation of symptoms caused by major airway obstruction can be achieved in selected patients using bronchoscopic laser treatment to clear tumour tissue and allow re-aeration of collapsed lung. The best results are achieved in tumours of the main bronchi. Endobronchial stents can be used to maintain airway patency in the face of extrinsic compression by malignant nodes. General aspects of management The best outcomes are obtained when lung cancer is managed in specialist centres by multidisciplinary teams, including oncologists, thoracic surgeons, respiratory physicians and specialist nurses. Effective communication, pain relief and attention to diet are important. Lung tumours can cause clinically significant depression and anxiety, and these may need specific therapy. The management of non-metastatic endocrine manifestations is described in Chapter 18. When a malignant pleural effusion is present, an attempt should be made to drain the pleural cavity using an intercostal drain; provided that the lung fully re-expands, pleurodesis with a sclerosing agent, such as talc, should be performed to prevent recurrent effusion. Prognosis The overall prognosis in lung cancer is very poor, 70% of patients dying within a year of diagnosis and only 6–8% surviving 5 years after diagnosis. The best prognosis is with well-differentiated squamous cell tumours that have not metastasised and are amenable to surgical resection. The clinical features and prognosis of some less common tumours are given in Box 17.65. Secondary tumours of the lung Blood-borne metastatic deposits in the lungs may be derived from many primary carcinomas, in particular breast, kidney, uterus, ovary, testes and thyroid, and also from osteogenic and 17.65 Rare types of lung tumour Tumour Status Histology Typical presentation Prognosis Adenosquamous carcinoma Malignant Tumours with areas of unequivocal squamous and adeno-differentiation Peripheral or central lung mass Stage-dependent Neuro-endocrine (carcinoid) tumour (p. 678) Low-grade malignant Neuro-endocrine differentiation Bronchial obstruction, cough 95% 5-year survival with resection Bronchial gland adenoma Benign Salivary gland differentiation Tracheobronchial irritation/obstruction Local resection curative Bronchial gland carcinoma Low-grade malignant Salivary gland differentiation Tracheobronchial irritation/obstruction Local recurrence Hamartoma Benign Mesenchymal cells, cartilage Peripheral lung nodule Local resection curative Bronchoalveolar carcinoma Malignant Tumour cells line alveolar spaces Alveolar shadowing, productive cough Variable, worse if multifocal 17.66 Causes of a mediastinal mass Superior mediastinum • Retrosternal goitre • Persistent left superior vena cava • Prominent left subclavian artery • Thymic tumour • Dermoid cyst • Lymphoma • Aortic aneurysm Anterior mediastinum • Retrosternal goitre • Dermoid cyst • Thymic tumour • Lymphoma • Aortic aneurysm • Germ cell tumour • Pericardial cyst • Hiatus hernia through the diaphragmatic foramen of Morgagni Posterior mediastinum • Neurogenic tumour • Paravertebral abscess • Oesophageal lesion • Aortic aneurysm • Foregut duplication Middle mediastinum • Lung cancer • Lymphoma • Sarcoidosis • Bronchogenic cyst • Hiatus hernia

604 • RESPIRATORY MEDICINE Investigations A benign mediastinal tumour generally appears on chest X-ray as a sharply circumscribed mediastinal opacity encroaching on one or both lung fields (Fig. 17.53). CT (or MRI) is the investigation of choice for mediastinal tumours (e.g. see Fig. 18.12, p. 648). A malignant mediastinal tumour seldom has a clearly defined margin and often presents as a general broadening of the mediastinum. Bronchoscopy may reveal a primary lung cancer causing mediastinal lymphadenopathy. EBUS may be used to guide sampling of peribronchial masses. The posterior mediastinum can be imaged and biopsied via the oesophagus using endoscopic ultrasound (p. 553). Mediastinoscopy under general anaesthetic can be used to visualise and biopsy masses in the superior and anterior mediastinum but surgical exploration of the chest, with removal of part or all of the tumour, is often required to obtain a histological diagnosis. Benign tumours and cysts in the mediastinum are often diagnosed when a chest X-ray is undertaken for some other reason. In general, they do not invade vital structures but may cause symptoms by compressing the trachea or the superior vena cava. A dermoid cyst may very occasionally rupture into a bronchus. Malignant mediastinal tumours are distinguished by their power to invade, as well as compress, surrounding structures. As a result, even a small malignant tumour can produce symptoms, although, more commonly, the tumour has attained a considerable size before this happens (Box 17.67). The most common cause is mediastinal lymph node metastasis from lung cancer but lymphomas, leukaemia, malignant thymic tumours and germ-cell tumours can cause similar features. Aortic and innominate aneurysms have destructive features resembling those of malignant mediastinal tumours. Fig. 17.52 The divisions of the mediastinum. (1) Superior mediastinum. (2) Anterior mediastinum. (3) Middle mediastinum. (4) Posterior mediastinum. Sites of the more common mediastinal tumours are also illustrated. From Johnson N McL. Respiratory medicine. Oxford: Blackwell Science; 1986.

Lower border of 4th thoracic vertebra Lymphoid masses Neurogenic tumour Retrosternal thyroid Thymus Lower border of manubrium sterni Teratoma Dermoid Pleuropericardial cyst 17.67 Clinical features of malignant mediastinal invasion Trachea and main bronchi • Stridor, breathlessness, cough, pulmonary collapse Oesophagus • Dysphagia, oesophageal displacement or obstruction on barium swallow examination Phrenic nerve • Diaphragmatic paralysis Left recurrent laryngeal nerve • Paralysis of left vocal cord with hoarseness and ‘bovine’ cough Sympathetic trunk • Horner’s syndrome Superior vena cava • SVC obstruction: non-pulsatile distension of neck veins, subconjunctival oedema, and oedema and cyanosis of head, neck, hands and arms; dilated anastomotic veins on chest wall Pericardium • Pericarditis and/or pericardial effusion Fig. 17.53 Intrathoracic goitre (arrows) extending from right upper mediastinum.

Interstitial and infiltrative pulmonary diseases • 605

They often present with cough, which is typically dry and distressing, and breathlessness, which is often insidious in onset but thereafter relentlessly progressive. Physical examination reveals the presence of inspiratory crackles and in many cases digital clubbing develops. Pulmonary function tests typically show a restrictive ventilatory defect in the presence of small lung volumes and reduced gas transfer. The typical radiographic findings include, in the earliest stages, ground glass and reticulonodular shadowing, with progression to honeycomb cysts and traction bronchiectasis. While these appearances may be seen on a ‘plain’ chest X-ray, they are most easily appreciated on HRCT, which has assumed a central role in the evaluation of DPLD (Fig. 17.54). The current classification is shown in Figure 17.55 and the potential differential diagnoses in Box 17.69. Idiopathic interstitial pneumonias The idiopathic interstitial pneumonias represent a major subgroup of DPLD that are grouped together as a result of their unknown aetiology (Box 17.70). They are often distinguished by the predominant histological pattern on tissue biopsy; hence they are frequently referred to by their pathological description, e.g. usual interstitial pneumonia (UIP) or non-specific interstitial pneumonia (NSIP). The most important of these is idiopathic pulmonary fibrosis. Idiopathic pulmonary fibrosis Idiopathic pulmonary fibrosis is defined as a progressive fibrosing interstitial pneumonia of unknown cause, occurring in adults and associated with the histological or radiological pattern of UIP. Important differentials include fibrosing diseases caused Management Benign mediastinal tumours should be removed surgically because most produce symptoms sooner or later. Cysts may become infected, while neural tumours have the potential to undergo malignant transformation. The operative mortality is low in the absence of coexisting cardiovascular disease, COPD or extreme age. Interstitial and infiltrative pulmonary diseases Diffuse parenchymal lung disease The diffuse parenchymal lung diseases (DPLDs) are a heterogeneous group of conditions affecting the pulmonary parenchyma (interstitium) and/or alveolar lumen, which are frequently considered collectively as they share a sufficient number of clinical physiological and radiographic similarities (Box 17.68). 17.68 Features common to the diffuse parenchymal lung diseases Clinical presentation • Cough: usually dry, persistent and distressing • Breathlessness: usually slowly progressive; insidious onset; acute in some cases Examination findings • Crackles: typically bilateral and basal • Clubbing: common in idiopathic pulmonary fibrosis but also seen in other types, e.g. asbestosis • Central cyanosis and signs of right heart failure in advanced disease Radiology • Chest X-ray: typically small lung volumes with reticulonodular shadowing but may be normal in early or limited disease • High-resolution computed tomography: combinations of ground glass changes, reticulonodular shadowing, honeycomb cysts and traction bronchiectasis, depending on stage of disease Pulmonary function • Typically restrictive ventilatory defect with reduced lung volumes and impaired gas transfer; exercise tests assess exercise tolerance and exercise-related fall in SaO2 Fig. 17.54 Algorithm for the investigation of patients with interstitial lung disease following initial clinical and chest X-ray examination. Clinical assessment including chest X-ray, pulmonary function tests, haematology, biochemical and immunological investigations Appearances consistent with another diffuse parenchymal lung disease, e.g. sarcoid Inconsistent clinical or CT appearances Appearances consistent with usual interstitial pneumonia High-resolution CT Further investigations, e.g. bronchoalveolar lavage, transbronchial biopsy, surgical biopsy Diagnose idiopathic pulmonary fibrosis Diagnose and treat accordingly 17.69 Conditions that mimic diffuse parenchymal lung disease Infection • Viral pneumonia • Pneumocystis jirovecii • Mycoplasma pneumoniae • Tuberculosis • Parasite, e.g. filariasis • Fungal infection Malignancy • Leukaemia and lymphoma • Lymphangitic carcinomatosis • Multiple metastases • Bronchoalveolar carcinoma Pulmonary oedema Aspiration pneumonitis

606 • RESPIRATORY MEDICINE CT scanning it may present as an incidental finding in an otherwise asymptomatic individual but more typically presents with progressive breathlessness (which may have been insidious) and a non-productive cough. Constitutional symptoms are unusual. Clinical findings include finger clubbing and the presence of bi-basal fine late inspiratory crackles likened to the unfastening of Velcro. Investigations These are summarised in Box 17.71. Established IPF will be apparent on chest X-ray as a bilateral lower lobe and subpleural reticular shadowing. The chest X-ray may be normal in individuals with early or limited disease, however. HRCT typically demonstrates a patchy, predominantly peripheral, subpleural and basal reticular pattern and, in more advanced disease, the presence of honeycombing cysts and traction bronchiectasis Fig. 17.55 Classification of diffuse parenchymal lung disease. DPLD of known cause, e.g. drugs or association with connective tissue disease Diffuse parenchymal lung disease (DPLD) Idiopathic interstitial pneumonia Granulomatous DPLD, e.g. sarcoidosis Other forms of DPLD, e.g. lymphangioleiomyomatosis, histiocytosis X etc. Idiopathic pulmonary fibrosis Idiopathic interstitial pneumonia other than idiopathic pulmonary fibrosis Desquamative interstitial pneumonia Respiratory bronchiolitis interstitial lung disease Acute interstitial pneumonia Cryptogenic organising pneumonia Non-specific interstitial pneumonia Lymphocytic interstitial pneumonia 17.70 Idiopathic interstitial pneumonias Clinical diagnosis Notes Usual interstitial pneumonia (UIP) Idiopathic pulmonary fibrosis – see text Non-specific interstitial pneumonia (NSIP) See page 608 Respiratory bronchiolitis–interstitial lung disease More common in men and smokers. Usually presents at age 40–60 years. Smoking cessation may lead to improvement. Natural history unclear Acute interstitial pneumonia Often preceded by viral upper respiratory tract infection. Severe exertional dyspnoea, widespread pneumonic consolidation and diffuse alveolar damage on biopsy. Prognosis often poor Desquamative interstitial pneumonia (DIP) More common in men and smokers. Presents at age 40–60 years. Insidious onset of dyspnoea. Clubbing in 50%. Biopsy shows increased macrophages in alveolar space, septal thickening and type II pneumocyte hyperplasia. Prognosis generally good Cryptogenic organising pneumonia (‘bronchiolitis obliterans organising pneumonia’ – BOOP) Presents as clinical and radiological pneumonia. Systemic features and markedly raised erythrocyte sedimentation rate common. Finger clubbing absent. Biopsy shows florid proliferation of immature collagen (Masson bodies) and fibrous tissue. Response to glucocorticoids classically excellent Lymphocytic interstitial pneumonia (LIP) More common in women, slow onset over years. Investigate for associations with connective tissue disease or HIV. Unclear whether glucocorticoids are helpful by occupational exposure, medication or connective tissue diseases, which must be excluded by careful history, examination and investigation. The histological features of the condition are suggestive of repeated episodes of focal damage to the alveolar epithelium consistent with an autoimmune process but the aetiology remains elusive: speculation has included exposure to viruses (e.g. Epstein–Barr virus), occupational dusts (metal or wood), drugs (antidepressants) or chronic gastro-oesophageal reflux. Familial cases are rare but genetic factors that control the inflammatory and fibrotic response are likely to be important. There is a strong association with cigarette smoking. Clinical features IPF usually presents in the older adult and is uncommon before the age of 50 years. With the advent of widespread

Interstitial and infiltrative pulmonary diseases • 607

Management The management options for IPF are improving. If the vital capacity is between 50% and 80% predicted, patients may be offered either pirfenidone (an antifibrotic agent) or nintedanib (a tyrosine kinase inhibitor). Both of these agents have been shown to reduce the rate of decline in lung function. Patients taking pirfenidone should be advised to avoid direct exposure to sunlight and use photoprotective clothing and high-protection sunscreens. Nintedanib may be accompanied by diarrhoea. Neither drug improves cough or breathlessness and treatment should be discontinued if lung function declines by more than 10% over the first year of treatment. Medication to control gastro-oesophageal reflux may improve the cough. Current smokers should be apprised of the increased risk of lung cancer and advised to stop. Influenza and pneumococcal vaccination should be recommended. Patients should be encouraged to exercise and participate in pulmonary rehabilitation using ambulatory oxygen if appropriate. Domiciliary oxygen should be considered for palliation of breathlessness in severe cases. Where appropriate, lung transplantation should be considered. The optimum treatment for acute exacerbations is unknown. Treatment is largely supportive. Broad-spectrum antibiotics may 17.71 Investigations in diffuse parenchymal lung disease Laboratory investigations • Full blood count: lymphopenia in sarcoid; eosinophilia in pulmonary eosinophilias and drug reactions; neutrophilia in hypersensitivity pneumonitis • Ca2+: may be elevated in sarcoid • Lactate dehydrogenase: may be elevated in active alveolitis • Serum angiotensin-converting enzyme: non-specific indicator of disease activity in sarcoid • Erythrocyte sedimentation rate and C-reactive protein: nonspecifically raised • Autoimmune screen: anti-cyclic citrullinated peptide (anti-CCP) and other autoantibodies may suggest connective tissue disease Radiology • See Box 17.68 Pulmonary function • See Box 17.68 Bronchoscopy • Bronchoalveolar lavage: differential cell counts may point to sarcoid and drug-induced pneumonitis, pulmonary eosinophilias, hypersensitivity pneumonitis or cryptogenic organising pneumonia; useful to exclude infection • Transbronchial biopsy: useful in sarcoid and differential of malignancy or infection • Bronchial biopsy: occasionally useful in sarcoid Video-assisted thoracoscopic lung biopsy (in selected cases) • Allows pathological classification: presence of asbestos bodies may suggest asbestosis; silica in occupational fibrosing lung disease Others • Liver biopsy: may be useful in sarcoidosis • Urinary calcium excretion: may be useful in sarcoidosis (Fig. 17.56). When these features are present, HRCT has a high positive predictive value for the diagnosis of IPF and recourse to biopsy is seldom necessary. HRCT appearances may also be sufficiently characteristic to suggest an alternative diagnosis such as hypersensitivity pneumonitis (p. 616) or sarcoidosis (p. 608). The presence of pleural plaques may suggest asbestosis (p. 618). Pulmonary function tests classically show a restrictive defect with reduced lung volumes and gas transfer. However, lung volumes may be preserved in patients with concomitant emphysema. Dynamic tests are useful to document exercise tolerance and demonstrate exercise-induced arterial hypoxaemia, but as IPF advances, arterial hypoxaemia and hypocapnia are present at rest. Bronchoscopy is seldom indicated unless there is serious consideration of differential diagnoses of infection or a malignant process; lymphocytosis may suggest chronic hypersensitivity pneumonitis. The tissue samples obtained by transbronchial lung biopsy are invariably insufficient to be of value, and if tissue is required, a surgical lung biopsy should be sought. Lung biopsy should be considered in cases of diagnostic uncertainty or with atypical features. UIP is the histological pattern predominantly encountered in IPF (Fig. 17.57); however, it is also found in asbestosis, hypersensitivity pneumonitis, connective tissue diseases and drug reactions. It is not uncommon to identify a mildly positive antinuclear antibody (ANA) or anti-cyclic citrullinated peptide 2 (anti-CCP2) and repeat serological testing may be performed, as lung disease may precede the appearance of connective tissue disease. Fig. 17.56 Idiopathic pulmonary fibrosis. Typical high-resolution CT images demonstrate the bilateral, predominantly basal and peripheral reticular opacities, accompanied by honeycombing in the later stages. A Anteroposterior view. B Transverse section. Courtesy of Dr Andrew Baird, Consultant Radiologist, NHS Lothian, Edinburgh, UK. A B

608 • RESPIRATORY MEDICINE rarely affected. The tendency for sarcoid to present in the spring and summer has led to speculation about the role of infective agents, including mycobacteria, propionibacteria and viruses, but the cause remains elusive. Genetic susceptibility is supported by familial clustering; a range of class II HLA alleles confer protection from, or susceptibility to, the condition. Sarcoidosis occurs less frequently in smokers. It may be associated with common variable immunodeficiency (p. 79). Clinical features Sarcoidosis is considered with other DPLDs, as over 90% of cases affect the lungs, but the condition can involve almost any organ (Fig. 17.59 and Box 17.72). Löfgren’s syndrome – an acute illness characterised by erythema nodosum, peripheral arthropathy, uveitis, bilateral hilar lymphadenopathy (BHL), lethargy and occasionally fever – is often seen in young women. Alternatively, BHL may be detected in an otherwise asymptomatic individual undergoing a chest X-ray for other purposes. Pulmonary disease may also present in a more insidious manner with cough, exertional breathlessness and radiographic infiltrates; chest auscultation is often surprisingly unremarkable. Fibrosis be combined with glucocorticoids and sometimes additional immunosuppression but there are few data to support this approach. Prognosis The natural history is usually one of steady decline; however, some patients are prone to exacerbations accompanied by an acute deterioration in breathlessness, disturbed gas exchange, and new ground glass changes or consolidation on HRCT. In advanced disease, central cyanosis is detectable and patients may develop pulmonary hypertension and features of right heart failure. A median survival of 3 years is widely quoted; the rate of disease progression varies considerably, however, from death within a few months to survival with minimal symptoms for many years. Serial lung function testing may provide useful prognostic information, relative preservation of lung function suggesting longer survival and significantly impaired gas transfer and/or desaturation on exercise heralding a poorer prognosis. The finding of high numbers of fibroblastic foci on biopsy suggests a more rapid deterioration. Non-specific interstitial pneumonia The clinical picture of fibrotic NSIP is similar to that of IPF, although patients tend to be women and younger in age. As with UIP, the condition may present as an isolated idiopathic pulmonary condition, but an NSIP pattern is often associated with connective tissue disease, certain drugs, chronic hypersensitivity pneumonitis or HIV infection and care must be taken to exclude these possibilities. As with UIP, the pulmonary condition may precede the appearance of connective tissue disease. HRCT findings are less specific than with IPF and lung biopsy may be required. The prognosis is significantly better than that of IPF, particularly in the cellular form of the condition, and the 5-year mortality rate is typically less than 15%. Sarcoidosis Sarcoidosis is a multisystem granulomatous disorder of unknown aetiology that is characterised by the presence of non-caseating granulomas (Fig. 17.58). The condition is more frequently described in colder parts of northern Europe. It also appears to be more common and more severe in those from a West Indian or Asian background; Eskimos, Arabs and Chinese are Fig. 17.57 Pathology of usual interstitial pneumonia. A Lung tissue showing subpleural scarring, most prominently down the posterior edge of the lower lobe. This distribution of fibrosis is typical of usual interstitial pneumonitis. The fibrosis may be associated with prominent cystic change known as ‘honeycomb lung’. B Histology showing severe interstitial fibrosis with loss of the normal alveolar architecture and the development of ‘honeycomb’ cysts. Courtesy of Dr William Wallace, Department of Pathology, Royal Infirmary of Edinburgh. A B Fig. 17.58 Sarcoidosis of the lung. Histology showing non-caseating granulomas (arrows). Courtesy of Dr William Wallace, Department of Pathology, Royal Infirmary of Edinburgh.

Interstitial and infiltrative pulmonary diseases • 609

may provide a non-specific marker of disease activity and can assist in monitoring the clinical course. Chest radiography has been used to stage sarcoid (Box 17.73). In patients with pulmonary infiltrates, pulmonary function testing may show a restrictive defect accompanied by impaired gas exchange. Exercise tests Fig. 17.59 Possible systemic involvement in sarcoidosis. Inset (Erythema nodosum): From Savin JA, Hunter JAA, Hepburn NC. Skin signs in clinical medicine. London: Mosby–Wolfe; 1997. Pachymeningitis Space-occupying lesion Diabetes insipidus Anterior uveitis Sicca syndrome Lymphadenopathy Bilateral hilar lymphadenopathy (BHL) Cardiac arrhythmia Heart block, sudden death Splenomegaly Nephrocalcinosis Hypercalciuria Renal stones Arthropathies Osteoporosis Arthropathies Osteoporosis Mononeuritis multiplex Peripheral neuropathy Skin plaques and nodules Infiltration of scars Granulomatous liver disease Phalangeal bone cysts Lacrimal gland enlargement Cranial nerve palsy Interstitial lung disease Nasal cutaneous sarcoid lesions (lupus pernio) Erythema nodosum Parotid gland enlargement 17.72 Presentation of sarcoidosis • Asymptomatic: abnormal routine chest X-ray (~30%) or abnormal liver function tests • Respiratory and constitutional symptoms (20–30%) • Erythema nodosum and arthralgia (20–30%) • Ocular symptoms (5–10%) • Skin sarcoid (including lupus pernio) (5%) • Superficial lymphadenopathy (5%) • Other (1%), e.g. hypercalcaemia, diabetes insipidus, cranial nerve palsies, cardiac arrhythmias, nephrocalcinosis occurs in around 20% of cases of pulmonary sarcoidosis and may cause a silent loss of lung function. Pleural disease is uncommon and finger clubbing is not a feature. Complications such as bronchiectasis, aspergilloma, pneumothorax, pulmonary hypertension and cor pulmonale have been reported but are rare. Investigations Lymphopenia is characteristic and liver function tests may be mildly deranged. Hypercalcaemia may be present (reflecting increased formation of calcitriol – 1,25-dihydroxyvitamin D – by alveolar macrophages), particularly if the patient has been exposed to strong sunlight. Hypercalciuria may also be seen and may lead to nephrocalcinosis. Serum angiotensin-converting enzyme (ACE) 17.73 Chest X-ray changes in sarcoidosis Stage I: BHL (usually symmetrical); paratracheal nodes often enlarged • Often asymptomatic but may be associated with erythema nodosum and arthralgia. The majority of cases resolve spontaneously within 1 year Stage II: BHL and parenchymal infiltrates • Patients may present with breathlessness or cough. The majority of cases resolve spontaneously Stage III: parenchymal infiltrates without BHL • Disease less likely to resolve spontaneously Stage IV: pulmonary fibrosis • Can cause progression to ventilatory failure, pulmonary hypertension and cor pulmonale (BHL = bilateral hilar lymphadenopathy)

610 • RESPIRATORY MEDICINE Lung diseases due to systemic inflammatory disease The acute respiratory distress syndrome See page 198. Respiratory involvement in connective tissue disorders Pulmonary complications of connective tissue disease are common, affecting the airways, alveoli, pulmonary vasculature, diaphragm and chest wall muscles, and the chest wall itself. In some instances, pulmonary disease may precede the appearance of the connective tissue disorder (Box 17.74). Indirect associations between connective tissue disorders and respiratory complications include those due to disease in other organs, e.g. thrombocytopenia causing haemoptysis; pulmonary toxic effects of drugs used to treat the connective tissue disorder (e.g. gold and methotrexate); and secondary infection due to the disease itself, neutropenia or immunosuppressive drug regimens. Rheumatoid disease Pulmonary involvement in rheumatoid disease is important, accounting for around 10–20% of the mortality associated with the condition (p. 1021). The majority of cases occur within 5 years of the rheumatological diagnosis but pulmonary manifestations may precede joint involvement in 10–20%. Pulmonary fibrosis is the most common pulmonary manifestation. All forms of interstitial disease have been described but NSIP is probably the most common. A rare variant of localised upper lobe fibrosis and cavitation is occasionally seen. Pleural effusion is common, especially in men with seropositive disease. Effusions are usually small and unilateral, but can be large and bilateral. Most resolve spontaneously. Biochemical testing shows an exudate with markedly reduced glucose levels and raised lactate dehydrogenase (LDH). Effusions that fail to resolve spontaneously may respond to a short course of oral prednisolone (30–40 mg daily) but some become chronic. Rheumatoid pulmonary nodules are usually asymptomatic and detected incidentally on imaging. They are most often multiple and subpleural in site (Fig. 17.60). Solitary nodules can mimic primary lung cancer; when multiple, the differential may reveal oxygen desaturation. Bronchoscopy may demonstrate a ‘cobblestone’ appearance of the mucosa, and bronchial and transbronchial biopsies usually show non-caseating granulomas, as may samples from the mediastinal nodes obtained by EBUS. Bronchoalveolar lavage fluid typically contains an increased CD4:CD8 T-cell ratio. Characteristic HRCT appearances include reticulonodular opacities that follow a perilymphatic distribution centred on bronchovascular bundles and the subpleural areas. PET scanning can detect extrapulmonary disease. The occurrence of erythema nodosum with BHL on chest X-ray is often sufficient for a confident diagnosis, without recourse to a tissue biopsy. Similarly, a typical presentation with classical HRCT features may also be accepted. In other instances, however, the diagnosis should be confirmed by histological examination of the involved organ. The presence of anergy (e.g. to tuberculin skin tests) may support the diagnosis. Management Patients who present with acute illness and erythema nodosum should receive NSAIDs and, on occasion, a short course of glucocorticoids. The majority of patients enjoy spontaneous remission and so, if there is no evidence of organ damage, systemic glucocorticoid therapy can be withheld for 6 months. However, prednisolone (at a starting dose of 20–40 mg/ day) should be commenced immediately in the presence of hypercalcaemia, pulmonary impairment, renal impairment and uveitis. Topical glucocorticoids may be useful in cases of mild uveitis, and inhaled glucocorticoids have been used to shorten the duration of systemic glucocorticoid use in asymptomatic parenchymal sarcoid. Patients should be warned that strong sunlight may precipitate hypercalcaemia and endanger renal function. Features suggesting a less favourable outlook include age over 40, Afro-Caribbean ethnicity, persistent symptoms for more than 6 months, the involvement of more than three organs, lupus pernio (see Fig. 17.59) and a stage III/IV chest X-ray. In patients with severe disease, methotrexate (10–20 mg/week), azathioprine (50–150 mg/day) and specific tumour necrosis factor alpha (TNF-α) inhibitors (p. 1006) have been effective. Chloroquine, hydroxychloroquine and low-dose thalidomide may be useful in cutaneous sarcoid with limited pulmonary involvement. Selected patients may be referred for consideration of single lung transplantation. The overall mortality is low (1–5%) and usually reflects cardiac involvement or pulmonary fibrosis. 17.74 Respiratory complications of connective tissue disorders Disorder Airways Parenchyma Pleura Diaphragm and chest wall Rheumatoid arthritis Bronchitis, obliterative bronchiolitis, bronchiectasis, crico-arytenoid arthritis, stridor Pulmonary fibrosis, nodules, upper lobe fibrosis, infections Pleurisy, effusion, pneumothorax Poor healing of intercostal drain sites Systemic lupus erythematosus – Pulmonary fibrosis, ‘vasculitic’ infarcts Pleurisy, effusion Diaphragmatic weakness (shrinking lungs) Systemic sclerosis Bronchiectasis Pulmonary fibrosis, aspiration pneumonia – Cutaneous thoracic restriction (hidebound chest) Dermatomyositis/ polymyositis Lung cancer Pulmonary fibrosis – Intercostal and diaphragmatic myopathy Granulomatosis with polyangiitis Epistaxis, nasal discharge crusting, subglottic stenosis Pulmonary nodules that may cavitate Pleurisy, effusion –

Interstitial and infiltrative pulmonary diseases • 611

systemic sclerosis but isolated pulmonary hypertension may develop. Other pulmonary complications include recurrent aspiration pneumonias secondary to oesophageal disease. Rarely, sclerosis of the skin of the chest wall may be so extensive and cicatrising as to restrict chest wall movement – the so-called ‘hidebound chest’. Pulmonary eosinophilia and vasculitides Pulmonary eosinophilia refers to the association of radiographic (usually pneumonic) abnormalities and peripheral blood eosinophilia. The term encompasses a group of disorders of different aetiology (Box 17.75). Eosinophils are the predominant cell recovered in sputum or BAL, and eosinophil products are likely to the prime mediators of tissue damage. Acute eosinophilic pneumonia Acute eosinophilic pneumonia is an acute febrile illness (of less than 5 days’ duration), characterised by diffuse pulmonary infiltrates and hypoxic respiratory failure. The pathology is usually that of diffuse alveolar damage. Diagnosis is confirmed by BAL, which characteristically demonstrates > 25% eosinophils. The condition is usually idiopathic but drug reactions should be considered. Glucocorticoids invariably induce prompt and complete resolution. Chronic eosinophilic pneumonia Chronic eosinophilic pneumonia typically presents in an insidious manner with malaise, fever, weight loss, breathlessness and unproductive cough. It is more common in middle-aged females. The classical chest X-ray appearance has been likened to the photographic negative of pulmonary oedema with bilateral, peripheral and predominantly upper lobe parenchymal shadowing. The peripheral blood eosinophil count is almost always very high, and the erythrocyte sedimentation rate (ESR) and total serum IgE are elevated. BAL reveals a high proportion of eosinophils diagnoses include pulmonary metastatic disease. Cavitation raises the possibility of TB and predisposes to pneumothorax. The combination of rheumatoid nodules and pneumoconiosis is known as Caplan’s syndrome (p. 615). Bronchitis and bronchiectasis are both more common in rheumatoid patients. Rarely, the potentially fatal condition called obliterative bronchiolitis may develop. Bacterial lower respiratory tract infections are frequent. Treatments given for rheumatoid arthritis may also be relevant: glucocorticoid therapy predisposes to infections, methotrexate may cause pulmonary fibrosis, and anti-TNF therapy has been associated with the reactivation of TB. Systemic lupus erythematosus Pleuropulmonary involvement is more common in lupus than in any other connective tissue disorder and may be a presenting problem, when it is sometimes attributed incorrectly to infection or pulmonary embolism. Up to two-thirds of patients have repeated episodes of pleurisy, with or without effusions. Effusions may be bilateral and may also involve the pericardium. The most serious manifestation of lupus is an acute alveolitis that may be associated with diffuse alveolar haemorrhage. This condition is life-threatening and requires either immediate immunosuppression with glucocorticoids or a step-up in immunosuppressive treatment, if already started. Pulmonary fibrosis is a relatively uncommon manifestation of systemic lupus erythematosus (SLE). Some patients with SLE present with exertional dyspnoea and orthopnoea but without overt signs of pulmonary fibrosis. The chest X-ray reveals elevated diaphragms and pulmonary function testing shows reduced lung volumes. This condition has been described as ‘shrinking lungs’ and has been attributed to diaphragmatic myopathy. SLE patients with antiphospholipid antibodies are at increased risk of venous and pulmonary thromboembolism and require life-long anticoagulation. Systemic sclerosis Most patients with systemic sclerosis (p. 1037) eventually develop diffuse pulmonary fibrosis; at necropsy more than 90% have evidence of lung fibrosis. In some patients it is indolent, but when progressive, as in IPF, the median survival time is around 4 years. Pulmonary fibrosis is rare in the CREST variant of progressive Fig. 17.60 Rheumatoid (necrobiotic) nodules. Thoracic CT just below the level of the main carina, showing the typical appearance of peripheral pleural-based nodules (arrows). The nodule in the left lower lobe shows characteristic cavitation. 17.75 Pulmonary eosinophilia Extrinsic (cause known) • Helminths: e.g. Ascaris, Toxocara, Filaria • Drugs: nitrofurantoin, para-aminosalicylic acid (PAS), sulfasalazine, imipramine, chlorpropamide, phenylbutazone • Fungi: e.g. Aspergillus fumigatus causing allergic bronchopulmonary aspergillosis (p. 596) Intrinsic (cause unknown) • Cryptogenic eosinophilic pneumonia • Eosinophilic granulomatosis with polyangiitis (formerly Churg– Strauss syndrome), diagnosed on the basis of four or more of the following features: Asthma Peripheral blood eosinophilia > 1.5 × 109/L (or > 10% of a total white cell count) Mononeuropathy or polyneuropathy Pulmonary infiltrates Paranasal sinus disease Eosinophilic vasculitis on biopsy of an affected site • Hypereosinophilic syndrome • Polyarteritis nodosa (p. 1042; rare)

612 • RESPIRATORY MEDICINE respond to glucocorticoid treatment. The pulmonary effects of radiation (p. 1332) are exacerbated by treatment with cytotoxic drugs, and the phenomenon of ‘recall pneumonitis’ describes the appearance of radiation injury in a previously irradiated area when chemotherapy follows radiotherapy. If the patient survives, there are long-term risks of lung cancer. Drugs Drugs may cause a variety of pulmonary conditions (Box 17.76). Pulmonary fibrosis may occur in response to a variety of drugs but is seen most frequently with bleomycin, methotrexate, amiodarone and nitrofurantoin. Eosinophilic pulmonary reactions can also be caused by drugs. The pathogenesis may be an immune reaction similar to that in hypersensitivity pneumonitis, which specifically attracts large numbers of eosinophils into the lungs. This type of reaction is well described as a rare reaction to a variety of antineoplastic agents (e.g. bleomycin), antibiotics (e.g. sulphonamides), sulfasalazine and the anticonvulsants phenytoin and carbamazepine. Patients usually present with breathlessness, cough and fever. The chest X-ray characteristically shows patchy shadowing. Most cases resolve completely on withdrawal of the drug, but if the reaction is severe, rapid resolution can be obtained with glucocorticoids. Drugs may also cause other lung diseases, such as asthma, pulmonary haemorrhage, pleural effusion and, rarely, pleural thickening. An ARDS-like syndrome of acute non-cardiogenic pulmonary oedema may present with dramatic onset of breathlessness, severe hypoxaemia and signs of alveolar oedema in the lavage fluid. Response to prednisolone (20–40 mg daily) is usually dramatic. Prednisolone can usually be withdrawn after a few weeks without relapse but long-term, low-dose therapy is occasionally necessary. Tropical pulmonary eosinophilia Tropical pulmonary eosinophilia occurs as a result of a mosquitoborne filarial infection with Wuchereria bancrofti or Brugia malayi (p. 290). The condition presents with fever, weight loss, dyspnoea and asthma-like symptoms. The peripheral blood eosinophilia is marked, as is the elevation of total IgE. High antifilarial antibody titres are seen. The diagnosis may be confirmed by a response to treatment with diethylcarbamazine (6 mg/kg/day for 3 weeks). Tropical pulmonary eosinophilia must be distinguished from infection with Strongyloides stercoralis (p. 289) as, in strongyloidiasis, glucocorticoids may cause a life-threatening hyperinfection syndrome. Ascariasis (‘larva migrans’) and other hookworm infestation are covered in Chapter 11. Granulomatosis with polyangiitis Granulomatosis with polyangiitis (formerly referred to as Wegener’s granulomatosis) is a rare vasculitic and granulomatous condition (p. 1041). The lung is commonly involved in systemic forms of the disease but a limited pulmonary form may also occur. Respiratory symptoms include cough, haemoptysis and chest pain. Associated upper respiratory tract manifestations include nasal discharge and crusting, and otitis media. Fever, weight loss and anaemia are common. Radiological features include multiple nodules and cavitation that may resemble primary or metastatic carcinoma, or a pulmonary abscess. Tissue biopsy confirms the distinctive pattern of necrotising granulomas and necrotising vasculitis. Other respiratory complications include tracheal subglottic stenosis and saddle nose deformity. The differential diagnoses include mycobacterial and fungal infection and other forms of pulmonary vasculitis, including polyarteritis nodosa (pulmonary infarction), microscopic polyangiitis, eosinophilic granulomatosis with polyangiitis (formerly Churg–Strauss syndrome: marked tissue eosinophilia and association with asthma), necrotising sarcoid, bronchocentric granulomatosis and lymphomatoid granulomatosis. Goodpasture’s disease This describes the association of pulmonary haemorrhage and glomerulonephritis, in which IgG antibodies bind to the glomerular or alveolar basement membranes (p. 401). Pulmonary disease usually precedes renal involvement and includes radiographic infiltrates and hypoxia with or without haemoptysis. It occurs more commonly in men and almost exclusively in smokers. Lung diseases due to irradiation and drugs Radiotherapy Targeting radiotherapy to certain tumours is inevitably accompanied by irradiation of normal lung tissue. Although delivered in divided doses, the effects are cumulative. Acute radiation pneumonitis is typically seen within 6–12 weeks and presents with cough and dyspnoea. This may resolve spontaneously but responds to glucocorticoid treatment. Chronic interstitial fibrosis may present several months later with symptoms of exertional dyspnoea and cough. Changes are often confined to the area irradiated but may be bilateral. Established post-irradiation fibrosis does not usually 17.76 Drug-induced respiratory disease Non-cardiogenic pulmonary oedema (ARDS) • Hydrochlorothiazide • Thrombolytics (streptokinase) • Intravenous β-adrenoceptor agonists (e.g. for premature labour) • Aspirin and opiates (in overdose) Non-eosinophilic alveolitis • Amiodarone, flecainide, gold, nitrofurantoin, cytotoxic agents – especially bleomycin, busulfan, mitomycin C, methotrexate, sulfasalazine Pulmonary eosinophilia • Antimicrobials (nitrofurantoin, penicillin, tetracyclines, sulphonamides, nalidixic acid) • Drugs used in joint disease (gold, aspirin, penicillamine, naproxen) • Cytotoxic drugs (bleomycin, methotrexate, procarbazine) • Psychotropic drugs (chlorpromazine, dosulepin, imipramine) • Anticonvulsants (carbamazepine, phenytoin) • Others (sulfasalazine, nadolol) Pleural disease • Bromocriptine, amiodarone, methotrexate, methysergide • Induction of systemic lupus erythematosus – phenytoin, hydralazine, isoniazid Asthma • Pharmacological mechanisms (β-blockers, cholinergic agonists, aspirin and NSAIDs) • Idiosyncratic reactions (tamoxifen, dipyridamole) (ARDS = acute respiratory distress syndrome; NSAIDs = non-steroidal anti-inflammatory drugs)

Occupational and environmental lung disease • 613

Rare interstitial lung diseases See Box 17.78. Occupational and environmental lung disease The role of occupation and environmental exposure in lung disease is a particularly important area of respiratory medicine. Occupational lung disease is common and, in addition to the challenges of its diagnosis and management, often involves discussions about the workplace and, in some circumstances, litigation. Many countries encourage the registration of cases of occupational lung disease. Occupational airway disease Occupational asthma Occupational asthma should be considered in any individual of working age who develops new-onset asthma, particularly if the individual reports improvement in asthma symptoms during periods away from work, e.g. at weekends and on holidays. Workers in certain occupations appear to be at particularly high risk (Box 17.79) and the condition is more common in smokers and atopic individuals. Depending on the intensity of exposure, asthmatic symptoms usually develop within the first few years of employment but are classically preceded by a latent period. Symptoms of rhinoconjunctivitis often precede 17.77 Interstitial lung disease in old age • Idiopathic pulmonary fibrosis: the most common interstitial lung disease, with a poor prognosis. • Chronic aspiration pneumonitis: must always be considered in elderly patients presenting with bilateral basal shadowing on a chest X-ray. • Granulomatosis with polyangiitis (Wegener’s granulomatosis): a rare condition but more common in old age. Renal involvement is more common at presentation and upper respiratory problems are fewer. • Asbestosis: symptoms may appear only in old age because of the prolonged latent period between exposure and disease. • Drug-induced interstitial lung disease: more common, presumably because of the increased chance of exposure to multiple drugs. • Rarer interstitial disease: sarcoidosis, idiopathic pulmonary haemosiderosis, alveolar proteinosis and eosinophilic pneumonia rarely present. • Increased dyspnoea: coexistent muscle weakness, chest wall deformity (e.g. thoracic kyphosis) and deconditioning may all exacerbate dyspnoea associated with interstitial lung disease. • Surgical lung biopsy: often inappropriate in the very frail. A diagnosis therefore frequently depends on clinical and highresolution computed tomography findings alone. 17.78 Rare interstitial lung diseases Disease Presentation Chest X-ray Course Idiopathic pulmonary haemosiderosis Haemoptysis, breathlessness, anaemia Bilateral infiltrates, often perihilar Diffuse pulmonary fibrosis Rapidly progressive in children Slow progression or remission in adults Death from massive pulmonary haemorrhage or cor pulmonale and respiratory failure Alveolar proteinosis Breathlessness and cough Occasionally fever, chest pain and haemoptysis Diffuse bilateral shadowing, often more pronounced in the hilar regions Air bronchogram Spontaneous remission in one-third Whole-lung lavage or granulocyte– macrophage colony-stimulating factor (GM–CSF) therapy may be effective Langerhans cell histiocytosis (histiocytosis X) Breathlessness, cough, pneumothorax Diffuse interstitial shadowing progressing to honeycombing Course unpredictable but may progress to respiratory failure Smoking cessation may be followed by significant improvement Poor response to immunosuppressive treatment Neurofibromatosis Breathlessness and cough in a patient with multiple organ involvement with neurofibromas, including skin Bilateral reticulonodular shadowing of diffuse interstitial fibrosis Slow progression to death from respiratory failure Poor response to glucocorticoid therapy Alveolar microlithiasis May be asymptomatic Breathlessness and cough Diffuse calcified micronodular shadowing more pronounced in the lower zones Slowly progressive to cor pulmonale and respiratory failure May stabilise in some Lymphangioleiomyomatosis Haemoptysis, breathlessness, pneumothorax and chylous effusion in females Diffuse bilateral shadowing CT shows characteristic thin-walled cysts with well-defined walls throughout both lungs Progressive to death within 10 years Oestrogen ablation and progesterone therapy of doubtful value Consider lung transplantation Pulmonary tuberous sclerosis Very similar to lymphangioleiomyomatosis, except occasionally occurs in men on the chest X-ray. This syndrome has been reported most frequently in cases of opiate overdose in drug addicts (p. 142) but also after salicylate overdose, and there are occasional reports of its occurrence after therapeutic doses of drugs, including hydrochlorothiazides and some cytotoxic agents.

614 • RESPIRATORY MEDICINE very high concentrations. Pulmonary function tests show airflow obstruction and airway hyper-reactivity, and the management is similar to that of asthma. Once developed, the condition often persists but it is common for symptoms to improve over years. Chronic obstructive pulmonary disease While tobacco smoking remains the most important preventable cause of COPD, there is increasing recognition that other noxious particles and gases can cause, or aggravate, the condition. Occupational COPD is recognised in workers exposed to coal dust, crystalline silica and cadmium. In many parts of the developing world, indoor air pollution from the burning of biomass fuels in confined spaces used for cooking contributes to the development of COPD. Byssinosis Byssinosis occurs in workers of cotton and flax mills exposed to cotton brack (dried leaf and plant debris). An acute form of the disease may occur, but more typically, byssinosis develops after 20–30 years’ exposure. Typical symptoms include chest tightness or breathlessness accompanied by a drop in lung function; classically, these are most severe on the first day of the working week (‘Monday fever’) or on return to work following a period away. As the week progresses, symptoms improve and the fall in lung function becomes less dramatic. Continued exposure leads to the development of persistent symptoms and a progressive decline in FEV1, similar to that observed in COPD. Pneumoconiosis Pneumoconiosis may be defined as a permanent alteration of lung structure due to the inhalation of mineral dust and the tissue reactions of the lung to its presence, excluding bronchitis and emphysema (Box 17.80). Not all dusts are pathogenic. For example, silica is highly fibrogenic, whereas iron (siderosis), tin (stannosis) and barium (baritosis) are almost inert. Beryllium causes an interstitial granulomatous disease similar to sarcoidosis. In the development of asthma. When occupational asthma follows exposure to high-molecular-weight proteins, sensitisation may be demonstrated by skin testing or measurement of specific IgE to the agent in question. Confirmation of occupational asthma should be sought from lung function tests. This usually involves serial recording of peak flow at work at least four times per day for a minimum of 3 weeks and, if possible, including a period away from work (Fig. 17.61). In certain circumstances, specific challenge tests are required to confirm the diagnosis. It may be possible to remove the worker from the implicated agent, but when this cannot be done, consideration of personal protective equipment and workplace hygiene may allow the worker to retain their job and livelihood. Specialist follow-up in such situations is highly advisable. A favourable prognosis is indicated by a short history of symptoms and normal lung function at diagnosis. Where reduction or avoidance of exposure fails to bring about resolution, the management is identical to that of any patient with asthma (p. 569). Reactive airways dysfunction syndrome Reactive airways dysfunction syndrome or acute irritant-induced asthma refers to the development of a persistent asthma-like syndrome following the inhalation of an airway irritant: typically, a single, specific exposure to a gas, smoke, fume or vapour in 17.79 Occupational asthma Most frequently reported causative agents • Isocyanates • Flour and grain dust • Colophony and fluxes • Latex • Animals • Aldehydes • Wood dust Workers most commonly reported to occupational asthma schemes • Paint sprayers • Bakers and pastry-makers • Nurses • Chemical workers Fig. 17.61 Peak flow readings in occupational asthma. In this example, an individual with suspected occupational asthma has performed serial peak flow recording both at and away from work. The maximum, mean and minimum values are plotted daily. Days at work are indicated by the shaded areas. The diurnal variation is displayed at the top. Here, a period away from work is followed by a marked improvement in peak flow readings and a reduction in diurnal variation. (PEF = peak expiratory flow)

0% 20% 50% Diurnal variation of PEF Peak flow (L/min) Weekdays m t w t f s s m t w t f s s m t w t f s s m t w t f s s m t w t f s s

Occupational and environmental lung disease • 615

Cause Occupation Description Characteristic pathological features Coal dust Coal mining Coal worker’s pneumoconiosis Focal and interstitial fibrosis, centrilobular emphysema, progressive massive fibrosis Silica Mining, quarrying, stone dressing, metal grinding, pottery, boiler scaling Silicosis Asbestos Demolition, ship breaking, manufacture of fireproof insulating materials, pipe and boiler lagging Asbestos-related disease Pleural plaques, diffuse pleural thickening, acute benign pleurisy, carcinoma of lung, interstitial fibrosis, mesothelioma Iron oxide Arc welding Siderosis Mineral deposition only Tin oxide Tin mining Stannosis Tin-laden macrophages Beryllium Aircraft, atomic energy and electronics industries Berylliosis Granulomas, interstitial fibrosis } 17.80 Lung diseases caused by exposure to inorganic dusts may develop (Fig. 17.62). Enlargement of the hilar glands with an ‘egg-shell’ pattern of calcification is said to be characteristic but is non-specific. Silica is highly fibrogenic and the disease is usually progressive, even when exposure ceases; hence the affected worker should invariably be removed from further exposure. Individuals with silicosis are at increased risk of TB many types of pneumoconiosis, a long period of dust exposure is required before radiological changes appear and these may precede clinical symptoms. The most important pneumoconioses include coal worker’s pneumoconiosis, silicosis and asbestosis. Coal worker’s pneumoconiosis Coal worker’s pneumoconiosis (CWP) follows prolonged inhalation of coal dust. Dust-laden alveolar macrophages aggregate to form macules in or near the centre of the secondary pulmonary lobule and a fibrotic reaction ensues, resulting in the appearance of scattered discrete fibrotic lesions. Classification is based on the size and extent of radiographic nodularity. Simple coal worker’s pneumoconiosis (SCWP) refers to the appearance of small radiographic nodules in an otherwise asymptomatic individual. SCWP does not impair lung function and, once exposure ceases, will seldom progress. Progressive massive fibrosis (PMF) refers to the formation of conglomerate masses (mainly in the upper lobes), which may cavitate. The development of PMF is usually associated with cough, sputum that may be black (melanoptysis) and breathlessness. The chest X-ray appearances may be confused with lung cancer, TB and granulomatosis with polyangiitis. PMF may progress, even after coal dust exposure ceases, and in extreme cases leads to respiratory failure and right ventricular failure. Caplan’s syndrome describes the coexistence of rheumatoid arthritis and rounded fibrotic nodules 0.5–5 cm in diameter. They show pathological features similar to a rheumatoid nodule, including central necrosis, palisading histiocytes, and a peripheral rim of lymphocytes and plasma cells. This syndrome may also occur in other types of pneumoconiosis. Silicosis Silicosis results from the inhalation of crystalline silica, usually in the form of quartz, by workers cutting, grinding and polishing stone. Classic silicosis is most common and usually manifests after 10–20 years of continuous silica exposure, during which time the patient remains asymptomatic. Accelerated silicosis is associated with a much shorter duration of dust exposure (typically 5–10 years), may present as early as after 1 year of exposure and, as the name suggests, follows a more aggressive course. Intense exposure to very fine crystalline silica dust can cause a more acute disease: silicoproteinosis, similar to alveolar proteinosis (see Box 17.78). Radiological features are similar to those of CWP, with multiple well-circumscribed 3–5 mm nodular opacities predominantly in the mid- and upper zones. As the disease progresses, PMF Fig. 17.62 Silicosis. A A chest X-ray from a patient with silicosis, showing the presence of small rounded nodules, predominantly seen in the upper zones. B High-resolution computed tomogram from the same patient, demonstrating conglomeration of nodules with posterior bias. A B

616 • RESPIRATORY MEDICINE Hypersensitivity pneumonitis Hypersensitivity pneumonitis (HP; also called extrinsic allergic alveolitis) results from the inhalation of a wide variety of organic antigens that give rise to a diffuse immune complex reaction in the walls of alveoli and bronchioles. Common causes include farmer’s lung and bird fancier’s lung. Other examples are shown in Box 17.81. HP is not exclusively occupational or environmental and other important causes include medications (see Box 17.76). The pathology of HP is consistent with both type III and type IV immunological mechanisms (p. 83). Precipitating IgG antibodies may be detected in the serum and a type III Arthus reaction is believed to occur in the lung, where the precipitation of immune complexes results in activation of complement and an inflammatory response in the alveolar walls, characterised by the influx of mononuclear cells and foamy histiocytes. The presence of poorly formed non-caseating granulomas in the alveolar walls suggests that type IV responses are also important. The distribution of the inflammatory infiltrate is predominantly peribronchiolar. Chronic forms of the disease may be accompanied by fibrosis. For reasons that remain uncertain, there is a lower incidence of HP in smokers compared to non-smokers. Clinical features The presentation of HP varies from an acute form to a more indolent pattern in accordance with the antigen load. For example, the farmer exposed to mouldy hay, as occurs when the hay is gathered and stored damp during a wet summer, or the pigeon fancier cleaning a large pigeon loft will, within a few hours, report influenza-like symptoms accompanied by cough, breathlessness and wheeze. The individual with low-level antigen exposure, however, such as the owner of an indoor pet bird, will typically present in a more indolent fashion with slowly progressive breathlessness; in some cases, established fibrosis may be present by the time the disease is recognised. Chest auscultation typically reveals widespread end-inspiratory crackles and squeaks. Investigations In cases of acute HP, the chest X-ray typically shows ill-defined patchy airspace shadowing, which, given the systemic features, may be confused with pneumonia. HRCT is more likely to show bilateral ground-glass shadowing and areas of consolidation superimposed on small centrilobar nodular opacities with an upper and middle lobe predominance (Fig. 17.63). In more chronic disease, features of fibrosis, such as volume loss, linear opacities and architectural distortion, appear. In common with other fibrotic diseases, pulmonary function tests show a restrictive ventilatory defect with reduced lung volumes and impaired gas transfer, dynamic tests may detect oxygen desaturation and, in more advanced disease, type I respiratory failure is present at rest. Diagnosis The diagnosis of HP is usually based on the characteristic clinical and radiological features, together with the identification of a potential source of antigen at the patient’s home or place of work (Box 17.82). It may be supported by a positive serum precipitin test or by more sensitive serological investigations. It is important, however, to be aware that the presence of precipitins in the absence of other features does not make the diagnosis; the great majority of farmers with positive precipitins do not have farmer’s lung, and up to 15% of pigeon breeders may have positive serum precipitins yet remain healthy. (silicotuberculosis), lung cancer and COPD; associations with renal and connective tissue disease have also been described. Berylliosis Exposure to beryllium is encountered in the aerospace, engineering, telecommunications and biomedical industries. The presence of cough, progressive breathlessness, night sweats and arthralgia in a worker exposed to dusts, fumes or vapours containing beryllium should raise suspicion of berylliosis. The radiographic appearances are similar in type and distribution to those of sarcoid and biopsy shows sarcoid-like granulomas. The diagnosis may be confirmed by specialised tests of lymphocyte function. Less common pneumoconioses Siderosis refers to the development of a benign iron oxide pneumoconiosis in welders and other iron foundry workers. Baritosis may be seen in barium process workers and stannosis in tin refining. Haematite lung occurs in iron ore miners and resembles silicosis but stains the lung red. Diamond polishers may develop hard metal disease, which is similar to UIP but the pathology shows a giant-cell interstitial pneumonia. Workers exposed to aluminium oxide develop bauxite pneumoconiosis, sometimes referred to as shaver’s disease. Popcorn worker’s lung is a form of obliterative bronchiolitis following ingestion of diacetyl used in butter flavouring. Lung diseases due to organic dusts A wide range of organic agents may cause respiratory disorders (Box 17.81). Disease results from a local immune response to animal proteins or fungal antigens in mouldy vegetable matter. Hypersensitivity pneumonitis is the most common of these conditions. 17.81 Examples of lung diseases caused by organic dusts Disorder Source Antigen/agent Farmer’s lung* Mouldy hay, straw, grain Saccharopolyspora rectivirgula (formerly Micropolyspora faeni) Aspergillus fumigatus Bird fancier’s lung* Avian excreta, proteins and feathers Avian serum proteins Malt worker’s lung* Mouldy maltings Aspergillus clavatus Cheese worker’s lung* Mouldy cheese Aspergillus clavatus Penicillium casei Maple bark stripper’s lung* Bark from stored maple Cryptostroma corticale Saxophone player’s lung* Reed of any wind instrument Fusarium spp. Penicillium spp. Cladosporium spp. Byssinosis Textile industries Cotton, flax, hemp dust Inhalation (‘humidifier’) fever Contamination of air conditioning Thermophilic actinomycetes *Presents as hypersensitivity pneumonitis.

Occupational and environmental lung disease • 617

hobbies (e.g. pigeon breeders). Dust masks with appropriate filters may minimise exposure and may be combined with methods of reducing levels of antigen (e.g. drying hay before storage). In acute cases, prednisolone should be given for 3–4 weeks, starting with an oral dose of 40 mg per day. Severely hypoxaemic patients may require high-concentration oxygen therapy initially. Most patients recover completely, but if unchecked, fibrosis may progress to cause severe respiratory disability, hypoxaemia, pulmonary hypertension, cor pulmonale and eventually death. Inhalation (‘humidifier’) fever Inhalation fever shares similarities with HP. It occurs as a result of contaminated humidifiers or air-conditioning units that release a fine spray of microorganisms into the atmosphere. The illness is characterised by self-limiting fever and breathlessness; permanent sequelae are unusual. An identical syndrome can also develop after disturbing an accumulation of mouldy hay, compost or mulch. So-called ‘hot tub lung’ appears to be attributable to Mycobacterium avium. Outbreaks of HP in workers using metalworking fluids appear to be linked to Acinetobacter or Ochrobactrum. Asbestos-related lung and pleural diseases Asbestos is a naturally occurring silicate. Asbestos fibres may be classified as either chrysotile (white asbestos), which accounts for 90% of the world’s production, or serpentine (crocidolite or blue asbestos, and amosite or brown asbestos). The favourable thermal and chemical insulation properties led to its extensive use by the shipbuilding and construction industries throughout the latter part of the 20th century. Exposure to asbestos may be followed, after a lengthy latent period, by the development of both pleural and pulmonary disease. Pleural plaques Pleural plaques are the most common manifestation of past asbestos exposure, being discrete circumscribed areas of hyaline fibrosis situated on the parietal pleura of the chest wall, Where HP is suspected but the cause is not readily apparent, a visit to the patient’s home or workplace should be arranged. Occasionally, such as when an agent previously unrecognised as causing HP is suspected, provocation testing may be necessary to prove the diagnosis; if positive, inhalation of the relevant antigen is followed after 3–6 hours by pyrexia and a reduction in vital capacity and gas transfer factor. BAL fluid usually shows an increase in the number of CD8+ T lymphocytes and transbronchial biopsy can occasionally provide sufficient tissue for a confident diagnosis; however, open lung biopsy may be necessary. Management If it is practical, the patient should cease exposure to the inciting agent. In some cases this may be difficult, however, because of either implications for livelihood (e.g. farmers) or addiction to Fig. 17.63 Hypersensitivity pneumonitis. A High-resolution computed tomogram showing typical patchy ground-glass opacification. B Histology shows evidence of an interstitial inflammatory infiltrate in the lung, and expanding alveolar walls, with a peribronchial distribution. Within the infiltrate, there are foci of small, poorly defined non-caseating granulomas (inset), which often lie adjacent to the airways. In this case, there is little in the way of established lung fibrosis but this can be marked. A, Courtesy of Dr S. Jackson, Western General Hospital, Edinburgh. B, Courtesy of Dr William Wallace, Dept of Pathology, Royal Infirmary of Edinburgh. B A 17.82 Predictive factors in the identification of hypersensitivity pneumonitis • Exposure to a known offending antigen • Positive precipitating antibodies to offending antigen • Recurrent episodes of symptoms • Inspiratory crackles on examination • Symptoms occurring 4–8 hours after exposure • Weight loss Fig. 17.64 Asbestos-related benign pleural plaques. Chest X-ray showing extensive calcified pleural plaques (‘candle wax’ appearance – arrows), particularly marked on the diaphragm and lateral pleural surfaces.

618 • RESPIRATORY MEDICINE performed, asbestosis may be diagnosed when alveolar septal fibrosis is accompanied by an average of at least two asbestos bodies per square centimetre of lung tissue. In some cases, asbestos fibre counts may be performed on lung biopsy material to establish the diagnosis. Asbestosis is usually slowly progressive and has a better prognosis than IPF, but in advanced cases respiratory failure, pulmonary hypertension and cor pulmonale may still develop. About 40% of patients (who usually smoke) develop lung cancer and 10% may develop mesothelioma. Mesothelioma Mesothelioma is a malignant tumour affecting the pleura or, less commonly, the peritoneum. Its occurrence almost invariably suggests past asbestos exposure, which may be low-level. There is typically a long latent interval between first exposure and the onset of clinical manifestations, and this accounts for the continued increasing incidence many years after control measures have been implemented. Around 1 in 170 of all British men born in the 1940s will die of mesothelioma. Pleural mesothelioma typically presents with increasing breathlessness resulting from pleural effusion or unremitting chest pain, reflecting involvement of the chest wall. As the tumour progresses, it encases the underlying lung and may invade the parenchyma, the mediastinum and the pericardium. Metastatic disease, although not often clinically detectable in life, is a common finding on postmortem. Mesothelioma is almost invariably fatal. Highly selected patients may be considered for radical surgery but, in the majority of patients, therapy is invariably directed towards palliation of symptoms. The use of chemotherapy may improve quality of life and is accompanied by a small survival benefit, typically regarded as being around 3 months. Radiotherapy can be used to control pain and limit the risk of tumour seeding at biopsy sites. Pleural effusions are managed with drainage and pleurodesis. Typical figures for survival from onset of symptoms are around 16 months for epithelioid tumours, 10 months for sarcomatoid tumours and 15 months for biphasic tumours, with only a minority of patients surviving for longer periods. Occupational lung cancer Individuals exposed to substantial quantities of asbestos are at increased risk of lung cancer, particularly if they smoke tobacco. Increased risks of lung cancer have also been reported in workers who develop silicosis and those exposed to radon gas, beryllium, diesel exhaust fumes, cadmium, chromium, and dust and fumes from coke plants. Occupational pneumonia Occupational and environmental exposures may be linked to the development of pneumonia. Pneumococcal vaccine is recommended for welders. Farm workers, abattoir workers and hide factory workers may be exposed to Coxiella burnetii, the causative agent of Q fever. The organisms are excreted from milk, urine, faeces and amniotic fluid; they may be transmitted by cattle ticks or contaminated dust from the milking floor, or by drinking milk that is inadequately pasteurised. Birds (often parrots) or budgerigars infected with Chlamydia psittaci can cause psittacosis. Sewage workers, farmers, animal handlers and vets run an increased risk of leptospiral pneumonia, and contact diaphragm, pericardium or mediastinum. They are virtually always asymptomatic, usually being identified as an incidental finding on a chest X-ray (Fig. 17.64) or thoracic CT scan, particularly when partially calcified. They do not cause impairment of lung function and are benign. Acute benign asbestos pleurisy Benign asbestos pleurisy is estimated to occur in around 20% of asbestos workers but many episodes are subclinical and pass unreported. When symptomatic, patients present with features of pleurisy, including mild fever and systemic disturbance. The diagnosis therefore necessitates the exclusion of other known causes of pleurisy and pleural effusion. Repeated episodes may be followed by the development of diffuse (visceral) pleural thickening. Diffuse pleural thickening Diffuse pleural thickening (DPT) refers to thickening of the visceral pleura. In contrast to pleural plaques, if this is sufficiently extensive, it may cause restrictive lung function impairment, exertional breathlessness and, occasionally, persistent chest pain. The typical appearances of DPT on chest X-ray include thickening of the pleura along the chest wall and obliteration of the costophrenic angles. Earlier manifestations detected by CT scanning include parenchymal bands (Fig. 17.65) and ‘round atelectasis’. There is no treatment and the condition may be progressive in around one-third of individuals. In exceptionally severe cases, surgical decortication may be considered. A pleural biopsy may be required to exclude mesothelioma. Fig. 17.65 Thoracic CT scan showing right-sided pleural thickening and an associated parenchymal band. Asbestosis Fibrosis of the lung following asbestos exposure generally requires substantial exposure over several years and is rarely associated with low-level or bystander exposure. In common with other fibrosing lung diseases, asbestosis usually presents with exertional breathlessness and fine, late inspiratory crackles over the lower zones. Finger clubbing may be present. Pulmonary function tests and HRCT appearances are similar to those of UIP. These features, accompanied by a history of substantial asbestos exposure, are generally sufficient to establish the diagnosis and lung biopsy is rarely necessary. When biopsy is

Pulmonary vascular disease • 619

Clinical features The diagnosis of pulmonary embolism (PE) may be aided by asking three questions: • Is the clinical presentation consistent with PE? • Does the patient have risk factors for PE? • Are there any alternative diagnoses that can explain the patient’s presentation? Clinical presentation varies, depending on number, size and distribution of emboli and on underlying cardiorespiratory reserve (Box 17.83). A recognised risk factor is present in 80–90% (see Box 23.65, p. 975). The presence of one or more risk factors increases the risk further still. Investigations A variety of non-specific radiographic appearances have been described (Fig. 17.66) but the chest X-ray is most useful in with rabbits, hares, muskrats and ground squirrels is associated with tularaemic pneumonia, caused by Francisella tularensis. Anthrax (wool-sorter’s disease) may occur in workers exposed to infected hides, hair, bristle, bonemeal and animal carcases. Pulmonary vascular disease Pulmonary embolism The majority of pulmonary emboli arise from the propagation of lower limb deep vein thrombosis (p. 186). Rare causes include septic emboli (from endocarditis affecting the tricuspid or pulmonary valves), tumour (especially choriocarcinoma), fat following fracture of long bones such as the femur, air, and amniotic fluid, which may enter the mother’s circulation following delivery. 17.83 Features of pulmonary thromboemboli Acute massive PE Acute small/medium PE Chronic PE Pathophysiology Major haemodynamic effects: ↓cardiac output; acute right heart failure Occlusion of segmental pulmonary artery → infarction ± effusion Chronic occlusion of pulmonary microvasculature, right heart failure Symptoms Faintness or collapse, crushing central chest pain, apprehension, severe dyspnoea Pleuritic chest pain, restricted breathing, haemoptysis Exertional dyspnoea Late: symptoms of pulmonary hypertension or right heart failure Signs Major circulatory collapse: tachycardia, hypotension, ↑JVP, RV gallop rhythm, loud P2, severe cyanosis, ↓urinary output Tachycardia, pleural rub, raised hemidiaphragm, crackles, effusion (often blood-stained), low-grade fever Early: may be minimal Later: RV heave, loud P2 Terminal: signs of right heart failure Chest X-ray Usually normal; may be subtle oligaemia Pleuropulmonary opacities, pleural effusion, linear shadows, raised hemidiaphragm Enlarged pulmonary artery trunk, enlarged heart, prominent right ventricle Electrocardiogram S1Q3T3 anterior T-wave inversion, RBBB Sinus tachycardia RV hypertrophy and strain Arterial blood gases Markedly abnormal with ↓PaO2 and ↓PaCO2, metabolic acidosis May be normal or ↓PaO2 or ↓PaCO2 Exertional ↓PaO2 or desaturation on formal exercise testing Alternative diagnoses Myocardial infarction, pericardial tamponade, aortic dissection Pneumonia, pneumothorax, musculoskeletal chest pain Other causes of pulmonary hypertension (JVP = jugular venous pressure; PE = pulmonary embolism; RBBB = right bundle branch block; RV = right ventricular) Fig. 17.66 Features of pulmonary thromboembolism/infarction on chest X-ray. Pulmonary opacities (any size or shape, rarely lobar or segmental, can cavitate) Elevated hemidiaphragm Horizontal linear opacities (bilateral and usually in lower zones) Pleural effusion (usually blood-stained on aspiration) Wedge-shaped opacity Oligaemia of lung field Enlarged pulmonary artery

620 • RESPIRATORY MEDICINE Colour Doppler ultrasound of the leg veins may be used in patients with suspected PE, particularly if there are clinical signs in a limb, as many will have identifiable proximal thrombus in the leg veins. Bedside echocardiography is extremely helpful in the differential diagnosis and assessment of acute circulatory collapse (p. 199). Acute dilatation of the right heart is usually present in massive PE, and thrombus (embolism in transit) may be visible. Important differential diagnoses, including left ventricular failure, aortic dissection and pericardial tamponade, can also be identified. Conventional pulmonary angiography is still useful in selected settings or for the delivery of catheter-based therapies. Management General measures Prompt recognition and treatment are potentially life-saving. Sufficient oxygen should be given to hypoxaemic patients to maintain arterial oxygen saturation above 90%. Circulatory shock should be treated with intravenous fluids or plasma expander, but inotropic agents are of limited value as the hypoxic dilated right ventricle is already close to maximally stimulated by endogenous catecholamines. Diuretics and vasodilators should also be avoided, as they will reduce cardiac output. Opiates may be necessary to relieve pain and distress but should be used with caution excluding key differential diagnoses, e.g. pneumonia or pneumothorax. Normal appearances in an acutely breathless and hypoxaemic patient should raise the suspicion of PE, as should bilateral changes in anyone presenting with unilateral pleuritic chest pain. The ECG is often normal but is useful in excluding other important differential diagnoses, such as acute myocardial infarction and pericarditis. The most common findings in PE include sinus tachycardia and anterior T-wave inversion but these are non-specific; larger emboli may cause right heart strain revealed by an S1Q3T3 pattern, ST-segment and T-wave changes, or the appearance of right bundle branch block. Arterial blood gases typically show a reduced PaO2 and a normal or low PaCO2, and an increased alveolar–arterial oxygen gradient, but may be normal in a significant minority. A metabolic acidosis may be seen in acute massive PE with cardiovascular collapse. An elevated D-dimer (see Fig. 10.6, p. 187) is of limited value, as it may be raised in a variety of other conditions, including myocardial infarction, pneumonia and sepsis. However, low levels, particularly in the context of a low clinical risk, have a high negative predictive value and further investigation is usually unnecessary (Fig. 17.67). The result of the D-dimer assay should be disregarded in high-risk patients, as further investigation is mandatory even when normal. The serum troponin I (see Box 10.3, p. 179) may be elevated, reflecting right heart strain. CTPA is the first-line diagnostic test (Fig. 17.68). It has the advantage of visualising the distribution and extent of the emboli or highlighting an alternative diagnosis, such as consolidation, pneumothorax or aortic dissection. The sensitivity of CT scanning may be increased by simultaneous visualisation of the femoral and popliteal veins, although this is not widely practised. As the contrast media may be nephrotoxic, care should be taken in patients with renal impairment, and CTPA avoided in those with a history of allergy to iodinated contrast media. In these cases, either Vࡆ/Qࡆ scanning or ventilation/perfusion single photon emission computed tomography (Vࡆ/Qࡆ SPECT) may be considered. Fig. 17.67 Algorithm for the investigation of patients with suspected pulmonary thromboembolism. Clinical risk is based on the presence of risk factors for venous thromboembolism and the probability of another diagnosis. (DVT = deep vein thrombosis; PE = pulmonary embolism) • Ultrasound leg veins ± • CT pulmonary

angiogram or • V/Q scan (no previous cardiopulmonary disease) D-dimer –ve Risk high Assess clinical risk Measure D-dimer levels Venous thromboembolism suspected D-dimer –ve Risk low Not DVT/PE D-dimer +ve Risk low . . Risk high Treat Confirm diagnosis Fig. 17.68 CT pulmonary angiogram. The arrow points to a saddle embolism in the bifurcation of the pulmonary artery. 17.84 Pulmonary embolism in pregnancy • Maternal mortality: venous thromboembolism is the leading direct cause in the UK. • CT pulmonary angiography: may be performed safely (0.01– 0.06 mGy). It is important to consider the risk of radiation to breast tissue (particularly if there is a family history of breast carcinoma). • Vࡆ/Qࡆ scanning: greater radiation dose to fetus (0.11–0.22 mGy) but significantly less to maternal breast tissue. • In utero radiation exposure: estimated incidence of childhood malignancy is about 1 in 16 000 per mGy. • Warfarin: teratogenic, so pulmonary embolism should be treated with low-molecular-weight heparin during pregnancy.

Pulmonary vascular disease • 621

Clinical features PH presents insidiously and is often diagnosed late. Typical symptoms include breathlessness, chest pain, fatigue, palpitation and syncope. Important signs include elevation of the JVP (with a prominent ‘a’ wave if in sinus rhythm), a parasternal heave (right ventricular hypertrophy), accentuation of the pulmonary component of the second heart sound and a right ventricular third heart sound. Signs of interstitial lung disease or cardiac, liver or connective tissue disease may suggest the underlying cause. Investigations PH is suspected if an ECG shows a right ventricular ‘strain’ pattern or a chest X-ray shows enlarged pulmonary arteries, peripheral pruning and right ventricle enlargement (Fig. 17.69). Doppler assessment of the tricuspid regurgitant jet by transthoracic echocardiography provides a non-invasive estimate of the PAP, which is equal to 4 × (tricuspid regurgitation velocity)2. Further assessment should be by right heart catheterisation to assess pulmonary haemodynamics, measure vasodilator responsiveness and thus guide further therapy. Management Specialist centres should direct the management of PH. Diuretic therapy should be prescribed for patients with right heart failure. Supplemental oxygen should be given to maintain resting PaO2 in the hypotensive patient. External cardiac massage may be successful in the moribund patient by dislodging and breaking up a large central embolus. Anticoagulation The main principle of treatment for PE is anticoagulation, which is discussed for PE and other forms of VTE on page 975. Thrombolytic and surgical therapy Thrombolysis is indicated in any patient presenting with acute massive PE accompanied by cardiogenic shock. In the absence of shock, the benefits are less clear but thrombolysis may be considered in those presenting with right ventricular dilatation and hypokinesis or severe hypoxaemia. Patients must be screened carefully for haemorrhagic risk, as there is a high risk of intracranial haemorrhage. Surgical pulmonary embolectomy may be considered in selected patients but carries a high mortality. Caval filters A patient in whom anticoagulation is contraindicated, who has suffered massive haemorrhage on anticoagulation, or recurrent VTE despite anticoagulation, should be considered for an inferior vena caval filter. Retrievable caval filters are particularly useful in individuals with temporary risk factors. The caval filter should be used only until anticoagulation can be safely initiated, at which time the filter should be removed if possible. Prognosis Immediate mortality is greatest in those with echocardiographic evidence of right ventricular dysfunction or cardiogenic shock. Once anticoagulation is commenced, however, the risk of mortality rapidly falls. The risk of recurrence is highest in the first 6–12 months after the initial event, and at 10 years around one-third of individuals will have suffered a further event. Pulmonary hypertension Pulmonary hypertension (PH) is defined as a mean pulmonary artery pressure (PAP) of at least 25 mmHg at rest, as measured by right heart catheterisation. The definition may be further refined by consideration of the pulmonary wedge pressure (PWP), the cardiac output and the transpulmonary pressure gradient (mean PAP − mean PWP). The clinical classification of PH is shown in Box 17.85. Further classification is based on the degree of functional disturbance, assessed using the New York Heart Association (NYHA) grades I–IV. Although respiratory failure due to intrinsic pulmonary disease is the most common cause of PH, severe PH may occur as a primary disorder, as a complication of connective tissue disease (e.g. systemic sclerosis), or as a result of chronic thromboembolic events. Primary pulmonary hypertension (PPH) is a rare but important disease that predominantly affects women aged between 20 and 30 years. Familial disease is rarer still but is known to be associated with mutations in the gene encoding type II bone morphogenetic protein receptor (BMPR2), a member of the transforming growth factor beta (TGF-β) superfamily. Mutations in this gene have been identified in some patients with sporadic PH. Pathological features include hypertrophy of both the media and the intima of the vessel wall and a clonal expansion of endothelial cells, which take on the appearance of plexiform lesions. There is marked narrowing of the vessel lumen and this, together with the frequently observed in situ thrombosis, leads to an increase in pulmonary vascular resistance and PH. Adapted from Dana Point 2008. Simonneau G, Robbins IM, Beghetti M, et al. Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol 2009; 54:S43–S54. 17.85 Classification of pulmonary hypertension Pulmonary arterial hypertension • Primary pulmonary hypertension: sporadic and familial • Secondary to: connective tissue disease (limited cutaneous systemic sclerosis), congenital systemic to pulmonary shunts, portal hypertension, HIV infection, exposure to various drugs or toxins, and persistent pulmonary hypertension of the newborn Pulmonary venous hypertension • Left-sided atrial or ventricular heart disease • Left-sided valvular heart disease • Pulmonary veno-occlusive disease • Pulmonary capillary haemangiomatosis Pulmonary hypertension associated with disorders of the respiratory system and/or hypoxaemia • Chronic obstructive pulmonary disease • Diffuse parenchymal lung disease • Sleep-disordered breathing • Alveolar hypoventilation disorders • Chronic exposure to high altitude • Neonatal lung disease • Alveolar capillary dysplasia • Severe kyphoscoliosis Pulmonary hypertension caused by chronic thromboembolic disease • Thromboembolic obstruction of the proximal pulmonary arteries • In situ thrombosis • Sickle-cell disease Miscellaneous • Inflammatory conditions • Extrinsic compression of central pulmonary veins

622 • RESPIRATORY MEDICINE This is a worldwide problem, however, which may be aggravated during harvest seasons. Perennial allergic rhinitis may be a specific reaction to antigens derived from house dust, fungal spores or animal dander, but similar symptoms can be caused by physical or chemical irritants, e.g. pungent odours or fumes, including strong perfumes, cold air and dry atmospheres. The phrase ‘vasomotor rhinitis’ is often used in this context, as the term ‘allergic’ is a misnomer. Clinical features In the seasonal type, there are frequent sudden attacks of sneezing, with profuse watery nasal discharge and nasal obstruction. These attacks last for a few hours and are often accompanied by smarting and watering of the eyes and conjunctival irritation. In perennial rhinitis, the symptoms are similar but more continuous and usually less severe. Skin hypersensitivity tests with the relevant antigen are usually positive in seasonal allergic rhinitis but are less useful in perennial rhinitis. Management In those sensitised to house dust, simple measures, such as thorough dust removal from the bed area, leaving a window open and renewing old pillows, are often helpful. Avoidance of pollen and antigens from domestic pets, however desirable and beneficial, is usually impractical. The following medications, singly or in combination, are usually effective in both seasonal and perennial allergic rhinitis: • an antihistamine such as loratadine • sodium cromoglicate nasal spray • glucocorticoid nasal spray, e.g. beclometasone dipropionate, fluticasone, mometasone or budesonide. When symptoms are very severe, resistant to usual treatments and seriously interfering with school, business or social activities, immunotherapy (desensitisation) is also used but carries the risk of serious reactions and must be managed in specialist centres. Vasomotor rhinitis is often difficult to treat but may respond to ipratropium bromide, administered into each nostril 3 times daily. Sleep-disordered breathing A variety of respiratory disorders affect sleep or are affected by sleep. Cough and wheeze disturbing sleep are characteristic of asthma, while the hypoventilation that accompanies normal sleep can precipitate respiratory failure in patients with disordered ventilation due to kyphoscoliosis, diaphragmatic paralysis or muscle disease (e.g. muscular dystrophy). In contrast, a small but important group of disorders cause problems only during sleep. Patients may have normal lungs and daytime respiratory function, but during sleep have either abnormalities of ventilatory drive (central sleep apnoea) or upper airway obstruction (obstructive sleep apnoea). Of these, the obstructive sleep apnoea/hypopnoea syndrome is by far the most common and important. When this coexists with COPD, severe respiratory failure can result, even if the COPD is mild. The sleep apnoea/hypopnoea syndrome Recurrent upper airway obstruction during sleep, sufficient to cause sleep fragmentation and daytime sleepiness, is thought to affect 2% of women and 4% of men aged 30–60 in Caucasian populations. Daytime sleepiness, especially in monotonous situations, results in a threefold increased risk of road traffic accidents and a ninefold increased risk of single-vehicle accidents. above 8 kPa (60 mmHg). Anticoagulation should be considered unless there is an increased risk of bleeding. Digoxin may be useful in patients who develop atrial tachyarrhythmias. Pregnancy carries a very high risk of death and women of child-bearing age should be counselled appropriately. Excessive physical activity that leads to distressing symptoms should be avoided but otherwise patients should be encouraged to remain active. Pneumococcal and influenza vaccination should be recommended. Nitrates should be avoided owing to the risk of hypotension, and β-blockers are poorly tolerated. Cyclizine can aggravate PH and should also be avoided. Disease-targeted strategies have focused on replacing endogenous prostacyclins with infusions of epoprostenol or treprostinil or nebulised iloprost; blocking endothelin-mediated vasoconstriction with agents such as bosentan, ambrisentan or macitentan; or enhancing endogenous nitric oxide-mediated vasodilatation with phosphodiesterase V inhibitors, such as sildenafil or tadalafil, or the guanylate cyclase stimulator riociguat. High-dose calcium channel blockers may be appropriate in those with an acute vasodilator response. Selected patients are referred for double-lung transplantation, and pulmonary thrombo-endarterectomy may be contemplated in those with chronic proximal pulmonary thromboembolic disease. Atrial septostomy (the creation of a right-to-left shunt) decompresses the right ventricle and improves haemodynamic performance; it may be used as a bridge to transplantation or as a palliative measure. Diseases of the upper airway Diseases of the nasopharynx Allergic rhinitis This is a disorder in which there are episodes of nasal congestion, watery nasal discharge and sneezing. It may be seasonal or perennial, and is due to an immediate hypersensitivity reaction in the nasal mucosa. Seasonal antigens include pollens from grasses, flowers, weeds or trees. Grass pollen is responsible for hay fever, the most common type of seasonal allergic rhinitis in northern Europe, which is at its peak between May and July. Fig. 17.69 Chest X-ray showing the typical appearance in pulmonary hypertension.

Diseases of the upper airway • 623

threshold for diagnosing moderate sleep apnoea/hypopnoea syndrome is 15 or more apnoeas/hypopnoeas per hour of sleep, where an apnoea is defined as a 10-second or longer breathing pause and a hypopnoea a 10-second or longer 50% reduction in breathing. Several other conditions can cause daytime sleepiness but can usually be excluded by a careful history (Box 17.87). Narcolepsy is a rare cause of sudden-onset sleepiness, occurring in 0.05% of the population (p. 1105). Idiopathic hypersomnolence occurs in younger individuals and is characterised by long nocturnal sleeps. Management The major hazard to patients and those around them is traffic accidents, so drivers must be strongly advised not to drive until treatment has relieved their sleepiness. In a minority, relief of nasal obstruction or the avoidance of alcohol may prevent obstruction. Advice to obese patients to lose weight is often unheeded and the majority of patients need to use continuous Aetiology Sleep apnoea results from recurrent occlusion of the pharynx during sleep, usually at the level of the soft palate. Inspiration results in negative pressure within the pharynx. During wakefulness, upper airway dilating muscles, including palatoglossus and genioglossus, contract actively during inspiration to preserve airway patency. During sleep, muscle tone declines, impairing the ability of these muscles to maintain pharyngeal patency. In a minority of people, a combination of an anatomically narrow palatopharynx and under-activity of the dilating muscles during sleep results in inspiratory airway obstruction. Incomplete obstruction causes turbulent flow, resulting in snoring (44% of men and 28% of women aged 30–60 snore). More severe obstruction triggers increased inspiratory effort and transiently wakes the patient, allowing the dilating muscles to re-open the airway. These awakenings are so brief that patients have no recollection of them. After a series of loud deep breaths that may wake their bed partner, the patient rapidly returns to sleep, snores and becomes apnoeic once more. This cycle of apnoea and awakening may repeat itself many hundreds of times per night and results in severe sleep fragmentation and secondary variations in blood pressure, which may predispose over time to cardiovascular disease. Predisposing factors to the sleep apnoea/hypopnoea syndrome include male gender, which doubles the risk, and obesity, which is found in about 50% because parapharyngeal fat deposits tend to narrow the pharynx. Nasal obstruction or a recessed mandible can further exacerbate the problem. Acromegaly and hypothyroidism also predispose by causing submucosal infiltration and narrowing of the upper airway. Sleep apnoea is often familial, where the maxilla and mandible are back-set, narrowing the upper airway. Alcohol and sedatives predispose to snoring and apnoea by relaxing the upper airway dilating muscles. As a result of marked sympathetic activation during apnoea, sleep-disordered breathing is associated over time with sustained hypertension and an increased risk of coronary events and stroke. Associations have also been described with insulin resistance, the metabolic syndrome and type 2 diabetes. Treatment of sleep apnoea reduces sympathetic drive and blood pressure, and may also improve these associated metabolic disorders. Clinical features Excessive daytime sleepiness is the principal symptom and snoring is virtually universal. The patient usually feels that he or she has been asleep all night but wakes unrefreshed. Bed partners report loud snoring in all body positions and often have noticed multiple breathing pauses (apnoeas). Difficulty with concentration, impaired cognitive function and work performance, depression, irritability and nocturia are other features. Investigations Provided that the sleepiness does not result from inadequate time in bed or from shift work, anyone who repeatedly falls asleep during the day when not in bed, who complains that his or her work is impaired by sleepiness, or who is a habitual snorer with multiple witnessed apnoeas should be referred for a sleep assessment. A more quantitative assessment of daytime sleepiness can be obtained by questionnaire (Box 17.86). Overnight studies of breathing, oxygenation and sleep quality are diagnostic (Fig. 17.70) but the level of investigation depends on local resources and the probability of the diagnosis. The current 17.86 Epworth sleepiness scale How likely are you to doze off or fall asleep in the situations described below? Choose the most appropriate number for each situation from the following scale: 0 = would never doze 1 = slight chance of dozing 2 = moderate chance of dozing 3 = high chance of dozing • Sitting and reading • Watching TV • Sitting inactive in a public place (e.g. a theatre or a meeting) • As a passenger in a car for an hour without a break • Lying down to rest in the afternoon when circumstances permit • Sitting and talking to someone • Sitting quietly after a lunch without alcohol • In a car, while stopped for a few minutes in the traffic Normal subjects average 5.9 (SD 2.2) and patients with severe obstructive sleep apnoea average 16.0 (SD 4.4). Fig. 17.70 Sleep apnoea/hypopnoea syndrome: overnight oxygen saturation trace. The left-hand panel shows the trace of a patient who had 53 apnoeas plus hypopnoeas/hour, 55 brief awakenings/hour and marked oxygen desaturation. The right-hand panel shows the effect of continuous positive airway pressure (CPAP) of 10 cm H2O delivered through a tight-fitting nasal mask: it abolished his breathing irregularity and awakenings, and improved oxygenation. Courtesy of Professor N.J. Douglas. ;PTLOYZ ;PTLOYZ 6_`NLU ZH[\YH[PVU

*7(7UPNO[ )HZLSPULUPNO[

624 • RESPIRATORY MEDICINE the left recurrent laryngeal nerve, usually left-sided. One or both recurrent laryngeal nerves may be damaged by thyroidectomy, carcinoma of the thyroid or anterior neck injury. Rarely, the vagal trunk itself is involved by tumour, aneurysm or trauma. Clinical features and management Hoarseness always accompanies laryngeal paralysis, whatever its cause. Paralysis of organic origin is seldom reversible, but when only one vocal cord is affected, hoarseness may improve or even disappear after a few weeks, as the normal cord compensates by crossing the midline to approximate with the paralysed cord on phonation. ‘Bovine cough’ is a characteristic feature of organic laryngeal paralysis, and lacks the explosive quality of normal coughing because the cords fail to close the glottis. Sputum clearance may also be impaired. A normal cough in patients with partial loss of voice or aphonia virtually excludes laryngeal paralysis. Stridor is occasionally present but seldom severe, except when laryngeal paralysis is bilateral. Laryngoscopy is required to establish the diagnosis of laryngeal paralysis. The paralysed cord lies in the so-called ‘cadaveric’ position, midway between abduction and adduction. The cause should be treated, if possible. In unilateral paralysis, persistent dysphonia may be improved by the injection of Teflon into the affected vocal cord. In bilateral organic paralysis, tracheal intubation, tracheostomy or plastic surgery on the larynx may be necessary. Psychogenic hoarseness and aphonia Psychogenic causes of hoarseness or aphonia may be suggested by associated symptoms in the history (p. 1187). Laryngoscopy may be necessary, however, to exclude a physical cause. In psychogenic aphonia, only the voluntary movement of adduction of the vocal cords is seen to be impaired. Speech therapy may be helpful. Laryngeal obstruction Laryngeal obstruction is more liable to occur in children than in adults because of the smaller size of the glottis. Important causes are given in Box 17.89. Sudden complete laryngeal obstruction by a foreign body produces the clinical picture of acute asphyxia: positive airway pressure (CPAP) delivered by a nasal mask every night to splint the upper airway open. When CPAP is tolerated, the effect is often dramatic (Fig. 17.70), with relief of somnolence and improved daytime performance, quality of life and survival. Unfortunately, 30–50% of patients do not tolerate CPAP. Mandibular advancement devices that fit over the teeth and hold the mandible forward, thus opening the pharynx, are an alternative that is effective in some patients. There is no evidence that palatal surgery is of benefit. Laryngeal disorders The larynx is commonly affected by acute self-limiting infections (p. 581). Other disorders include chronic laryngitis, laryngeal tuberculosis, laryngeal paralysis and laryngeal obstruction. Tumours of the larynx are relatively common, particularly in smokers. For further details, the reader should refer to an otolaryngology text. Chronic laryngitis The common causes are listed in Box 17.88. The chief symptoms are hoarseness or loss of voice (aphonia). There is irritation of the throat and a spasmodic cough. The disease pursues a chronic course, frequently uninfluenced by treatment, and the voice may become permanently impaired. Other causes of chronic hoarseness include use of inhaled glucocorticoid treatment, tuberculosis, laryngeal paralysis or tumour. In some patients, a chest X-ray may reveal an unsuspected lung cancer or pulmonary tuberculosis. If these are not found, laryngoscopy should be performed to exclude a local structural cause. When no specific treatable cause is found, the voice must be rested completely. This is particularly important in public speakers and singers. Smoking should be avoided. Some benefit may be obtained from frequent inhalations of medicated steam. Laryngeal paralysis Interruption of the motor nerve supply of the larynx is nearly always unilateral and, because of the intrathoracic course of 17.87 Differential diagnosis of persistent sleepiness Lack of sleep • Inadequate time in bed • Extraneous sleep disruption (e.g. babies/children) • Shift work • Excessive caffeine intake • Physical illness (e.g. pain) Sleep disruption • Sleep apnoea/hypopnoea syndrome • Periodic limb movement disorder (recurrent limb movements during non-REM sleep, frequent nocturnal awakenings; p. 1106) Sleepiness with relatively normal sleep • Narcolepsy • Idiopathic hypersomnolence (rare) • Neurological lesions (e.g. hypothalamic or upper brainstem infarcts or tumours) • Drugs Psychological/psychiatric • Depression 17.89 Causes of laryngeal obstruction • Inflammatory or allergic oedema, or exudate • Spasm of laryngeal muscles • Inhaled foreign body • Inhaled blood clot or vomitus in an unconscious patient • Tumours of the larynx • Bilateral vocal cord paralysis • Fixation of both cords in rheumatoid disease 17.88 Causes of chronic laryngitis • Repeated attacks of acute laryngitis • Excessive use of the voice, especially in dusty atmospheres • Heavy tobacco smoking • Mouth-breathing from nasal obstruction • Chronic infection of nasal sinuses

Pleural disease • 625

the mediastinum, such as carcinoma or lymphoma, eroding both the trachea and oesophagus to produce a communication between them. Swallowed liquids enter the trachea and bronchi through the fistula and provoke coughing. Surgical closure of a congenital fistula, if undertaken promptly, is usually successful. There is usually no curative treatment for malignant fistulae, and death from overwhelming pulmonary infection rapidly supervenes. Pleural disease Pleurisy, pleural effusion, empyema and asbestos-associated pleural disease have been described above. Pneumothorax Pneumothorax is the presence of air in the pleural space, which can either occur spontaneously, or result from iatrogenic injury or trauma to the lung or chest wall (Box 17.90). Primary spontaneous pneumothorax occurs in patients with no history of lung disease. Smoking, tall stature and the presence of apical subpleural blebs are risk factors. Secondary pneumothorax affects patients with pre-existing lung disease and is associated with higher mortality rates (Fig. 17.71). Where the communication between the airway and the pleural space seals off as the lung deflates and does not re-open, the violent but ineffective inspiratory efforts with indrawing of the intercostal spaces and the unsupported lower ribs, accompanied by cyanosis. Unrelieved, the condition progresses to coma and death within a few minutes. When, as in most cases, the obstruction is incomplete at first, the main clinical features are progressive breathlessness accompanied by stridor and cyanosis. Urgent treatment to prevent complete obstruction is needed. Management Transient laryngeal obstruction due to exudate and spasm, which may occur with acute pharyngitis in children and with whooping cough, is potentially dangerous but can usually be relieved by steam inhalation. Laryngeal obstruction from all other causes carries a high mortality and demands prompt treatment. When a foreign body causes laryngeal obstruction in children, it can often be dislodged by turning the patient head downwards and squeezing the chest vigorously. In adults, a sudden forceful compression of the upper abdomen (Heimlich manœuvre) may be effective. Otherwise, the cause of the obstruction should be investigated by direct laryngoscopy, which may also permit the removal of an unsuspected foreign body or the insertion of a tube past the obstruction into the trachea. Tracheostomy must be performed without delay if these procedures fail to relieve obstruction but, except in dire emergencies, this should be performed in theatre by a surgeon. In diphtheria, antitoxin should be administered, and for other infections the appropriate antibiotic should be given. In angioedema, complete laryngeal occlusion can usually be prevented by treatment with adrenaline (epinephrine; 0.5–1 mg (0.5–1 mL of 1 : 1000) IM), chlorphenamine maleate (10–20 mg by slow intravenous injection) and intravenous hydrocortisone sodium succinate (200 mg). Tracheal disorders Tracheal obstruction External compression by lymph nodes containing metastases, usually from a lung cancer, is a more frequent cause of tracheal obstruction than primary benign or malignant tumours. The trachea may also be compressed by a retrosternal goitre (see Fig. 18.12, p. 648). Rare causes include an aneurysm of the aortic arch and (in children) tuberculous mediastinal lymph nodes. Tracheal stenosis is an occasional complication of tracheostomy, prolonged intubation, granulomatosis with polyangiitis (Wegener’s granulomatosis; p. 1041) or trauma. Clinical features and management Stridor can be detected in every patient with severe tracheal narrowing. Bronchoscopic examination of the trachea should be undertaken without delay to determine the site, degree and nature of the obstruction. Localised tumours of the trachea can be resected but reconstruction after resection may be technically difficult. Endobronchial laser therapy, bronchoscopically placed tracheal stents, chemotherapy and radiotherapy are alternatives to surgery. The choice of treatment depends on the nature of the tumour and the general health of the patient. Benign tracheal strictures can sometimes be dilated but may require resection. Tracheo-oesophageal fistula This may be present in newborn infants as a congenital abnormality. In adults, it is usually due to malignant lesions in 17.90 Classification of pneumothorax Spontaneous Primary • No evidence of overt lung disease; air escapes from the lung into the pleural space through rupture of a small pleural bleb, or the pulmonary end of a pleural adhesion Secondary • Underlying lung disease, most commonly chronic obstructive pulmonary disease and tuberculosis; also seen in asthma, lung abscess, pulmonary infarcts, lung cancer and all forms of fibrotic and cystic lung disease Traumatic • Iatrogenic (e.g. following thoracic surgery or biopsy) or chest wall injury Fig. 17.71 Bimodal age distribution for hospital admissions for pneumothorax in England. The incidence of primary spontaneous pneumothorax peaks in males aged 15–30 years. Secondary spontaneous pneumothorax occurs mainly in males over 55 years.

Patient age (years) Male Female Rate per million population

626 • RESPIRATORY MEDICINE pneumothorax. CT is used in difficult cases to avoid misdirected attempts at aspiration. X-rays may also show the extent of any mediastinal displacement and reveal any pleural fluid or underlying pulmonary disease. Management Primary pneumothorax, in which the lung edge is less than 2 cm from the chest wall and the patient is not breathless, normally resolves without intervention. In young patients presenting with a moderate or large spontaneous primary pneumothorax, percutaneous needle aspiration of air is a simple and well-tolerated alternative to intercostal tube drainage, with a 60–80% chance of avoiding the need for a chest drain (Fig. 17.73). In patients with significant underlying chronic lung disease, however, secondary pneumothorax may cause respiratory distress. In these individuals, the success rate of aspiration is much lower, and intercostal tube drainage and inpatient observation are usually required, particularly in those over 50 years old and those with respiratory compromise. If there is a tension pneumothorax, immediate release of the positive pressure by insertion of a blunt cannula into the pleural space may be beneficial, allowing time to prepare for chest drain insertion. When needed, intercostal drains are inserted in the fourth, fifth or sixth intercostal space in the mid-axillary line, connected to an underwater seal or one-way Heimlich valve, and secured firmly pneumothorax is referred to as ‘closed’ (Fig. 17.72A). The mean pleural pressure remains negative, spontaneous reabsorption of air and re-expansion of the lung occur over a few days or weeks, and infection is uncommon. This contrasts with an ‘open’ pneumothorax, where the communication fails to seal and air continues to pass freely between the bronchial tree and pleural space (Fig. 17.72B). An example of the latter is a bronchopleural fistula, which can facilitate the transmission of infection from the airways into the pleural space, leading to empyema. An open pneumothorax is commonly seen following rupture of an emphysematous bulla, tuberculous cavity or lung abscess into the pleural space. Occasionally, the communication between the airway and the pleural space acts as a one-way valve, allowing air to enter the pleural space during inspiration but not to escape on expiration. This is a tension pneumothorax. Large amounts of trapped air accumulate progressively in the pleural space and the intrapleural pressure rises to well above atmospheric levels. This causes mediastinal displacement towards the opposite side, with compression of the opposite normal lung and impairment of systemic venous return, causing cardiovascular compromise (Fig. 17.72C). Clinical features The most common symptoms are sudden-onset unilateral pleuritic chest pain or breathlessness. In those individuals with underlying lung disease, breathlessness can be severe and may not resolve spontaneously. In patients with a small pneumothorax, physical examination may be normal. A larger pneumothorax (> 15% of the hemithorax) results in decreased or absent breath sounds (p. 547). The combination of absent breath sounds and a resonant percussion note is diagnostic of pneumothorax. By contrast, in tension pneumothorax there is rapidly progressive breathlessness associated with a marked tachycardia, hypotension, cyanosis and tracheal displacement away from the side of the silent hemithorax. Occasionally, tension pneumothorax may occur without mediastinal shift, if malignant disease or scarring has splinted the mediastinum. Investigations The chest X-ray shows the sharply defined edge of the deflated lung with complete translucency (no lung markings) between this and the chest wall (p. 547). Care must be taken to differentiate between a large pre-existing emphysematous bulla and a Fig. 17.72 Types of spontaneous pneumothorax. A Closed type. B Open type. C Tension (valvular) type. Tension type Mean pleural pressure positive, mediastinal shift to opposite side Closed type Mean pleural pressure negative Open type Mean pleural pressure atmospheric A B C 17.91 Pleural disease in old age • Spontaneous pneumothorax: invariably associated with underlying lung disease in old age and has a significant mortality. Surgical or chemical pleurodesis is advised in all such patients. • Rib fracture: common cause of pleural-type pain; may be spontaneous (due to coughing), traumatic or pathological. Underlying osteomalacia may contribute to poor healing, especially in the housebound with no exposure to sunlight. • Tuberculosis: should always be considered and actively excluded in any elderly patient presenting with a unilateral pleural effusion. • Mesothelioma: more common in older individuals than younger people due to a long latency period between asbestos exposure (often more than 20 years) and the development of disease. • Analgesia: frail older people are particularly sensitive to the respiratory depressant effects of opiate-based analgesia and careful monitoring is required when using these agents for pleural pain.

Diseases of the diaphragm and chest wall • 627

by pleural abrasion or parietal pleurectomy at thoracotomy or thoracoscopy. Diseases of the diaphragm and chest wall Disorders of the diaphragm Congenital disorders Diaphragmatic hernias Congenital defects of the diaphragm can allow herniation of abdominal viscera. Posteriorly situated hernias through the foramen of Bochdalek are more common than anterior hernias through the foramen of Morgagni. Eventration of the diaphragm Abnormal elevation or bulging of one hemidiaphragm, more often the left, results from total or partial absence of muscular development of the septum transversum. Most eventrations are asymptomatic and are detected by chance on X-ray in adult life but severe respiratory distress can be caused in infancy if the diaphragmatic muscular defect is extensive. Acquired disorders Elevation of a hemidiaphragm may result from paralysis or other structural causes (Box 17.92). The phrenic nerve may be damaged by lung cancer, disease of cervical vertebrae, tumours of the cervical cord, shingles, trauma (including road traffic and birth injuries), surgery, and stretching of the nerve by mediastinal masses and aortic aneurysms. Idiopathic diaphragmatic paralysis occasionally occurs in otherwise fit patients. Paralysis of one hemidiaphragm results in loss of around 20% of ventilatory capacity but may not be noticed by otherwise healthy individuals. Ultrasound screening can be used to demonstrate paradoxical upward movement of the paralysed hemidiaphragm on sniffing. CT of the chest and neck is the best way to exclude occult disease affecting the phrenic nerve. Bilateral diaphragmatic weakness occurs in peripheral neuropathies of any type, including Guillain–Barré syndrome (p. 1140); in disorders affecting the anterior horn cells, e.g. poliomyelitis (p. 1123); in muscular dystrophies; and in connective tissue disorders, such as SLE and polymyositis (pp. 1034 and 1039). Hiatus hernia is common (p. 791). Diaphragmatic rupture is usually caused by a crush injury and may not be detected until years later. Respiratory disorders that cause pulmonary hyperinflation, e.g. emphysema, and those that result in small stiff lungs, e.g. diffuse pulmonary fibrosis, compromise diaphragmatic function and predispose to fatigue. to the chest wall. Clamping of an intercostal drain is potentially dangerous and rarely indicated. The drain should be removed the morning after the lung has fully re-inflated and bubbling has stopped. Continued bubbling after 5–7 days is an indication for surgery. If bubbling in the drainage bottle stops before full re-inflation, the tube is either blocked or kinked or displaced. Supplemental oxygen may speed resolution, as it accelerates the rate at which nitrogen is reabsorbed by the pleura. Patients with a closed pneumothorax should be advised not to fly, as the trapped gas expands at altitude. After complete resolution, there is no clear evidence to indicate how long patients should avoid flying for, although British Thoracic Society guidelines suggest that waiting 1–2 weeks, with confirmation of full inflation prior to flight, is prudent. Patients should also be advised to stop smoking and informed about the risks of a recurrent pneumothorax. Diving is potentially dangerous after pneumothorax, unless a surgical pleurodesis has sealed the lung to the chest wall. Recurrent spontaneous pneumothorax After primary spontaneous pneumothorax, recurrence occurs within a year of either aspiration or tube drainage in approximately 25% of patients and should prompt definitive treatment. Surgical pleurodesis is recommended in all patients following a second pneumothorax and should be considered following the first episode of secondary pneumothorax if low respiratory reserve makes recurrence hazardous. Pleurodesis can be achieved Fig. 17.73 Management of spontaneous pneumothorax. (1) Immediate decompression prior to insertion of the intercostal drain. (2) Aspirate in the second intercostal space anteriorly in the mid-clavicular line using a 16 F cannula; discontinue if resistance is felt, the patient coughs excessively, or more than 2.5 L of air are removed. (3) The post-aspiration chest X-ray is not a reliable indicator of whether a pleural leak remains, and all patients should be told to attend again immediately in the event of deterioration. Mediastinal shift and/or hypotension (tension pneumothorax) Chronic lung disease Pneumothorax

15% of hemithorax or significant dyspnoea 50 years of age Observe patient for 6 hours Outpatient follow-up3 Intercostal tube drainage attached to underwater seal device Percutaneous needle aspiration2 2.5 L air aspirated or pneumothorax persists Yes1 Yes No No No No No Yes Yes Yes 17.92 Causes of elevation of a hemidiaphragm • Phrenic nerve paralysis • Eventration of the diaphragm • Decrease in volume of one lung (e.g. lobectomy, unilateral pulmonary fibrosis) • Severe pleuritic pain • Pulmonary infarction • Subphrenic abscess • Large volume of gas in the stomach or colon • Large tumours or cysts of the liver

628 • RESPIRATORY MEDICINE curved inwards. The heart is displaced to the left and may be compressed between the sternum and the vertebral column but only rarely is there associated disturbance of cardiac function. The deformity may restrict chest expansion and reduce vital capacity. Operative correction is rarely performed, and then only for cosmetic reasons. Pectus carinatum Pectus carinatum (pigeon chest) is frequently caused by severe asthma during childhood. Very occasionally, this deformity can be produced by rickets or be idiopathic. Further information Websites brit-thoracic.org.uk British Thoracic Society: access to guidelines on a range of respiratory conditions. ersnet.org European Respiratory Society: provides information on education and research, and patient information. ginasthma.com Global Initiative for Asthma: comprehensive overview of asthma. goldcopd.org Global Initiative for Chronic Obstructive Lung Disease: comprehensive overview of COPD. thoracic.org American Thoracic Society: provides information on education and research, and patient information. Deformities of the chest wall Thoracic kyphoscoliosis Abnormalities of alignment of the dorsal spine and their consequent effects on thoracic shape may be caused by: • congenital abnormality • vertebral disease, including tuberculosis, osteoporosis and ankylosing spondylitis • trauma • neuromuscular disease, such as poliomyelitis. Simple kyphosis (increased anterior curvature of the thoracic spine) causes less pulmonary embarrassment than kyphoscoliosis (anteroposterior and lateral curvature). Kyphoscoliosis, if severe, restricts and distorts expansion of the chest wall and impairs diaphragmatic function, causing ventilation–perfusion mismatch in the lungs. Patients with severe deformity may develop type II respiratory failure (initially manifest during sleep), pulmonary hypertension and right ventricular failure. They can often be successfully treated with non-invasive ventilatory support (p. 202). Pectus excavatum Pectus excavatum (funnel chest) is an idiopathic condition in which the body of the sternum, usually only the lower end, is

Ch04-3 Clinical Medicine

08-18 Endocrinology

18 Endocrinology

Endocrinology MWJ Strachan JDC Newell-Price Clinical examination in endocrine disease 630 An overview of endocrinology 632 Functional anatomy and physiology 632 Endocrine pathology 632 Investigation of endocrine disease 633 Presenting problems in endocrine disease 633 The thyroid gland 634 Functional anatomy, physiology and investigations 634 Presenting problems in thyroid disease 635 Thyrotoxicosis 635 Hypothyroidism 639 Asymptomatic abnormal thyroid function tests 642 Thyroid lump or swelling 642 Autoimmune thyroid disease 643 Transient thyroiditis 646 Iodine-associated thyroid disease 647 Simple and multinodular goitre 648 Thyroid neoplasia 649 Congenital thyroid disease 650 The reproductive system 651 Functional anatomy, physiology and investigations 651 Presenting problems in reproductive disease 653 Delayed puberty 653 Precocious puberty 654 Amenorrhoea 654 Male hypogonadism 655 Infertility 656 Gynaecomastia 657 Hirsutism 657 Polycystic ovarian syndrome 658 Turner’s syndrome 659 Klinefelter’s syndrome 660 The parathyroid glands 661 Functional anatomy, physiology and investigations 661 Presenting problems in parathyroid disease 661 Hypercalcaemia 661 Hypocalcaemia 662 Primary hyperparathyroidism 663 Familial hypocalciuric hypercalcaemia 664 Hypoparathyroidism 664 The adrenal glands 665 Functional anatomy and physiology 665 Presenting problems in adrenal disease 666 Cushing’s syndrome 666 Therapeutic use of glucocorticoids 670 Adrenal insufficiency 671 Incidental adrenal mass 673 Primary hyperaldosteronism 674 Phaeochromocytoma and paraganglioma 675 Congenital adrenal hyperplasia 676 The endocrine pancreas and gastrointestinal tract 676 Presenting problems in endocrine pancreas disease 676 Spontaneous hypoglycaemia 676 Gastroenteropancreatic neuro-endocrine tumours 678 The hypothalamus and the pituitary gland 679 Functional anatomy, physiology and investigations 679 Presenting problems in hypothalamic and pituitary disease 681 Hypopituitarism 681 Pituitary tumour 683 Hyperprolactinaemia/galactorrhoea 684 Prolactinoma 684 Acromegaly 685 Craniopharyngioma 687 Diabetes insipidus 687 Disorders affecting multiple endocrine glands 688 Multiple endocrine neoplasia 688 Autoimmune polyendocrine syndromes 689 Late effects of childhood cancer therapy 689

630 • ENDOCRINOLOGY Hands Palmar erythema Tremor Acromegaly Carpal tunnel syndrome Skin Hair distribution Dry/greasy Pigmentation/pallor Bruising Vitiligo Striae Thickness Pulse Atrial fibrillation Sinus tachycardia Bradycardia Breasts Galactorrhoea Gynaecomastia Neck Voice Hoarse, e.g. hypothyroid Virilised Thyroid gland (see opposite) Goitre Nodules

Observation • Most examination in endocrinology is by observation • Astute observation can often yield ‘spot’ diagnosis of endocrine disorders • The emphasis of examination varies depending on which gland or hormone is thought to be involved Body fat Central obesity in Cushing’s syndrome and growth hormone deficiency

Height and weight Bones Fragility fractures (e.g. of vertebrae, neck of femur or distal radius)

Genitalia Virilisation Pubertal development Testicular volume

Legs Proximal myopathy Myxoedema

Blood pressure Hypertension in Cushing’s and Conn’s syndromes, phaeochromocytoma Hypotension in adrenal insufficiency Eyes Graves’ disease (see opposite) Diplopia Visual field defect (see opposite) Hair Alopecia Frontal balding Facial features Hypothyroid Hirsutism Acromegaly Cushing’s

Prognathism in acromegaly Acromegalic hands. Note soft tissue enlargement causing ‘spade-like’ changes Pigmentation of creases due to high ACTH levels in Addison’s disease Vitiligo in organ-specific autoimmune disease Multinodular goitre Pretibial myxoedema in Graves' disease Head Mental state Lethargy Depression Delirium Libido

Clinical examination in endocrine disease Endocrine disease causes clinical syndromes with symptoms and signs involving many organ systems. The emphasis of the clinical examination depends on the gland or hormone that is thought to be abnormal. Diabetes mellitus (described in detail in Ch. 20) and thyroid disease are the most common endocrine disorders.

Clinical examination in endocrine disease • 631

6 Examination of the visual fields by confrontation • Sit opposite patient • You and patient cover opposite eyes • Bring red pin (or wiggling finger) slowly into view from extreme of your vision, as shown • Ask patient to say ‘now’ when it comes into view • Continue to move pin into centre of vision and ask patient to tell you if it disappears • Repeat in each of four quadrants • Repeat in other eye A bitemporal hemianopia is the classical finding in pituitary macroadenomas (p. 683) 6 Examination in Graves’ ophthalmopathy • Inspect from front and side Periorbital oedema (Fig. 18.8) Conjunctival inflammation (chemosis) Corneal ulceration Proptosis (exophthalmos)* Lid retraction* • Range of eye movements Lid lag on descending gaze* Diplopia on lateral gaze • Pupillary reflexes Afferent defect (pupils constrict further on swinging light to unaffected eye, Box 25.22) • Vision Visual acuity impaired Loss of colour vision Visual field defects • Ophthalmoscopy Optic disc pallor Papilloedema *Note position of eyelids relative to iris. Normal

Proptosis

Right proptosis and afferent pupillary defect

Lid retraction

Normal

Normal descent

Lid lag descent

7 Examination of the thyroid gland Diffuse firm goitre

Hashimoto’s thyroiditis (p. 646) Diffuse tender goitre

Subacute thyroiditis (p. 646) Abnormal findings Diffuse soft goitre with bruit

Graves’ disease (p. 643) Multinodular goitre (p. 648)

± Retrosternal extension, tracheal compression Solitary nodule (p. 642)

Adenoma, cyst or carcinoma Cervical lymphadenopathy

Suggests carcinoma • Inspect from front to side • Palpate from behind Thyroid moves on swallowing Check if lower margin is palpable Cervical lymph nodes Tracheal deviation • Auscultate for bruit Ask patient to hold breath If present, check for radiating murmur • Percuss for retrosternal thyroid • Consider systemic signs of thyroid dysfunction (Box 18.7) incl. tremor, palmar erythema, warm peripheries, tachycardia, lid lag • Consider signs of Graves’ disease incl. ophthalmopathy, pretibial myxoedema • Check for Pemberton’s sign, i.e. facial engorgement when arms raised above head

632 • ENDOCRINOLOGY to affect adjacent cells, or act in an autocrine way to affect behaviour of the cell that produces the hormone. Endocrine pathology For each endocrine axis or major gland, diseases can be classified as shown in Box 18.1. Pathology arising within the gland is often called ‘primary’ disease (e.g. primary hypothyroidism in Hashimoto’s thyroiditis), while abnormal stimulation of the gland is often called ‘secondary’ disease (e.g. secondary hypothyroidism in patients with a pituitary tumour and thyroid-stimulating hormone Endocrinology concerns the synthesis, secretion and action of hormones. These are chemical messengers released from endocrine glands that coordinate the activities of many different cells. Endocrine diseases can therefore affect multiple organs and systems. This chapter describes the principles of endocrinology before dealing with the function and diseases of each gland in turn. Some endocrine disorders are common, particularly those of the thyroid, parathyroid glands, reproductive system and β cells of the pancreas (Ch. 20). For example, thyroid dysfunction occurs in more than 10% of the population in areas with iodine deficiency, such as the Himalayas, and 4% of women aged 20–50 years in the UK. Less common endocrine syndromes are described later in the chapter. Few endocrine therapies have been evaluated by randomised controlled trials, in part because hormone replacement therapy (e.g. with levothyroxine) has obvious clinical benefits and placebocontrolled trials would be unethical. Where trials have been performed, they relate mainly to use of therapy that is ‘optional’ and/or more recently available, such as oestrogen replacement in post-menopausal women, androgen therapy in older men and growth hormone replacement. An overview of endocrinology Functional anatomy and physiology Some endocrine glands, such as the parathyroids and pancreas, respond directly to metabolic signals, but most are controlled by hormones released from the pituitary gland. Anterior pituitary hormone secretion is controlled in turn by substances produced in the hypothalamus and released into portal blood, which drains directly down the pituitary stalk (Fig. 18.1). Posterior pituitary hormones are synthesised in the hypothalamus and transported down nerve axons, to be released from the posterior pituitary. Hormone release in the hypothalamus and pituitary is regulated by numerous stimuli and through feedback control by hormones produced by the target glands (thyroid, adrenal cortex and gonads). These integrated endocrine systems are called ‘axes’ and are listed in Figure 18.2. A wide variety of molecules can act as hormones, including peptides such as insulin and growth hormone, glycoproteins such as thyroid-stimulating hormone, and amines such as noradrenaline (norepinephrine). The biological effects of hormones are mediated by binding to receptors. Many receptors are located on the cell surface. These interact with various intracellular signalling molecules on the cytosolic side of the plasma membrane to affect cell function, usually through changes in gene expression. Some hormones, most notably steroids, triiodothyronine (T3) and vitamin D, bind to specific intracellular receptors. The hormone/ receptor complex forms a ligand-activated transcription factor, which regulates gene expression directly (p. 39). The classical model of endocrine function involves hormones synthesised in endocrine glands, which are released into the circulation and act at sites distant from those of secretion (as in Fig. 18.1). However, additional levels of regulation are now recognised. Many other organs secrete hormones or contribute to the peripheral metabolism and activation of prohormones. A notable example is the production of oestrogens from adrenal androgens in adipose tissue by the enzyme aromatase. Some hormones, such as neurotransmitters, act in a paracrine fashion Fig. 18.1 An archetypal endocrine axis. Regulation by negative feedback and direct control is shown, along with the equilibrium between active circulating free hormone and bound or metabolised hormone. Feedback regulation Trophic hormone Hormone Binding protein Target organ Metabolism Endocrine gland Pituitary Neural control Action Receptor Direct regulation 18.1 Classification of endocrine disease Hormone excess • Primary gland over-production • Secondary to excess trophic substance Hormone deficiency • Primary gland failure • Secondary to deficient trophic hormone Hormone hypersensitivity • Failure of inactivation of hormone • Target organ over-activity/hypersensitivity Hormone resistance • Failure of activation by hormone • Target organ resistance Non-functioning tumours • Benign • Malignant

An overview of endocrinology • 633

deficiency). Some pathological processes can affect multiple endocrine glands (p. 688); these may have a genetic basis (such as organ-specific autoimmune endocrine disorders and the multiple endocrine neoplasia (MEN) syndromes) or be a consequence of therapy for another disease (e.g. following treatment of childhood cancer with chemotherapy and/or radiotherapy). Investigation of endocrine disease Biochemical investigations play a central role in endocrinology. Most hormones can be measured in blood but the circumstances in which the sample is taken are often crucial, especially for hormones with pulsatile secretion, such as growth hormone; those that show diurnal variation, such as cortisol; or those that demonstrate monthly variation, such as oestrogen or progesterone. Some hormones are labile and need special collection, handling and processing requirements, e.g. collection in a special tube and/or rapid transportation to the laboratory on ice. Local protocols for hormone measurement should be carefully followed. Other investigations, such as imaging and biopsy, are more frequently reserved for patients who present with a tumour. The principles of investigation are shown in Box 18.2. The choice of test is often pragmatic, taking local access to reliable sampling facilities and laboratory measurements into account. Presenting problems in endocrine disease Endocrine diseases present in many different ways and to clinicians in many different disciplines. Classical syndromes are described in relation to individual glands in the following sections. Often, however, the presentation is with non-specific symptoms (Box 18.3) or with asymptomatic biochemical abnormalities. In Fig. 18.2 The principal endocrine ‘axes’. Some major endocrine glands are not controlled by the pituitary. These include the parathyroid glands (regulated by calcium concentrations, p. 661), the adrenal zona glomerulosa (regulated by the renin–angiotensin system, p. 665) and the endocrine pancreas (Ch. 20). Italics show negative regulation. (ACTH = adrenocorticotrophic hormone; CRH = corticotrophin-releasing hormone; FSH = folliclestimulating hormone; GH = growth hormone; GHRH = growth hormone-releasing hormone; GnRH = gonadotrophin-releasing hormone; IGF-1 = insulin-like growth factor-1; IGF-BP3 = IGF-binding protein-3; LH = luteinising hormone: T3 = triiodothyronine; T4 = thyroxine; TRH = thyrotrophin-releasing hormone; TSH = thyroid-stimulating hormone; vasopressin = antidiuretic hormone (ADH)) Regulation Circadian rhythm Stress Cortisol Osmolality Intravascular volume Oestrogen Progesterone Androgen Prolactin Inhibin T3 IGF-1 GnRH TRH Dopamine GHRH Somatostatin CRH Oxytocin Hypothalamus TSH Prolactin GH ACTH Posterior Pituitary LH FSH Gonads: testes or ovaries Thyroid Breast Liver Adrenal cortex Distal nephron Uterus Breast Oestrogen Progesterone Androgen T4 T3 IGF-1 IGF-BP3 Cortisol Androgen Glands/targets Target hormones Function Reproduction Metabolism Lactation Growth Stress Metabolism Water balance Parturition Lactation Oestrogen Stress Anterior Vasopressin 18.2 Principles of endocrine investigation Timing of measurement • Release of many hormones is rhythmical (pulsatile, circadian or monthly), so random measurement may be invalid and sequential or dynamic tests may be required Choice of dynamic biochemical test • Abnormalities are often characterised by loss of normal regulation of hormone secretion • If hormone deficiency is suspected, choose a stimulation test • If hormone excess is suspected, choose a suppression test • The more tests there are to choose from, the less likely it is that any single test is infallible, so avoid interpreting one result in isolation Imaging • ‘Functional’ as well as conventional ‘structural’ imaging can be performed as secretory endocrine cells can also take up labelled substrates, e.g. radio-labelled iodine or octreotide • Most endocrine glands have a high prevalence of ‘incidentalomas’, so do not scan unless the biochemistry confirms endocrine dysfunction or the primary problem is a tumour Biopsy • Many endocrine tumours are difficult to classify histologically (e.g. adrenal carcinoma and adenoma) addition, endocrine diseases are encountered in the differential diagnosis of common complaints discussed in other chapters of this book, including electrolyte abnormalities (Ch. 14), hypertension (Ch. 16), obesity (Ch. 19) and osteoporosis (Ch. 24). Although diseases of the adrenal glands, hypothalamus and pituitary are relatively rare, their diagnosis often relies on astute clinical observation in a patient with non-specific complaints, so it is important that clinicians are familiar with their key features.

634 • ENDOCRINOLOGY free hormone measurements is that they are not influenced by changes in the concentration of binding proteins. For example, TBG levels are increased by oestrogen (such as in the combined oral contraceptive pill) and this will result in raised total T3 and T4, although free thyroid hormone levels are normal. Production of T3 and T4 in the thyroid is stimulated by thyrotrophin (thyroid-stimulating hormone, TSH), a glycoprotein released from the thyrotroph cells of the anterior pituitary in response to the hypothalamic tripeptide, thyrotrophin-releasing hormone (TRH). A circadian rhythm of TSH secretion can be demonstrated with a peak at 0100 hrs and trough at 1100 hrs, but the variation is small so that thyroid function can be assessed reliably from a single blood sample taken at any time of day and does not usually require any dynamic stimulation or suppression tests. There is a negative feedback of thyroid hormones on the hypothalamus and pituitary such that in thyrotoxicosis, when plasma concentrations of T3 and T4 are raised, TSH secretion is suppressed. Conversely, in hypothyroidism due to disease of the thyroid gland, low T3 and T4 are associated with high circulating TSH levels. The relationship between TSH and T4 is classically described as inverse log-linear (Fig. 18.4). The anterior pituitary is, though, very sensitive to minor changes in thyroid hormone levels within the reference range. For example, in an individual whose free T4 level is usually 15 pmol/L (1.17 ng/dL), a rise or fall of 5 pmol/L (0.39 ng/dL) would be associated on the one hand with undetectable TSH, and on the other hand with a raised TSH. For this reason, TSH is usually regarded as the most useful investigation of thyroid function. However, interpretation of TSH values without considering thyroid hormone levels may be misleading in patients with pituitary disease; for example, TSH is inappropriately low or ‘normal’ in secondary hypothyroidism (see Box 18.5 and Box 18.53, p. 680). Moreover, TSH may take several weeks to ‘catch up’ with T4 and T3 levels; for example, levothyroxine therapy will raise T4 and T3 levels within approximately 2 weeks but it may take 4–6 weeks for the TSH to reach a steady state. Heterophilic antibodies (host antibodies with affinity to the animal antibodies used in biological assays, p. 242) can also interfere with the TSH assay and cause a spurious high or low measurement. Common patterns of abnormal thyroid function test results and their interpretation are shown in Box 18.5. Other modalities commonly employed in the investigation of thyroid disease include measurement of antibodies against The thyroid gland Diseases of the thyroid, summarised in Box 18.4, predominantly affect females and are common, occurring in about 5% of the population. The thyroid axis is involved in the regulation of cellular differentiation and metabolism in virtually all nucleated cells, so that disorders of thyroid function have diverse manifestations. Structural diseases of the thyroid gland, such as goitre, commonly occur in patients with normal thyroid function. Functional anatomy, physiology and investigations Thyroid physiology is illustrated in Figure 18.3. The parafollicular C cells secrete calcitonin, which is of no apparent physiological significance in humans. The follicular epithelial cells synthesise thyroid hormones by incorporating iodine into the amino acid tyrosine on the surface of thyroglobulin (Tg), a protein secreted into the colloid of the follicle. Iodide is a key substrate for thyroid hormone synthesis; a dietary intake in excess of 100 μg/day is required to maintain thyroid function in adults. The thyroid secretes predominantly thyroxine (T4) and only a small amount of triiodothyronine (T3); approximately 85% of T3 in blood is produced from T4 by a family of monodeiodinase enzymes that are active in many tissues, including liver, muscle, heart and kidney. Selenium is an integral component of these monodeiodinases. T4 can be regarded as a prohormone, since it has a longer half-life in blood than T3 (approximately 1 week compared with approximately 18 hours), and binds and activates thyroid hormone receptors less effectively than T3. T4 can also be converted to the inactive metabolite, reverse T3. T3 and T4 circulate in plasma almost entirely (> 99%) bound to transport proteins, mainly thyroxine-binding globulin (TBG). It is the unbound or free hormones that diffuse into tissues and exert diverse metabolic actions. Some laboratories use assays that measure total T4 and T3 in plasma but it is increasingly common to measure free T4 and free T3. The theoretical advantage of the 18.4 Classification of thyroid disease Primary Secondary Hormone excess Graves’ disease Multinodular goitre Adenoma Subacute thyroiditis TSHoma Hormone deficiency Hashimoto’s thyroiditis Atrophic hypothyroidism Hypopituitarism Hormone hypersensitivity – Hormone resistance Thyroid hormone resistance syndrome 5′-monodeiodinase deficiency Non-functioning tumours Differentiated carcinoma Medullary carcinoma Lymphoma 18.3 Examples of non-specific presentations of endocrine disease Symptom Most likely endocrine disorder(s) Lethargy and depression Hypothyroidism, diabetes mellitus, hyperparathyroidism, hypogonadism, adrenal insufficiency, Cushing’s syndrome Weight gain Hypothyroidism, Cushing’s syndrome Weight loss Thyrotoxicosis, adrenal insufficiency, diabetes mellitus Polyuria and polydipsia Diabetes mellitus, diabetes insipidus, hyperparathyroidism, hypokalaemia (Conn’s syndrome) Heat intolerance Thyrotoxicosis, menopause Palpitation Thyrotoxicosis, phaeochromocytoma Headache Acromegaly, pituitary tumour, phaeochromocytoma Muscle weakness (usually proximal) Thyrotoxicosis, Cushing’s syndrome, hypokalaemia (e.g. Conn’s syndrome), hyperparathyroidism, hypogonadism Coarsening of features Acromegaly, hypothyroidism

The thyroid gland • 635

the TSH receptor or other thyroid antigens (see Box 18.8), radioisotope imaging, fine needle aspiration biopsy and ultrasound. Their use is described below. Presenting problems in thyroid disease The most common presentations are hyperthyroidism (thyrotoxicosis), hypothyroidism and enlargement of the thyroid (goitre or thyroid nodule). Widespread availability of thyroid function tests has led to the increasingly frequent identification of patients with abnormal results who either are asymptomatic or have non-specific complaints such as tiredness and weight gain. Thyrotoxicosis Thyrotoxicosis describes a constellation of clinical features arising from elevated circulating levels of thyroid hormone. The most common causes are Graves’ disease, multinodular goitre and autonomously functioning thyroid nodules (toxic adenoma) (Box 18.6). Thyroiditis is more common in parts of the world where relevant viral infections occur, such as North America. Clinical assessment The clinical manifestations of thyrotoxicosis are shown in Box 18.7 and an approach to differential diagnosis is given in Fig. 18.3 Structure and function of the thyroid gland. (1) Thyroglobulin (Tg) is synthesised and secreted into the colloid of the follicle. (2) Inorganic iodide (I–) is actively transported into the follicular cell (‘trapping’). (3) Iodide is transported on to the colloidal surface by a transporter (pendrin, defective in Pendred’s syndrome, p. 650) and ‘organified’ by the thyroid peroxidase enzyme, which incorporates it into the amino acid tyrosine on the surface of Tg to form monoiodotyrosine (MIT) and diiodotyrosine (DIT). (4) Iodinated tyrosines couple to form T3 and T4. (5) Tg is endocytosed. (6) Tg is cleaved by proteolysis to free the iodinated tyrosine and thyroid hormones. (7) Iodinated tyrosine is dehalogenated to recycle the iodide. (8) T4 is converted to T3 by 5′-monodeiodinase. Colloid Follicular cell Extracellular fluid T4 MIT DIT T4 T3 Stimulates all steps

Protein-bound T4, T3 ( > 99%) Increased metabolic rate Mimic β-adrenergic action, e.g. on heart rate, gut motility CNS activation Bone demineralisation Cellular differentiation etc. rT3 T4 T3

Blood Target tissues HO CH2 COOH NH2 CH Tyrosine Monoiodotyrosine (MIT) Diiodotyrosine (DIT) HO O CH2 COOH NH2 CH Triiodothyronine (T3) HO O CH2 COOH NH2 CH Thyroxine (T4) HO O CH2 COOH NH2 CH Reverse T3 (rT3) Negative feedback

HO CH2 COOH NH2 CH HO CH2 COOH NH2 CH Parafollicular (C) cells Colloid Follicular epithelium Red blood cells Free T4,T3 ( < 1%) Fig. 18.4 The relationship between serum thyroid-stimulating hormone (TSH) and free T4. Due to the classic negative feedback loop between T4 and TSH, there is an inverse relationship between serum free T4 and the log of serum TSH. To convert pmol/L to ng/dL, divide by 12.87. LogTSH (mlU/L) Free T4 (pmol/L) 2.5 2.0 1.5 1.0 0.5

-0.5 -1.0 -1.5 -2.0 -2.5

636 • ENDOCRINOLOGY Figure 18.5. The most common symptoms are weight loss with a normal or increased appetite, heat intolerance, palpitations, tremor and irritability. Tachycardia, palmar erythema and lid lag are common signs. Not all patients have a palpable goitre, but experienced clinicians can discriminate the diffuse soft goitre of Graves’ disease from the irregular enlargement of a multinodular goitre. All causes of thyrotoxicosis can cause lid retraction and lid lag, due to potentiation of sympathetic innervation of the levator palpebrae muscles, but only Graves’ disease causes other features of ophthalmopathy, including periorbital oedema, conjunctival irritation, exophthalmos and diplopia. Pretibial myxoedema (p. 646) and the rare thyroid acropachy (a periosteal hypertrophy, indistinguishable from finger clubbing) are also specific to Graves’ disease. Investigations The first-line investigations are serum T3, T4 and TSH. If abnormal values are found, the tests should be repeated and the abnormality confirmed in view of the likely need for prolonged medical treatment or destructive therapy. In most patients, serum T3 and T4 are both elevated, but T4 is in the upper part of the reference range and T3 is raised (T3 toxicosis) in about 5%. Serum TSH is undetectable in primary thyrotoxicosis, but values can be raised in the very rare syndrome of secondary thyrotoxicosis caused by a TSH-producing pituitary adenoma. When biochemical thyrotoxicosis has been confirmed, further investigations should be undertaken to determine the underlying cause, including measurement of TSH receptor antibodies (TRAb, elevated in Graves’ disease; Box 18.8) and radioisotope scanning, as shown in Figure 18.5. Other non-specific abnormalities are common 18.5 How to interpret thyroid function test results TSH T4 T3 Most likely interpretation(s) U.D. Raised Raised Primary thyrotoxicosis U.D. or low Raised Normal Over-treatment of hypothyroidism with levothyroxine Factitious thyrotoxicosis U.D. Normal1 Raised Primary T3 toxicosis U.D. Normal1 Normal1 Subclinical thyrotoxicosis U.D. or low Raised Low or normal Non-thyroidal illness Amiodarone therapy U.D. or low Low Raised Over-treatment of hypothyroidism with liothyronine (T3) U.D. Low Low Secondary hypothyroidism4 Transient thyroiditis in evolution Normal Low Low2 Secondary hypothyroidism4 Mildly elevated 5–20 mIU/L Low Low2 Primary hypothyroidism Secondary hypothyroidism4 Elevated > 20 mIU/L Low Low2 Primary hypothyroidism Mildly elevated 5–20 mIU/L Normal3 Normal2 Subclinical hypothyroidism Elevated 20–500 mIU/L Normal Normal Artefact Heterophilic antibodies (host antibodies with affinity to the animal antibodies used in TSH assays) Elevated Raised Raised Non-adherence to levothyroxine replacement – recent ‘loading’ dose Secondary thyrotoxicosis4 Thyroid hormone resistance 1Usually upper part of reference range. 2T3 is not a sensitive indicator of hypothyroidism and should not be requested. 3Usually lower part of reference range. 4i.e. Secondary to pituitary or hypothalamic disease. Note that TSH assays may report detectable TSH. (TSH = thyroid-stimulating hormone; U.D. = undetectable) 18.6 Causes of thyrotoxicosis and their relative frequencies Cause Frequency1 (%) Graves’ disease

Multinodular goitre

Solitary thyroid adenoma

Thyroiditis Subacute (de Quervain’s)2

Post-partum2 0.5 Iodide-induced Drugs (amiodarone)2

Radiographic contrast media2 – Iodine supplementation programme2 – Extrathyroidal source of thyroid hormone Factitious thyrotoxicosis2 0.2 Struma ovarii2,3 – TSH-induced TSH-secreting pituitary adenoma 0.2 Choriocarcinoma and hydatidiform mole4 – Follicular carcinoma ± metastases 0.1 1ln a series of 2087 patients presenting to the Royal Infirmary of Edinburgh over a 10-year period. 2Characterised by negligible radioisotope uptake. 3i.e. Ovarian teratoma containing thyroid tissue. 4Human chorionic gonadotrophin has thyroid-stimulating activity. (TSH = thyroid-stimulating hormone)

The thyroid gland • 637

conventional thyrotoxicosis) is increased to above 70 : 1 because circulating T3 in factitious thyrotoxicosis is derived exclusively from the peripheral monodeiodination of T4 and not from thyroid secretion. The combination of negligible iodine uptake, high T4:T3 ratio and a low or undetectable thyroglobulin is diagnostic. Management Definitive treatment of thyrotoxicosis depends on the underlying cause and may include antithyroid drugs, radioactive iodine or surgery. A non-selective β-adrenoceptor antagonist (β-blocker), such as propranolol (160 mg daily) or nadolol (40–80 mg daily), will alleviate but not abolish symptoms in most patients within 24–48 hours. Beta-blockers should not be used for long-term (Box 18.9). An electrocardiogram (ECG) may demonstrate sinus tachycardia or atrial fibrillation. Radio-iodine uptake tests measure the proportion of isotope that is trapped in the whole gland but have been largely superseded by 99mtechnetium scintigraphy scans, which also indicate trapping, are quicker to perform with a lower dose of radioactivity, and provide a higher-resolution image. In low-uptake thyrotoxicosis, the cause is usually a transient thyroiditis (p. 646). Occasionally, patients induce ‘factitious thyrotoxicosis’ by consuming excessive amounts of a thyroid hormone preparation, most often levothyroxine. The exogenous levothyroxine suppresses pituitary TSH secretion and hence iodine uptake, serum thyroglobulin and release of endogenous thyroid hormones. The T4:T3 ratio (typically 30 : 1 in 18.7 Clinical features of thyroid dysfunction Thyrotoxicosis Hypothyroidism Symptoms Signs Symptoms Signs Common Weight loss despite normal or increased appetite Heat intolerance, sweating Palpitations, tremor Dyspnoea, fatigue Irritability, emotional lability Weight loss Tremor Palmar erythema Sinus tachycardia Lid retraction, lid lag Weight gain Cold intolerance Fatigue, somnolence Dry skin Dry hair Menorrhagia Weight gain Less common Osteoporosis (fracture, loss of height) Diarrhoea, steatorrhoea Angina Ankle swelling Anxiety, psychosis Muscle weakness Periodic paralysis (predominantly in Chinese and other Asian groups) Pruritus, alopecia Amenorrhoea/oligomenorrhoea Infertility, spontaneous abortion Loss of libido, impotence Excessive lacrimation Goitre with bruit1 Atrial fibrillation2 Systolic hypertension/increased pulse pressure Cardiac failure2 Hyper-reflexia Ill-sustained clonus Proximal myopathy Bulbar myopathy2 Constipation Hoarseness Carpal tunnel syndrome Alopecia Aches and pains Muscle stiffness Deafness Depression Infertility Hoarse voice Facial features: Purplish lips Malar flush Periorbital oedema Loss of lateral eyebrows Anaemia Carotenaemia Erythema ab igne Bradycardia hypertension Delayed relaxation of reflexes Dermal myxoedema Rare Vomiting Apathy Anorexia Exacerbation of asthma Gynaecomastia Spider naevi Onycholysis Pigmentation Psychosis (myxoedema madness) Galactorrhoea Impotence Ileus, ascites Pericardial and pleural effusions Cerebellar ataxia Myotonia 1ln Graves’ disease only. 2Features found particularly in elderly patients. 18.8 Prevalence of thyroid autoantibodies (%) Antibodies to: Thyroid peroxidase1 Thyroglobulin TSH receptor2 Normal population 8–27 5–20

Graves’ disease 50–80 50–70 80–95 Autoimmune hypothyroidism 90–100 80–90 10–20 Multinodular goitre ~30–40 ~30–40

Transient thyroiditis ~30–40 ~30–40

1Thyroid peroxidase (TPO) antibodies are the principal component of what was previously measured as thyroid ‘microsomal’ antibodies. 2Thyroid-stimulating hormone receptor antibodies (TRAb) can be agonists (stimulatory, causing Graves’ thyrotoxicosis) or antagonists (‘blocking’, causing hypothyroidism).

638 • ENDOCRINOLOGY Fig. 18.5 Establishing the differential diagnosis in thyrotoxicosis. 1Graves’ ophthalmopathy refers to clinical features of exophthalmos and periorbital and conjunctival oedema, not simply the lid lag and lid retraction that can occur in all forms of thyrotoxicosis. 2Thyroid-stimulating hormone (TSH) receptor antibodies are very rare in patients without autoimmune thyroid disease but occur in only 80–95% of patients with Graves’ disease; a positive test is therefore confirmatory but a negative test does not exclude Graves’ disease. Other thyroid antibodies (e.g. anti-peroxidase and anti-thyroglobulin antibodies) are unhelpful in the differential diagnosis since they occur frequently in the population and are found with several of the disorders that cause thyrotoxicosis. 3Scintigraphy is not necessary in most cases of drug-induced thyrotoxicosis. 4 99mTechnetium pertechnetate scans of patients with thyrotoxicosis. In low-uptake thyrotoxicosis, most commonly due to a viral, post-partum or iodine-induced thyroiditis, there is negligible isotope detected in the region of the thyroid, although uptake is apparent in nearby salivary glands (not shown here). In a toxic adenoma there is lack of uptake of isotope by the rest of the thyroid gland due to suppression of serum TSH. In multinodular goitre there is relatively low, patchy uptake within the nodules; such an appearance is not always associated with a palpable thyroid. In Graves’ disease there is diffuse uptake of isotope. ↓TSH and ↑T3 ± T4 Scenario? Clinically thyrotoxic Repeat when acute illness has resolved Possible non-thyroidal illness Any features of non-Graves’ thyrotoxicosis? • Recent (< 6 months) pregnancy • Neck pain/flu-like illness • Drugs (amiodarone, T4)3 • Palpable multinodular goitre or solitary nodule Any features of Graves’ disease? • Diffuse goitre with bruit • Ophthalmopathy1 • Pretibial myxoedema • Positive TSH receptor antibodies2 Yes No Yes Thyroid scintigraphy4 Low-uptake thyrotoxicosis • Transient thyroiditis • Extrathyroidal T4 source Toxic multinodular goitre Graves’ disease Toxic adenoma No These abnormalities are not useful in differential diagnosis, so the tests should be avoided and any further investigation undertaken only if abnormalities persist when the patient is euthyroid. 18.9 Non-specific laboratory abnormalities in thyroid dysfunction Thyrotoxicosis • Serum enzymes: raised alanine aminotransferase, γ-glutamyl transferase (GGT), and alkaline phosphatase from liver and bone • Raised bilirubin • Mild hypercalcaemia • Glycosuria: associated diabetes mellitus, ‘lag storage’ glycosuria Hypothyroidism • Serum enzymes: raised creatine kinase, aspartate aminotransferase, lactate dehydrogenase (LDH) • Hypercholesterolaemia • Anaemia: normochromic normocytic or macrocytic • Hyponatraemia treatment of thyrotoxicosis but are extremely useful in the short term, while patients are awaiting hospital consultation or following 131I therapy. Verapamil may be used as an alternative to β-blockers, e.g. in patients with asthma, but usually is only effective in improving tachycardia and has little effect on the other systemic manifestations of thyrotoxicosis. Atrial fibrillation in thyrotoxicosis Atrial fibrillation occurs in about 10% of patients with thyrotoxicosis. The incidence increases with age, so that almost half of all males with thyrotoxicosis over the age of 60 are affected. Moreover, subclinical thyrotoxicosis (p. 642) is a risk factor for atrial fibrillation. Characteristically, the ventricular rate is little influenced by digoxin but responds to the addition of a β-blocker. Thromboembolic vascular complications are particularly common in thyrotoxic atrial fibrillation so that anticoagulation is required, unless contraindicated. Once thyroid hormone and TSH concentrations have been returned to normal, atrial fibrillation will spontaneously revert to sinus rhythm in about 50% of patients but cardioversion may be required in the remainder.

The thyroid gland • 639

hormones but also reduces the conversion of T4 to T3, and is therefore more effective than potassium iodide or Lugol’s solution. Dexamethasone (2 mg 4 times daily) and amiodarone have similar effects. Oral carbimazole 40–60 mg daily (p. 644) should be given to inhibit the synthesis of new thyroid hormone. If the patient is unconscious or uncooperative, carbimazole can be administered rectally with good effect but no preparation is available for parenteral use. After 10–14 days the patient can usually be maintained on carbimazole alone. Hypothyroidism Hypothyroidism is a common condition with various causes (Box 18.11), but autoimmune disease (Hashimoto’s thyroiditis) and thyroid failure following 131I or surgical treatment of thyrotoxicosis account for over 90% of cases, except in areas where iodine deficiency is endemic. Women are affected approximately six times more frequently than men. Clinical assessment The clinical presentation depends on the duration and severity of the hypothyroidism. Those in whom complete thyroid failure has developed insidiously over months or years may present with many of the clinical features listed in Box 18.7. A consequence of prolonged hypothyroidism is the infiltration of many body tissues by the mucopolysaccharides hyaluronic acid and chondroitin Thyrotoxic crisis (‘thyroid storm’) This is a rare but life-threatening complication of thyrotoxicosis. The most prominent signs are fever, agitation, delirium, tachycardia or atrial fibrillation and, in the older patient, cardiac failure. The Burch–Wartofsky system may be used to help establish the diagnosis (Box 18.10). Thyrotoxic crisis is a medical emergency and has a mortality of 10% despite early recognition and treatment. It is most commonly precipitated by infection in a patient with previously unrecognised or inadequately treated thyrotoxicosis. It may also develop in known thyrotoxicosis shortly after thyroidectomy in an ill-prepared patient or within a few days of 131I therapy, when acute radiation damage may lead to a transient rise in serum thyroid hormone levels. Patients should be rehydrated and given propranolol, either orally (80 mg 4 times daily) or intravenously (1–5 mg 4 times daily). Sodium ipodate (500 mg per day orally) will restore serum T3 levels to normal in 48–72 hours. This is a radiographic contrast medium that not only inhibits the release of thyroid 18.10 The Burch–Wartofsky scoring system for thyrotoxic crisis Diagnostic parameters Score Temperature (°C) ≤ 37.1

37.2–37.7

37.8–38.2

38.3–38.8

38.9–39.2

39.3–39.9

≥ 40.0

Central nervous system Absent

Mild (agitation)

Moderate (delirium, psychosis, extreme lethargy)

Severe (seizures, coma)

Gastrointestinal system Absent

Moderate (diarrhoea, nausea, vomiting, abdominal pain)

Severe (unexplained jaundice)

Cardiovascular system: pulse rate (beats/min) ≤ 89

90–109

110–119

120–129

130–139

≥ 140

Atrial fibrillation Absent

Present

Congestive heart failure Absent

Mild (peripheral oedema)

Moderate (bi-basal crepitations)

Severe (pulmonary oedema)

Precipitant history Absent

Present

Scores should be totalled. Score ≥ 45 = likely thyrotoxic crisis; 25–44 = impending thyrotoxic crisis; < 25 = unlikely to represent thyroid crisis. Adapted from Burch HB, Wartofsky L. Life-threatening thyrotoxicosis. Thyroid storm. Endocrinol Metab Clin N Am 1993; 22:263–277. 18.11 Causes of hypothyroidism Causes Anti-TPO antibodies1 Goitre2 Autoimmune Hashimoto’s thyroiditis ++ ± Spontaneous atrophic hypothyroidism – – Graves’ disease with TSH receptorblocking antibodies + ± Iatrogenic Radioactive iodine ablation + ± Thyroidectomy + – Drugs: Carbimazole, methimazole, propylthiouracil + ± Amiodarone + ± Lithium – ± Transient thyroiditis Subacute (de Quervain’s) thyroiditis + ± Post-partum thyroiditis + ± Iodine deficiency e.g. In mountainous regions – ++ Congenital Dyshormonogenesis – ++ Thyroid aplasia – – Infiltrative Amyloidosis, Riedel’s thyroiditis, sarcoidosis etc. + ++ Secondary hypothyroidism TSH deficiency – – 1As shown in Box 18.8, thyroid autoantibodies are common in the healthy population, so might be present in anyone. ++ high titre; + more likely to be detected than in the healthy population; – not especially likely. 2Goitre: – absent; ± may be present; ++ characteristic. (TPO = thyroid peroxidase; TSH = thyroid-stimulating hormone)

640 • ENDOCRINOLOGY by failure of TSH secretion in an individual with hypothalamic or anterior pituitary disease. Other non-specific abnormalities are shown in Box 18.9. In severe, prolonged hypothyroidism, the ECG classically demonstrates sinus bradycardia with lowvoltage complexes and ST-segment and T-wave abnormalities. Measurement of thyroid peroxidase antibodies is helpful but further investigations are rarely required (Fig. 18.6). Management Treatment is with levothyroxine replacement. It is customary to start with a low dose of 50 μg per day for 3 weeks, increasing thereafter to 100 μg per day for a further 3 weeks and finally to a maintenance dose of 100–150 μg per day. In younger patients, it is safe to initiate levothyroxine at a higher dose (e.g. 100 μg per day), to allow a more rapid normalisation of thyroid hormone levels. Levothyroxine has a half-life of 7 days so it should always be taken as a single daily dose and at least 6 weeks should pass before repeating thyroid function tests (as TSH takes several weeks to reach a steady state) and adjusting the dose. Patients feel better within 2–3 weeks. Reduction in weight and periorbital puffiness occurs quickly but the restoration of skin and hair texture and resolution of any effusions may take 3–6 months. As illustrated in Figure 18.6, most patients do not require specialist review but will need life-long levothyroxine therapy. The dose of levothyroxine should be adjusted to maintain serum TSH within the reference range. To achieve this, serum T4 often needs to be in the upper part of the reference range because the T3 required for receptor activation is derived exclusively from conversion of T4 within the target tissues, without the usual contribution from thyroid secretion. Some physicians advocate Fig. 18.6 An approach to adults with suspected primary hypothyroidism. This scheme ignores congenital causes of hypothyroidism (see Box 18.11), such as thyroid aplasia and dyshormonogenesis (associated with nerve deafness in Pendred’s syndrome, p. 650), which are usually diagnosed in childhood. 1Immunoreactive thyroid-stimulating hormone (TSH) may be detected at normal or even modestly elevated levels in patients with pituitary failure; unless T4 is only marginally low, TSH should be > 20 mIU/L to confirm the diagnosis of primary hypothyroidism. 2The usual abnormality in sick euthyroidism is a low TSH but any pattern can occur. 3Thyroid peroxidase (TPO) antibodies are highly sensitive but not very specific for autoimmune thyroid disease (see Boxes 18.8 and 18.11). 4Specialist advice is most appropriate where indicated. Secondary hypothyroidism is rare, but is suggested by deficiency of pituitary hormones or by clinical features of pituitary tumour such as headache or visual field defect (p. 683). Rare causes of hypothyroidism with goitre include dyshormonogenesis and infiltration of the thyroid (see Box 18.11). ↑TSH and ↓T4 Scenario? TSH < 20 mlU/L1 Repeat when acute illness has resolved Possible non-thyroidal illness2 Relevant drugs? • Amiodarone • Lithium Any features of transient thyroiditis? • Neck pain • < 12 months post-partum • Recent symptoms of thyrotoxicosis • < 6 months since 131I or thyroidectomy No Yes Permanent T4 replacement Any features of secondary hypothyroidism? 4 Thyroid ablation? • > 6 months since 131I or thyroidectomy No Positive antithyroid peroxidase antibodies?3 No No TSH > 20 mlU/L Consider rare causes and refer to specialist4 Spontaneous atrophic hypothyroidism Hashimoto’s thyroiditis Temporary T4 replacement4 • After 4 months with normal TSH, reduce to 50 μg/day for 6 weeks and repeat TSH • If normal, stop T4 for 6 weeks and repeat Yes T4 replacement for as long as other drug is required Yes Yes No Yes No Goitre? sulphate, resulting in a low-pitched voice, poor hearing, slurred speech due to a large tongue, and compression of the median nerve at the wrist (carpal tunnel syndrome). Infiltration of the dermis gives rise to non-pitting oedema (myxoedema), which is most marked in the skin of the hands, feet and eyelids. The resultant periorbital puffiness is often striking and may be combined with facial pallor due to vasoconstriction and anaemia, or a lemon-yellow tint to the skin caused by carotenaemia, along with purplish lips and malar flush. Most cases of hypothyroidism are not clinically obvious, however, and a high index of suspicion needs to be maintained so that the diagnosis is not overlooked in individuals complaining of non-specific symptoms such as tiredness, weight gain, depression or carpal tunnel syndrome. The key discriminatory features in the history and examination are highlighted in Figure 18.6. Care must be taken to identify patients with transient hypothyroidism, in whom life-long levothyroxine therapy is inappropriate. This is often observed during the first 6 months after thyroidectomy or 131I treatment of Graves’ disease, in the post-thyrotoxic phase of subacute thyroiditis and in post-partum thyroiditis. In these conditions, levothyroxine treatment is not always necessary, as the patient may be asymptomatic during the short period of thyroid failure. Investigations In the vast majority of cases, hypothyroidism results from an intrinsic disorder of the thyroid gland (primary hypothyroidism). In this situation, serum T4 is low and TSH is elevated, usually in excess of 20 mIU/L. Measurements of serum T3 are unhelpful since they do not discriminate reliably between euthyroidism and hypothyroidism. Secondary hypothyroidism is rare and is caused

The thyroid gland • 641

replacement should be introduced at low dose and increased very slowly under specialist supervision. It has been suggested that T3 has an advantage over T4, since T3 has a shorter half-life and any adverse effect will reverse more quickly, but the more distinct peak in hormone levels after each dose of T3 is a disadvantage. Coronary intervention may be required if angina is exacerbated by levothyroxine replacement therapy. Hypothyroidism in pregnancy Women with hypothyroidism usually require an increased dose of levothyroxine in pregnancy; inadequately treated hypothyroidism in pregnancy has been associated with impaired cognitive development in the fetus. This is discussed in more detail on page 1279 (see also Box 18.18). Myxoedema coma This is a very rare presentation of hypothyroidism in which there is a depressed level of consciousness, usually in an elderly patient who appears myxoedematous. Body temperature may be as low as 25°C, convulsions are not uncommon, and cerebrospinal fluid (CSF) pressure and protein content are raised. The mortality rate is 50% and survival depends on early recognition and treatment of hypothyroidism and other factors contributing to the altered consciousness level, such as medication, cardiac failure, pneumonia, dilutional hyponatraemia and respiratory failure. Myxoedema coma is a medical emergency and treatment must begin before biochemical confirmation of the diagnosis. Suspected cases should be treated with an intravenous injection of 20 μg liothyronine, followed by further injections of 20 μg 3 times daily until there is sustained clinical improvement. In survivors, there is a rise in body temperature within 24 hours and, after 48–72 hours, it is usually possible to switch patients to oral levothyroxine in a dose of 50 μg daily. Unless it is apparent that the patient has primary hypothyroidism, the thyroid failure should also be assumed to be secondary to hypothalamic or pituitary disease and treatment given with hydrocortisone 100 mg IM 3 times daily, pending the results of T4, TSH and cortisol measurement (p. 680). Other measures include slow rewarming (p. 166), cautious use of intravenous fluids, broad-spectrum antibiotics and high-flow oxygen. Symptoms of hypothyroidism with normal thyroid function tests The classic symptoms of hypothyroidism are, by their very nature, non-specific (see Box 18.3). There is a wide differential diagnosis for symptoms such as ‘fatigue’, ‘weight gain’ and ‘low mood’. As has been noted, outside the context of pituitary and hypothalamic disease, serum TSH is an excellent measure of an individual’s thyroid hormone status. However, some individuals believe that they have hypothyroidism despite normal serum TSH concentrations. There are a large number of websites that claim that serum TSH is not a good measure of thyroid hormone status and suggest that other factors, such as abnormalities of T4 to T3 conversion, may lead to low tissue levels of active thyroid hormones. Such websites often advocate a variety of tests of thyroid function of dubious scientific validity, including measurement of serum reverse T3, 24-hour urine T3, basal body temperature, skin iodine absorption, and levels of selenium in blood and urine. Individuals who believe they have hypothyroidism, despite normal conventional tests of thyroid function, can be difficult to manage. They require reassurance that their symptoms are being taken seriously and that organic disease has been carefully considered; if their symptoms persist, referral to a combined replacement with T4 (levothyroxine) and T3 (liothyronine) or preparations of animal thyroid extract but this approach remains controversial and is not supported by robust evidence. Some patients remain symptomatic despite normalisation of TSH and may wish to take extra levothyroxine, which suppresses TSH. However, suppressed TSH is a risk factor for osteoporosis and atrial fibrillation (see below; subclinical thyrotoxicosis), so this approach cannot be recommended. It is important to measure thyroid function every 1–2 years once the dose of levothyroxine is stabilised. This encourages adherence to therapy and allows adjustment for variable underlying thyroid activity and other changes in levothyroxine requirements (Box 18.12). Some patients have a persistent elevation of serum TSH despite an ostensibly adequate replacement dose of levothyroxine; most commonly, this is a consequence of suboptimal adherence to therapy. There may be differences in bioavailability between the numerous generic preparations of levothyroxine and so, if an individual is experiencing marked changes in serum TSH despite optimal adherence, the prescription of a branded preparation of levothyroxine could be considered. There is some limited evidence that suggests levothyroxine absorption may be better when the drug is taken before bed and can be further optimised by adding a vitamin C supplement; such strategies may be considered in patients with malabsorption. In some poorly compliant patients, levothyroxine is taken diligently or even in excess for a few days prior to a clinic visit, resulting in the seemingly anomalous combination of a high serum T4 and high TSH (see Box 18.5). Levothyroxine replacement in ischaemic heart disease Hypothyroidism and ischaemic heart disease are common conditions that often occur together. Although angina may remain unchanged in severity or paradoxically disappear with restoration of metabolic rate, exacerbation of myocardial ischaemia, infarction and sudden death are recognised complications of levothyroxine replacement, even using doses as low as 25 μg per day. In patients with known ischaemic heart disease, thyroid hormone Mechanism not fully established. 18.12 Situations in which an adjustment of the dose of levothyroxine may be necessary Increased dose required Use of other medication • Increase T4 clearance: phenobarbital, phenytoin, carbamazepine, rifampicin, sertraline, chloroquine* • Interfere with intestinal T4 absorption: colestyramine, sucralfate, aluminium hydroxide, ferrous sulphate, dietary fibre supplements, calcium carbonate Pregnancy or oestrogen therapy • Increases concentration of serum thyroxine-binding globulin After surgical or 131I ablation of Graves’ disease • Reduces thyroidal secretion with time Malabsorption Decreased dose required Ageing • Decreases T4 clearance Graves’ disease developing in patient with long-standing primary hypothyroidism • Switch from production of blocking to stimulating TSH receptor antibodies

642 • ENDOCRINOLOGY team specialising in medically unexplained symptoms should be considered. Asymptomatic abnormal thyroid function tests One of the most common problems in medical practice is how to manage patients with abnormal thyroid function tests who have no obvious signs or symptoms of thyroid disease. These can be divided into three categories. Subclinical thyrotoxicosis Serum TSH is undetectable and serum T3 and T4 are at the upper end of the reference range. This combination is most often found in older patients with multinodular goitre. These patients are at increased risk of atrial fibrillation and osteoporosis, and hence the consensus view is that they have mild thyrotoxicosis and require therapy, usually with 131I. Otherwise, annual review is essential, as the conversion rate to overt thyrotoxicosis with elevated T4 and/or T3 concentrations is 5% each year. Subclinical hypothyroidism Serum TSH is raised and serum T3 and T4 concentrations are at the lower end of the reference range. This may persist for many years, although there is a risk of progression to overt thyroid failure, particularly if antibodies to thyroid peroxidase are present or if the TSH rises above 10 mIU/L. In patients with non-specific symptoms, a trial of levothyroxine therapy may be appropriate. In those with positive autoantibodies or a TSH greater than 10 mIU/L, it is better to treat the thyroid failure early rather than risk loss to follow-up and subsequent presentation with profound hypothyroidism. Levothyroxine should be given in a dose sufficient to restore the serum TSH concentration to normal. Non-thyroidal illness (‘sick euthyroidism’) This typically presents with a low serum TSH, raised T4 and normal or low T3 in a patient with systemic illness who does not have clinical evidence of thyroid disease. These abnormalities are caused by decreased peripheral conversion of T4 to T3 (with conversion instead to reverse T3), altered levels of binding proteins and their affinity for thyroid hormones, and often reduced secretion of TSH. During convalescence, serum TSH concentrations may increase to levels found in primary hypothyroidism. As thyroid function tests are difficult to interpret in patients with non-thyroidal illness, it is wise to avoid performing thyroid function tests unless there is clinical evidence of concomitant thyroid disease. If an abnormal result is found, treatment should only be given with specialist advice and the diagnosis should be re-evaluated after recovery. Thyroid lump or swelling A lump or swelling in the thyroid gland can be a source of considerable anxiety for patients. There are numerous causes but, broadly speaking, a thyroid swelling is either a solitary nodule, a multinodular goitre or a diffuse goitre (Box 18.13). Nodular thyroid disease is more common in women and occurs in approximately 30% of the adult female population. The majority of thyroid nodules are impalpable but may be identified when imaging of the neck is performed for another reason, such as during Doppler ultrasonography of the carotid arteries or computed tomographic pulmonary angiography. Increasingly, thyroid nodules are identified during staging of patients with cancer with computed tomography (CT), magnetic resonance 18.13 Causes of thyroid enlargement Diffuse goitre • Simple goitre • Hashimoto’s thyroiditis1 • Graves’ disease • Drugs: iodine, amiodarone, lithium • Iodine deficiency (endemic goitre)1 • Suppurative thyroiditis2 • Transient thyroiditis2 • Dyshormonogenesis1 • Infiltrative: amyloidosis, sarcoidosis etc. • Riedel’s thyroiditis2 Multinodular goitre Solitary nodule • Colloid cyst • Hyperplastic nodule • Follicular adenoma • Papillary carcinoma • Follicular carcinoma • Medullary cell carcinoma • Anaplastic carcinoma • Lymphoma • Metastasis 1Goitre likely to shrink with levothyroxine therapy. 2Usually tender. imaging (MRI) or positron emission tomography (PET) scans. Palpable thyroid nodules occur in 4–8% of adult women and 1–2% of adult men, and classically present when the individual (or a friend or relative) notices a lump in the neck. Multinodular goitre and solitary nodules sometimes present with acute painful enlargement due to haemorrhage into a nodule. Patients with thyroid nodules often worry that they have cancer but the reality is that only 5–10% of thyroid nodules are malignant. A nodule presenting in childhood or adolescence, particularly if there is a past history of head and neck irradiation, or one presenting in an elderly patient should heighten suspicion of a primary thyroid malignancy (p. 649). The presence of cervical lymphadenopathy also increases the likelihood of malignancy. Rarely, a secondary deposit from a renal, breast or lung carcinoma presents as a painful, rapidly growing, solitary thyroid nodule. Thyroid nodules identified on PET scanning have an approximately 33% chance of being malignant. Clinical assessment and investigations Swellings in the anterior part of the neck most commonly originate in the thyroid and this can be confirmed by demonstrating that the swelling moves on swallowing (p. 631). It is often possible to distinguish clinically between the three main causes of thyroid swelling. There is a broad differential diagnosis of anterior neck swellings, which includes lymphadenopathy, branchial cysts, dermoid cysts and thyroglossal duct cysts (the latter are classically located in the midline and move on protrusion of the tongue). An ultrasound scan should be performed urgently, if there is any doubt as to the aetiology of an anterior neck swelling. Serum T3, T4 and TSH should be measured in all patients with a goitre or solitary thyroid nodule. The finding of biochemical thyrotoxicosis or hypothyroidism (both of which may be subclinical) should lead to investigations, as already described on pages 636 and 640. Thyroid scintigraphy Thyroid scintigraphy with 99mtechnetium should be performed in an individual with a low serum TSH and a nodular thyroid to confirm the presence of an autonomously functioning (‘hot’) nodule (see Fig. 18.5). In such circumstances, further evaluation is not necessary. ‘Cold’ nodules on scintigraphy have a much higher likelihood of malignancy, but the majority are benign and so scintigraphy is not routinely used in the evaluation of thyroid nodules when TSH is normal.

The thyroid gland • 643

Autoimmune thyroid disease Thyroid diseases are amongst the most prevalent antibodymediated autoimmune diseases and are associated with other organ-specific autoimmunity (Ch. 4 and p. 689). Autoantibodies may produce inflammation and destruction of thyroid tissue, resulting in hypothyroidism, goitre (in Hashimoto’s thyroiditis) or sometimes even transient thyrotoxicosis (‘Hashitoxicosis’), or they may stimulate the TSH receptor to cause thyrotoxicosis (in Graves’ disease). There is overlap between these conditions, since some patients have multiple autoantibodies. Graves’ disease Graves’ disease can occur at any age but is unusual before puberty and most commonly affects women aged 30–50 years. The most common manifestation is thyrotoxicosis with or without a diffuse goitre. The clinical features and differential diagnosis are described on page 635. Graves’ disease also causes ophthalmopathy and, rarely, pretibial myxoedema (p. 646). These extrathyroidal features usually occur in thyrotoxic patients but can arise in the absence of thyroid dysfunction. Graves’ thyrotoxicosis Pathophysiology The thyrotoxicosis results from the production of immunoglobulin G (IgG) antibodies directed against the TSH receptor on the thyroid follicular cell, which stimulate thyroid hormone production and proliferation of follicular cells, leading to goitre in the majority of patients. These antibodies are termed thyroid-stimulating immunoglobulins or TSH receptor antibodies (TRAb) and can be detected in the serum of 80–95% of patients with Graves’ disease. The concentration of TRAb in the serum is presumed to fluctuate to account for the natural history of Graves’ thyrotoxicosis (Fig. 18.7). Thyroid failure seen in some patients may result from the presence of blocking antibodies against the TSH receptor, and from tissue destruction by cytotoxic antibodies and cell-mediated immunity. Thyroid ultrasound If thyroid function tests are normal, an ultrasound scan will often determine the nature of the thyroid swelling. Ultrasound can establish whether there is generalised or localised swelling of the thyroid. Inflammatory disorders causing a diffuse goitre, such as Graves’ disease and Hashimoto’s thyroiditis, demonstrate a diffuse pattern of hypoechogenicity and, in the case of Graves’ disease, increased thyroid blood flow may be seen on colour-flow Doppler. The presence of thyroid autoantibodies will support the diagnosis of Graves’ disease or Hashimoto’s thyroiditis, while their absence in a younger patient with a diffuse goitre and normal thyroid function suggests a diagnosis of ‘simple goitre’ (p. 648). Ultrasound can readily determine the size and number of nodules within the thyroid and can distinguish solid nodules from those with a cystic element. Ultrasound is used increasingly as the key investigation in defining the risk of malignancy in a nodule. Size of the nodule is not a predictor of the risk of malignancy but there are other ultrasound characteristics that are associated with a higher likelihood of malignancy. These include hypoechoicity, intranodular vascularity, the presence of microcalcification and irregular or lobulated margins. A purely cystic nodule is highly unlikely to be malignant and a ‘spongiform’ appearance is also highly predictive of a benign aetiology. Individual nodules within a multinodular goitre have the same risk of malignancy as a solitary nodule. Thyroid ultrasonography is a highly specialised investigation and the accurate stratification of risk of malignancy of a thyroid nodule requires skill and expertise. Fine needle aspiration cytology Fine needle aspiration cytology is recommended for thyroid nodules that are suspicious for malignancy or are radiologically indeterminate. Fine needle aspiration of a thyroid nodule can be performed in the outpatient clinic, usually under ultrasound guidance. Aspiration may be therapeutic for a cyst, although recurrence on more than one occasion is an indication for surgery. Fine needle aspiration cytology cannot differentiate between a follicular adenoma and a follicular carcinoma, and in 10–20% of cases an inadequate specimen is obtained. Management Nodules with a benign appearance on ultrasound may be observed in an ultrasound surveillance programme; when the suspicion of malignancy is very low, the patient may be reassured and discharged. In parts of the world with borderline low iodine intake, there is evidence that levothyroxine therapy, in doses that suppress serum TSH, may reduce the size of some nodules. This should not be routine practice in iodine-sufficient populations. Nodules that are suspicious for malignancy are treated by surgical excision, by either lobectomy or thyroidectomy. Nodules that are radiologically and/or cytologically indeterminate are more of a management challenge and often end up being surgically excised. Molecular techniques may, in the future, improve the diagnostic accuracy of thyroid cytology and allow a more conservative strategy for individuals with an indeterminate biopsy. Nodules in which malignancy is confirmed by formal histology are treated as described on page 649. A diffuse or multinodular goitre may also require surgical treatment for cosmetic reasons or if there is compression of local structures (resulting in stridor or dysphagia). 131I therapy may also cause some reduction in size of a multinodular goitre. Levothyroxine therapy may shrink the goitre of Hashimoto’s disease, particularly if serum TSH is elevated. Fig. 18.7 Natural history of the thyrotoxicosis of Graves’ disease. A and B The majority (60%) of patients have either prolonged periods of thyrotoxicosis of fluctuating severity, or periods of alternating relapse and remission. C It is the minority who experience a single short-lived episode followed by prolonged remission and, in some cases, by the eventual onset of hypothyroidism. Time in years

Thyrotoxic Euthyroid Hypothyroid A B C

644 • ENDOCRINOLOGY UK). Propylthiouracil is equally effective. These drugs reduce the synthesis of new thyroid hormones by inhibiting the iodination of tyrosine (see Fig. 18.3). Carbimazole also has an immunosuppressive action, leading to a reduction in serum TRAb concentrations, but this is not enough to influence the natural history of the thyrotoxicosis significantly. Antithyroid drugs should be introduced at high doses (carbimazole 40–60 mg daily or propylthiouracil 400–600 mg daily). Usually, this results in subjective improvement within 10–14 days and renders the patient clinically and biochemically euthyroid at 6–8 weeks. At this point, the dose can be reduced and titrated to maintain T4 and TSH within their reference range. In most patients, carbimazole is continued at 5–20 mg per day for 12–18 months in the hope that remission will occur. Between 50% and 70% of patients with Graves’s disease will subsequently relapse, usually within 2 years of stopping treatment. Risk factors for relapse include younger age, male sex, presence of a goitre, and higher TRAb titres at both diagnosis and cessation of antithyroid therapy. Rarely, T4 and TSH levels fluctuate between those of thyrotoxicosis and hypothyroidism at successive review appointments, despite good drug adherence, presumably due to rapidly changing concentrations of TRAb. In these patients, satisfactory control can be achieved by blocking thyroid hormone synthesis with carbimazole 30–40 mg daily and adding levothyroxine 100–150 μg daily as replacement therapy (a ‘block and replace’ regime). Antithyroid drugs can have adverse effects. The most common is a rash. Agranulocytosis is a rare but potentially serious complication that cannot be predicted by routine measurement of white blood cell count but which is reversible on stopping treatment. Patients should be warned to stop the drug and seek medical advice immediately, should a severe sore throat or fever develop while on treatment. Propylthiouracil is associated with a small but definite risk of hepatotoxicity, which, in some instances, has resulted in liver failure requiring liver transplantation, and even in death. It should therefore be considered second-line therapy to carbimazole and be used only during pregnancy or breastfeeding (p. 1279), or if an adverse reaction to carbimazole has occurred. Graves’ disease has a strong genetic component. There is 50% concordance for thyrotoxicosis between monozygotic twins but only 5% concordance between dizygotic twins. Genomewide association studies have identified polymorphisms at the MHC, CTLA4, PTPN22, TSHR1 and FCRL3 loci as predisposing genetic variants. Many of these loci have been implicated in the pathogenesis of other autoimmune diseases. A suggested trigger for the development of thyrotoxicosis in genetically susceptible individuals may be infection with viruses or bacteria. Certain strains of the gut organisms Escherichia coli and Yersinia enterocolitica possess cell membrane TSH receptors and it has been suggested that antibodies to these microbial antigens may cross-react with the TSH receptors on the host thyroid follicular cell. In regions of iodine deficiency (p. 647), iodine supplementation can precipitate thyrotoxicosis, but only in those with pre-existing subclinical Graves’ disease. Smoking is weakly associated with Graves’ thyrotoxicosis but strongly linked with the development of ophthalmopathy. Management Symptoms of thyrotoxicosis respond to β-blockade (p. 637) but definitive treatment requires control of thyroid hormone secretion. The different options are compared in Box 18.14. Some clinicians adopt an empirical approach of prescribing a course of antithyroid drug therapy and then recommending 131I or surgery if relapse occurs. In many centres, however, 131I is used extensively as a first-line therapy, given the high risk of relapse following a course of antithyroid drugs. A number of observational studies have linked therapeutic 131I with increased incidence of some malignancies, particularly of the thyroid and gastrointestinal tract, but the results have been inconsistent; the association may be with Graves’ disease rather than its therapy, and the magnitude of the effect, if any, is small. Experience from the disaster at the Chernobyl nuclear power plant in 1986 suggests that younger people are more sensitive to radiation-induced thyroid cancer. Antithyroid drugs The most commonly used are carbimazole and its active metabolite, methimazole (not available in the 18.14 Comparison of treatments for the thyrotoxicosis of Graves’ disease Management Common indications Contraindications Disadvantages/complications Antithyroid drugs (carbimazole, propylthiouracil) First episode in patients < 40 years Breastfeeding (propylthiouracil suitable) Hypersensitivity rash 2% Agranulocytosis 0.2% Hepatotoxicity (with propylthiouracil) – very rare but potentially fatal

50% relapse rate usually within 2 years of stopping drug Subtotal thyroidectomy1 Large goitre Poor drug adherence, especially in young patients Recurrent thyrotoxicosis after course of antithyroid drugs in young patients Previous thyroid surgery Dependence on voice, e.g. opera singer, lecturer2 Hypothyroidism (~25%) Transient hypocalcaemia (10%) Permanent hypoparathyroidism (1%) Recurrent laryngeal nerve palsy2 (1%) Radio-iodine Patients > 40 years3 Recurrence following surgery irrespective of age Other serious comorbidity Pregnancy or planned pregnancy within 6 months of treatment Active Graves’ ophthalmopathy4 Hypothyroidism: ~40% in first year, 80% after 15 years Most likely treatment to result in exacerbation of ophthalmopathy4 1A near-total thyroidectomy is now the favoured operation for Graves’ thyrotoxicosis in many institutions and is associated with a higher risk of some complications, including hypothyroidism (nearly 100%), but a reduced risk of persistent or recurrent thyrotoxicosis. 2lt is not only vocal cord palsy due to recurrent laryngeal nerve damage that alters the voice following thyroid surgery; the superior laryngeal nerves are frequently transected and this results in minor changes in voice quality. 3ln many institutions, 131I is used more liberally and is prescribed for much younger patients. 4The extent to which radio-iodine exacerbates ophthalmopathy is controversial and practice varies; some use prednisolone to reduce this risk.

The thyroid gland • 645

18.15 Thyrotoxicosis in adolescence • Presentation: may present with a deterioration in school performance or symptoms suggestive of attention deficit hyperactivity disorder. • Antithyroid drug therapy: prolonged courses may be required because remission rates following an 18-month course of therapy are much lower than in adults. • Adherence: adherence to antithyroid drug therapy is often suboptimal, resulting in poor disease control that may adversely affect performance at school. • Radio-iodine therapy: usually avoided in adolescents because of concerns about risk of future malignancy. Ophthalmopathy, like thyrotoxicosis (see Fig. 18.7), typically follows an episodic course and it is helpful to distinguish patients with active inflammation (periorbital oedema and conjunctival inflammation with changing orbital signs) from those in whom the inflammation has ‘burnt out’. Eye disease is detectable in up to 50% of thyrotoxic patients at presentation, but active ocular inflammation may occur before or after thyrotoxic episodes (exophthalmic Graves’ disease). It is more common in cigarette smokers and is exacerbated by poor control of thyroid function, especially hypothyroidism. The most frequent presenting symptoms are related to increased exposure of the cornea, resulting from proptosis and lid retraction. There may be excessive lacrimation made worse by wind and bright light, a ‘gritty’ sensation in the eye, and pain due to conjunctivitis or corneal ulceration. In addition, there may be reduction of Thyroid surgery Patients should be rendered euthyroid with antithyroid drugs before operation. Oral potassium iodide, 60 mg three times daily, is often added for 10 days before surgery to inhibit thyroid hormone release and reduce the size and vascularity of the gland, making surgery technically easier. Traditionally, a ‘subtotal’ thyroidectomy is performed, in which a portion of one lobe of the thyroid is left in situ, with the aim of rendering the patient euthyroid. While complications of surgery are rare and 80% of patients are euthyroid, 15% are permanently hypothyroid and 5% remain thyrotoxic. As a consequence, many endocrine surgeons now opt to perform a ‘near-total’ thyroidectomy, leaving behind only a small portion of gland adjacent to the recurrent laryngeal nerves. This strategy invariably results in permanent hypothyroidism and is probably associated with a higher risk of hypoparathyroidism, but maximises the potential for cure of thyrotoxicosis. Radioactive iodine 131I is administered orally as a single dose and is trapped and organified in the thyroid (see Fig. 18.3). 131I emits both β and γ radiation and, although it decays within a few weeks, it has long-lasting inhibitory effects on survival and replication of follicular cells. The variable radio-iodine uptake and radiosensitivity of the gland means that the choice of dose is empirical; in most centres, approximately 400–600 MBq (approximately 10–15 mCi) is administered. This regimen is effective in 75% of patients within 4–12 weeks. During the lag period, symptoms can be controlled by a β-blocker or, in more severe cases, by carbimazole. However, carbimazole reduces the efficacy of 131I therapy because it prevents organification of 131I in the gland, and so should be avoided until 48 hours after radio-iodine administration. If thyrotoxicosis persists after 6 months, a further dose of 131I can be given. The disadvantage of 131I treatment is that the majority of patients eventually develop hypothyroidism. 131I is usually avoided in patients with Graves’ ophthalmopathy and evidence of significant active orbital inflammation. It can be administered with caution in those with mild or ‘burnt-out’ eye disease, when it is customary to cover the treatment with a 6-week tapering course of oral prednisolone. In women of reproductive age, pregnancy must be excluded before administration of 131I and avoided for 6 months thereafter; men are also advised against fathering children for 6 months after receiving 131I. Thyrotoxicosis in pregnancy Thyrotoxicosis in pregnancy may be associated with significant maternal and fetal morbidity. Management is very specialised and is discussed on page 1279 (see also Box 18.18). Thyrotoxicosis in adolescence Thyrotoxicosis can occasionally occur in adolescence and is almost always due to Graves’ disease. The presentation may be atypical and management challenging, as summarised in Box 18.15. Graves’ ophthalmopathy This condition is immunologically mediated but the autoantigen has not been identified. Within the orbit (and the dermis) there is cytokine-mediated proliferation of fibroblasts that secrete hydrophilic glycosaminoglycans. The resulting increase in interstitial fluid content, combined with a chronic inflammatory cell infiltrate, causes marked swelling and ultimately fibrosis of the extraocular muscles (Fig. 18.8) and a rise in retrobulbar pressure. The eye is displaced forwards (proptosis, exophthalmos, p. 631) and in severe cases there is optic nerve compression. Fig. 18.8 Graves’ disease. A Bilateral ophthalmopathy in a 42-year-old man. The main symptoms were diplopia in all directions of gaze and reduced visual acuity in the left eye. The periorbital swelling is due to retrobulbar fat prolapsing into the eyelids, and increased interstitial fluid as a result of raised intraorbital pressure. B Transverse CT of the orbits, showing the enlarged extraocular muscles. This is most obvious at the apex of the left orbit (arrow), where compression of the optic nerve caused reduced visual acuity. A B

646 • ENDOCRINOLOGY In this context, the dose of levothyroxine should be sufficient to suppress serum TSH to low but detectable levels. Transient thyroiditis Subacute (de Quervain’s) thyroiditis In its classical painful form, subacute thyroiditis is a transient inflammation of the thyroid gland occurring after infection with Coxsackie, mumps or adenoviruses. There is pain in the region of the thyroid that may radiate to the angle of the jaw and the ears, and is made worse by swallowing, coughing and movement of the neck. The thyroid is usually palpably enlarged and tender. Systemic upset is common. Affected patients are usually females aged 20–40 years. Painless transient thyroiditis can also occur after viral infection and in patients with underlying autoimmune disease. The condition can also be precipitated by drugs, including interferon-α and lithium. Irrespective of the clinical presentation, inflammation in the thyroid gland occurs and is associated with release of colloid and stored thyroid hormones, but also with damage to follicular cells and impaired synthesis of new thyroid hormones. As a result, T4 and T3 levels are raised for 4–6 weeks until the pre-formed colloid is depleted. Thereafter, there is usually a period of hypothyroidism of variable severity before the follicular cells recover and normal thyroid function is restored within 4–6 months (Fig. 18.9). In the thyrotoxic phase, the iodine uptake is low because the damaged follicular cells are unable to trap iodine and because TSH secretion is suppressed. Low-titre thyroid autoantibodies appear transiently in the serum, and the erythrocyte sedimentation rate (ESR) is usually raised. High-titre autoantibodies suggest an underlying autoimmune pathology and greater risk of recurrence and ultimate progression to hypothyroidism. The pain and systemic upset usually respond to simple measures such as non-steroidal anti-inflammatory drugs (NSAIDs). Occasionally, however, it may be necessary to prescribe prednisolone 40 mg daily for 3–4 weeks. The thyrotoxicosis is mild and treatment with a β-blocker is usually adequate. Antithyroid drugs are of no benefit because thyroid hormone synthesis is impaired rather than enhanced. Careful monitoring of thyroid function and symptoms is required so that levothyroxine can be prescribed temporarily in the hypothyroid phase. Care must be taken to identify patients presenting with hypothyroidism who visual acuity and/or visual fields as a consequence of corneal oedema or optic nerve compression. Other signs of optic nerve compression include reduced colour vision and a relative afferent pupillary defect (pp. 631 and 1088). If the extraocular muscles are involved and do not act in concert, diplopia results. The majority of patients require no treatment other than reassurance. Smoking cessation should be actively encouraged. Methylcellulose eye drops and gel counter the gritty discomfort of dry eyes, and tinted glasses or side shields attached to spectacle frames reduce the excessive lacrimation triggered by sun or wind. In patients with mild Graves’ ophthalmopathy, oral selenium (100 μg twice daily for 6 months) improves quality of life, reduces ocular involvement and slows progression of disease; the mechanism of action is not known but may relate to an antioxidant effect. More severe inflammatory episodes are treated with glucocorticoids (e.g. pulsed intravenous methylprednisolone) and sometimes orbital radiotherapy. There is also an increasing trend to use alternative immunosuppressive therapies, such as rituximab and ciclosporin. Loss of visual acuity is an indication for urgent surgical decompression of the orbit. In ‘burnt-out’ disease, surgery to the extraocular muscles, and later the eyelids, may improve diplopia, conjunctival exposure and cosmetic appearance. Pretibial myxoedema This infiltrative dermopathy occurs in fewer than 5% of patients with Graves’ disease and has similar pathological features as occur in the orbit. It takes the form of raised pink-coloured or purplish plaques on the anterior aspect of the leg, extending on to the dorsum of the foot (p. 630). The lesions may be itchy and the skin may have a ‘peau d’orange’ appearance with growth of coarse hair; less commonly, the face and arms are affected. Treatment is rarely required but in severe cases topical glucocorticoids may be helpful. Hashimoto’s thyroiditis Hashimoto’s thyroiditis is characterised by destructive lymphoid infiltration of the thyroid, ultimately leading to a varying degree of fibrosis and thyroid enlargement. There is an increased risk of thyroid lymphoma (p. 650), although this is exceedingly rare. The nomenclature of autoimmune hypothyroidism is confusing. Some authorities reserve the term ‘Hashimoto’s thyroiditis’ for the condition of patients with positive antithyroid peroxidase autoantibodies and a firm goitre who may or may not be hypothyroid, and use the term ‘spontaneous atrophic hypothyroidism’ for the condition of hypothyroid patients without a goitre in whom TSH receptor-blocking antibodies may be more important than antithyroid peroxidase antibodies. However, these syndromes can both be considered as variants of the same underlying disease process. Hashimoto’s thyroiditis increases in incidence with age and affects approximately 3.5 per 1000 women and 0.8 per 1000 men each year. Many present with a small or moderately sized diffuse goitre, which is characteristically firm or rubbery in consistency. Around 25% of patients are hypothyroid at presentation. In the remainder, serum T4 is normal and TSH normal or raised, but these patients are at risk of developing overt hypothyroidism in future years. Antithyroid peroxidase antibodies are present in the serum in more than 90% of patients with Hashimoto’s thyroiditis. In those under the age of 20 years, antinuclear factor (ANF) may also be positive. Levothyroxine therapy is indicated as treatment for hypothyroidism (p. 640) and also to shrink an associated goitre. Fig. 18.9 Thyroid function tests in an episode of transient thyroiditis. This pattern might be observed in classical subacute (de Quervain’s) thyroiditis, painless thyroiditis or post-partum thyroiditis. The duration of each phase varies between patients. Thyrotoxic Hypothyroid Euthyroid Reference range

Months T4, T3 TSH

The thyroid gland • 647

schemes to administer oral or intramuscular iodised oil to at-risk populations and the addition of iodine to wells supplying water to local communities. These schemes have been extremely effective in reducing the prevalence of iodine deficiency, but lower consumption of table salt has actually led to an increase in iodine deficiency in some developed countries like Australia and New Zealand. Iodine-induced thyroid dysfunction Iodine has complex effects on thyroid function. Very high concentrations of iodine inhibit thyroid hormone synthesis and release (known as the Wolff–Chaikoff effect) and this forms the rationale for iodine treatment in thyroid crisis (p. 637) and prior to thyroid surgery for thyrotoxicosis (p. 645). This is an autoregulatory response to protect the body from the sudden release of large amounts of thyroid hormone in response to the ingestion of a substantial load of iodine. This effect only lasts for about 10 days, after which it is followed by an ‘escape phenomenon’: essentially, the return to normal organification of iodine and thyroid peroxidase action (see Fig. 18.3). Therefore, if iodine is given to prepare an individual with Graves’ disease for surgery, the operation must happen within 10–14 days; otherwise, a significant relapse of the thyrotoxicosis could occur. Iodine deficiency and underlying thyroid disease can both moderate the effects of iodine on thyroid function. In iodinedeficient parts of the world, transient thyrotoxicosis may be precipitated by prophylactic iodinisation programmes. In iodine-sufficient areas, thyrotoxicosis can be precipitated by iodine-containing radiographic contrast medium or expectorants in individuals who have underlying thyroid disease predisposing to thyrotoxicosis, such as multinodular goitre or Graves’ disease in remission. Induction of thyrotoxicosis by iodine is called the Jod–Basedow effect. Chronic excess iodine administration can also result in hypothyroidism; this is, in effect, a failure to escape from the Wolff–Chaikoff effect and usually occurs in the context of prior insult to the thyroid by, for example, autoimmune disease, thyroiditis, lithium, antithyroid drugs or surgery. Amiodarone The anti-arrhythmic agent amiodarone has a structure that is analogous to that of T4 (Fig. 18.10) and contains huge amounts of iodine; a 200 mg dose contains 75 mg iodine. Amiodarone also has a cytotoxic effect on thyroid follicular cells and inhibits conversion of T4 to T3 (increasing the ratio of T4:T3). Most patients receiving amiodarone have normal thyroid function but up to 20% develop hypothyroidism or thyrotoxicosis, and so thyroid function should be monitored regularly. TSH provides the best indicator of thyroid function. The thyrotoxicosis can be classified as either: • type I: iodine-induced excess thyroid hormone synthesis in patients with an underlying thyroid disorder, such as are in the later stages of a transient thyroiditis, since they are unlikely to require life-long levothyroxine therapy (see Fig. 18.6). Post-partum thyroiditis The maternal immune response, which is modified during pregnancy to allow survival of the fetus, is enhanced after delivery and may unmask previously unrecognised subclinical autoimmune thyroid disease. Surveys have shown that transient biochemical disturbances of thyroid function occur in 5–10% of women within 6 months of delivery (see Box 18.18). Those affected are likely to have antithyroid peroxidase antibodies in the serum in early pregnancy. Symptoms of thyroid dysfunction are rare and there is no association between postnatal depression and abnormal thyroid function tests. However, symptomatic thyrotoxicosis presenting for the first time within 12 months of childbirth is likely to be due to post-partum thyroiditis and the diagnosis is confirmed by a negligible radio-isotope uptake. The clinical course and treatment are similar to those of painless subacute thyroiditis (see above). Post-partum thyroiditis tends to recur after subsequent pregnancies, and eventually patients progress over a period of years to permanent hypothyroidism. Iodine-associated thyroid disease Iodine deficiency Iodine is an essential micronutrient and is a key component of T4 and T3. The World Health Organisation (WHO) recommends a daily intake of iodine of 150 μg/day for adult men and women; higher levels are recommended for pregnant women (p. 1279). Dietary sources of iodine include seafood, dairy products, eggs and grains. Dietary iodine deficiency is a major worldwide public health issue, with an estimated one-third of the world population living in areas of iodine insufficiency. Iodine deficiency is particularly common in Central Africa, South-east Asia and the Western Pacific. It is associated with the development of thyroid nodules and goitre (endemic goitre); the reduced substrate available for thyroid hormone production increases thyroid activity to maximise iodine uptake and recycling, and this acts as a potent stimulus for enlargement of the thyroid and nodule formation. Most affected patients are euthyroid with normal or raised TSH levels, although hypothyroidism can occur with severe iodine deficiency. Suspected iodine deficiency can be assessed by measuring iodine in urine (either a 24-hour collection or a spot sample). Endemic goitre can be treated by iodine supplementation, and a reduction in nodule and goitre size can be seen, particularly if it is commenced in childhood. Iodine deficiency is not associated with an increased risk of Graves’ disease or thyroid cancer, but the high prevalence of nodular autonomy does result in an increased risk of thyrotoxicosis and this risk may be further increased by iodine supplementation. Conversely, iodine supplementation may also increase the prevalence of subclinical hypothyroidism and autoimmune hypothyroidism. These complex effects of iodine supplementation are further discussed below. In pregnancy, iodine deficiency is associated with impaired brain development, and severe deficiency can cause cretinism. Worldwide, iodine deficiency is the most common cause of preventable impaired cognitive development in children (p. 1279). The WHO and other international organisations have made reversal of iodine deficiency a priority and have helped organise national supplementation programmes. These have mainly involved the iodisation of table salt, but have also included Fig. 18.10 The structure of amiodarone. Note the similarities to T4 (see Fig. 18.3). C4H9 O I C CH2 CH2 N O C2H5 C2H5 I O

648 • ENDOCRINOLOGY Fig. 18.12 Computed tomogram showing retrosternal multinodular goitre (black arrow). This is causing acute severe breathlessness and stridor due to tracheal compression (white arrow). R Fig. 18.11 Natural history of simple goitre. Age (in years) Goitre Tracheal compression/ deviation T3, T4 TSH 15–25 Diffuse No Normal Normal 26–55 Nodular Minimal Normal Normal or undetectable

55 Nodular Yes Raised Undetectable nodular goitre or latent Graves’ disease (an example of the Jod–Basedow effect). • type II: thyroiditis due to a direct cytotoxic effect of amiodarone administration. These patterns can overlap and may be difficult to distinguish clinically, as iodine uptake is low in both. There is no widely accepted management algorithm, although the iodine excess renders the gland resistant to 131I. Antithyroid drugs may be effective in patients with the type I form but are ineffective in type II thyrotoxicosis. Prednisolone is beneficial in the type II form. A pragmatic approach is to commence combination therapy with an antithyroid drug and glucocorticoid in patients with significant thyrotoxicosis. A rapid response (within 1–2 weeks) usually indicates a type II picture and permits withdrawal of the antithyroid therapy; a slower response suggests a type I picture, in which case antithyroid drugs may be continued and prednisolone withdrawn. Potassium perchlorate can also be used to inhibit iodine trapping in the thyroid. If the cardiac state allows, amiodarone should be discontinued, but it has a long half-life (50–60 days) and so its effects are long-lasting. To minimise the risk of type I thyrotoxicosis, thyroid function should be measured in all patients prior to commencement of amiodarone therapy, and amiodarone should be avoided if TSH is suppressed. Hypothyroidism should be treated with levothyroxine, which can be given while amiodarone is continued. Simple and multinodular goitre These terms describe diffuse or multinodular enlargement of the thyroid, which occurs sporadically and is of unknown aetiology. Simple diffuse goitre This form of goitre usually presents between the ages of 15 and 25 years, often during pregnancy, and tends to be noticed by friends and relatives rather than the patient. Occasionally, there is a tight sensation in the neck, particularly when swallowing. The goitre is soft and symmetrical, and the thyroid enlarged to two or three times normal. There is no tenderness, lymphadenopathy or overlying bruit. Concentrations of T3, T4 and TSH are normal and no thyroid autoantibodies are detected in the serum. No treatment is necessary and the goitre usually regresses. In some, however, the unknown stimulus to thyroid enlargement persists and, as a result of recurrent episodes of hyperplasia and involution during the following 10–20 years, the gland becomes multinodular with areas of autonomous function. Multinodular goitre The natural history is shown in Figure 18.11. Patients with thyroid enlargement in the absence of thyroid dysfunction or positive autoantibodies (i.e. with ‘simple goitre’; see above) as young adults may progress to develop nodules. These nodules grow at varying rates and secrete thyroid hormone ‘autonomously’, thereby suppressing TSH-dependent growth and function in the rest of the gland. Ultimately, complete suppression of TSH occurs in about 25% of cases, with T4 and T3 levels often within the reference range (subclinical thyrotoxicosis, p. 642), but sometimes elevated (toxic multinodular goitre; see Fig. 18.5). Clinical features and investigations Multinodular goitre is usually diagnosed in patients presenting with thyrotoxicosis, a large goitre with or without tracheal compression, or sudden painful swelling caused by haemorrhage into a nodule or cyst. The goitre is nodular or lobulated on palpation and may extend retrosternally; however, not all multinodular goitres causing thyrotoxicosis are easily palpable. Very large goitres can cause mediastinal compression with stridor (Fig. 18.12), dysphagia and obstruction of the superior vena cava. Hoarseness due to recurrent laryngeal nerve palsy can occur but is far more suggestive of thyroid carcinoma. The diagnosis can be confirmed by ultrasonography and/or thyroid scintigraphy (see Fig. 18.5). In patients with large goitres, a flow-volume loop is a good screening test for significant tracheal compression (see Fig. 17.7, p. 554). If intervention is contemplated, a CT or MRI of the thoracic inlet should be performed to quantify the degree of tracheal displacement or compression and the extent of retrosternal extension. Nodules should be evaluated for the possibility of thyroid neoplasia, as described on page 649. Management If the goitre is small, no treatment is necessary but annual thyroid function testing should be arranged, as the natural history is progression to a toxic multinodular goitre. Thyroid surgery is indicated for large goitres that cause mediastinal compression

The thyroid gland • 649

thyrotoxicosis is usually mild and in almost 50% of patients the plasma T3 alone is elevated (T3 thyrotoxicosis). 131I (400–800 MBq (10–20 mCi)) is highly effective and is an ideal treatment since the atrophic cells surrounding the nodule do not take up iodine and so receive little or no radiation. For this reason, permanent hypothyroidism is unusual. Hemithyroidectomy is an alternative management option. Differentiated carcinoma Papillary carcinoma This is the most common of the malignant thyroid tumours and accounts for 90% of radiation-induced thyroid cancer. It may be multifocal and spread is initially to regional lymph nodes. Some patients present with cervical lymphadenopathy and no apparent thyroid enlargement; in such instances, the primary lesion may be less than 10 mm in diameter. Follicular carcinoma This is usually a single encapsulated lesion. Spread to cervical lymph nodes is rare. Metastases are blood-borne and are most often found in bone, lungs and brain. Management The management of thyroid cancers should be individualised and planned in multidisciplinary team meetings that include all specialists involved in the service; this should include thyroid surgeons, endocrinologists, oncologists, pathologists, radiologists and nurse specialists. Large tumours, those with adverse histological features and/or tumours with metastatic disease at presentation are usually managed by total thyroidectomy followed by a large dose of 131I (1100 or 3700 MBq (approximately 30 or 100 mCi)) to ablate any remaining normal or malignant thyroid tissue. Thereafter, long-term treatment with levothyroxine in a dose sufficient to suppress TSH (usually 150–200 μg daily) is given, as there is evidence that growth of differentiated thyroid carcinomas is TSH-dependent. Smaller tumours with no adverse histological features may require only thyroid lobectomy. Follow-up involves measurement of serum thyroglobulin, which should be undetectable in patients whose normal thyroid has been ablated and who are taking a suppressive dose of levothyroxine. Thyroglobulin antibodies may interfere with the assay and, depending on the method employed, may result in a falsely low or high result. Detectable thyroglobulin, in the absence of assay interference, is suggestive of tumour recurrence or metastases, particularly if the thyroglobulin titre is rising across serial measurements. Local recurrence or metastatic disease may be localised by ultrasound, CT, MRI and/or whole-body scanning with 131I, and may be treated with further surgery and/or 131I therapy. 131I treatment in thyroid cancer and isotope scanning both require serum TSH concentrations to be elevated (> 20 mIU/L). This may be achieved by stopping levothyroxine for 4–6 weeks, inducing symptomatic hypothyroidism, or by administering intramuscular injections of recombinant human TSH. Patients usually find the latter approach preferable but it is more expensive. Those with locally advanced or metastatic papillary and follicular carcinoma that is refractive to 131I may be considered for therapy with sorafenib or lenvatinib. These drugs are multi-targeted tyrosine kinase inhibitors and have been shown in trials to prolong progression-free survival by between 5 and 14 months. They have multiple toxicities, however, including poor appetite, weight loss, fatigue, diarrhoea, mucositis, rashes, hypertension and blood dyscrasias. The potential benefits of or that are cosmetically unattractive. 131I can result in a significant reduction in thyroid size and may be of value in elderly patients. Levothyroxine therapy is of no benefit in shrinking multinodular goitres in iodine-sufficient countries and may simply aggravate any associated thyrotoxicosis. In toxic multinodular goitre, treatment is usually with 131I. The iodine uptake is lower than in Graves’ disease, so a higher dose may be administered (up to 800 Mbq (approximately 20 mCi)) and hypothyroidism is less common. In thyrotoxic patients with a large goitre, thyroid surgery may be indicated. Long-term treatment with antithyroid drugs is not usually employed, as relapse is invariable after drug withdrawal; drug therapy is normally reserved for frail older patients in whom surgery or 131I is not an appropriate option. Asymptomatic patients with subclinical thyrotoxicosis (p. 642) are increasingly being treated with 131I on the grounds that a suppressed TSH is a risk factor for atrial fibrillation and, particularly in post-menopausal women, osteoporosis. Thyroid neoplasia Patients with thyroid tumours usually present with a solitary nodule (p. 642). Most are benign and a few of these, called ‘toxic adenomas’, secrete excess thyroid hormones. Primary thyroid malignancy is rare, accounting for less than 1% of all carcinomas, and has an incidence of 25 per million per annum. As shown in Box 18.16, it can be classified according to the cell type of origin. With the exception of medullary carcinoma, thyroid cancer is more common in females. Toxic adenoma A solitary toxic nodule is the cause of less than 5% of all cases of thyrotoxicosis. The nodule is a follicular adenoma, which autonomously secretes excess thyroid hormones and inhibits endogenous TSH secretion, with subsequent atrophy of the rest of the thyroid gland. The adenoma is usually greater than 3 cm in diameter. Most patients are female and over 40 years of age. Although many nodules are palpable, the diagnosis can be made with certainty only by thyroid scintigraphy (see Fig. 18.5). The 18.16 Malignant thyroid tumours Type of tumour Frequency (%) Age at presentation (years) 10-year survival (%) Follicular cells Differentiated carcinoma: Papillary 75–85 20–40

Follicular 10–20 40–60

Anaplastic < 5

60

Parafollicular C cells Medullary carcinoma 5–8

40*

Lymphocytes Lymphoma < 5

60

*Patients with medullary carcinoma as part of multiple endocrine neoplasia (MEN) types 2 and 3 (p. 688) may present in childhood.

650 • ENDOCRINOLOGY Riedel’s thyroiditis This is not a form of thyroid cancer but the presentation is similar and the differentiation can usually be made only by thyroid biopsy. It is an exceptionally rare condition of unknown aetiology, in which there is extensive infiltration of the thyroid and surrounding structures with fibrous tissue. There may be associated mediastinal and retroperitoneal fibrosis. Presentation is with a slow-growing goitre that is irregular and stony-hard. There is usually tracheal and oesophageal compression necessitating partial thyroidectomy. Other recognised complications include recurrent laryngeal nerve palsy, hypoparathyroidism and eventually hypothyroidism. Congenital thyroid disease Early treatment with levothyroxine is essential to prevent irreversible brain damage in children (cretinism) with congenital hypothyroidism. Routine screening of TSH levels in heel-prick blood samples obtained 5–7 days after birth (as part of the Guthrie test) has revealed an incidence of approximately 1 in 3000, resulting from thyroid agenesis, ectopic or hypoplastic glands, or dyshormonogenesis. Congenital hypothyroidism is thus six times more common than phenylketonuria. It is now possible to start levothyroxine replacement therapy within 2 weeks of birth. Developmental assessment of infants treated at this early stage has revealed no differences between cases and controls in most children. Dyshormonogenesis Several autosomal recessive defects in thyroid hormone synthesis have been described; the most common results from deficiency of the intrathyroidal peroxidase enzyme. Homozygous individuals present with congenital hypothyroidism; heterozygotes present in the first two decades of life with goitre, normal thyroid hormone levels and a raised TSH. The combination of dyshormonogenetic goitre and nerve deafness is known as Pendred’s syndrome and is due to mutations in pendrin, the protein that transports iodide to the luminal surface of the follicular cell (see Fig. 18.3). therapy therefore have to be carefully weighed against side-effects that can significantly impair quality of life. Prognosis Most patients with papillary and follicular thyroid cancer will be cured with appropriate treatment. Adverse prognostic factors include older age at presentation, the presence of distant metastases, male sex and certain histological subtypes. However, 131I therapy can be effective in treating those with distant metastases, particularly small-volume disease in the lungs, and so prolonged survival is quite common. Anaplastic carcinoma and lymphoma These two conditions are difficult to distinguish clinically but are distinct cytologically and histologically. Patients are usually over 60 years of age and present with rapid thyroid enlargement over 2–3 months. The goitre is hard and there may be stridor due to tracheal compression and hoarseness due to recurrent laryngeal nerve palsy. There is no effective treatment for anaplastic carcinoma, although surgery and radiotherapy may be considered in some circumstances. In older patients, median survival is only 7 months. The prognosis for lymphoma, which may arise from preexisting Hashimoto’s thyroiditis, is better (p. 961), with a median survival of 9 years. Some 98% of tumours are non-Hodgkin’s lymphomas, usually the diffuse large B-cell subtype. Treatment is with combination chemotherapy and external beam radiotherapy (p. 965). Medullary carcinoma This tumour arises from the parafollicular C cells of the thyroid. In addition to calcitonin, the tumour may secrete 5-hydroxytryptamine (5-HT, serotonin), various peptides of the tachykinin family, adrenocorticotrophic hormone (ACTH) and prostaglandins. As a consequence, carcinoid syndrome (p. 678) and Cushing’s syndrome (p. 666) may occur. Patients usually present in middle age with a firm thyroid mass. Cervical lymph node involvement is common but distant metastases are rare initially. Serum calcitonin levels are raised and are useful in monitoring response to treatment. Despite the very high levels of calcitonin found in some patients, hypocalcaemia is extremely rare; however, hypercalcitoninaemia can be associated with severe, watery diarrhoea. Treatment is by total thyroidectomy with removal of regional cervical lymph nodes. Since the C cells do not concentrate iodine and are not responsive to TSH, there is no role for 131I therapy or TSH suppression with levothyroxine. External beam radiotherapy may be considered in some patients at high risk of local recurrence. Vandetanib and cabozantinib are tyrosine kinase inhibitors licensed for patients with progressive advanced medullary cancer. The prognosis is less good than for papillary and follicular carcinoma, but individuals can live for many decades with persistent disease that behaves in an indolent fashion. Medullary carcinoma of the thyroid occurs sporadically in 70–90% cases; in 10–30% of cases, there is a genetic predisposition that is inherited in an autosomal dominant fashion and is due to an activating mutation in the RET gene. This inherited tendency normally forms part of one of the MEN syndromes (MEN 2 (also known as MEN 2a) or MEN 3 (also known as MEN 2b), p. 688) but, occasionally, susceptibility to medullary carcinoma is the only inherited trait (familial medullary thyroid cancer). 18.17 The thyroid gland in old age Thyrotoxicosis • Causes: commonly due to multinodular goitre. • Clinical features: apathy, anorexia, proximal myopathy, atrial fibrillation and cardiac failure predominate. • Non-thyroidal illness: thyroid function tests are performed more frequently in the elderly but interpretation may be altered by intercurrent illness. Hypothyroidism • Clinical features: non-specific features, such as physical and mental slowing, are often attributed to increasing age and the diagnosis is delayed. • Myxoedema coma (p. 641): more likely in the elderly. • Levothyroxine dose: to avoid exacerbating latent or established heart disease, the starting dose should be 25 μg daily. Levothyroxine requirements fall with increasing age and few patients need more than 100 μg daily. • Other medication (see Box 18.12): may interfere with absorption or metabolism of levothyroxine, necessitating an increase in dose.

The reproductive system • 651

Functional anatomy, physiology and investigations The physiology of male and female reproductive function is illustrated in Figures 18.13 and 18.14, respectively. Pathways for synthesis of sex steroids are shown in Figure 18.19 (p. 667). The male In the male, the testis serves two principal functions: synthesis of testosterone by the interstitial Leydig cells under the control of luteinising hormone (LH), and spermatogenesis by Sertoli cells under the control of follicle-stimulating hormone (FSH) (but also requiring adequate testosterone). Negative feedback suppression of LH is mediated principally by testosterone, while secretion of another hormone by the testis, inhibin, suppresses FSH. The axis can be assessed easily by a random blood sample for testosterone, LH and FSH. Testosterone levels are higher in the morning and therefore, if testosterone is marginally low, sampling should be repeated with the patient fasted at 0900 hrs. Testosterone is largely bound in plasma to sex hormone-binding globulin and this can also be measured to calculate the ‘free androgen index’ or the ‘bioavailable’ testosterone. Testicular function can also be tested by semen analysis. There is no equivalent of the menopause in men, although testosterone concentrations decline slowly from the fourth decade onwards. 18.18 Thyroid disease in pregnancy Normal pregnancy • Trimester-specific reference ranges: should be used to interpret thyroid function test results in pregnancy. Iodine deficiency • Iodine requirements: increased in pregnancy. The World Health Organisation (WHO) recommends a minimum intake of 250 μg/day. • Iodine deficiency: the major cause of preventable impaired cognitive development in children worldwide. Hypothyroidism • Impaired cognitive development in the offspring: may be associated with hypothyroidism that is not adequately treated. • Levothyroxine replacement therapy dose requirements: increase by 30–50% from early in pregnancy. Monitoring to maintain TSH results within the trimester-specific reference range is recommended in early pregnancy and at least once in each trimester. Thyrotoxicosis • Gestational thyrotoxicosis: associated with multiple pregnancies and hyperemesis gravidarum. Transient and usually does not require antithyroid drug treatment. • Graves’ disease: the most common cause of sustained thyrotoxicosis in pregnancy • Antithyroid drugs: propylthiouracil should be used in the first trimester, with carbimazole substituted in the second and third trimesters. Post-partum thyroiditis • Screening: not recommended for every woman, but thyroid function should be tested 4–6 weeks post-partum in those with a personal history of thyroid disease, goitre or other autoimmune disease including type 1 diabetes, in those known to have positive antithyroid peroxidase antibodies, or when there is clinical suspicion of thyroid dysfunction. Thyroid hormone resistance This is a rare disorder in which the pituitary and hypothalamus are resistant to feedback suppression of TSH by T3, sometimes due to mutations in the thyroid hormone receptor β or because of defects in monodeiodinase activity. The result is high levels of TSH, T4 and T3, often with a moderate goitre that may not be noted until adulthood. Thyroid hormone signalling is highly complex and involves different isozymes of both monodeiodinases and thyroid hormone receptors in different tissues. For that reason, other tissues may or may not share the resistance to thyroid hormone and there may be features of thyrotoxicosis (e.g. tachycardia). This condition can be difficult to distinguish from an equally rare TSH-producing pituitary tumour (TSHoma; see Box 18.5, p. 636); administration of TRH results in elevation of TSH in thyroid hormone resistance and not in TSHoma, but an MRI scan of the pituitary may be necessary to exclude a macroadenoma. The reproductive system Clinical practice in reproductive medicine is shared between several specialties, including gynaecology, urology, paediatrics, psychiatry and endocrinology. The following section is focused on disorders managed by endocrinologists. Fig. 18.13 Male reproductive physiology. (FSH = follicle-stimulating hormone; LH = luteinising hormone) Negative feedback LH FSH Interstitial (Leydig) cells Sertoli cells in seminiferous tubules Inhibin Spermatogenesis Testosterone • Facial, axillary and body hair growth • Scalp balding • Skin sebum production • Penis and scrotal development • Prostate development and function • Laryngeal enlargement • Muscle power • Bone metabolism/epiphyseal closure • Libido • Aggression Testis

652 • ENDOCRINOLOGY The female In the female, physiology varies during the normal menstrual cycle. FSH stimulates growth and development of ovarian follicles during the first 14 days after the menses. This leads to a gradual increase in oestradiol production from granulosa cells, which initially suppresses FSH secretion (negative feedback) but then, above a certain level, stimulates an increase in both the frequency and amplitude of gonadotrophin-releasing hormone (GnRH) pulses, resulting in a marked increase in LH secretion (positive feedback). The mid-cycle ‘surge’ of LH induces ovulation. After release of the ovum, the follicle differentiates into a corpus luteum, which secretes progesterone. Unless pregnancy occurs during the cycle, the corpus luteum regresses and the fall in progesterone levels results in menstrual bleeding. Circulating levels of oestrogen and progesterone in pre-menopausal women are, therefore, critically dependent on the time of the cycle. The most useful ‘test’ of ovarian function is a careful menstrual history: if menses are regular, measurement of gonadotrophins and oestrogen is not necessary. In addition, ovulation can be confirmed by measuring plasma progesterone levels during the luteal phase (‘day 21 progesterone’). Cessation of menstruation (the menopause) occurs at an average age of approximately 50 years in developed countries. In the 5 years before, there is a gradual increase in the number of anovulatory cycles and this is referred to as the climacteric. Oestrogen and inhibin secretion falls and negative feedback results in increased pituitary secretion of LH and FSH (both typically to levels above 30 IU/L (3.3 μg/L)). The pathophysiology of male and female reproductive dysfunction is summarised in Box 18.19. Fig. 18.14 Female reproductive physiology and the normal menstrual cycle. (FSH = follicle-stimulating hormone; LH = luteinising hormone) Feedback LH FSH Inhibin Oestradiol • Endometrial proliferation • Genital development and lubrication • Breast proliferation • Bone epiphyseal closure and mineral content • Brain • Body fat distribution • Skin sebum Progesterone • Endometrial secretory change • Increased myometrial contractility • Thermogenesis • Breast swelling Days after start of last menstrual period FSH LH Oestradiol Progesterone Ovulation Luteal phase Follicular phase Primary Dominant vesicular Mature Haemorrhagic Mature Regressing Oestradiol Oestradiol Oestradiol Progesterone Oestradiol Progesterone Corpus luteum Ovary Menses Follicle

18.19 Classification of diseases of the reproductive system Primary Secondary Hormone excess Polycystic ovarian syndrome Granulosa cell tumour Leydig cell tumour Teratoma Pituitary gonadotrophinoma Hormone deficiency Menopause Hypogonadism (see Box 18.20) Turner’s syndrome Klinefelter’s syndrome Hypopituitarism Kallmann’s syndrome (isolated GnRH deficiency) Severe systemic illness, including anorexia nervosa Hormone hypersensitivity Idiopathic hirsutism Hormone resistance Androgen resistance syndromes Complete (‘testicular feminisation’) Partial (Reifenstein’s syndrome) 5α-reductase type 2 deficiency Non-functioning tumours Ovarian cysts Carcinoma Teratoma Seminoma (GnRH = gonadotrophin-releasing hormone)

The reproductive system • 653

usually be obtained from health records, are extremely useful. Healthy growth usually follows a centile. Usually, children with constitutional delay have always been small but have maintained a normal growth velocity that is appropriate for bone age. Poor linear growth, with ‘crossing of the centiles’, is more likely to be associated with acquired disease. Issues that are commonly encountered in the management of adolescents with delayed puberty are summarised in Box 18.21. Constitutional delay of puberty This is the most common cause of delayed puberty, but is a much more frequent explanation for lack of pubertal development in boys than in girls. Affected children are healthy and have usually been more than 2 SD below the mean height for their age throughout childhood. There is often a history of delayed puberty in siblings or parents. Since sex steroids are essential for fusion of the epiphyses, ‘bone age’ can be estimated by X-rays of epiphyses, usually in the wrist and hand; in constitutional delay, bone age is lower than chronological age. Constitutional delay of puberty should be considered as a normal variant, as puberty will commence spontaneously. However, affected children can experience significant psychological distress because of their lack of physical development, particularly when compared with their peers. Hypogonadotrophic hypogonadism This may be due to structural, inflammatory or infiltrative disorders of the pituitary and/or hypothalamus (see Box 18.54, p. 681). In such circumstances, other pituitary hormones, such as growth hormone, are also likely to be deficient. ‘Functional’ gonadotrophin deficiency is caused by a variety of factors, including low body weight, chronic systemic illness (as a consequence of the disease itself or secondary malnutrition), endocrine disorders and profound psychosocial stress. Isolated gonadotrophin deficiency is usually due to a genetic abnormality that affects the synthesis of either GnRH or gonadotrophins. The most common form is Kallmann’s syndrome, in which there is primary GnRH deficiency and, in most affected individuals, agenesis or hypoplasia of the olfactory bulbs, resulting in anosmia or hyposmia. If isolated gonadotrophin deficiency is left untreated, the epiphyses fail to fuse, resulting in tall stature with disproportionately long arms and legs relative to trunk height (eunuchoid habitus). Cryptorchidism (undescended testes) and gynaecomastia are commonly observed in all forms of hypogonadotrophic hypogonadism. Presenting problems in reproductive disease Delayed puberty Normal pubertal development is discussed on page 1290. Puberty is considered to be delayed if the onset of the physical features of sexual maturation has not occurred by a chronological age that is 2.5 standard deviations (SD) above the national average. In the UK, this is by the age of 14 in boys and 13 in girls. Genetic factors have a major influence in determining the timing of the onset of puberty, such that the age of menarche (the onset of menstruation) is often comparable within sibling and mother–daughter pairs and within ethnic groups. However, because there is also a threshold for body weight that acts as a trigger for normal puberty, the onset of puberty can be influenced by other factors including nutritional status and chronic illness (p. 694). Clinical assessment The differential diagnosis is shown in Box 18.20. The key issue is to determine whether the delay in puberty is simply because the ‘clock is running slow’ (constitutional delay of puberty) or because there is pathology in the hypothalamus/ pituitary (hypogonadotrophic hypogonadism) or the gonads (hypergonadotrophic hypogonadism). A general history and physical examination should be performed with particular reference to previous or current medical disorders, social circumstances and family history. Body proportions, sense of smell and pubertal stage should be carefully documented and, in boys, the presence or absence of testes in the scrotum noted. Current weight and height may be plotted on centile charts, along with parental heights. Previous growth measurements in childhood, which can 18.20 Causes of delayed puberty and hypogonadism Constitutional delay Hypogonadotrophic hypogonadism • Structural hypothalamic/pituitary disease (see Box 18.54, p. 681) • Functional gonadotrophin deficiency: Chronic systemic illness (e.g. asthma, malabsorption, coeliac disease, cystic fibrosis, renal failure) Psychological stress Anorexia nervosa Excessive physical exercise Hyperprolactinaemia Other endocrine disease (e.g. Cushing’s syndrome, primary hypothyroidism) • Isolated gonadotrophin deficiency (Kallmann’s syndrome) Hypergonadotrophic hypogonadism • Acquired gonadal damage: Chemotherapy/radiotherapy to gonads Trauma/surgery to gonads Autoimmune gonadal failure Mumps orchitis Tuberculosis Haemochromatosis • Developmental/congenital gonadal disorders: Steroid biosynthetic defects Anorchidism/cryptorchidism in males Klinefelter’s syndrome (47XXY, male phenotype) Turner’s syndrome (45XO, female phenotype) 18.21 Delayed puberty • Aetiology: in boys the most common cause is constitutional delay, whereas in girls there is inevitably a structural hypothalamic/pituitary abnormality or a factor that affects their function. • Psychological effects: whatever the underlying cause, delayed puberty is often associated with substantial psychological distress. • Investigations: a karyotype should be performed in all adolescents with hypergonadotrophic hypogonadism, to exclude Turner’s and Klinefelter’s syndromes, unless there is an obvious precipitating cause. • Medical induction of puberty: if this is being considered, it needs to be managed carefully and carried out in a controlled fashion, to avoid premature fusion of the epiphyses.

654 • ENDOCRINOLOGY Management Social and psychological difficulties may accompany the onset of PP and the premature closure of the epiphyses can result in reduced final height. In central PP, development can be arrested with long-acting GnRH analogues. In both central and peripheral PP, treatment of any underlying cause is indicated. Amenorrhoea Primary amenorrhoea may be diagnosed in a female who has never menstruated; this usually occurs as a manifestation of delayed puberty but may also be a consequence of anatomical defects of the female reproductive system, such as endometrial hypoplasia or vaginal agenesis. Secondary amenorrhoea describes the cessation of menstruation in a female who has previously had periods. The causes of this common presentation are shown in Box 18.22. In non-pregnant women, secondary amenorrhoea is almost invariably a consequence of either ovarian or hypothalamic/pituitary dysfunction. Premature ovarian failure (premature menopause) is defined, arbitrarily, as occurring before 40 years of age. Rarely, endometrial adhesions (Asherman’s syndrome) can form after uterine curettage, surgery or infection with tuberculosis or schistosomiasis, preventing endometrial proliferation and shedding. Clinical assessment The underlying cause can often be suspected from associated clinical features and the patient’s age. Hypothalamic/pituitary disease and premature ovarian failure result in oestrogen deficiency, which causes a variety of symptoms usually associated with the menopause (Box 18.23). A history of galactorrhoea should be sought. Significant weight loss of any cause can cause amenorrhoea by suppression of gonadotrophins. Weight gain may suggest hypothyroidism, Cushing’s syndrome or, very rarely, a hypothalamic lesion. Hirsutism, obesity and long-standing irregular periods suggest polycystic ovarian Hypergonadotrophic hypogonadism Hypergonadotrophic hypogonadism associated with delayed puberty is usually due to Klinefelter’s syndrome in boys and Turner’s syndrome in girls (pp. 659 and 660). Other causes of primary gonadal failure are shown in Box 18.20. Investigations Key measurements are LH and FSH, testosterone (in boys) and oestradiol (in girls). Chromosome analysis should be performed if gonadotrophin concentrations are elevated. If gonadotrophin concentrations are low, then the differential diagnosis lies between constitutional delay and hypogonadotrophic hypogonadism. A plain X-ray of the wrist and hand may be compared with a set of standard films to obtain a bone age. Full blood count, renal function, liver function, thyroid function and coeliac disease autoantibodies (p. 806) should be measured, but further tests may be unnecessary if the blood tests are normal and the child has all the clinical features of constitutional delay. If hypogonadotrophic hypogonadism is suspected, neuroimaging and further investigations are required (p. 680). Management Puberty can be induced using low doses of oral oestrogen in girls (e.g. ethinylestradiol 2 μg daily) or testosterone in boys (testosterone gel or depot testosterone esters). Higher doses carry a risk of early fusion of epiphyses. This therapy should be given in a specialist clinic where the progress of puberty and growth can be carefully monitored. In children with constitutional delay, this ‘priming’ therapy can be discontinued when endogenous puberty is established, usually in less than a year. In children with hypogonadism, the underlying cause should be treated and reversed if possible. If hypogonadism is permanent, sex hormone doses are gradually increased during puberty and full adult replacement doses given when development is complete. Precocious puberty Precocious puberty (PP) is the early development of any secondary sexual characteristics before the age of 9 years in a boy and 6–8 years of age in a girl. Central PP is due to the early maturation of the hypothalamic–pituitary–gonadal axis and thus is gonadotrophin-dependent. It is more common in girls than boys and often no structural cause is identified, i.e. ‘the physiological clock is running fast’. Structural causes are found more commonly in younger children and in boys and include: • central nervous system (CNS) tumours such as astrocytomas, germ-cell tumours secreting human chorionic gonadotrophin (hCG) and hypothalamic harmartomas • CNS injury caused by infection, inflammation or trauma/ surgery • congenital CNS structural abnormalities. Pseudo (or peripheral) PP is much less common, and is due to excess sex steroids in the absence of pituitary gonadotrophins, with causes including congenital adrenal hyperplasia and McCune–Albright syndrome (p. 1055). Investigations Measurement of basal and GnRH-stimulated gonadotrophin levels will allow categorisation into central or peripheral PP, with gonadotrophin levels rising in central PP. Imaging of the CNS is required in cases of central PP, while adrenal and ovarian imaging is indicated in peripheral PP. 18.23 Symptoms of oestrogen deficiency Vasomotor effects • Hot flushes • Sweating Psychological • Anxiety • Irritability • Emotional lability Genitourinary • Dyspareunia • Urgency of micturition • Vaginal infections 18.22 Causes of secondary amenorrhoea Physiological • Pregnancy • Menopause Hypogonadotrophic hypogonadism (see Box 18.20) Ovarian dysfunction • Hypergonadotrophic hypogonadism (see Box 18.20) • Polycystic ovarian syndrome • Androgen-secreting tumours Uterine dysfunction • Asherman’s syndrome

The reproductive system • 655

patient’s age. In patients with premature menopause, HRT should be continued up to the age of around 50 years, but continued beyond this age only if there are continued symptoms of oestrogen deficiency on discontinuation. Management of infertility in oestrogen-deficient women is described on page 656. Male hypogonadism The clinical features of both hypo- and hypergonadotrophic hypogonadism include loss of libido, lethargy with muscle weakness, and decreased frequency of shaving. Patients may also present with gynaecomastia, infertility, delayed puberty, osteoporosis or anaemia of chronic disease. The causes of hypogonadism are listed in Box 18.20. Mild hypogonadism may also occur in older men, particularly in the context of central adiposity and the metabolic syndrome (p. 730). Postulated mechanisms are complex and include reduction in sex hormonebinding globulin by insulin resistance and reduction in GnRH and gonadotrophin secretion by cytokines or oestrogen released by adipose tissue. Testosterone levels also fall gradually with age in men (see Box 18.30) and this is associated with gonadotrophin levels that are low or inappropriately within the ‘normal’ range. There is an increasing trend to measure testosterone in older men, typically as part of an assessment of erectile dysfunction and lack of libido. Investigations Male hypogonadism is confirmed by demonstrating a low fasting 0900-hr serum testosterone level. The distinction between hypo- and hypergonadotrophic hypogonadism is by measurement of random LH and FSH. Patients with hypogonadotrophic hypogonadism should be investigated as described for pituitary disease on page 680. Patients with hypergonadotrophic hypogonadism should have the testes examined for cryptorchidism or atrophy, and a karyotype should be performed (to identify Klinefelter’s syndrome). Management Testosterone replacement is clearly indicated in younger men with significant hypogonadism to prevent osteoporosis and to restore muscle power and libido. Debate exists as to whether replacement therapy is of benefit in mild hypogonadism associated with ageing and central adiposity, particularly in the absence of structural pituitary/hypothalamic disease or other pituitary hormone deficiency. In such instances, a therapeutic trial of testosterone therapy may be considered if symptoms are present (e.g. low libido and erectile dysfunction), but the benefits of therapy must be carefully weighed against the potential for harm. Routes of testosterone administration are shown in Box 18.24. First-pass hepatic metabolism of testosterone is highly efficient, so bioavailability of ingested preparations is poor. Doses of systemic testosterone can be titrated against symptoms; circulating testosterone levels may provide only a rough guide to dosage because they may be highly variable (Box 18.24). Testosterone therapy can aggravate prostatic carcinoma; prostate-specific antigen (PSA) should be measured before commencing testosterone therapy in men older than 50 years and monitored annually thereafter. Haemoglobin concentration should also be monitored in older men, as androgen replacement can cause polycythaemia. Testosterone replacement inhibits spermatogenesis; treatment for fertility is described below. syndrome (PCOS, p. 658). The presence of other autoimmune disease raises the possibility of autoimmune premature ovarian failure. Investigations Pregnancy should be excluded in women of reproductive age by measuring urine or serum hCG. Serum LH, FSH, oestradiol, prolactin, testosterone, T4 and TSH should be measured and, in the absence of a menstrual cycle, can be taken at any time. Investigation of hyperprolactinaemia is described on page 684. High concentrations of LH and FSH with low or low-normal oestradiol suggest primary ovarian failure. Ovarian autoantibodies may be positive when there is an underlying autoimmune aetiology, and a karyotype should be performed in younger women to exclude mosaic Turner’s syndrome. Elevated LH, prolactin and testosterone levels with normal oestradiol are common in PCOS. Low levels of LH, FSH and oestradiol suggest hypothalamic or pituitary disease and a pituitary MRI is indicated. There is some overlap in gonadotrophin and oestrogen concentrations between women with hypogonadotrophic hypogonadism and PCOS. If there is doubt as to the underlying cause of secondary amenorrhoea, then the response to 5 days of treatment with an oral progestogen (e.g. medroxyprogesterone acetate 10 mg twice daily) can be assessed. In women with PCOS, the progestogen will cause maturation of the endometrium and menstruation will occur a few days after the progestogen is stopped. In women with hypogonadotrophic hypogonadism, menstruation does not occur following progestogen withdrawal because the endometrium is atrophic as a result of oestrogen deficiency. If doubt persists in distinguishing oestrogen deficiency from a uterine abnormality, the capacity for menstruation can be tested with 1 month of treatment with cyclical oestrogen and progestogen (usually administered as a combined oral contraceptive pill). Assessment of bone mineral density by dual X-ray absorptiometry (DXA, p. 989) may be appropriate in patients with low androgen and oestrogen levels. Management Where possible, the underlying cause should be treated. For example, women with functional amenorrhoea due to excessive exercise and low weight should be encouraged to reduce their exercise and regain some weight. The management of structural pituitary and hypothalamic disease is described on page 684 and that of PCOS on page 658. In oestrogen-deficient women, replacement therapy may be necessary to treat symptoms and/or to prevent osteoporosis. Women who have had a hysterectomy can be treated with oestrogen alone but those with a uterus should be treated with combined oestrogen/progestogen therapy, since unopposed oestrogen increases the risk of endometrial cancer. Cyclical hormone replacement therapy (HRT) regimens typically involve giving oestrogen on days 1–21 and progestogen on days 14–21 of the cycle, and this can be conveniently administered as the oral contraceptive pill. If oestrogenic side-effects (fluid retention, weight gain, hypertension and thrombosis) are a concern, then lower-dose oral or transdermal HRT may be more appropriate. The timing of the discontinuation of oestrogen replacement therapy is still a matter of debate. In post-menopausal women, HRT has been shown to relieve menopausal symptoms and to prevent osteoporotic fractures but is associated with adverse effects, which are related to the duration of therapy and to the

656 • ENDOCRINOLOGY Clinical assessment A history of previous pregnancies, relevant infections and surgery is important in both men and women. A sexual history must be explored sensitively, as some couples have intercourse infrequently or only when they consider the woman to be ovulating, and psychosexual difficulties are common. Irregular and/or infrequent menstrual periods are an indicator of anovulatory cycles in the woman, in which case causes such as PCOS should be considered. In men, the testes should be examined to confirm that both are in the scrotum and to identify any structural abnormality, such as small size, absent vas deferens or the presence of a varicocele. Investigations Investigations should generally be performed after a couple has failed to conceive despite unprotected intercourse for 12 months, unless there is an obvious abnormality like amenorrhoea. Both partners need to be investigated. The male partner needs a semen analysis to assess sperm count and quality. Home testing for ovulation (by commercial urine dipstick kits, temperature measurement, or assessment of cervical mucus) is not recommended, as the information is often counterbalanced by increased anxiety if interpretation is inconclusive. In women with regular periods, ovulation can be confirmed by an elevated serum progesterone concentration on day 21 of the menstrual cycle. Transvaginal ultrasound can be used to assess uterine and ovarian anatomy. Tubal patency may be examined at laparoscopy or by hysterosalpingography (HSG; a radio-opaque medium is injected into the uterus and should normally outline the Fallopian tubes). In vitro assessments of sperm survival in cervical mucus may be done in cases of unexplained infertility but are rarely helpful. Management Couples should be advised to have regular sexual intercourse, ideally every 2–3 days throughout the menstrual cycle. It is not uncommon for ‘spontaneous’ pregnancies to occur in couples undergoing investigations for infertility or with identified causes of male or female subfertility. In women with anovulatory cycles secondary to PCOS (p. 658), clomifene, which has partial anti-oestrogen action, blocks negative feedback of oestrogen on the hypothalamus/pituitary, causing gonadotrophin secretion and thus ovulation. In women with gonadotrophin deficiency or in whom anti-oestrogen therapy is unsuccessful, ovulation may be induced by direct stimulation of the ovary by daily injection of FSH and an injection of hCG to Infertility Infertility affects around 1 in 7 couples of reproductive age, often causing psychological distress. The main causes are listed in Box 18.25. In women, it may result from anovulation or abnormalities of the reproductive tract that prevent fertilisation or embryonic implantation, often damaged Fallopian tubes from previous infection. In men, infertility may result from impaired sperm quality (e.g. reduced motility) or reduced sperm number. Azoospermia or oligospermia is usually idiopathic but may be a consequence of hypogonadism (see Box 18.20). Microdeletions of the Y chromosome are increasingly recognised as a cause of severely abnormal spermatogenesis. In many couples, more than one factor causing subfertility is present, and in a large proportion no cause can be identified. 18.24 Options for androgen replacement therapy Route of administration Preparation Dose Frequency Comments Intramuscular Testosterone enantate 50–250 mg Every 3–4 weeks Produces peaks and troughs of testosterone levels that are outside the physiological range and may be symptomatic Testosterone undecanoate 1000 mg Every 3 months Smoother profile than testosterone enantate, with less frequent injections Subcutaneous Testosterone pellets 600–800 mg Every 4–6 months Smoother profile than testosterone enantate but implantation causes scarring and infection Transdermal Testosterone patch 5–10 mg Daily Stable testosterone levels but high incidence of skin hypersensitivity Testosterone gel 50–100 mg Daily Stable testosterone levels; transfer of gel can occur following skin-to-skin contact with another person Oral Testosterone undecanoate 40–120 mg Twice daily Very variable testosterone levels; risk of hepatotoxicity 18.25 Causes of infertility Female factor (35–40%) • Ovulatory dysfunction: Polycystic ovarian syndrome Hypogonadotrophic hypogonadism (see Box 18.20) Hypergonadotrophic hypogonadism (see Box 18.20) • Tubular dysfunction: Pelvic inflammatory disease (chlamydia, gonorrhoea) Endometriosis Previous sterilisation Previous pelvic or abdominal surgery • Cervical and/or uterine dysfunction: Congenital abnormalities Fibroids Treatment for cervical carcinoma Asherman’s syndrome Male factor (35–40%) • Reduced sperm quality or production: Y chromosome microdeletions Varicocele Hypergonadotrophic hypogonadism (see Box 18.20) Hypogonadotrophic hypogonadism (see Box 18.20) • Tubular dysfunction: Varicocele Congenital abnormality of vas deferens/epididymis Previous sexually transmitted infection (chlamydia, gonorrhoea) Previous vasectomy Unexplained or mixed factor (20–35%)

The reproductive system • 657

reach adult levels before testosterone) and in elderly men (due to decreasing testosterone concentrations). Prolactin excess alone does not cause gynaecomastia (p. 684). Clinical assessment A drug history is important. Gynaecomastia is often asymmetrical and palpation may allow breast tissue to be distinguished from the prominent adipose tissue (lipomastia) around the nipple that is often observed in obesity. Features of hypogonadism should be sought (see above) and the testes examined for evidence of cryptorchidism, atrophy or a tumour. Investigations If a clinical distinction between gynaecomastia and adipose tissue cannot be made, then ultrasonography or mammography is required. A random blood sample should be taken for testosterone, LH, FSH, oestradiol, prolactin and hCG. Elevated oestrogen concentrations are found in testicular tumours and hCG-producing neoplasms. Management An adolescent with gynaecomastia who is progressing normally through puberty may be reassured that the gynaecomastia will usually resolve once development is complete. If puberty does not proceed normally, then there may be an underlying abnormality that requires investigation (p. 653). Gynaecomastia may cause significant psychological distress, especially in adolescent boys, and surgical excision may be justified for cosmetic reasons. Androgen replacement will usually improve gynaecomastia in hypogonadal males and any other identifiable underlying cause should be addressed if possible. The anti-oestrogen tamoxifen may also be effective in reducing the size of the breast tissue. Hirsutism Hirsutism refers to the excessive growth of terminal hair (the thick, pigmented hair usually associated with the adult male chest) in an androgen-dependent distribution in women (upper lip, chin, chest, back, lower abdomen, thigh, forearm) and is one of the most common presentations of endocrine disease. It should be distinguished from hypertrichosis, which is generalised excessive growth of vellus hair (the thin, non-pigmented hair that is typically found all over the body from childhood onwards). The aetiology of androgen excess is shown in Box 18.27. Clinical assessment The severity of hirsutism is subjective. Some women suffer profound embarrassment from a degree of hair growth that others would not consider remarkable. Important observations are a drug and menstrual history, calculation of body mass index, measurement of blood pressure, and examination for virilisation (clitoromegaly, deep voice, male-pattern balding, breast atrophy) and associated features, including acne vulgaris or Cushing’s syndrome (p. 666). Hirsutism of recent onset associated with virilisation is suggestive of an androgen-secreting tumour but this is rare. Investigations A random blood sample should be taken for testosterone, prolactin, LH and FSH. If there are clinical features of Cushing’s syndrome, further investigations should be performed (p. 667). If testosterone levels are more than twice the upper limit of normal for females, idiopathic hirsutism and PCOS are less likely, especially if LH and FSH levels are low. Under these induce follicular rupture at the appropriate time. In hypothalamic disease, pulsatile GnRH therapy with a portable infusion pump can be used to stimulate pituitary gonadotrophin secretion (note that non-pulsatile administration of GnRH or its analogues paradoxically suppresses LH and FSH secretion). Whatever method of ovulation induction is employed, monitoring of response is essential to avoid multiple ovulation. For clomifene, ultrasound monitoring is recommended for at least the first cycle. During gonadotrophin therapy, closer monitoring of follicular growth by transvaginal ultrasonography and blood oestradiol levels is mandatory. ‘Ovarian hyperstimulation syndrome’ is characterised by grossly enlarged ovaries and capillary leak with circulatory shock, pleural effusions and ascites. Anovulatory women who fail to respond to ovulation induction or who have primary ovarian failure may wish to consider using donated eggs or embryos, surrogacy and adoption. Surgery to restore Fallopian tube patency can be effective but in vitro fertilisation (IVF) is normally recommended. IVF is widely used for many causes of infertility and in unexplained cases of prolonged (> 3 years) infertility. The success of IVF depends on age, with low success rates in women over 40 years. Men with hypogonadotrophic hypogonadism who wish fertility are usually given injections of hCG several times a week (recombinant FSH may also be required in men with hypogonadism of pre-pubertal origin); it may take up to 2 years to achieve satisfactory sperm counts. Surgery is rarely an option in primary testicular disease but removal of a varicocele can improve semen quality. Extraction of sperm from the epididymis for IVF, and intracytoplasmic sperm injection (ICSI, when single spermatozoa are injected into each oöcyte) are being used increasingly in men with oligospermia or poor sperm quality who have primary testicular disease. Azoospermic men may opt to use donated sperm but this may be in short supply. Gynaecomastia Gynaecomastia is the presence of glandular breast tissue in males. Normal breast development in women is oestrogen-dependent, while androgens oppose this effect. Gynaecomastia results from an imbalance between androgen and oestrogen activity, which may reflect androgen deficiency or oestrogen excess. Causes are listed in Box 18.26. The most common are physiological: for example, in the newborn baby (due to maternal and placental oestrogens), in pubertal boys (in whom oestradiol concentrations 18.26 Causes of gynaecomastia Idiopathic Physiological Drug-induced • Cimetidine • Digoxin • Anti-androgens (cyproterone acetate, spironolactone) • Some exogenous anabolic steroids (diethylstilbestrol) • Cannabis Hypogonadism (see Box 18.20) Androgen resistance syndromes Oestrogen excess • Liver failure (impaired steroid metabolism) • Oestrogen-secreting tumour (e.g. of testis) • Human chorionic gonadotrophin-secreting tumour (e.g. of testis or lung)

658 • ENDOCRINOLOGY Women with PCOS are at increased risk of glucose intolerance and some authorities recommend screening for type 2 diabetes and other cardiovascular risk factors associated with the metabolic syndrome (p. 730). Management This should be directed at the presenting complaint but all PCOS patients who are overweight should be encouraged to lose weight, as this can improve several symptoms, including menstrual irregularity, and reduces the risk of type 2 diabetes. circumstances, other causes of androgen excess should be sought. Congenital adrenal hyperplasia due to 21-hydroxylase deficiency is diagnosed by a short ACTH stimulation test with measurement of 17-OH-progesterone (p. 676). In patients with androgen-secreting tumours, serum testosterone does not suppress following a 48-hour low-dose dexamethasone suppression test. The tumour should then be sought by CT or MRI of the adrenals and ovaries. Management This depends on the cause (Box 18.27). Options for the treatment of PCOS and idiopathic hirsutism are similar and are described below. Polycystic ovarian syndrome Polycystic ovarian syndrome (PCOS) affects up to 10% of women of reproductive age. It is a heterogeneous disorder (Box 18.28), often associated with obesity, for which the primary cause remains uncertain. Genetic factors probably play a role, since PCOS often affects several family members. The severity and clinical features of PCOS vary markedly between individual patients but diagnosis is usually made during the investigation of hirsutism (p. 657) or amenorrhoea/oligomenorrhoea (p. 655). Infertility may also be present (p. 656). There is no universally accepted definition but it has been recommended that a diagnosis of PCOS requires the presence of two of the following three features: • menstrual irregularity • clinical or biochemical androgen excess • multiple cysts in the ovaries (most readily detected by transvaginal ultrasound; Fig. 18.15). 18.27 Causes of hirsutism Cause Clinical features Investigation findings Treatment Idiopathic Often familial Mediterranean or Asian background Normal Cosmetic measures Anti-androgens Polycystic ovarian syndrome Obesity Oligomenorrhoea or secondary amenorrhoea Infertility LH:FSH ratio > 2.5:1 Minor elevation of androgens* Mild hyperprolactinaemia Weight loss Cosmetic measures Anti-androgens (Metformin, glitazones may be useful) Congenital adrenal hyperplasia (95% 21-hydroxylase deficiency) Pigmentation History of salt-wasting in childhood, ambiguous genitalia, or adrenal crisis when stressed Jewish background Elevated androgens* that suppress with dexamethasone Abnormal rise in 17-OH-progesterone with ACTH Glucocorticoid replacement administered in reverse rhythm to suppress early morning ACTH Exogenous androgen administration Athletes Virilisation Low LH and FSH Analysis of urinary androgens may detect drug of misuse Stop steroid misuse Androgen-secreting tumour of ovary or adrenal cortex Rapid onset Virilisation: clitoromegaly, deep voice, balding, breast atrophy High androgens* that do not suppress with dexamethasone Low LH and FSH CT or MRI usually demonstrates a tumour Surgical excision Cushing’s syndrome Clinical features of Cushing’s syndrome (p. 667) Normal or mild elevation of adrenal androgens* See investigations (p. 667) Treat the cause (p. 667) e.g. Serum testosterone levels in women: < 2 nmol/L (< 58 ng/dL) is normal; 2–5 nmol/L (58–144 ng/dL) is minor elevation; > 5 nmol/L (> 144 ng/dL) is high and requires further investigation. (ACTH = adrenocorticotrophic hormone; CT = computed tomography; FH = follicle-stimulating hormone; LH = luteinising hormone; MRI = magnetic resonance imaging) 18.28 Features of polycystic ovarian syndrome Mechanisms Manifestations Pituitary dysfunction High serum LH High serum prolactin Anovulatory menstrual cycles Oligomenorrhoea Secondary amenorrhoea Cystic ovaries Infertility Androgen excess Hirsutism Acne Obesity Hyperglycaemia Elevated oestrogens Insulin resistance Dyslipidaemia Hypertension *These mechanisms are interrelated; it is not known which, if any, is primary. PCOS probably represents the common endpoint of several different pathologies. (LH = luteinising hormone)

The reproductive system • 659

doctor. Electrolysis and laser treatment are effective for small areas like the upper lip and for chest hair but are expensive. Eflornithine cream inhibits ornithine decarboxylase in hair follicles and may reduce hair growth when applied daily to affected areas of the face. If conservative measures are unsuccessful, anti-androgen therapy is given (Box 18.29). The life cycle of a hair follicle is at least 3 months and no improvement is likely before this time, when follicles have shed their hair and replacement hair growth has been suppressed. Metformin and thiazolidinediones are less effective at treating hirsutism than at restoring menstrual regularity. Unless weight is lost, hirsutism will return if therapy is discontinued. The patient should know that prolonged exposure to some agents may not be desirable and they should be stopped before pregnancy. Turner’s syndrome Turner’s syndrome affects around 1 in 2500 females. It is classically associated with a 45XO karyotype but other cytogenetic abnormalities may be responsible, including mosaic forms (e.g. 45XO/46XX or 45XO/46XY) and partial deletions of an X chromosome. Clinical features These are shown in Figure 18.16. Individuals with Turner’s syndrome invariably have short stature from an early age and this is often the initial presenting symptom. It is probably due to haploinsufficiency of the SHOX gene, one copy of which is found on both the X and Y chromosomes, which encodes a protein that is predominantly found in bone fibroblasts. The genital tract and external genitalia in Turner’s syndrome are female in character, since this is the default developmental outcome in the absence of testes. Ovarian tissue develops normally until the third month of gestation, but thereafter there is gonadal dysgenesis with accelerated degeneration of oöcytes and increased ovarian stromal fibrosis, resulting in ‘streak ovaries’. The inability of ovarian tissue to produce oestrogen results in loss of negative feedback and elevation of FSH and LH concentrations. There is a wide variation in the spectrum of associated somatic abnormalities. The severity of the phenotype is, in part, related to Menstrual irregularity and infertility Most women with PCOS have oligomenorrhoea, with irregular, heavy menstrual periods. This may not require treatment unless fertility is desired. Metformin (p. 746), by reducing insulin resistance, may restore regular ovulatory cycles in overweight women, although it is less effective than clomifene (p. 656) at restoring fertility as measured by successful pregnancy. Thiazolidinediones (p. 747) also enhance insulin sensitivity and restore menstrual regularity in PCOS but are contraindicated in women planning pregnancy. In women who have very few periods each year or are amenorrhoeic, the high oestrogen concentrations associated with PCOS can cause endometrial hyperplasia. Progestogens can be administered on a cyclical basis to induce regular shedding of the endometrium and a withdrawal bleed, or a progestogenimpregnated intrauterine coil can be fitted. Hirsutism For hirsutism, most patients will have used cosmetic measures, such as shaving, bleaching and waxing, before consulting a Fig. 18.15 Polycystic ovary. A transvaginal ultrasound scan showing multiple cysts (some indicated by small arrows) in the ovary (highlighted by bigger arrows) of a woman with polycystic ovarian syndrome. 18.29 Anti-androgen therapy Mechanism of action Drug Dose Hazards Androgen receptor antagonism Cyproterone acetate 2, 50 or 100 mg on days 1–11 of 28-day cycle with ethinylestradiol 30 μg on days 1–21 Hepatic dysfunction Feminisation of male fetus Progesterone receptor agonist Dysfunctional uterine bleeding Spironolactone 100–200 mg daily Electrolyte disturbance Flutamide Not recommended Hepatic dysfunction 5α-reductase inhibition (prevent conversion of testosterone to active dihydrotestosterone) Finasteride 5 mg daily Limited clinical experience; possibly less efficacious than other treatments Suppression of ovarian steroid production and elevation of sex hormone-binding globulin Oestrogen See combination with cyproterone acetate above or Conventional oestrogen-containing contraceptive Venous thromboembolism Hypertension Weight gain Dyslipidaemia Increased breast and endometrial carcinoma

660 • ENDOCRINOLOGY Clinical features The diagnosis is typically made in adolescents who have presented with gynaecomastia and failure to progress normally through puberty. Affected individuals usually have small, firm testes. Tall stature is apparent from early childhood, reflecting characteristically long leg length associated with 47XXY, and may be exacerbated by androgen deficiency with lack of epiphyseal closure in puberty. Other clinical features may include learning difficulties and behavioural disorders, as well as an increased risk of breast cancer and type 2 diabetes in later life. The spectrum of clinical features is wide and some individuals, especially the underlying cytogenetic abnormality. Mosaic individuals may have only mild short stature and may enter puberty spontaneously before developing gonadal failure. Diagnosis and management The diagnosis of Turner’s syndrome can be confirmed by karyotype analysis. Short stature, although not directly due to growth hormone deficiency, responds to high doses of growth hormone. Prophylactic gonadectomy is recommended for individuals with 45XO/46XY mosaicism because there is an increased risk of gonadoblastoma. Pubertal development can be induced with oestrogen therapy but causes fusion of the epiphyses and cessation of growth. The timing of pubertal induction therefore needs to be carefully planned. Adults with Turner’s syndrome require long-term oestrogen replacement therapy and should be monitored periodically for the development of aortic root dilatation, hearing loss and other somatic complications. Klinefelter’s syndrome Klinefelter’s syndrome affects approximately 1 in 1000 males and is usually associated with a 47XXY karyotype. However, other cytogenetic variants may be responsible, especially 46XY/47XXY mosaicism. The principal pathological abnormality is dysgenesis of the seminiferous tubules. This is evident from infancy (and possibly even in utero) and progresses with age. By adolescence, hyalinisation and fibrosis are present within the seminiferous tubules and Leydig cell function is impaired, resulting in hypogonadism. Fig. 18.16 Clinical features of Turner’s syndrome (45XO). (IGT = impaired glucose tolerance; LFTs = liver function tests) Psychological problems Impaired visuospatial processing Reduced IQ (ring chromosome X) Low-set ears Sensorineural/conduction hearing loss Webbing of neck (25–40%) Widely spaced nipples Shield chest Type 2 diabetes/IGT (10–30%) Wide carrying angle of elbows Lymphoedema of hands and feet ( 30%) Reduced bone mineral density Inflammatory bowel disease (0.2–0.3%) Horseshoe kidneys and other renal and collecting system abnormalities Bicuspid aortic valve Aortic root dilatation Coronary artery disease Autoimmune thyroid disease (20%) Streak gonads Gonadoblastoma (XY mosaic) Abnormal LFTs (30 – 80%) Short stature Fish-like mouth High-arched palate Coarctation of aorta Hypertension 18.30 Gonadal function in old age • Post-menopausal osteoporosis: a major public health issue due to the high incidence of associated fragility fractures, especially of hip. • Hormone replacement therapy: should be prescribed only above the age of 50 for the short-term relief of symptoms of oestrogen deficiency. • Sexual activity: many older people remain sexually active. • ‘Male menopause’: does not occur, although testosterone concentrations do fall with age. Testosterone therapy in mildly hypogonadal men may be of benefit for body composition, muscle and bone. Large randomised trials are required to determine whether benefits outweigh potentially harmful effects on the prostate and cardiovascular system. • Androgens in older women: hirsutism and balding occur. In those rare patients with elevated androgen levels, this may be pathological, e.g. from an ovarian tumour.

The parathyroid glands • 661

metabolite, 1,25-dihydroxyvitamin D; the 1,25-dihydroxyvitamin D, in turn, enhances calcium absorption from the gut. More than 99% of total body calcium is in bone. Prolonged exposure of bone to high levels of PTH is associated with increased osteoclastic activity and new bone formation, but the net effect is to cause bone loss with mobilisation of calcium into the extracellular fluid. In contrast, pulsatile release of PTH causes net bone gain, an effect that is exploited therapeutically in the treatment of osteoporosis (p. 1048). The differential diagnosis of disorders of calcium metabolism requires measurement of calcium phosphate, alkaline phosphatase, renal function, PTH and 25-hydroxyvitamin D. Although the parathyroid glands detect and respond to ionised calcium levels, most clinical laboratories measure only total serum calcium levels. About 50% of total calcium is bound to organic ions, such as citrate or phosphate, and to proteins, especially albumin. Accordingly, if the serum albumin level is reduced, total calcium concentrations should be ‘corrected’ by adjusting the value for calcium upwards by 0.02 mmol/L (0.08 mg/dL) for each 1 g/L reduction in albumin below 40 g/L. If albumin concentrations are significantly low, as in severe acute illness and other chronic illness such as liver cirrhosis, this correction is less accurate and measurement of ionised calcium is needed. Calcitonin is secreted from the parafollicular C cells of the thyroid gland. Although it is a useful tumour marker in medullary carcinoma of thyroid (p. 650) and can be given therapeutically in Paget’s disease of bone (p. 1053), its release from the thyroid is of no clinical relevance to calcium homeostasis in humans. Disorders of the parathyroid glands are summarised in Box 18.31. Presenting problems in parathyroid disease Hypercalcaemia Hypercalcaemia is one of the most common biochemical abnormalities and is often detected during routine biochemical analysis in asymptomatic patients. However, it can present with chronic symptoms, as described below, and occasionally as an acute emergency with severe hypercalcaemia and dehydration. those with 46XY/47XXY mosaicism, may pass through puberty normally and be identified only during investigation for infertility. Diagnosis and management Klinefelter’s syndrome is suggested by the typical phenotype in a patient with hypergonadotrophic hypogonadism and can be confirmed by karyotype analysis. Individuals with clinical and biochemical evidence of androgen deficiency require androgen replacement (see Box 18.24). There are reports of successful pregnancy occurring following ICSI therapy where spermatocytes have been retrieved from the gonads of men with Klinefelter’s syndrome. The parathyroid glands Parathyroid hormone (PTH) plays a key role in the regulation of calcium and phosphate homeostasis and vitamin D metabolism, as shown in Figure 24.61 (p. 1051). The consequences of altered function of this axis in gut and renal disease are covered on pages 783 and 418, respectively. Other metabolic bone diseases are explored on page 1044. Here, the investigation of hypercalcaemia and hypocalcaemia and disorders of the parathyroid glands are discussed. Functional anatomy, physiology and investigations The four parathyroid glands lie behind the lobes of the thyroid and weigh between 25 and 40 mg. The parathyroid chief cells respond directly to changes in calcium concentrations via a G protein-coupled cell surface receptor (the calcium-sensing receptor) located on the cell surface (see Fig. 25.55). When serum ionised calcium levels fall, PTH secretion rises. PTH is a single-chain polypeptide of 84 amino acids. It acts on the renal tubules to promote reabsorption of calcium and reduce reabsorption of phosphate, and on the skeleton to increase osteoclastic bone resorption and bone formation. PTH also promotes the conversion of 25-hydroxyvitamin D to the active 18.31 Classification of diseases of the parathyroid glands Primary Secondary Hormone excess Primary hyperparathyroidism Parathyroid adenoma Parathyroid carcinoma1 Parathyroid hyperplasia2 Tertiary hyperparathyroidism Following prolonged secondary hyperparathyroidism Secondary hyperparathyroidism Chronic kidney disease Malabsorption Vitamin D deficiency Hormone deficiency Hypoparathyroidism Post-surgical Autoimmune Inherited Hormone hypersensitivity Autosomal dominant hypercalciuric hypocalcaemic (CASR-activating mutation) Hormone resistance Pseudohypoparathyroidism Familial hypocalciuric hypercalcaemia Non-functioning tumours Parathyroid carcinoma1 1Parathyroid carcinomas may or may not produce parathyroid hormone. 2ln multiple endocrine neoplasia (MEN) syndromes (p. 688). (CASR = calcium-sensing receptor)

662 • ENDOCRINOLOGY 5% of first stone formers and 15% of recurrent stone formers have primary hyperparathyroidism (p. 663). Hypertension is a common feature of hyperparathyroidism. Parathyroid tumours are almost never palpable. A family history of hypercalcaemia raises the possibility of FHH or MEN (p. 688). Investigations The most discriminatory investigation is measurement of PTH. If PTH levels are detectable or elevated in the presence of hypercalcaemia, then primary hyperparathyroidism is the most likely diagnosis. High plasma phosphate and alkaline phosphatase accompanied by renal impairment suggest tertiary hyperparathyroidism. Hypercalcaemia may cause nephrocalcinosis and renal tubular impairment, resulting in hyperuricaemia and hyperchloraemia. Patients with FHH can present with a similar biochemical picture to primary hyperparathyroidism but typically have low urinary calcium excretion (a ratio of urinary calcium clearance to creatinine clearance of < 0.01). The diagnosis of FHH can be confirmed by screening family members for hypercalcaemia and/ or identifying an inactivating mutation in the gene encoding the calcium-sensing receptor. If PTH is low and no other cause is apparent, then malignancy with or without bony metastases is likely. PTH-related peptide, which is often responsible for the hypercalcaemia associated with malignancy, is not detected by PTH assays, but can be measured by a specific assay (although this is not usually necessary). Unless the source is obvious, the patient should be screened for malignancy with a chest X-ray, myeloma screen (p. 967) and CT as appropriate. Management Treatment of severe hypercalcaemia and primary hyperparathyroidism is described on pages 663 and 1327, respectively. FHH does not require any specific intervention. Hypocalcaemia Aetiology Hypocalcaemia is much less common than hypercalcaemia. The differential diagnosis is shown in Box 18.33. The most common Causes of hypercalcaemia are listed in Box 18.32. Of these, primary hyperparathyroidism and malignant hypercalcaemia are by far the most common. Familial hypocalciuric hypercalcaemia (FHH) is a rare but important cause that needs differentiation from primary hyperparathyroidism (HPT). Lithium may cause hyperparathyroidism by reducing the sensitivity of the calciumsensing receptor. Clinical assessment Symptoms and signs of hypercalcaemia include polyuria and polydipsia, renal colic, lethargy, anorexia, nausea, dyspepsia and peptic ulceration, constipation, depression, drowsiness and impaired cognition. Patients with malignant hypercalcaemia can have a rapid onset of symptoms and may have clinical features that help to localise the tumour. The classic symptoms of primary hyperparathyroidism are described by the adage ‘bones, stones and abdominal groans’, but few patients present in this way nowadays and the disorder is most often picked up as an incidental finding on biochemical testing. About 50% of patients with primary hyperparathyroidism are asymptomatic while others have non-specific symptoms such as fatigue, depression and generalised aches and pains. Some present with renal calculi and it has been estimated that 18.32 Causes of hypercalcaemia With normal or elevated parathyroid hormone (PTH) levels • Primary or tertiary hyperparathyroidism • Lithium-induced hyperparathyroidism • Familial hypocalciuric hypercalcaemia With low PTH levels • Malignancy (lung, breast, myeloma, renal, lymphoma, thyroid) • Elevated 1,25-dihydroxyvitamin D (vitamin D intoxication, sarcoidosis, human immunodeficiency virus, other granulomatous disease) • Thyrotoxicosis • Paget’s disease with immobilisation • Milk-alkali syndrome • Thiazide diuretics • Glucocorticoid deficiency 18.33 Differential diagnosis of hypocalcaemia Total serum calcium Ionised serum calcium Serum phosphate Serum PTH Comments Hypoalbuminaemia ↓ ↔ ↔ ↔ Adjust calcium upwards by 0.02 mmol/L (0.1 mg/dL) for every 1 g/L reduction in albumin below 40 g/L Alkalosis ↔ ↓ ↔ ↔ or ↑ p. 366 Vitamin D deficiency ↓ ↓ ↓ ↑ p. 1049 Chronic renal failure ↓ ↓ ↑ ↑ Due to impaired vitamin D hydroxylation Serum creatinine ↑ Hypoparathyroidism ↓ ↓ ↑ ↓ See text Pseudohypoparathyroidism ↓ ↓ ↑ ↑ Characteristic phenotype (see text) Acute pancreatitis ↓ ↓ ↔ or ↓ ↑ Usually clinically obvious Serum amylase ↑ Hypomagnesaemia ↓ ↓ Variable ↓ or ↔ Treatment of hypomagnesaemia may correct hypocalcaemia (↑ = levels increased; ↓ = levels reduced; ↔ = levels normal)

The parathyroid glands • 663

Primary hyperparathyroidism Primary hyperparathyroidism is caused by autonomous secretion of PTH, usually by a single parathyroid adenoma, which can vary in diameter from a few millimetres to several centimetres. It should be distinguished from secondary hyperparathyroidism, in which there is a physiological increase in PTH secretion to compensate for prolonged hypocalcaemia (such as in vitamin D deficiency, p. 1049), and from tertiary hyperparathyroidism, in which continuous stimulation of the parathyroids over a prolonged period of time results in adenoma formation and autonomous PTH secretion (Box 18.35). This is most commonly seen in individuals with advanced chronic kidney disease (p. 418). The prevalence of primary hyperparathyroidism is about 1 in 800 and it is 2–3 times more common in women than men; 90% of patients are over 50 years of age. It also occurs in the familial MEN syndromes (p. 688), in which case hyperplasia or multiple adenomas of all four parathyroid glands are more likely than a solitary adenoma. Clinical and radiological features The clinical presentation of primary hyperparathyroidism is described on page 667. Parathyroid bone disease is now rare due to earlier diagnosis and treatment. Osteitis fibrosa results from increased bone resorption by osteoclasts with fibrous replacement in the lacunae. This may present as bone pain and tenderness, fracture and deformity. Chondrocalcinosis can occur due to deposition of calcium pyrophosphate crystals within articular cartilage. It typically affects the menisci at the knees and can result in secondary degenerative arthritis or predispose to attacks of acute pseudogout (p. 1016). Skeletal X-rays are usually normal in mild primary hyperparathyroidism, but in patients with advanced disease characteristic changes are observed. In the early stages there is demineralisation, with subperiosteal erosions and terminal resorption in the phalanges. A ‘pepper-pot’ appearance may be seen on lateral X-rays of the skull. Reduced bone mineral density, resulting in either osteopenia or osteoporosis, is now the most common skeletal manifestation of hyperparathyroidism. This is usually not evident radiographically and requires assessment by DXA (p. 989). In nephrocalcinosis, scattered opacities may be visible within the renal outline. There may be soft tissue calcification in arterial walls and hands and in the cornea. Investigations The diagnosis can be confirmed by finding a raised PTH level in the presence of hypercalcaemia, provided that FHH is excluded cause of hypocalcaemia is a low serum albumin with normal ionised calcium concentration. Conversely, ionised calcium may be low in the face of normal total serum calcium in patients with alkalosis: for example, as a result of hyperventilation. Hypocalcaemia may also develop as a result of magnesium depletion and should be considered in patients with malabsorption, those on diuretic or proton pump inhibitor therapy, and/or those with a history of alcohol excess. Magnesium deficiency causes hypocalcaemia by impairing the ability of the parathyroid glands to secrete PTH (resulting in PTH concentrations that are low or inappropriately in the reference range) and may also impair the actions of PTH on bone and kidney. Clinical assessment Mild hypocalcaemia is often asymptomatic but, with more profound reductions in serum calcium, tetany can occur. This is characterised by muscle spasms due to increased excitability of peripheral nerves. Children are more liable to develop tetany than adults and present with a characteristic triad of carpopedal spasm, stridor and convulsions, although one or more of these may be found independently of the others. In carpopedal spasm, the hands adopt a characteristic position with flexion of the metacarpophalangeal joints of the fingers and adduction of the thumb (‘main d’accoucheur’). Pedal spasm can also occur but is less frequent. Stridor is caused by spasm of the glottis. Adults can also develop carpopedal spasm in association with tingling of the hands and feet and around the mouth, but stridor and fits are rare. Latent tetany may be detected by eliciting Trousseau’s sign: inflation of a sphygmomanometer cuff on the upper arm to more than the systolic blood pressure is followed by carpal spasm within 3 minutes. Less specific is Chvostek’s sign, in which tapping over the branches of the facial nerve as they emerge from the parotid gland produces twitching of the facial muscles. Hypocalcaemia can cause papilloedema and prolongation of the ECG QT interval, which may predispose to ventricular arrhythmias. Prolonged hypocalcaemia and hyperphosphataemia (as in hypoparathyroidism) may cause calcification of the basal ganglia, grand mal epilepsy, psychosis and cataracts. Hypocalcaemia associated with hypophosphataemia, as in vitamin D deficiency, causes rickets in children and osteomalacia in adults (p. 1049). Management Emergency management of hypocalcaemia associated with tetany is given in Box 18.34. Treatment of chronic hypocalcaemia is described on page 1051. 18.34 Management of severe hypocalcaemia Immediate management • 10–20 mL 10% calcium gluconate IV over 10–20 mins • Continuous IV infusion may be required for several hours (equivalent of 10 mL 10% calcium gluconate/hr) • Cardiac monitoring is recommended If associated with hypomagnesaemia • 50 mmol (1.23 g) magnesium chloride IV over 24 hrs • Most parenteral magnesium will be excreted in the urine, so further doses may be required to replenish body stores 18.35 Hyperparathyroidism Type Serum calcium PTH Primary Single adenoma (90%) Multiple adenomas (4%) Nodular hyperplasia (5%) Carcinoma (1%) Raised Not suppressed Secondary Chronic renal failure Malabsorption Osteomalacia and rickets Low Raised Tertiary Raised Not suppressed

664 • ENDOCRINOLOGY always asymptomatic and complications do not occur. The main risk of FHH is that of the patient being subjected to an unnecessary (and ineffective) parathyroidectomy if misdiagnosed as having primary hyperparathyroidism. Testing of family members for hypercalcaemia is helpful in confirming the diagnosis and it is also possible to perform genetic testing. No treatment is necessary. Hypoparathyroidism The most common cause of hypoparathyroidism is damage to the parathyroid glands (or their blood supply) during thyroid surgery. Rarely, hypoparathyroidism can occur as a result of infiltration of the glands with iron in haemochromatosis (p. 895) or copper in Wilson’s disease (p. 896). There are a number of rare congenital or inherited forms of hypoparathyroidism. One form is associated with autoimmune polyendocrine syndrome type 1 (p. 689) and another with DiGeorge syndrome (p. 79). Autosomal dominant hypoparathyroidism is the mirror image of FHH (see above), in that an activating mutation in the calcium-sensing receptor reduces PTH levels, resulting in hypocalcaemia and hypercalciuria. Pseudohypoparathyroidism In this disorder, the individual is functionally hypoparathyroid but, instead of PTH deficiency, there is tissue resistance to the effects of PTH, such that PTH concentrations are markedly elevated. The PTH receptor itself is normal but the downstream signalling pathways are defective due to mutations that affect GNAS1, which encodes the Gsα protein, a molecule involved in signal transduction downstream of the PTH receptor and other G protein-coupled receptors. There are several subtypes but the most common (pseudohypoparathyroidism type 1a) is characterised by hypocalcaemia and hyperphosphataemia, in association with short stature, short fourth metacarpals and metatarsals, rounded face, obesity and subcutaneous calcification; these features are collectively referred to as Albright’s hereditary osteodystrophy (AHO). Type 1a pseudohypoparathyroidism occurs only when the GNAS1 mutation is inherited on the maternal chromosome (maternal imprinting, p. 49). The term pseudopseudohypoparathyroidism is used to describe patients who have clinical features of AHO but normal serum calcium and PTH concentrations; it occurs when the GNAS1 mutation is inherited on the paternal chromosome. The inheritance of these disorders is an example of genetic imprinting (p. 49). The difference in clinical features occurs as a result of the fact that renal cells exclusively express the maternal GNAS1 allele, whereas both maternal and paternal alleles are expressed in other cell types; this explains why maternal inheritance is associated with hypocalcaemia and resistance to PTH (which regulates (p. 664). Parathyroid scanning by 99mTc-sestamibi scintigraphy (MIBI; Fig. 18.17) and an ultrasound examination can be performed prior to surgery, in an attempt to localise an adenoma; a concordant finding of tissue consistent with a parathyroid gland and uptake on the MIBI scan allows a targeted resection. Negative imaging does not exclude the diagnosis, however, and four-gland exploration may be needed. Management The treatment of choice for primary hyperparathyroidism is surgery, with excision of a solitary parathyroid adenoma or hyperplastic glands. Experienced surgeons will identify solitary tumours in more than 90% of cases. Patients with parathyroid bone disease run a significant risk of developing hypocalcaemia post-operatively but the risk of this can be reduced by correcting vitamin D deficiency pre-operatively. Surgery is usually indicated for individuals aged less than 50 years, with clear-cut symptoms or documented complications (such as renal stones, renal impairment or osteoporosis), and (in asymptomatic patients) significant hypercalcaemia (corrected serum calcium > 2.85 mmol/L (> 11.4 mg/dL)). Patients who are treated conservatively without surgery should have calcium biochemistry and renal function checked annually and bone density monitored periodically. They should be encouraged to maintain a high oral fluid intake to avoid renal stones. Occasionally, primary hyperparathyroidism presents with severe life-threatening hypercalcaemia. This is often due to dehydration and should be managed medically with intravenous fluids and bisphosphonates, as described on page 1327. If this is not effective, then urgent parathyroidectomy should be considered. Cinacalcet (p. 419) is a calcimimetic that enhances the sensitivity of the calcium-sensing receptor, so reducing PTH levels, and is licensed for tertiary hyperparathyroidism and as a treatment for patients with primary hyperparathyroidism who are unwilling to have surgery or are medically unfit. Familial hypocalciuric hypercalcaemia This autosomal dominant disorder is caused by an inactivating mutation in one of the alleles of the calcium-sensing receptor gene, which reduces the ability of the parathyroid gland to ‘sense’ ionised calcium concentrations. As a result, higher than normal calcium levels are required to suppress PTH secretion. The typical presentation is with mild hypercalcaemia with PTH concentrations that are ‘inappropriately’ at the upper end of the reference range or are slightly elevated. Calcium-sensing receptors in the renal tubules are also affected and this leads to increased renal tubular reabsorption of calcium and hypocalciuria (as measured in the vitamin D-replete individual by a fractional calcium excretion or 24-hour calcium excretion). The hypercalcaemia of FHH is Fig. 18.17 99mTc-sestamibi scan of a patient with primary hyperparathyroidism secondary to a parathyroid adenoma. A After 1 hour, there is uptake in the thyroid gland (thick arrow) and the enlarged left inferior parathyroid gland (thin arrow). B After 3 hours, uptake is evident only in the parathyroid (thin arrow). A B

The adrenal glands • 665

the control of the renin–angiotensin system. These functions are important in the integrated control of cardiovascular, metabolic and immune responses to stress. There is increasing evidence that subtle alterations in adrenal function contribute to the pathogenesis of common diseases such as hypertension, obesity and type 2 diabetes mellitus. However, classical syndromes of adrenal hormone deficiency and excess are relatively rare. Functional anatomy and physiology Adrenal anatomy and function are shown in Figure 18.18. Histologically, the cortex is divided into three zones, but these function as two units (zona glomerulosa and zonae fasciculata/ reticularis) that produce corticosteroids in response to humoral stimuli. Pathways for the biosynthesis of corticosteroids are shown in Figure 18.19. Investigation of adrenal function is described under specific diseases below. The different types of adrenal disease are shown in Box 18.37. Glucocorticoids Cortisol is the major glucocorticoid in humans. Levels are highest in the morning on waking and lowest in the middle of the night. Cortisol rises dramatically during stress, including any illness. This elevation protects key metabolic functions (such as the maintenance of cerebral glucose supply during starvation) and inhibits potentially damaging inflammatory responses to infection and injury. The clinical importance of cortisol deficiency is, therefore, most obvious at times of stress. More than 95% of circulating cortisol is bound to protein, principally cortisol-binding globulin, which is increased by oestrogens. It is the free fraction that is biologically active. Cortisol regulates cell function by binding to glucocorticoid receptors that regulate the transcription of many genes. Cortisol can also activate mineralocorticoid receptors, but it does not normally do so because most cells containing mineralocorticoid receptors also express an enzyme called 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2), which inactivates cortisol by converting it to cortisone. Inhibitors of 11β-HSD2 (such as liquorice) or mutations in the gene that encodes 11β-HSD2 cause cortisol to act as a mineralocorticoid, resulting in sodium retention and hypertension (see Box 18.46). serum calcium and phosphate levels largely by an effect on the renal tubule), and why paternal inheritance is associated with skeletal and other abnormalities in the absence of hypocalcaemia and raised PTH values. Management of hypoparathyroidism Persistent hypoparathyroidism and pseudohypoparathyroidism are treated with oral calcium salts and vitamin D analogues, either 1α-hydroxycholecalciferol (alfacalcidol) or 1,25dihydroxycholecalciferol (calcitriol). This therapy needs careful monitoring because of the risks of iatrogenic hypercalcaemia, hypercalciuria and nephrocalcinosis. Recombinant PTH is available as subcutaneous injection therapy for osteoporosis (p. 1048) and, although not currently licensed, has been used in hypoparathyroidism (but not in pseudohypoparathyroidism). It is much more expensive than calcium and vitamin D analogue therapy but has the advantage that it is less likely to cause hypercalciuria. There is no specific treatment for AHO other than to try to maintain calcium levels within the reference range using active vitamin D metabolites. 18.36 The parathyroid glands in old age • Osteoporosis: always exclude osteomalacia and hyperparathyroidism by checking vitamin D and calcium concentrations. • Primary hyperparathyroidism: more common with ageing. Older people can often be observed without surgical intervention. • Hypercalcaemia: may cause delirium. • Vitamin D deficiency: common because of limited exposure to the sun and reduced ability of older skin to synthesise cholecalciferol. 18.37 Classification of diseases of the adrenal glands Primary Secondary Hormone excess Non-ACTH-dependent Cushing’s syndrome Primary hyperaldosteronism Phaeochromocytoma ACTH-dependent Cushing’s syndrome Secondary hyperaldosteronism Hormone deficiency Addison’s disease Congenital adrenal hyperplasia Hypopituitarism Hormone hypersensitivity 11β-hydroxysteroid dehydrogenase type 2 deficiency Liddle’s syndrome Hormone resistance Pseudohypoaldosteronism Glucocorticoid resistance syndrome Non-functioning tumours Adenoma Carcinoma (usually functioning) Metastatic tumours (ACTH = adrenocorticotrophic hormone) The adrenal glands The adrenals comprise several separate endocrine glands within a single anatomical structure. The adrenal medulla is an extension of the sympathetic nervous system that secretes catecholamines into capillaries rather than synapses. Most of the adrenal cortex is made up of cells that secrete cortisol and adrenal androgens, and form part of the hypothalamic–pituitary–adrenal (HPA) axis. The small outer glomerulosa of the cortex secretes aldosterone under

666 • ENDOCRINOLOGY Fig. 18.18 Structure and function of the adrenal glands. (ACE = angiotensin-converting enzyme; ACTH = adrenocorticotrophic hormone; JGA = juxtaglomerular apparatus; MR = mineralocorticoid receptor) Sympathetic nervous system Medulla Adrenaline (epinephrine) Noradrenaline (norepinephrine) β-adrenoceptor α-adrenoceptor Vasodilatation Tachycardia Insulin resistance Vasoconstriction Sympathetic nervous system Adrenal medulla ACTH Cortex Zonae fasciculata and reticularis Hypothalamic – pituitary– adrenal axis Adrenal cortex Zonae fasciculata and reticularis Androgens Cortisol Androgen receptor Glucocorticoid receptor Pubic and axillary hair Libido, especially females Protein catabolism Insulin resistance Immune response Hypertension Increased appetite Memory Na retention K wasting Metabolic alkalosis Low renal perfusion Low filtered Na Sympathetic activation Angiotensin II Cortex Zona glomerulosa Aldosterone Renin – angiotensin – aldosterone axis Adrenal cortex Zona glomerulosa Angiotensin I Angiotensinogen Renin ACE MR JGA Adrenal gland Negative feedback Mineralocorticoids Aldosterone is the most important mineralocorticoid. It binds to mineralocorticoid receptors in the kidney and causes sodium retention and increased excretion of potassium and protons (p. 351). The principal stimulus to aldosterone secretion is angiotensin II, a peptide produced by activation of the renin–angiotensin system (see Fig. 18.18). Renin activity in the juxtaglomerular apparatus of the kidney is stimulated by low perfusion pressure in the afferent arteriole, low sodium filtration leading to low sodium concentrations at the macula densa, or increased sympathetic nerve activity. As a result, renin activity is increased in hypovolaemia and renal artery stenosis, and is approximately doubled when standing up from a recumbent position. Catecholamines In humans, only a small proportion of circulating noradrenaline (norepinephrine) is derived from the adrenal medulla; much more is released from sympathetic nerve endings. Conversion of noradrenaline to adrenaline (epinephrine) is catalysed by catechol O-methyltransferase (COMT), which is induced by glucocorticoids. Blood flow in the adrenal is centripetal, so that the medulla is bathed in high concentrations of cortisol and is the major source of circulating adrenaline. However, after surgical removal of the adrenal medullae, there appear to be no clinical consequences attributable to deficiency of circulating catecholamines. Adrenal androgens Adrenal androgens are secreted in response to ACTH and are the most abundant steroids in the blood stream. They are probably important in the initiation of puberty (adrenarche). The adrenals are also the major source of androgens in adult females and may be important in female libido. Presenting problems in adrenal disease Cushing’s syndrome Cushing’s syndrome is caused by excessive activation of glucocorticoid receptors. It is most commonly iatrogenic, due to prolonged administration of synthetic glucocorticoids such as

The adrenal glands • 667

pigmentation because of binding to melanocortin 1 receptors on melanocytes in the skin. The high cortisol levels also overcome the capacity of 11β-HSD2 to inactivate cortisol in the kidney (p. 665), causing hypokalaemic alkalosis that aggravates myopathy and hyperglycaemia (by inhibiting insulin secretion). When the tumour that is secreting ACTH is malignant, then the onset is usually rapid and may be associated with cachexia. For these reasons, the classical features of Cushing’s syndrome are less common in ectopic ACTH syndrome; if present, they suggest that a less aggressive tumour, such as a bronchial carcinoid, is responsible. In Cushing’s disease, the pituitary tumour is usually a microadenoma (< 10 mm in diameter); hence other features of a pituitary macroadenoma (hypopituitarism, visual failure or disconnection hyperprolactinaemia, p. 684) are rare. Investigations The large number of tests available for Cushing’s syndrome reflects the fact that each one has limited specificity and sensitivity prednisolone. Endogenous Cushing’s syndrome is uncommon but is caused by chronic over-production of cortisol by the adrenal glands, either as the result of an adrenal tumour or because of excessive production of ACTH by a pituitary tumour or ectopic ACTH production by other tumours. Aetiology The causes are shown in Box 18.38. Amongst endogenous causes, pituitary-dependent cortisol excess (by convention, called Cushing’s disease) accounts for approximately 80% of cases. Both Cushing’s disease and cortisol-secreting adrenal tumours are four times more common in women than men. In contrast, ectopic ACTH syndrome (often due to a small-cell carcinoma of the bronchus) is more common in men. Clinical assessment The diverse manifestations of glucocorticoid excess are shown in Figure 18.20. Many of these are not specific to Cushing’s syndrome and, because spontaneous Cushing’s syndrome is rare, the positive predictive value of any single clinical feature alone is low. Moreover, some common disorders can be confused with Cushing’s syndrome because they are associated with alterations in cortisol secretion, e.g. obesity and depression (Box 18.38). Features that favour Cushing’s syndrome in an obese patient are bruising, myopathy and thin skin. Any clinical suspicion of cortisol excess is best resolved by further investigation. It is vital to exclude iatrogenic causes in all patients with Cushing’s syndrome since even inhaled or topical glucocorticoids can induce the syndrome in susceptible individuals. A careful drug history must therefore be taken before embarking on complex investigations. An 0800–0900-hr serum cortisol of < 100 nmol/L (3.6 μg/dL) in a patient with a normal sleep–wake pattern and Cushingoid appearance is consistent with exogenous synthetic glucocorticoid use (common) or cyclical secretion of cortisol from endogenous Cushing’s (uncommon). Some clinical features are more common in ectopic ACTH syndrome. While ACTH-secreting pituitary tumours retain some negative feedback sensitivity to cortisol, this is absent in tumours that produce ectopic ACTH, typically resulting in higher levels of both ACTH and cortisol than are observed in pituitary-driven disease. The high ACTH levels are associated with marked Fig. 18.19 The major pathways of synthesis of steroid hormones. (DHEAS = dehydroepiandrosterone sulphate; HSD = hydroxysteroid dehydrogenase) Cholesterol Pregnenolone 17-OHpregnenolone DHEAS Progesterone 17-OHprogesterone Androstenedione Oestrone 11-deoxycorticosterone 11-deoxycortisol Testosterone Oestradiol Corticosterone Cortisol Dihydrotestosterone Aldosterone 3β-HSD 17-hydroxylase 17,20-lyase 21-hydroxylase 17β-HSD Aromatase 11β-hydroxylase Aldo synthase 5α-reductase Enzymes outside the adrenal Enzymes in the adrenal Glucocorticoids Key Mineralocorticoids Androgens Oestrogens Progesterone 18.38 Classification of endogenous Cushing’s syndrome ACTH-dependent – 80% • Pituitary adenoma secreting ACTH (Cushing’s disease) – 70% • Ectopic ACTH syndrome (bronchial carcinoid, small-cell lung carcinoma, other neuro-endocrine tumour) – 10% Non-ACTH-dependent – 20% • Adrenal adenoma – 15% • Adrenal carcinoma – 5% • ACTH-independent macronodular hyperplasia; primary pigmented nodular adrenal disease; McCune–Albright syndrome (together < 1%) Hypercortisolism due to other causes (also referred to as pseudo-Cushing’s syndrome) • Alcohol excess (biochemical and clinical features) • Major depressive illness (biochemical features only, some clinical overlap) • Primary obesity (mild biochemical features, some clinical overlap) (ACTH = adrenocorticotrophic hormone)

668 • ENDOCRINOLOGY measured following administration of 0.5 mg dexamethasone 4 times daily for 48 hours. For either test, a normal response is a serum cortisol of < 50 nmol/L (1.8 μg/dL). It is important for any oestrogens to be stopped for 6 weeks prior to investigation to allow corticosteroid-binding globulin (CBG) levels to return to normal and to avoid false-positive responses, as most cortisol assays measure total cortisol, including that bound to CBG. Cyclicity of cortisol secretion is a feature of all types of Cushing’s syndrome and, if very variable, can confuse diagnosis. Use of multiple salivary cortisol samples over weeks or months can be helpful in diagnosis but an elevated salivary cortisol alone should not be taken as proof of diagnosis. In iatrogenic Cushing’s syndrome, cortisol levels are low unless the patient is taking a glucocorticoid (such as prednisolone) that cross-reacts in immunoassays with cortisol. Determining the underlying cause Once the presence of Cushing’s syndrome is confirmed, measurement of plasma ACTH is the key to establishing the differential diagnosis; it is best measured in the morning around 0900 hrs. In the presence of excess cortisol secretion, an undetectable ACTH (< 1.1 pmol/L (5 ng/L)) indicates an adrenal cause, while ACTH levels of > 3.3 pmol/L (15 ng/L) suggest a pituitary cause or ectopic ACTH. ACTH levels between these values represent a ‘grey area’ and further evaluation by a specialist is required. Tests to discriminate pituitary from ectopic sources of ACTH rely on the fact that pituitary tumours, but not ectopic tumours, retain some features of normal regulation of Fig. 18.20 Cushing’s syndrome. A Clinical features common to all causes. B A patient with Cushing’s disease before treatment. C The same patient 1 year after the successful removal of an ACTH-secreting pituitary microadenoma by trans-sphenoidal surgery. Psychosis Cataracts Mild exophthalmos Hair thinning Hirsutism Acne Plethora Moon face Peptic ulcer Hyperglycaemia Menstrual disturbance May have exuberant callus with fractures Osteoporosis Tendency to infections with poor wound healing and little inflammatory response Hypertension Centripetal obesity Striae Wasting and weakness of proximal thigh muscles Bruising Loss of height and back pain from compression fracture Decreased skin thickness A B C in isolation. Accordingly, several tests are usually combined to establish the diagnosis. Testing for Cushing’s syndrome should be avoided under conditions of stress, such as an acute illness, because this activates the HPA axis, causing potentially spurious results. The diagnosis of Cushing’s is a two-step process:

  1. to establish whether the patient has Cushing’s syndrome (Fig. 18.21)
  2. to define its cause (Fig. 18.22). Some additional tests are useful in all cases of Cushing’s syndrome, including plasma electrolytes, glucose, glycosylated haemoglobin and bone mineral density measurement. Establishing the presence of Cushing’s syndrome In patients where there is appropriate clinical suspicion, Cushing’s syndrome is confirmed by using two of three main tests:
  3. failure to suppress serum cortisol with low doses of oral dexamethasone
  4. loss of the normal circadian rhythm of cortisol, with inappropriately elevated late-night serum or salivary cortisol
  5. increased 24-hour urine free cortisol (see Fig. 18.21). Dexamethasone is used for suppression testing because it does not cross-react in immunoassays for cortisol. An overnight dexamethasone suppression test (ONDST) involves administration of 1 mg dexamethasone at 2300 hrs and measurement of serum cortisol at 0900 hrs the following day. In a low-dose dexamethasone suppression test (LDDST), serum cortisol is

The adrenal glands • 669

with approximately 70% of patients going into immediate remission. Around 20% of patients suffer a recurrence, often years later, emphasising the need for life-long follow-up. Laparoscopic bilateral adrenalectomy performed by an expert surgeon effectively cures ACTH-dependent Cushing’s syndrome, but in patients with pituitary-dependent Cushing’s syndrome this can result in Nelson’s syndrome. In Nelson’s syndrome, the loss of negative feedback from endogenous cortisol results in growth of the pituitary tumour, often leading to an invasive pituitary macroadenoma (which causes local mass effects) and very high ACTH levels (which cause pigmentation). The risk of Nelson’s syndrome is reported as being reduced by pituitary irradiation in some series, but not all. The somatostatin analogue pasireotide is also licensed for the treatment of Cushing’s disease and works by suppressing ACTH secretion by the tumour. It may cause tumour shrinkage but cortisol levels are likely to return to pre-treatment levels following cessation of therapy. Pasireotide has to be administered by twice-daily subcutaneous injection and is relatively expensive. It is an alternative to drugs that inhibit glucocorticoid biosynthesis in patients who are not suitable for a surgical approach. Adrenal tumours Laparoscopic adrenal surgery is the treatment of choice for adrenal adenomas. Surgery offers the only prospect of cure for adrenocortical carcinomas but, in general, prognosis is poor with high rates of recurrence, even in patients with localised disease at presentation. Radiotherapy to the tumour bed reduces ACTH secretion. Thus, in pituitary-dependent Cushing’s disease, ACTH secretion is suppressed by high-dose dexamethasone and ACTH is stimulated by corticotrophin-releasing hormone (CRH). In a high-dose dexamethasone suppression test (HDDST), serum cortisol is measured before and after administration of 2 mg of dexamethasone 4 times daily for 48 hours. Techniques for localisation of tumours secreting ACTH or cortisol are listed in Figure 18.22. MRI detects around 60% of pituitary microadenomas secreting ACTH. If available, bilateral inferior petrosal sinus sampling (BIPSS) with measurement of ACTH is the best means of confirming Cushing’s disease, unless MRI shows a tumour bigger than 6 mm, in which case it may not be needed. CT or MRI detects most adrenal tumours; adrenal carcinomas are usually large (> 5 cm) and have other features of malignancy (p. 673). Management Untreated severe Cushing’s syndrome has a 50% 5-year mortality. Most patients are treated surgically, but medical therapy may be given in severe cases for a few weeks prior to operation to improve the clinical state. A number of drugs are available that inhibit glucocorticoid biosynthesis, including metyrapone and ketoconazole. The dose of these agents is best titrated against serum cortisol levels or 24-hour urine free cortisol. Cushing’s disease Trans-sphenoidal surgery carried out by an experienced surgeon with selective removal of the adenoma is the treatment of choice, Fig. 18.21 Sequence of investigations in suspected spontaneous Cushing’s syndrome. A serum cortisol of 50 nmol/L is equivalent to 1.8 μg/dL. (LDDST = low-dose dexamethasone suppression test; ONDST = overnight dexamethasone suppression test; UFC = urinary free cortisol) Cushing’s syndrome suspected Exclude exogenous glucocorticoid exposure Perform one of the following tests Any abnormal result Suggest additional evaluation, repeat testing at interval or seek further opinion Normal result Cushing’s syndrome unlikely Perform 1 or 2 other studies shown above and consider repeating abnormal study At least two concordant abnormal tests Discrepant test results Cushing’s syndrome Normal result Cushing’s syndrome unlikely 24-UFC (≥ 2 tests) – Elevated if above reference range for assay Late-night salivary cortisol – Abnormal if above local reference range ONDST or LDDST – Abnormal if serum cortisol > 50 nmol/L

670 • ENDOCRINOLOGY Adverse effects of glucocorticoids The clinical features of glucocorticoid excess are illustrated in Figure 18.20. Adverse effects are related to dose, duration of therapy, and pre-existing conditions that might be worsened by glucocorticoid therapy, such as diabetes mellitus or osteoporosis. Osteoporosis is a particularly important problem because, for a given bone mineral density, the fracture risk is greater in glucocorticoid-treated patients than in post-menopausal osteoporosis. Therefore, when systemic glucocorticoids are prescribed and the anticipated duration of steroid therapy is more than 3 months, bone-protective therapy should be considered, as detailed on page 1005. Rapid changes in glucocorticoid levels can also lead to marked mood disturbances, including depression, mania and insomnia. Glucocorticoid use also increases the white blood cell count (predominantly neutrophils), which must be taken into account when assessing patients with possible infection. the risk of local recurrence; systemic therapy consists of the adrenolytic drug mitotane and chemotherapy, but responses are often poor. Ectopic ACTH syndrome Localised tumours, such as bronchial carcinoid, should be removed surgically. In patients with incurable malignancy, it is important to reduce the severity of the Cushing’s syndrome using medical therapy (see above) or, if appropriate, bilateral adrenalectomy. Therapeutic use of glucocorticoids The remarkable anti-inflammatory properties of glucocorticoids have led to their use in a wide variety of clinical conditions but the hazards are significant. Equivalent doses of commonly used glucocorticoids are listed in Box 18.39. Topical preparations (dermal, rectal and inhaled) can also be absorbed into the systemic circulation, and although this rarely occurs to a sufficient degree to produce clinical features of Cushing’s syndrome, it can result in significant suppression of endogenous ACTH and cortisol secretion. Severe Cushing’s syndrome can result if there is concomitant administration of inhaled glucocorticoids and strong inhibitors of the liver enzyme CYP450 3A4, such as the antiretroviral drug ritonavir (p. 324). Fig. 18.22 Determining the cause of confirmed Cushing’s syndrome. To convert pmol/L to ng/L, multiply by 4.541. (ACTH = adrenocorticotrophic hormone; AIMAH = ACTH-independent macronodular adrenal hyperplasia; BIPSS = bilateral inferior petrosal sinus sampling; hCRH = human corticotrophinreleasing hormone; HDDST = high-dose dexamethasone suppression test; PPNAD = primary pigmented nodular adrenal disease) BIPSS: ACTH central to peripheral gradient > 2:1 at baseline or > 3:1 at 5–10 mins after 100 mg CRH IV Cushing’s syndrome confirmed Measure plasma ACTH

3.3 pmol/L ACTH-independent Cushing’s syndrome Adrenal imaging with CT Adrenal lesion No adrenal lesion Adenoma Carcinoma AIMAH PPNAD Exogenous glucocorticoid Ectopic ACTH Cushing’s disease ACTH-dependent Cushing’s syndrome Pituitary MRI: adenoma > 6 mm Positive CRH test: after 100 mg hCRH IV (> 20% rise of cortisol; or 50% rise ACTH) HDDST: > 50% suppression in serum cortisol from baseline CT/MRI thorax and abdomen ± somatostatin scintigraphy < 1.1 pmol/L on more than two occasions Yes Yes Yes Yes No No No No 18.39 Approximate equivalent doses of glucocorticoids • Hydrocortisone: 20 mg • Cortisone acetate: 25 mg • Prednisolone: 5 mg • Dexamethasone: 0.5 mg

The adrenal glands • 671

dexamethasone per day), then serum cortisol can be measured at 0900 hrs before the next dose. If this is < 100 nmol/L (3.6 μg/ dL), slow reduction should be continued with a repeat 0900 hrs serum cortisol when the dose of prednisolone is 3 mg per day. Once 0900 hrs serum cortisol is > 100 nmol/L, then an ACTH stimulation test should be performed (see Box 18.43) to confirm if glucocorticoids can be withdrawn completely. Even when glucocorticoids have been successfully withdrawn, short-term replacement therapy is often advised during significant intercurrent illness occurring in subsequent months, as the HPA axis may not be able to respond fully to severe stress. Adrenal insufficiency Adrenal insufficiency results from inadequate secretion of cortisol and/or aldosterone. It is potentially fatal and notoriously variable in its presentation. A high index of suspicion is therefore required in patients with unexplained fatigue, hyponatraemia or hypotension. Causes are shown in Box 18.41. The most common is ACTH deficiency (secondary adrenocortical failure), usually because of inappropriate withdrawal of chronic glucocorticoid therapy or a pituitary tumour (p. 683). Congenital adrenal hyperplasia and Addison’s disease (primary adrenocortical failure) are rare causes. Clinical assessment The clinical features of adrenal insufficiency are shown in Box 18.42. In Addison’s disease, either glucocorticoid or mineralocorticoid deficiency may come first, but eventually all patients fail to secrete both classes of corticosteroid. Patients may present with chronic features and/or in acute circulatory shock. With a chronic presentation, initial symptoms are often misdiagnosed as chronic fatigue syndrome or depression. In primary adrenal insufficiency, weight loss is a uniform presenting feature. Adrenocortical insufficiency should also be considered in patients with hyponatraemia, even in the absence of symptoms (p. 357). Features of an acute adrenal crisis include circulatory shock with severe hypotension, hyponatraemia, hyperkalaemia and, in some instances, hypoglycaemia and hypercalcaemia. Muscle cramps, nausea, vomiting, diarrhoea and unexplained fever The anti-inflammatory effect of glucocorticoids may mask signs of disease. For example, perforation of a viscus may be masked and the patient may show no febrile response to an infection. Although there is debate about whether or not glucocorticoids increase the risk of peptic ulcer when used alone, they act synergistically with NSAIDs, including aspirin, to increase the risk of serious gastrointestinal adverse effects. Latent tuberculosis may be reactivated and patients on glucocorticoids are at risk of severe varicella zoster virus infection, so should avoid contact with chickenpox or shingles if they are non-immune. Management of glucocorticoid withdrawal All glucocorticoid therapy, even if inhaled or applied topically, can suppress the HPA axis. In practice, this is likely to result in a crisis due to adrenal insufficiency on withdrawal of treatment only if glucocorticoids have been administered orally or systemically for longer than 3 weeks, if repeated courses have been prescribed within the previous year, or if the dose is higher than the equivalent of 7.5 mg prednisolone per day. In these circumstances, the drug, when it is no longer required for the underlying condition, must be withdrawn slowly at a rate dictated by the duration of treatment. If glucocorticoid therapy has been prolonged, then it may take many months for the HPA axis to recover. All patients must be advised to avoid sudden drug withdrawal. They should be issued with a steroid card and/or wear an engraved bracelet (Box 18.40). Recovery of the HPA axis is aided if there is no exogenous glucocorticoid present during the nocturnal surge in ACTH secretion. This can be achieved by giving glucocorticoid in the morning. Giving ACTH to stimulate adrenal recovery is of no value, as the pituitary remains suppressed. In patients who have received glucocorticoids for longer than a few weeks, especially if the period is months to years, it is often valuable to confirm that the HPA axis is recovering during glucocorticoid withdrawal. Withdrawal has to be very slow, usually by a dose reduction equivalent of prednisolone 1 mg per month or slower. Once the dose of glucocorticoid is reduced to a minimum (e.g. 5 mg prednisolone or 0.5 mg 18.40 Advice to patients on glucocorticoid replacement therapy Intercurrent stress • Febrile illness: double dose of hydrocortisone Surgery • Minor operation: hydrocortisone 100 mg IM with pre-medication • Major operation: hydrocortisone 100 mg 4 times daily for 24 hrs, then 50 mg IM 4 times daily until ready to take tablets Vomiting • Patients must have parenteral hydrocortisone if unable to take it by mouth Steroid card • Patient should carry this at all times; it should give information regarding diagnosis, steroid, dose and doctor Bracelet and emergency pack • Patients should be encouraged to buy a bracelet and have it engraved with the diagnosis, current treatment and a reference number for a central database • Patients should be given a hydrocortisone emergency pack and trained in the self-administration of hydrocortisone 100 mg IM; they should be advised to take the pack on holidays/trips abroad 18.41 Causes of adrenocortical insufficiency Secondary (↓ACTH) • Withdrawal of suppressive glucocorticoid therapy • Hypothalamic or pituitary disease Primary (↑ACTH) Addison’s disease Common causes • Autoimmune: Sporadic Polyglandular syndromes (p. 688) • Tuberculosis • HIV/AIDS • Metastatic carcinoma • Bilateral adrenalectomy Rare causes • Lymphoma • Intra-adrenal haemorrhage (Waterhouse–Friderichsen syndrome following meningococcal sepsis) • Amyloidosis • Haemochromatosis Corticosteroid biosynthetic enzyme defects • Congenital adrenal hyperplasias • Drugs: metyrapone, ketoconazole, etomidate (ACTH = adrenocorticotrophic hormone)

672 • ENDOCRINOLOGY is circulatory compromise. Investigations should be performed before treatment is given in patients who present with features suggestive of chronic adrenal insufficiency. Assessment of glucocorticoids Random plasma cortisol is usually low in patients with adrenal insufficiency but it may be within the reference range, yet inappropriately low, for a seriously ill patient. Random measurement of normal levels of plasma cortisol cannot therefore be used to confirm or refute the diagnosis, unless the value is above 500 nmol/L (> 18 μg/dL), which effectively excludes adrenal insufficiency. More useful is the short ACTH stimulation test (also called the tetracosactrin or short Synacthen test) described in Box 18.43. Cortisol levels fail to increase in response to exogenous ACTH in patients with primary or secondary adrenal insufficiency. These can be distinguished by measurement of ACTH (which is low in ACTH deficiency and high in Addison’s disease). Assessment of mineralocorticoids Mineralocorticoid secretion in patients with suspected Addison’s disease cannot be adequately assessed by electrolyte measurements since hyponatraemia occurs in both aldosterone and cortisol deficiency (see Box 18.42 and p. 357). Hyperkalaemia is common, but not universal, in aldosterone deficiency. Plasma renin and aldosterone should be measured in the supine position. In mineralocorticoid deficiency, plasma renin activity is high, with plasma aldosterone being either low or in the lower part of the reference range. Assessment of adrenal androgens This is not necessary in men because testosterone from the testes is the principal androgen. In women, dehydroepiandrosterone sulphate (DHEAS) and androstenedione may be measured in a random specimen of blood, though levels are highest in the morning. Other tests to establish the cause Patients with unexplained secondary adrenocortical insufficiency should be investigated as described on page 680. In patients with elevated ACTH, further tests are required to establish may be present. The crisis is often precipitated by intercurrent disease, surgery or infection. Vitiligo occurs in 10–20% of patients with autoimmune Addison’s disease (p. 630). Investigations Treatment should not be delayed to wait for results in patients with suspected acute adrenal crisis. Here, a random blood sample should be stored for subsequent measurement of serum cortisol and, if possible, plasma ACTH; if the patient’s clinical condition permits, it may be appropriate to spend 30 minutes performing a short ACTH stimulation test (Box 18.43) before administering hydrocortisone, but delays must be avoided if there The exact cortisol concentration depends on the cortisol assay being used. 18.43 How and when to do an ACTH stimulation test Use • Diagnosis of primary or secondary adrenal insufficiency • Assessment of HPA axis in patients taking suppressive glucocorticoid therapy • Relies on ACTH-dependent adrenal atrophy in secondary adrenal insufficiency, so may not detect acute ACTH deficiency (e.g. in pituitary apoplexy, p. 683) Dose • 250 μg ACTH1–24 (Synacthen) by IM injection at any time of day Blood samples • 0 and 30 mins for plasma cortisol • 0 mins also for ACTH (on ice) if Addison’s disease is being considered (patient not known to have pituitary disease or to be taking exogenous glucocorticoids) Results • Normal subjects: plasma cortisol > 500 nmol/L (approximately 18 μg/dL) either at baseline or at 30 mins • Incremental change in cortisol is not a criterion (ACTH = adrenocorticotrophic hormone; HPA = hypothalamic–pituitary–adrenal) 18.42 Clinical and biochemical features of adrenal insufficiency Glucocorticoid insufficiency Mineralocorticoid insufficiency ACTH excess Adrenal androgen insufficiency Withdrawal of exogenous glucocorticoid + – – + Hypopituitarism + – – + Addison’s disease + + + + Congenital adrenal hyperplasia (21-hydroxylase deficiency) + + + – Clinical features Weight loss, anorexia Malaise, weakness Nausea, vomiting Diarrhoea or constipation Postural hypotension Shock Hypoglycaemia Hyponatraemia (dilutional) Hypercalcaemia Hypotension Shock Hyponatraemia (depletional) Hyperkalaemia Pigmentation of: Sun-exposed areas Pressure areas (e.g. elbows, knees) Palmar creases, knuckles Mucous membranes Conjunctivae Recent scars Decreased body hair and loss of libido, especially in females (ACTH = adrenocorticotrophic hormone)

The adrenal glands • 673

Androgen replacement Androgen replacement with DHEAS (50 mg/day) is occasionally given to women with primary adrenal insufficiency who have symptoms of reduced libido and fatigue, but the evidence in support of this is not robust and treatment may be associated with side-effects such as acne and hirsutism. Incidental adrenal mass It is not uncommon for a mass in the adrenal gland to be identified on a CT or MRI scan of the abdomen that has been performed for another indication. Such lesions are known as adrenal ‘incidentalomas’. The prevalence increases with age and they are present in up to 10% of adults aged 70 years and older. Eighty-five per cent of adrenal incidentalomas are nonfunctioning adrenal adenomas. The remainder includes functional tumours of the adrenal cortex (secreting cortisol, aldosterone or androgens), phaeochromocytomas, primary and secondary carcinomas, hamartomas and other rare disorders, including granulomatous infiltrations. Clinical assessment and investigations There are two key questions to be resolved: is the lesion secreting hormones, and is it benign or malignant? Patients with an adrenal incidentaloma are usually asymptomatic. However, clinical signs and symptoms of excess glucocorticoids (p. 665), mineralocorticoids (see below), catecholamines (p. 666) and, in women, androgens (p. 666) should be sought. Investigations should include a dexamethasone suppression test, urine or plasma metanephrines and, in virilised women, measurement of serum testosterone, DHEAS and androstenedione. Patients with hypertension should be investigated for mineralocorticoid excess, as described below. In bilateral masses consistent with adrenocortical lesions, 17-OH-progesterone should also be measured. CT and MRI are equally effective in assessing the malignant potential of an adrenal mass, using the following parameters: • Size. The larger the lesion, the greater the malignant potential. Around 90% of adrenocortical carcinomas are over 4 cm in diameter, but specificity is poor since only approximately 25% of such lesions are malignant. • Configuration. Homogeneous and smooth lesions are more likely to be benign. The presence of metastatic lesions elsewhere increases the risk of malignancy, but as many as two-thirds of adrenal incidentalomas in patients with cancer are benign. • Presence of lipid. Adenomas are usually lipid-rich, resulting in an attenuation of below 10 Hounsfield units (HU) on the cause of Addison’s disease. Adrenal autoantibodies are frequently positive in autoimmune adrenal failure. If antibody tests are negative, imaging of the adrenal glands with CT or MRI is indicated. Tuberculosis causes adrenal calcification, visible on plain X-ray or ultrasound scan. A human immunodeficiency virus (HIV) test should be performed if risk factors for infection are present (p. 310). Adrenal metastases are a rare cause of adrenal insufficiency. Patients with evidence of autoimmune adrenal failure should be screened for other organ-specific autoimmune diseases, such as thyroid disease, pernicious anaemia and type 1 diabetes. Management Patients with adrenocortical insufficiency always need glucocorticoid replacement therapy and usually, but not always, mineralocorticoid therapy. There is some evidence that adrenal androgen replacement may also be beneficial in women. Other treatments depend on the underlying cause. The emergency management of adrenal crisis is described in Box 18.44. Glucocorticoid replacement Adrenal replacement therapy consists of oral hydrocortisone (cortisol) 15–20 mg daily in divided doses, typically 10 mg on waking and 5 mg at around 1500 hrs. These are physiological replacement doses that should not cause Cushingoid side-effects. The dose may need to be adjusted for the individual patient but this is subjective. Excess weight gain usually indicates overreplacement, while persistent lethargy or hyperpigmentation may be due to an inadequate dose or lack of absorption. Measurement of serum cortisol levels is not usually helpful. Advice to patients dependent on glucocorticoid replacement is given in Box 18.40. Mineralocorticoid replacement Fludrocortisone (9α-fluoro-hydrocortisone) is administered at the usual dose of 0.05–0.15 mg daily, and adequacy of replacement may be assessed by measurement of blood pressure, plasma electrolytes and plasma renin. It is indicated for virtually every patient with primary adrenal insufficiency but is not needed in secondary adrenal insufficiency. 18.44 Management of adrenal crisis Correct volume depletion • IV saline as required to normalise blood pressure and pulse • In severe hyponatraemia (< 125 mmol/L) avoid increases of plasma Na > 10 mmol/L/day to prevent pontine demyelination (p. 358) • Fludrocortisone is not required during the acute phase of treatment Replace glucocorticoids • IV hydrocortisone succinate 100 mg stat, and 100 mg 4 times daily for first 12–24 hrs • Continue parenteral hydrocortisone (50–100 mg IM 4 times daily) until patient is well enough for reliable oral therapy Correct other metabolic abnormalities • Acute hypoglycaemia: IV 10% glucose • Hyperkalaemia: should respond to volume replacement but occasionally requires specific therapy (see Box 14.17, p. 363) Identify and treat underlying cause • Consider acute precipitant, such as infection • Consider adrenal or pituitary pathology (see Box 18.41) 18.45 Glucocorticoids in old age • Adrenocortical insufficiency: often insidious and may present with tiredness, drowsiness, delirium, falls, immobility and orthostatic hypotension. • Glucocorticoid therapy: especially hazardous in older people, who are already relatively immunocompromised and susceptible to osteoporosis, diabetes, hypertension and other complications. • ‘Physiological’ glucocorticoid replacement therapy: increased risk of adrenal crisis because adherence may be poor and there is a greater incidence of intercurrent illness. Patient and carer education, with regular reinforcement of the principles described in Box 18.40, is crucial.

674 • ENDOCRINOLOGY hyperaldosteronism, which is usually a consequence of enhanced activity of renin in response to inadequate renal perfusion and hypotension. Most individuals with primary hyperaldosteronism have bilateral adrenal hyperplasia (idiopathic hyperaldosteronism), while only a minority have an aldosterone-producing adenoma (APA; Conn’s syndrome). Glucocorticoid-suppressible hyperaldosteronism is a rare autosomal dominant condition in which aldosterone is secreted ‘ectopically’ from the adrenal zonae fasciculata/reticularis in response to ACTH. Rarely, the mineralocorticoid receptor pathway in the distal nephron is activated, even though aldosterone concentrations are low. Clinical features Individuals with primary hyperaldosteronism are usually asymptomatic but may have features of sodium retention or potassium loss. Sodium retention may cause oedema, while hypokalaemia may cause muscle weakness (or even paralysis, especially in South-east Asian populations), polyuria (secondary to renal tubular damage, which produces nephrogenic diabetes insipidus) and occasionally tetany (because of associated metabolic alkalosis and low ionised calcium). Blood pressure is elevated but accelerated phase hypertension is rare. Investigations Biochemical Routine blood tests may show a hypokalaemic alkalosis. Sodium is usually at the upper end of the reference range in primary hyperaldosteronism, but is characteristically low in secondary hyperaldosteronism (because low plasma volume stimulates vasopressin (antidiuretic hormone, ADH) release and high angiotensin II levels stimulate thirst). The key measurements are plasma renin and aldosterone (Box 18.46), and in many centres the aldosterone : renin ratio (ARR) is employed as a screening test for primary hyperaldosteronism in hypertensive patients. Almost all antihypertensive drugs interfere with this ratio (β-blockers inhibit while diuretics stimulate renin secretion). Thus, individuals with an elevated ARR require further testing after stopping antihypertensive drugs for at least 4 weeks. If necessary, antihypertensive agents that have minimal effects on the renin–angiotensin system, such as calcium antagonists and α-blockers, may be substituted. Oral potassium supplementation may also be required, as hypokalaemia itself suppresses renin activity. If, on repeat testing, plasma renin is low and aldosterone concentrations are elevated, then further investigation under specialist supervision may include suppression tests (sodium loading) and/or stimulation tests (captopril or furosemide administration) to differentiate angiotensin II-dependent aldosterone secretion in idiopathic hyperplasia from autonomous aldosterone secretion typical of an APA. Imaging and localisation Imaging with CT or MRI will identify most APAs (Fig. 18.23) but it is important to recognise the risk of false positives (non-functioning adrenal adenomas are common) and false negatives (imaging may have insufficient resolution to identify adenomas with a diameter of less than 0.5 cm). If the imaging is inconclusive and there is an intention to proceed with surgery on the basis of strong biochemical evidence of an APA, then adrenal vein catheterisation with measurement of aldosterone (and cortisol to confirm positioning of the catheters) is required. In some centres, this is performed even in the presence of a unilateral ‘adenoma’, to avoid inadvertent removal of an incidental non-functioning adenoma contralateral to a radiologically inapparent cause of aldosterone excess. an unenhanced CT, and in signal dropout on chemical shift MRI. • Enhancement. Benign lesions demonstrate rapid washout of contrast, whereas malignant lesions tend to retain contrast. Histology in a sample obtained by CT-guided biopsy is rarely indicated, and is not useful in distinguishing an adrenal adenoma from an adrenocortical carcinoma. Biopsy is occasionally helpful in confirming adrenal metastases from other cancers, but should be avoided if either phaeochromocytoma or primary adrenal cancer is suspected in order to avoid precipitation of a hypertensive crisis or seeding of tumour cells, respectively. Management In patients with radiologically benign, non-functioning lesions of less than 4 cm in diameter, surgery is required only if serial imaging suggests tumour growth. Functional lesions and tumours of more than 4 cm in diameter should be considered for surgery, though many centres will not operate on tumours of more than 4 cm if all other characteristics suggest benign disease. Optimal management of patients with low-grade cortisol secretion, as demonstrated by the dexamethasone suppression test, remains to be established. Primary hyperaldosteronism Estimates of the prevalence of primary hyperaldosteronism vary according to the screening tests employed, but it may occur in as many as 10% of people with hypertension. Indications to test for mineralocorticoid excess in hypertensive patients include hypokalaemia (including hypokalaemia induced by thiazide diuretics), poor control of blood pressure with conventional therapy, a family history of early-onset hypertension, or presentation at a young age. Causes of excessive activation of mineralocorticoid receptors are shown in Box 18.46. It is important to differentiate primary hyperaldosteronism, caused by an intrinsic abnormality of the adrenal glands resulting in aldosterone excess, from secondary 18.46 Causes of mineralocorticoid excess With renin high and aldosterone high (secondary hyperaldosteronism) • Inadequate renal perfusion (diuretic therapy, cardiac failure, liver failure, nephrotic syndrome, renal artery stenosis) • Renin-secreting renal tumour (very rare) With renin low and aldosterone high (primary hyperaldosteronism) • Adrenal adenoma secreting aldosterone (Conn’s syndrome) • Idiopathic bilateral adrenal hyperplasia • Glucocorticoid-suppressible hyperaldosteronism (rare) With renin low and aldosterone low (non-aldosterone-dependent activation of mineralocorticoid pathway) • Ectopic ACTH syndrome • Liquorice misuse (inhibition of 11β-HSD2) • Liddle’s syndrome • 11-deoxycorticosterone-secreting adrenal tumour • Rare forms of congenital adrenal hyperplasia and 11β-HSD2 deficiency (11β-HSD2 = 11β-hydroxysteroid dehydrogenase type 2; ACTH = adrenocorticotrophic hormone)

The adrenal glands • 675

dehydrogenase B, C and D genes. Other genetic causes include mutations in SDHA, SDHAF2, TMEN127 and MAX. Clinical features These depend on the pattern of catecholamine secretion and are listed in Box 18.47. Some patients present with hypertension, although it has been estimated that phaeochromocytoma accounts for less than 0.1% of cases of hypertension. The presentation may be with a complication of hypertension, such as stroke, myocardial infarction, left ventricular failure, hypertensive retinopathy or accelerated phase hypertension. The apparent paradox of postural hypotension between episodes is explained by ‘pressure natriuresis’ during hypertensive episodes so that intravascular volume is reduced. There may also be features of the familial syndromes associated with phaeochromocytoma. Paragangliomas are often non-functioning. Investigations Excessive secretion of catecholamines can be confirmed by measuring metabolites in plasma and/or urine (metanephrine and normetanephrine). There is a high ‘false-positive’ rate, as misleading metanephrine concentrations may be seen in stressed patients (during acute illness, following vigorous exercise or severe pain) and following ingestion of some drugs such as tricyclic antidepressants. For this reason, a repeat sample should usually be requested if elevated levels are found, although, as a rule, the higher the concentration of metanephrines, the more likely the diagnosis of phaeochromocytoma/paraganglioma. Serum chromogranin A is often elevated and may be a useful tumour marker in patients with non-secretory tumours and/or metastatic disease. Genetic testing should be considered in individuals with other features of a genetic syndrome, in those with a family history of phaeochromocytoma/paraganglioma, and in those presenting under the age of 50 years. Localisation Phaeochromocytomas are usually identified by abdominal CT or MRI (Fig. 18.24). Localisation of paragangliomas may be more difficult. Scintigraphy using meta-iodobenzyl guanidine (MIBG) can be useful, particularly if combined with CT, for adrenal phaeochromocytoma but is often negative in paraganglioma. 18F-deoxyglucose PET is especially useful for detection of malignant disease and for confirming an imaging abnormality as a paraganglioma in an individual with underlying risk due to genetic mutation. Less widely available, 68gallium dotatate PET/ CT imaging has high sensitivity for paraganglioma. Management In functioning tumours, medical therapy is required to prepare the patient for surgery, preferably for a minimum of 6 weeks, Management Mineralocorticoid receptor antagonists (spironolactone and eplerenone) are valuable in treating both hypokalaemia and hypertension in all forms of mineralocorticoid excess. Up to 20% of males develop gynaecomastia on spironolactone. Amiloride (10–40 mg/day), which blocks the epithelial sodium channel regulated by aldosterone, is an alternative. In patients with an APA, medical therapy is usually given for a few weeks to normalise whole-body electrolyte balance before unilateral adrenalectomy. Laparoscopic surgery cures the biochemical abnormality but, depending on the pre-operative duration, hypertension remains in as many as 70% of cases, probably because of irreversible damage to the systemic microcirculation. Phaeochromocytoma and paraganglioma These are rare neuro-endocrine tumours that may secrete catecholamines (adrenaline/epinephrine, noradrenaline/ norepinephrine). Approximately 80% of these tumours occur in the adrenal medulla (phaeochromocytomas), while 20% arise elsewhere in the body in sympathetic ganglia (paragangliomas). Most are benign but approximately 15% show malignant features. Around 40% are associated with inherited disorders, including neurofibromatosis (p. 1131), von Hippel–Lindau syndrome (p. 1132), MEN 2 and MEN 3 (p. 688). Paragangliomas are particularly associated with mutations in the succinate Fig. 18.23 Aldosterone-producing adenoma causing Conn’s syndrome. A CT scan of left adrenal adenoma (arrow). B The tumour is ‘canary yellow’ because of intracellular lipid accumulation. A B 18.47 Clinical features of phaeochromocytoma • Hypertension (usually paroxysmal; often postural drop of blood pressure) • Paroxysms of: Pallor (occasionally flushing) Palpitations, sweating Headache Anxiety (angor animi) • Abdominal pain, vomiting • Constipation • Weight loss • Glucose intolerance

676 • ENDOCRINOLOGY such as ambiguous genitalia in girls. In the other two-thirds, mineralocorticoid secretion is adequate but there may be features of cortisol insufficiency and/or ACTH and androgen excess, including precocious pseudo-puberty, which is distinguished from ‘true’ precocious puberty by low gonadotrophins. Sometimes the mildest enzyme defects are not apparent until adult life, when females may present with amenorrhoea and/or hirsutism (pp. 762 and 763). This is called ‘non-classical’ or ‘late-onset’ congenital adrenal hyperplasia. Defects of all the other enzymes in Figure 18.19 are rare. Both 17-hydroxylase and 11β-hydroxylase deficiency may produce hypertension due to excess production of 11-deoxycorticosterone, which has mineralocorticoid activity. Investigations Circulating 17-OH-progesterone levels are raised in 21-hydroxylase deficiency but this may be demonstrated only after ACTH administration in late-onset cases. To avoid salt-wasting crises in infancy, 17-OH-progesterone can be routinely measured in heelprick blood spot samples taken from all infants in the first week of life. Assessment is otherwise as described for adrenal insufficiency on page 672. In siblings of affected children, antenatal genetic diagnosis can be made by amniocentesis or chorionic villus sampling. This allows prevention of virilisation of affected female fetuses by administration of dexamethasone to the mother to suppress ACTH levels. Management The aim is to replace deficient corticosteroids and to suppress ACTH-driven adrenal androgen production. A careful balance is required between adequate suppression of adrenal androgen excess and excessive glucocorticoid replacement resulting in features of Cushing’s syndrome. In children, growth velocity is an important measurement, since either under- or over-replacement with glucocorticoids suppresses growth. In adults, there is no uniformly agreed adrenal replacement regime, and clinical features (menstrual cycle, hirsutism, weight gain, blood pressure) and biochemical profiles (plasma renin, 17-OH-progesterone and testosterone levels) provide a guide. Women with late-onset 21-hydroxylase deficiency may not require corticosteroid replacement. If hirsutism is the main problem, anti-androgen therapy may be just as effective (p. 659). The endocrine pancreas and gastrointestinal tract A series of hormones are secreted from cells distributed throughout the gastrointestinal tract and pancreas. Functional anatomy and physiology are described on pages 723 and 848. Diseases associated with abnormalities of these hormones are listed in Box 18.48. Most are rare, with the exception of diabetes mellitus (Ch. 20). Presenting problems in endocrine pancreas disease Spontaneous hypoglycaemia Hypoglycaemia most commonly occurs as a side-effect of treatment with insulin or sulphonylurea drugs in people with to allow restoration of normal plasma volume. The most useful drug in the face of very high circulating catecholamines is the α-blocker phenoxybenzamine (10–20 mg orally 3–4 times daily) because it is a non-competitive antagonist, unlike prazosin or doxazosin. If α-blockade produces a marked tachycardia, then a β-blocker such as propranolol can be added. On no account should a β-blocker be given before an α-blocker, as this may cause a paradoxical rise in blood pressure due to unopposed α-mediated vasoconstriction. During surgery, sodium nitroprusside and the short-acting α-antagonist phentolamine are useful in controlling hypertensive episodes, which may result from anaesthetic induction or tumour mobilisation. Post-operative hypotension may occur and require volume expansion and, very occasionally, noradrenaline (norepinephrine) infusion, but is uncommon if the patient has been prepared with phenoxybenzamine. Metastatic tumours may behave in an aggressive or a very indolent fashion. Management options include debulking surgery, radionuclide therapy with 131I-MIBG, chemotherapy and (chemo) embolisation of hepatic metastases; some may respond to tyrosine kinase and angiogenesis inhibitors. Congenital adrenal hyperplasia Pathophysiology and clinical features Inherited defects in enzymes of the cortisol biosynthetic pathway (see Fig. 18.19) result in insufficiency of hormones downstream of the block, with impaired negative feedback and increased ACTH secretion. ACTH then stimulates the production of steroids upstream of the enzyme block. This produces adrenal hyperplasia and a combination of clinical features that depend on the severity and site of the defect in biosynthesis. All of these enzyme abnormalities are inherited as autosomal recessive traits. The most common enzyme defect is 21-hydroxylase deficiency. This results in impaired synthesis of cortisol and aldosterone, and accumulation of 17-OH-progesterone, which is then diverted to form adrenal androgens. In about one-third of cases, this defect is severe and presents in infancy with features of glucocorticoid and mineralocorticoid deficiency (see Box 18.42) and androgen excess, Fig. 18.24 CT scan of abdomen showing large left adrenal phaeochromocytoma. The normal right adrenal (white arrow) contrasts with the large heterogeneous phaeochromocytoma arising from the left adrenal gland (black arrow).

The endocrine pancreas and gastrointestinal tract • 677

always be confirmed by a laboratory-based glucose measurement. At the same time, a sample should be taken for later measurement of alcohol, insulin, C-peptide, cortisol and sulphonylurea levels, if hypoglycaemia is confirmed. Taking these samples during an acute presentation prevents subsequent unnecessary dynamic tests and is of medico-legal importance in cases where poisoning is suspected. Patients who attend the outpatient clinic with episodic symptoms suggestive of hypoglycaemia present a more challenging problem. The main diagnostic test is the prolonged (72-hour) fast. If symptoms of hypoglycaemia develop during the fast, then blood samples should be taken to confirm hypoglycaemia and for later measurement of insulin and C-peptide. Hypoglycaemia is then corrected with oral or intravenous glucose and Whipple’s triad completed by confirmation of the resolution of symptoms. The absence of clinical and biochemical evidence of hypoglycaemia during a prolonged fast effectively excludes the diagnosis of a hypoglycaemic disorder. What is the cause of the hypoglycaemia? In the acute setting, the underlying diagnosis is often obvious. In non-diabetic individuals, alcohol excess is the most common cause of hypoglycaemia in the UK but other drugs – e.g. salicylates, quinine and pentamidine – may also be implicated. Hypoglycaemia is one of many metabolic derangements that occur in patients with hepatic failure, renal failure, adrenal insufficiency, sepsis or malaria. Hypoglycaemia in the absence of insulin, or any insulin-like factor, in the blood indicates impaired gluconeogenesis and/or availability of glucose from glycogen in the liver. Hypoglycaemia associated with high insulin and low C-peptide concentrations is indicative of administration of exogenous insulin, either factitiously or feloniously. Adults with high insulin and C-peptide concentrations during an episode of hypoglycaemia are most likely to have an insulinoma but sulphonylurea ingestion should also be considered (particularly in individuals with access to such medication, such as health-care professionals or family members of someone with type 2 diabetes). Suppressed plasma β-hydroxybutyrate helps confirm inappropriate insulin secretion during fasting. Usually, insulinomas in the pancreas diabetes mellitus. In non-diabetic individuals, symptomatic hypoglycaemia is rare, but it is not uncommon to detect venous blood glucose concentrations below 3.0 mmol/L (54 mg/dL) in asymptomatic patients. For this reason, and because the symptoms of hypoglycaemia are non-specific, a hypoglycaemic disorder should be diagnosed only if all three conditions of Whipple’s triad are met (Fig. 18.25). There is no specific blood glucose concentration at which spontaneous hypoglycaemia can be said to occur, although the lower the blood glucose concentration, the more likely it is to have pathological significance. Investigations are unlikely to be needed unless glucose concentrations below 3.0 mmol/L are observed, many patients with true hypoglycaemia demonstrating glucose levels below 2.2 mmol/L (40 mg/dL). Clinical assessment The clinical features of hypoglycaemia are described in the section on insulin-induced hypoglycaemia on page 738. Individuals with chronic spontaneous hypoglycaemia often have attenuated autonomic responses and ‘hypoglycaemia unawareness’, and may present with a wide variety of features of neuroglycopenia, including odd behaviour and convulsions. The symptoms are usually episodic and relieved by consumption of carbohydrate. Symptoms occurring while fasting (such as before breakfast) or following exercise are much more likely to be representative of pathological hypoglycaemia than those that develop after food (post-prandial or ‘reactive’ symptoms). Hypoglycaemia should be considered in all comatose patients, even if there is an apparently obvious cause, such as hemiplegic stroke or alcohol intoxication. Investigations Does the patient have a hypoglycaemic disorder? Patients who present acutely with delirium, coma or convulsions should be tested for hypoglycaemia at the bedside with a capillary blood sample and an automated meter. While this is sufficient to exclude hypoglycaemia, blood glucose meters are relatively inaccurate in the hypoglycaemic range and the diagnosis should 18.48 Classification of endocrine diseases of the pancreas and gastrointestinal tract Primary Secondary Hormone excess Insulinoma Gastrinoma (Zollinger– Ellison syndrome, p. 802) Carcinoid syndrome (secretion of 5-HT) Glucagonoma VIPoma Somatostatinoma Hypergastrinaemia of achlorhydria Hyperinsulinaemia after bariatric surgery Hormone deficiency Diabetes mellitus Hormone resistance Insulin resistance syndromes (e.g. type 2 diabetes mellitus, lipodystrophy, Donohue’s syndrome) Non-functioning tumours Pancreatic carcinoma Pancreatic neuro-endocrine tumour (5-HT = 5-hydroxytryptamine, serotonin) Fig. 18.25 Differential diagnosis of spontaneous hypoglycaemia. Measurement of insulin and C-peptide concentrations during an episode is helpful in determining the underlying cause. Whipple’s triad confirmed Patient had symptoms of hypoglycaemia Low blood glucose measured at the time of symptoms Symptoms resolved on correction of hypoglycaemia ↑ Insulin ↓ C-peptide ↓ Insulin ↓ C-peptide ↑ Insulin ↑ C-peptide Alcohol Drugs Critical illnesses Hypopituitarism (rare) Primary adrenocortical failure (rare in adults) Non-islet cell tumour (e.g. sarcoma) Inborn errors of metabolism Exogenous insulin Insulinoma Sulphonylureas Other drugs Hyperinsulinism of infancy

678 • ENDOCRINOLOGY Clinical features Patients with gastroenteropancreatic NETs often have a history of abdominal pain over many years prior to diagnosis and usually present with local mass effects, such as small-bowel obstruction, appendicitis, and pain from hepatic metastases. Thymic and bronchial carcinoids occasionally present with ectopic ACTH syndrome (p. 667). Pancreatic NETs can also cause hormone excess (Box 18.50) but most are non-functional. The classic ‘carcinoid syndrome’ (Box 18.51) occurs when vasoactive hormones reach the systemic circulation. In the case of gastrointestinal carcinoids, this invariably means that the tumour has metastasised to the liver or there are peritoneal deposits, which allow secreted hormones to gain access to the systemic circulation; hormones secreted by the primary tumour into the portal vein are metabolised and inactivated in the liver. The features of Zollinger–Ellison syndrome are described on page 802. Investigations A combination of imaging with ultrasound, CT, MRI and/or radio-labelled somatostatin analogue (Fig. 18.26) will usually identify the primary tumour and allow staging, which is crucial for determining prognosis. Biopsy of the primary tumour or a metastatic deposit is required to confirm the histological type. NETs demonstrate immunohistochemical staining for the proteins chromogranin A and synaptophysin, and the histological grade provides important prognostic information: the higher the Ki67 proliferation index, the worse the prognosis. Carcinoid syndrome is confirmed by measuring elevated concentrations of 5-hydroxyindoleacetic acid (5-HIAA), a metabolite of serotonin, in a 24-hour urine collection. False positives can occur, particularly if the individual has been eating certain foods, such as avocado and pineapple. Plasma chromogranin A can be measured in a fasting blood sample, along with the hormones listed in Box 18.50. All of these can be useful as tumour markers. are small (< 5 mm diameter) but can be identified by CT, MRI or ultrasound (endoscopic or laparoscopic). Imaging should include the liver since around 10% of insulinomas are malignant and may metastasise to the liver. Rarely, large non-pancreatic tumours, such as sarcomas, may cause recurrent hypoglycaemia because of their ability to produce excess pro-insulin-like growth factor-2 (pro-IGF-2), which has considerable structural homology to insulin. Management Treatment of acute hypoglycaemia should be initiated as soon as laboratory blood samples have been taken and should not be deferred until formal laboratory confirmation has been obtained. Intravenous dextrose (5% or 10%) is effective in the short term in the obtunded patient and should be followed on recovery with oral unrefined carbohydrate (starch). Continuous dextrose infusion may be necessary, especially in sulphonylurea poisoning. Intramuscular glucagon (1 mg) stimulates hepatic glucose release but is ineffective in patients with depleted glycogen reserves, such as in alcohol excess or liver disease. Chronic recurrent hypoglycaemia in insulin-secreting tumours can be treated by regular consumption of oral carbohydrate combined with agents that inhibit insulin secretion (diazoxide or somatostatin analogues). Insulinomas are resected when benign, providing the individual is fit enough to undergo surgery. Metastatic malignant insulinomas may be incurable and are managed along the same lines as other metastatic neuro-endocrine tumours (see below). Gastroenteropancreatic neuro-endocrine tumours Neuro-endocrine tumours (NETs) are a heterogeneous group derived from neuro-endocrine cells in many organs, including the gastrointestinal tract, lung, adrenals (phaeochromocytoma, p. 675) and thyroid (medullary carcinoma, p. 650). Most NETs occur sporadically but a proportion are associated with genetic cancer syndromes, such as MEN 1, 2 and 3 and neurofibromatosis type 1 (pp. 688 and 1131). NETs may secrete hormones into the circulation. Gastroenteropancreatic NETs arise in organs that are derived embryologically from the gastrointestinal tract. Most commonly, they occur in the small bowel but they can also arise elsewhere in the bowel, pancreas, thymus and bronchi. The term ‘carcinoid’ is often used when referring to non-pancreatic gastroenteropancreatic NETs because, when initially described, they were thought to behave in an indolent fashion compared with conventional cancers. It is now recognised that there is a wide spectrum of malignant potential for all NETs; some are benign (most insulinomas and appendiceal carcinoid tumours), while others have an aggressive clinical course with widespread metastases (small-cell carcinoma of the lung). The majority of gastroenteropancreatic NETs behave in an intermediate manner, with relatively slow growth but a propensity to invade and metastasise to remote organs, especially the liver. 18.50 Pancreatic neuro-endocrine tumours Tumour Hormone Effects Gastrinoma Gastrin Peptic ulcer and steatorrhoea (Zollinger– Ellison syndrome, p. 802) Insulinoma Insulin Recurrent hypoglycaemia (see above) VIPoma Vasoactive intestinal peptide (VIP) Watery diarrhoea and hypokalaemia Glucagonoma Glucagon Diabetes mellitus, necrolytic migratory erythema Somatostatinoma Somatostatin Diabetes mellitus and steatorrhoea 18.49 Spontaneous hypoglycaemia in old age • Presentation: may present with focal neurological abnormality. Blood glucose should be checked in all patients with acute neurological symptoms and signs, especially stroke, as these will reverse with early treatment of hypoglycaemia. 18.51 Clinical features of the carcinoid syndrome • Episodic flushing, wheezing and diarrhoea • Facial telangiectasia • Cardiac involvement (tricuspid regurgitation, pulmonary stenosis, right ventricular endocardial plaques) leading to heart failure

The hypothalamus and the pituitary gland • 679

carotid arteries. The gland is composed of two lobes, anterior and posterior, and is connected to the hypothalamus by the infundibular stalk, which has portal vessels carrying blood from the median eminence of the hypothalamus to the anterior lobe and nerve fibres to the posterior lobe. Management Treatment of solitary tumours is by surgical resection. If metastatic or multifocal primary disease is present, then surgery is usually not indicated, unless there is a complication such as gastrointestinal obstruction. Diazoxide can reduce insulin secretion in insulinomas, and high doses of proton pump inhibitors suppress acid production in gastrinomas. Somatostatin analogues are effective in reducing the symptoms of carcinoid syndrome and of excess glucagon and vasoactive intestinal peptide (VIP) production. The slow-growing nature of NETs means that conventional cancer therapies, such as chemotherapy and radiotherapy, have limited efficacy, but use of somatostatin analogues is associated with improved progressionfree survival. Other treatments, such as interferon, targeted radionuclide therapy with 131I-MIBG and radio-labelled somatostatin analogues (which may be taken up by NET metastases), and resection/embolisation/ablation of hepatic metastases, may have a role in the palliation of symptoms but debate exists as to whether this prolongs life. The tyrosine kinase inhibitor sunitinib and the mammalian target of rapamycin (mTOR) inhibitor everolimus have shown significant improvements in progression-free survival in patients with advanced and progressive pancreatic and lung NETS that are not poorly differentiated, and should be considered as part of standard therapy. The hypothalamus and the pituitary gland Diseases of the hypothalamus and pituitary have an annual incidence of approximately 3:100 000 and a prevalence of 30–70 per 100 000. The pituitary plays a central role in several major endocrine axes, so that investigation and treatment invariably involve several other endocrine glands. Functional anatomy, physiology and investigations The anatomical relationships of the pituitary are shown in Figure 18.27 and its numerous functions are shown in Figure 18.2 (p. 633). The pituitary gland is enclosed in the sella turcica and bridged over by a fold of dura mater called the diaphragma sellae, with the sphenoidal air sinuses below and the optic chiasm above. The cavernous sinuses are lateral to the pituitary fossa and contain the 3rd, 4th and 6th cranial nerves and the internal Fig. 18.26 Octreotide scintigraphy in a metastatic neuro-endocrine tumour. A Coronal CT scan showing hepatomegaly and a mass inferior to the liver (at the intersection of the horizontal and vertical red lines). B Octreotide scintogram showing patches of increased uptake in the upper abdomen. C When the octreotide and CT scans are superimposed, it shows that the areas of increased uptake are in hepatic metastases and in the tissue mass, which may be lymph nodes or a primary tumour. B C A Fig. 18.27 Anatomical relationships of the normal pituitary gland and hypothalamus. See also Figure 18.2 (p. 633). A Sagittal MRI. B Coronal MRI. (AP = anterior pituitary; CS = cavernous sinus; H = hypothalamus; IC = internal carotid artery; OC = optic chiasm; PP = posterior pituitary; PS = pituitary stalk; SS = sphenoid sinus; TV = third ventricle) SS PP H TV OC AP A B OC IC TV PS CS AP

680 • ENDOCRINOLOGY Diseases of the hypothalamus and pituitary are classified in Box 18.52. By far the most common disorder is an adenoma of the anterior pituitary gland. Investigation of patients with pituitary disease Although pituitary disease presents with diverse clinical manifestations (see below), the approach to investigation is similar in all cases (Box 18.53). The approach to testing for hormone deficiency is outlined in Box 18.53. Details are given in the sections on individual glands elsewhere in this chapter. Tests for hormone excess vary according to the hormone in question. For example, prolactin is not secreted in pulsatile fashion, although it rises with significant psychological stress. Assuming that the patient was not distressed by venepuncture, a random measurement of serum prolactin is sufficient to diagnose hyperprolactinaemia. In contrast, growth hormone is secreted in a pulsatile fashion. A high random level does not confirm acromegaly; the diagnosis is confirmed only by failure of growth hormone to be suppressed during an oral glucose tolerance test, and a high serum insulin-like growth factor-1 (IGF-1). Similarly, in suspected ACTH-dependent Cushing’s disease (p. 666), random measurement of plasma cortisol is unreliable and the diagnosis is usually made by a dexamethasone suppression test. The most common local complication of a large pituitary tumour is compression of the optic pathway. The resulting visual field defect can be documented using a Goldman’s perimetry chart. MRI reveals ‘abnormalities’ of the pituitary gland in as many as 10% of ‘healthy’ middle-aged people. It should therefore be performed only if there is a clear biochemical abnormality or if a patient presents with clinical features of pituitary tumour (see below). A pituitary tumour may be classified as either a macroadenoma (> 10 mm diameter) or a microadenoma (< 10 mm diameter). Surgical biopsy is usually only performed as part of a therapeutic operation. Conventional histology identifies tumours as chromophobe (usually non-functioning), acidophil (typically prolactin- or growth hormone-secreting) or basophil (typically ACTH-secreting); immunohistochemistry may confirm their secretory capacity but is poorly predictive of growth potential of the tumour. 18.52 Classification of diseases of the pituitary and hypothalamus Primary Secondary Non-functioning tumours Pituitary adenoma Craniopharyngioma Metastatic tumours Hormone excess Anterior pituitary Prolactinoma Acromegaly Cushing’s disease Rare TSH-, LH- and FSH-secreting adenomas Disconnection hyperprolactinaemia Hypothalamus and posterior pituitary Syndrome of inappropriate antidiuretic hormone (SIADH, p. 357) Hormone deficiency Anterior pituitary Hypothalamus and posterior pituitary Hypopituitarism Cranial diabetes insipidus GnRH deficiency (Kallmann’s syndrome) Hormone resistance Growth hormone resistance (Laron dwarfism) Nephrogenic diabetes insipidus (FSH = follicle-stimulating hormone; GnRH = gonadotrophin-releasing hormone; LH = luteinising hormone; TSH = thyroid-stimulating hormone) 18.53 How to investigate patients with suspected pituitary hypothalamic disease Identify pituitary hormone deficiency ACTH deficiency • Short ACTH stimulation test (see Box 18.43) • Insulin tolerance test (see Box 18.56): only if there is uncertainty in interpretation of short ACTH stimulation test (e.g. acute presentation) LH/FSH deficiency • In the male, measure random serum testosterone, LH and FSH • In the pre-menopausal female, ask if the menses are regular • In the post-menopausal female, measure random serum LH and FSH (FSH normally > 30 IU/L and LH > 20 IU/L) TSH deficiency • Measure random serum T4 • Note that TSH is often detectable in secondary hypothyroidism Growth hormone deficiency Only investigate if growth hormone replacement therapy is being contemplated (p. 682) • Measure immediately after exercise • Consider other stimulatory tests (see Box 18.55) Cranial diabetes insipidus Only investigate if patient complains of polyuria/polydipsia, which may be masked by ACTH or TSH deficiency • Exclude other causes of polyuria with blood glucose, potassium and calcium measurements • Water deprivation test (see Box 18.61) or 5% saline infusion test Identify hormone excess • Measure random serum prolactin • Investigate for acromegaly (glucose tolerance test) or Cushing’s syndrome (p. 667) if there are clinical features Establish the anatomy and diagnosis • Consider visual field testing • Image the pituitary and hypothalamus by MRI or CT (ACTH = adrenocorticotrophic hormone; FSH = follicle-stimulating hormone; LH = luteinising hormone; TSH = thyroid-stimulating hormone)

The hypothalamus and the pituitary gland • 681

Presenting problems in hypothalamic and pituitary disease The clinical features of pituitary disease are shown in Figure 18.28. Younger women with pituitary disease most commonly present with secondary amenorrhoea (p. 654) or galactorrhoea (in hyperprolactinaemia). Post-menopausal women and men of any age are less likely to report symptoms of hypogonadism and so are more likely to present late with larger tumours causing visual field defects. Nowadays, many patients present with the incidental finding of a pituitary tumour on a CT or MRI scan. Hypopituitarism Hypopituitarism describes combined deficiency of any of the anterior pituitary hormones. The clinical presentation is variable and depends on the underlying lesion and the pattern of resulting hormone deficiency. The most common cause is a pituitary macroadenoma but other causes are listed in Box 18.54. Clinical assessment The presentation is highly variable. For example, following radiotherapy to the pituitary region, there is a characteristic sequence of loss of pituitary hormone secretion. Growth hormone secretion is often the earliest to be lost. In adults, this produces lethargy, muscle weakness and increased fat mass but these features are not obvious in isolation. Next, gonadotrophin (LH and FSH) secretion becomes impaired with loss of libido in the male and oligomenorrhoea or amenorrhoea in the female. Later, in the male there may be gynaecomastia and decreased frequency of shaving. In both sexes, axillary and pubic hair eventually become Fig. 18.28 Common symptoms and signs to consider in a patient with suspected pituitary disease. (ACTH = adrenocorticotrophic hormone; TSH = thyroid-stimulating hormone) Macroadenoma (arrows)

10 mm diameter Local complications • Headache • Visual field defect • Disconnection hyperprolactinaemia • Diplopia (cavernous sinus involvement) • Acute infarction/expansion (pituitary apoplexy) Hormone excess Hyperprolactinaemia • Galactorrhoea • Amenorrhoea • Hypogonadism Acromegaly • Headache • Sweating • Change in shoe and ring size Cushing’s disease • Weight gain • Bruising • Myopathy • Hypertension • Striae • Depression Hypopituitarism Growth hormone • Lethargy Gonadotrophins • Lethargy •Loss of libido • Hair loss • Amenorrhoea ACTH • Lethargy • Postural hypotension • Pallor • Hair loss TSH • Lethargy Vasopressin (usually post-surgical) • Thirst and polyuria Microadenoma (arrow) < 10 mm diameter 18.54 Causes of anterior pituitary hormone deficiency Structural • Primary pituitary tumour • Adenoma* • Carcinoma (exceptionally rare) • Craniopharyngioma* • Meningioma* • Secondary tumour (including leukaemia and lymphoma) • Chordoma • Germinoma (pinealoma) • Arachnoid cyst • Rathke’s cleft cyst • Haemorrhage (apoplexy) Inflammatory/infiltrative • Sarcoidosis • Infections, e.g. pituitary abscess, tuberculosis, syphilis, encephalitis • Lymphocytic hypophysitis • Haemochromatosis • Langerhans cell histiocytosis Congenital deficiencies • GnRH (Kallmann’s syndrome)* • GHRH* • TRH • CRH Functional* • Chronic systemic illness • Anorexia nervosa • Excessive exercise Other • Head injury* • (Para)sellar surgery* • (Para)sellar radiotherapy* • Post-partum necrosis (Sheehan’s syndrome) • Opiate analgesia *The most common causes of pituitary hormone deficiency. (CRH = corticotrophin-releasing hormone; GHRH = growth hormone-releasing hormone; GnRH = gonadotrophin-releasing hormone; TRH = thyrotrophinreleasing hormone)

682 • ENDOCRINOLOGY TSH is not helpful in adjusting the replacement dose because patients with hypopituitarism often secrete glycoproteins that are measured in the TSH assays but are not bioactive. The aim is to maintain serum T4 in the upper part of the reference range. It is dangerous to give thyroid replacement in adrenal insufficiency without first giving glucocorticoid therapy, since this may precipitate adrenal crisis. Sex hormone replacement This is indicated if there is gonadotrophin deficiency in women under the age of 50 and in men to restore normal sexual function and to prevent osteoporosis (p. 1044). Growth hormone replacement Growth hormone (GH) is administered by daily subcutaneous self-injection to children and adolescents with GH deficiency and, until recently, was discontinued once the epiphyses had fused. However, although hypopituitary adults receiving ‘full’ replacement with hydrocortisone, levothyroxine and sex steroids are usually much improved by these therapies, some individuals remain lethargic and unwell compared with a healthy population. Some of these patients feel better, and have objective improvements in their fat:muscle mass ratio and other metabolic parameters, if they are also given GH replacement. Treatment with GH may also help young adults to achieve a higher peak bone mineral density. The principal side-effect is sodium retention, manifest as peripheral oedema or carpal tunnel syndrome if given in excess. For this reason, GH replacement should be started at a low dose, with monitoring of the response by measurement of serum IGF-1. sparse or even absent and the skin becomes characteristically finer and wrinkled. Chronic anaemia may also occur. The next hormone to be lost is usually ACTH, resulting in symptoms of cortisol insufficiency (including postural hypotension and a dilutional hyponatraemia). In contrast to primary adrenal insufficiency (p. 671), angiotensin II-dependent zona glomerulosa function is not lost and hence aldosterone secretion maintains normal plasma potassium. In contrast to the pigmentation of Addison’s disease due to high levels of circulating ACTH acting on the skin melanocytes, a striking degree of pallor is usually present. Finally, TSH secretion is lost with consequent secondary hypothyroidism. This contributes further to apathy and cold intolerance. In contrast to primary hypothyroidism, frank myxoedema is rare, presumably because the thyroid retains some autonomous function. The onset of all of the above symptoms is notoriously insidious. However, patients sometimes present acutely unwell with glucocorticoid deficiency. This may be precipitated by a mild infection or injury, or may occur secondary to pituitary apoplexy (p. 683). Other features of pituitary disease may be present (Fig. 18.28). Investigations The strategy for investigation of pituitary disease is described in Box 18.53. In acutely unwell patients, the priority is to diagnose and treat cortisol deficiency (p. 672). Other tests can be undertaken later. Specific dynamic tests for diagnosing hormone deficiency are described in Boxes 18.43 and 18.55. More specialised biochemical tests, such as insulin tolerance tests (Box 18.56), GnRH and TRH tests, are rarely required. All patients with biochemical evidence of pituitary hormone deficiency should have an MRI or CT scan to identify pituitary or hypothalamic tumours. If a tumour is not identified, then further investigations are indicated to exclude infectious or infiltrative causes. Management Treatment of acutely ill patients is similar to that described for adrenocortical insufficiency on page 673, except that sodium depletion is not an important component to correct. Chronic hormone replacement therapies are described below. Once the cause of hypopituitarism is established, specific treatment – of a pituitary macroadenoma, for example (see below) – may be required. Cortisol replacement Hydrocortisone should be given if there is ACTH deficiency. Suitable doses are described in the section on adrenal disease on page 672. Mineralocorticoid replacement is not required. Thyroid hormone replacement Levothyroxine 50–150 μg once daily should be given as described on page 640. Unlike in primary hypothyroidism, measuring 18.55 Tests of growth hormone secretion GH levels are commonly undetectable, so a choice from the range of ‘stimulation’ tests is required: • Insulin-induced hypoglycaemia • Arginine (may be combined with GHRH) • Glucagon • Clonidine (in children) (GH = growth hormone; GHRH = growth hormone-releasing hormone) The precise cut-off figure for a satisfactory cortisol and GH response depends on the assay used and so varies between centres. 18.56 How and when to do an insulin tolerance test Use • Assessment of the HPA axis • Assessment of GH deficiency • Indicated when there is doubt after the other tests in Box 18.53 • Usually performed in specialist centres, especially in children • IV glucose and hydrocortisone must be available for resuscitation Contraindications • Ischaemic heart disease • Epilepsy • Severe hypopituitarism (0800 hrs plasma cortisol < 180 nmol/L (6.6 μg/dL)) Dose • 0.15 U/kg body weight soluble insulin IV Aim • To produce adequate hypoglycaemia (tachycardia and sweating with blood glucose < 2.2 mmol/L (40 mg/dL)) Blood samples • 0, 30, 45, 60, 90, 120 mins for blood glucose, plasma cortisol and growth hormone Results • Normal subjects: GH > 6.7 μg/L (20 mIU/L) • Normal subjects: cortisol > 550 nmol/L (approximately 20.2 μg/dL)* (GH = growth hormone; HPA = hypothalamic–pituitary–adrenal)

The hypothalamus and the pituitary gland • 683

Management Modalities of treatment of common pituitary and hypothalamic tumours are shown in Box 18.57. Associated hypopituitarism should be treated as described above. Urgent treatment is required if there is evidence of pressure on visual pathways. The chances of recovery of a visual field defect are proportional to the duration of symptoms, with full recovery unlikely if the defect has been present for longer than 4 months. In the presence of a sellar mass lesion, it is crucial that serum prolactin is measured before emergency surgery is performed. If the prolactin is over 5000 mIU/L (236 ng/mL), then the lesion is likely to be a macroprolactinoma and should respond to a dopamine agonist with shrinkage of the lesion, making surgery unnecessary (see Fig. 18.29). Most operations on the pituitary are performed using the trans-sphenoidal approach via the nostrils, while transfrontal surgery via a craniotomy is reserved for suprasellar tumours and is much less frequently needed. It is uncommon to be able to resect lateral extensions into the cavernous sinuses, although with modern endoscopic techniques this is more feasible. All operations on the pituitary carry a risk of damaging normal endocrine function; this risk increases with the size of the primary lesion. Pituitary function (see Box 18.53) should be retested 4–6 weeks following surgery, primarily to detect the development of any new hormone deficits. Rarely, the surgical treatment of a sellar lesion can result in recovery of hormone secretion that was deficient pre-operatively. Following surgery, usually after 3–6 months, imaging should be repeated. If there is a significant residual mass and the histology confirms an anterior pituitary tumour, external radiotherapy may be given to reduce the risk of recurrence but the risk:benefit ratio needs careful individualised discussion. Radiotherapy is not useful in patients requiring urgent therapy because it takes many months or years to be effective and there is a risk of acute swelling of the mass. Fractionated radiotherapy carries a life-long risk of hypopituitarism (50–70% in the first 10 years) and annual pituitary function tests are obligatory. There is also concern that radiotherapy might impair cognitive function, cause vascular changes and even induce primary brain tumours, but these side-effects have not been quantified reliably and are likely Pituitary tumour Pituitary tumours produce a variety of mass effects, depending on their size and location, but also present as incidental findings on CT or MRI, or with hypopituitarism, as described above. A wide variety of disorders can present as mass lesions in or around the pituitary gland (see Box 18.54). Most intrasellar tumours are pituitary macroadenomas (most commonly non-functioning adenomas; see Fig. 18.28), whereas suprasellar masses may be craniopharyngiomas (see Fig. 18.31). The most common cause of a parasellar mass is a meningioma. Clinical assessment Clinical features are shown in Figure 18.28. A common but non-specific presentation is with headache, which may be the consequence of stretching of the diaphragma sellae. Although the classical abnormalities associated with compression of the optic chiasm are bitemporal hemianopia (see Fig. 18.29) or upper quadrantanopia, any type of visual field defect can result from suprasellar extension of a tumour because it may compress the optic nerve (unilateral loss of acuity or scotoma) or the optic tract (homonymous hemianopia). Optic atrophy may be apparent on ophthalmoscopy. Lateral extension of a sellar mass into the cavernous sinus with subsequent compression of the 3rd, 4th or 6th cranial nerve may cause diplopia and strabismus, but in anterior pituitary tumours this is an unusual presentation. Occasionally, pituitary tumours infarct or there is bleeding into cystic lesions. This is termed ‘pituitary apoplexy’ and may result in sudden expansion with local compression symptoms and acute-onset hypopituitarism. Non-haemorrhagic infarction can also occur in a normal pituitary gland; predisposing factors include catastrophic obstetric haemorrhage (Sheehan’s syndrome), diabetes mellitus and raised intracranial pressure. Investigations Patients suspected of having a pituitary tumour should undergo MRI or CT. While some lesions have distinctive neuro-radiological features, the definitive diagnosis is made on histology after surgery. All patients with (para)sellar space-occupying lesions should have pituitary function assessed as described in Box 18.53. 18.57 Therapeutic modalities for functioning and non-functioning hypothalamic and pituitary tumours Surgery Radiotherapy Medical Comment Non-functioning pituitary macroadenoma 1st line 2nd line – Prolactinoma 2nd line 2nd line 1st line Dopamine agonists Dopamine agonists usually cause macroadenomas to shrink Acromegaly 1st line 2nd line 2nd line Somatostatin analogues Dopamine agonists GH receptor antagonists Medical therapy does not reliably cause macroadenomas to shrink Radiotherapy and medical therapy are used in combination for inoperable tumours Cushing’s disease 1st line 2nd line 2nd line Steroidogenesis inhibitors Pasireotide Radiotherapy may take many years to reduce ACTH excess and medical therapies may be used as a bridge. Bilateral adrenalectomy may also be considered if the pituitary tumour is not completely resectable Craniopharyngioma 1st line 2nd line – (ACTH = adrenocorticotrophic hormone; GH = growth hormone)

684 • ENDOCRINOLOGY to be rare. Stereotactic radiosurgery allows specific targeting of residual disease in a more focused fashion. Non-functioning tumours should be followed up by repeated imaging at intervals that depend on the size of the lesion and on whether or not radiotherapy has been administered. For smaller lesions that are not causing mass effects, therapeutic surgery may not be indicated and the lesion may simply be monitored by serial neuroimaging without a clear-cut diagnosis having been established. Hyperprolactinaemia/galactorrhoea Hyperprolactinaemia is a common abnormality that usually presents with hypogonadism and/or galactorrhoea (lactation in the absence of breastfeeding). Since prolactin stimulates milk secretion but not breast development, galactorrhoea rarely occurs in men and only does so if gynaecomastia has been induced by hypogonadism (p. 655). The differential diagnosis of hyperprolactinaemia is shown in Box 18.58. Many drugs, especially dopamine antagonists, elevate prolactin concentrations. Pituitary tumours can cause hyperprolactinaemia by directly secreting prolactin (prolactinomas, see below), or by compressing the infundibular stalk and thus interrupting the tonic inhibitory effect of hypothalamic dopamine on prolactin secretion (‘disconnection’ hyperprolactinaemia). Prolactin usually circulates as a free (monomeric) hormone in plasma but, in some individuals, prolactin becomes bound to an IgG antibody. This complex is known as macroprolactin and such patients have macroprolactinaemia (not to be confused with macroprolactinoma, a prolactin-secreting pituitary tumour of more than 1 cm in diameter). Since macroprolactin cannot cross blood-vessel walls to reach prolactin receptors 18.58 Causes of hyperprolactinaemia Physiological • Stress (e.g. post-seizure) • Pregnancy • Lactation • Nipple stimulation • Sleep • Coitus • Exercise • Baby crying Drug-induced Dopamine antagonists • Antipsychotics (phenothiazines and butyrophenones) • Antidepressants • Antiemetics (e.g. metoclopramide, domperidone) Dopamine-depleting drugs • Reserpine • Methyldopa Oestrogens • Oral contraceptive pill Pathological Common • Disconnection hyperprolactinaemia (e.g. non-functioning pituitary macroadenoma) • Prolactinoma (usually microadenoma) • Primary hypothyroidism • Polycystic ovarian syndrome • Macroprolactinaemia Uncommon • Pituitary tumour secreting prolactin and growth hormone • Hypothalamic disease • Renal failure Rare • Chest wall reflex (e.g. post herpes zoster) in target tissues, it is of no pathological significance. Some commercial prolactin assays do not distinguish prolactin from macroprolactin and so macroprolactinaemia is a cause of spurious hyperprolactinaemia. Identification of macroprolactin requires gel filtration chromatography or polyethylene glycol precipitation techniques, and one of these tests should be performed in all patients with hyperprolactinaemia if the prolactin assay is known to cross-react. Clinical assessment In women, in addition to galactorrhoea, hypogonadism associated with hyperprolactinaemia causes secondary amenorrhoea and anovulation with infertility (p. 654). Important points in the history include drug use, recent pregnancy and menstrual history. The quantity of milk produced is variable and it may be observed only by manual expression. In men there is decreased libido, reduced shaving frequency and lethargy (p. 655). Unilateral galactorrhoea may be confused with nipple discharge, and breast examination to exclude malignancy or fibrocystic disease is important. Further assessment should address the features in Figure 18.28. Investigations Pregnancy should first be excluded before further investigations are performed in women of child-bearing potential. The upper limit of normal for many assays of serum prolactin is approximately 500 mIU/L (24 ng/mL). In non-pregnant and non-lactating patients, monomeric prolactin concentrations of 500–1000 mIU/L (24–47 ng/mL) are likely to be induced by stress or drugs, and a repeat measurement is indicated. Levels between 1000 and 5000 mIU/L (47–236 ng/mL) are likely to be due to either drugs, a microprolactinoma or ‘disconnection’ hyperprolactinaemia. Levels above 5000 mIU/L (236 ng/mL) are highly suggestive of a macroprolactinoma. Patients with prolactin excess should have tests of gonadal function (p. 651), and T4 and TSH should be measured to exclude primary hypothyroidism causing TRH-induced prolactin excess. Unless the prolactin falls after withdrawal of relevant drug therapy, a serum prolactin consistently above the reference range is an indication for MRI or CT scan of the hypothalamus and pituitary. Patients with a macroadenoma also need tests for hypopituitarism (see Box 18.53). Management If possible, the underlying cause should be corrected (e.g. cessation of offending drugs and giving levothyroxine replacement in primary hypothyroidism). If dopamine antagonists are the cause, then dopamine agonist therapy is contraindicated; if gonadal dysfunction is the primary concern, sex steroid replacement therapy may be indicated. Troublesome physiological galactorrhoea can also be treated with dopamine agonists (see Box 18.59). Management of prolactinomas is described below. Prolactinoma Most prolactinomas in pre-menopausal women are microadenomas because the symptoms of prolactin excess usually result in early presentation. Prolactin-secreting cells of the anterior pituitary share a common lineage with GH-secreting cells, so occasionally prolactinomas can secrete excess GH and cause acromegaly. In prolactinomas there is a relationship between prolactin concentration and tumour size: the higher the level, the bigger the tumour. Some macroprolactinomas can elevate prolactin concentrations above 100 000 mIU/L

The hypothalamus and the pituitary gland • 685

patients with a microadenoma. Also, after the menopause, suppression of prolactin is required in microadenomas only if galactorrhoea is troublesome, since hypogonadism is then physiological and tumour growth unlikely. In patients with macroadenomas, drugs can be withdrawn only after curative surgery or radiotherapy and under close supervision. Ergot-derived dopamine agonists (bromocriptine and cabergoline) can bind to 5-HT2B receptors in the heart and elsewhere and have been associated with fibrotic reactions, particularly tricuspid valve regurgitation, when used in high doses in patients with Parkinson’s disease. At the relatively low doses used in prolactinomas most data suggest that systematic screening for cardiac fibrosis is unnecessary, but if dopamine agonist therapy is prolonged, periodic screening by echocardiography or use of non-ergot agents (quinagolide) may be indicated. Surgery and radiotherapy Surgical decompression is usually necessary only when a macroprolactinoma has failed to shrink sufficiently with dopamine agonist therapy, and this may be because the tumour has a significant cystic component. Surgery may also be performed in patients who are intolerant of dopamine agonists. Microadenomas can be removed selectively by trans-sphenoidal surgery with a cure rate of about 80%, but recurrence is possible; the cure rate for surgery in macroadenomas is substantially lower. External irradiation may be required for some macroadenomas to prevent regrowth if dopamine agonists are stopped. Pregnancy Hyperprolactinaemia often presents with infertility, so dopamine agonist therapy may be followed by pregnancy. Patients with microadenomas should be advised to withdraw dopamine agonist therapy as soon as pregnancy is confirmed. In contrast, macroprolactinomas may enlarge rapidly under oestrogen stimulation and these patients should continue dopamine agonist therapy and need measurement of prolactin levels and visual fields during pregnancy. All patients should be advised to report headache or visual disturbance promptly. Acromegaly Acromegaly is caused by growth hormone (GH) secretion from a pituitary tumour, usually a macroadenoma, and carries an approximate twofold excess mortality when untreated. (4700 ng/mL). The investigation of prolactinomas is the same as for other pituitary tumours (see above). Management As shown in Box 18.57, several therapeutic modalities can be employed in the management of prolactinomas. Medical Dopamine agonist drugs are first-line therapy for the majority of patients (Box 18.59). They usually reduce serum prolactin concentrations and cause significant tumour shrinkage after several months of therapy (Fig. 18.29), but visual field defects, if present, may improve within days of first administration. It is possible to withdraw dopamine agonist therapy without recurrence of hyperprolactinaemia after a few years of treatment in some 18.59 Dopamine agonist therapy: drugs used to treat prolactinomas Drug Oral dose* Advantages Disadvantages Bromocriptine 2.5–15 mg/day 2–3 times daily Available for parenteral use Short half-life; useful in treating infertility Proven long-term efficacy Ergotamine-like side-effects (nausea, headache, postural hypotension, constipation) Frequent dosing so poor adherence Rare reports of fibrotic reactions in various tissues Cabergoline 250–1000 μg/week 2 doses/week Long-acting, so missed doses less important Reported to have fewer ergotamine-like side-effects Limited data on safety in pregnancy Associated with cardiac valvular fibrosis in Parkinson’s disease Quinagolide 50–150 μg/day Once daily A non-ergot with few side-effects in patients intolerant of the above Limited data on safety in pregnancy *Tolerance develops for the side-effects. All of these agents, especially bromocriptine, must be introduced at low dose and increased slowly. If several doses of bromocriptine are missed, the process must start again. Fig. 18.29 Shrinkage of a macroprolactinoma following treatment with a dopamine agonist. A MRI scan showing a pituitary macroadenoma (T) compressing the optic chiasm (C). B MRI scan of the same tumour following treatment with a dopamine agonist. The macroadenoma, which was a prolactinoma, has decreased in size substantially and is no longer compressing the optic chiasm. A B T C T C

686 • ENDOCRINOLOGY Surgical Trans-sphenoidal surgery is usually the first line of treatment and may result in cure of GH excess, especially in patients with microadenomas. More often, surgery serves to debulk the tumour and further second-line therapy is required, according to post-operative imaging and glucose tolerance test results. Radiotherapy External radiotherapy is usually employed as second-line treatment if acromegaly persists after surgery, to stop tumour growth and lower GH levels. However, GH levels fall slowly (over many years) and there is a risk of hypopituitarism. Medical If acromegaly persists after surgery, medical therapy is usually employed to lower GH levels to below 1.0 μg/L (approximately 3 mIU/L) and to normalise IGF-1 concentrations. Medical therapy may be discontinued after several years in patients who have received radiotherapy. Somatostatin analogues (such as octreotide, lanreotide or pasireotide) can be administered as slow-release injections every few weeks. Somatostatin analogues can also be used as primary therapy for acromegaly either as an alternative or in advance of surgery, given evidence that they can induce modest tumour shrinkage in some patients. Dopamine agonists are less effective at lowering GH but may sometimes be helpful, especially with associated prolactin excess. Clinical features If GH hypersecretion occurs before puberty, then the presentation is with gigantism. More commonly, GH excess occurs in adult life and presents with acromegaly. If hypersecretion starts in adolescence and persists into adult life, then the two conditions may be combined. The clinical features are shown in Figure 18.30. The most common complaints are headache and sweating. Additional features include those of any pituitary tumour (see Fig. 18.28). Investigations The clinical diagnosis must be confirmed by measuring GH levels during an oral glucose tolerance test and measuring serum IGF-1. In normal subjects, plasma GH suppresses to below 0.5 μg/L (approximately 2 mIU/L). In acromegaly, GH does not suppress and in about 30% of patients there is a paradoxical rise; IGF-1 is also elevated. The rest of pituitary function should be investigated as described in Box 18.53. Prolactin concentrations are elevated in about 30% of patients due to co-secretion of prolactin from the tumour. Additional tests in acromegaly may include screening for colonic neoplasms with colonoscopy. Management The main aims are to improve symptoms and to normalise serum GH and IGF-1 to reduce morbidity and mortality. Treatment is summarised in Box 18.57. Fig. 18.30 Clinical features of acromegaly. (IGT = impaired glucose tolerance) Skull growth – prominent supraorbital ridges with large frontal sinuses Prognathism (growth of lower jaw) Enlargement of lips, nose and tongue Headache Hypertension Increased sweating Cardiomyopathy Cardiovascular disease (2–3 × ↑) Enlargement of liver Thickened skin IGT (25%)/type 2 diabetes (10%) Colonic cancer (2–3 × ↑) Enlargement of hands Arthropathy Carpal tunnel syndrome Myopathy Enlargement of feet Increased heel pad thickness

The hypothalamus and the pituitary gland • 687

tumour has a large cystic component, it may be safer to place in the cyst cavity a drain that is attached to a subcutaneous access device, rather than attempt a resection. Whatever form it takes, surgery is unlikely to be curative and radiotherapy may often be given to reduce the risk of relapse. Unfortunately, craniopharyngiomas often recur, requiring repeated surgery. They often cause considerable morbidity, usually from hypothalamic obesity, water balance problems and/or visual failure. Diabetes insipidus This uncommon disorder is characterised by the persistent excretion of excessive quantities of dilute urine and by thirst. It is classified into two types: • cranial diabetes insipidus, in which there is deficient production of vasopressin by the hypothalamus • nephrogenic diabetes insipidus, in which the renal tubules are unresponsive to vasopressin. The underlying causes are listed in Box 18.60. Clinical features The most marked symptoms are polyuria and polydipsia. The patient may pass 5–20 L or more of urine in 24 hours. This is of low specific gravity and osmolality. If the patient has an intact thirst mechanism, is conscious and has access to oral fluids, then he or she can maintain adequate fluid intake. However, in an unconscious patient or a patient with damage to the hypothalamic thirst centre, diabetes insipidus is potentially lethal. If there is associated cortisol deficiency, then diabetes insipidus may not be manifest until glucocorticoid replacement therapy is given. The most common differential diagnosis is primary polydipsia, caused by drinking excessive amounts of fluid in the absence of a defect in vasopressin or thirst control. Pegvisomant is a peptide GH receptor antagonist administered by daily self-injection and may be indicated in some patients whose GH and IGF-1 concentrations fail to suppress sufficiently following somatostatin analogue therapy. Craniopharyngioma Craniopharyngiomas are benign tumours that develop in cell rests of Rathke’s pouch, and may be located within the sella turcica, or commonly in the suprasellar space. They are often cystic, with a solid component that may or may not be calcified (Fig. 18.31). In young people, they are diagnosed more commonly than pituitary adenomas. They may present with pressure effects on adjacent structures, hypopituitarism and/or cranial diabetes insipidus. Other clinical features directly related to hypothalamic damage may also occur. These include hyperphagia and obesity, loss of the sensation of thirst and disturbance of temperature regulation, and these features can be significant clinical challenges to manage. Craniopharyngiomas can be treated by the trans-sphenoidal route but surgery may also involve a craniotomy, with a relatively high risk of hypothalamic damage and other complications. If the Fig. 18.31 Craniopharyngioma. A This developmental tumour characteristically presents in younger patients; it is often cystic and calcified, as shown in this MRI scan (arrows). B Pathology specimen. A B 18.60 Causes of diabetes insipidus Cranial Structural hypothalamic or high stalk lesion • See Box 18.54 Idiopathic Genetic defect • Dominant (AVP gene mutation) • Recessive (DIDMOAD syndrome – association of diabetes insipidus with diabetes mellitus, optic atrophy, deafness) Nephrogenic Genetic defect • V2 receptor mutation • Aquaporin-2 mutation • Cystinosis Metabolic abnormality • Hypokalaemia • Hypercalcaemia Drug therapy • Lithium • Demeclocycline Poisoning • Heavy metals Chronic kidney disease • Polycystic kidney disease • Sickle-cell anaemia • Infiltrative disease

688 • ENDOCRINOLOGY of serum sodium concentrations and/or osmolality. The principal hazard is excessive treatment, resulting in water intoxication and hyponatraemia. Conversely, inadequate treatment results in thirst and polyuria. The ideal dose prevents nocturia but allows a degree of polyuria from time to time before the next dose (e.g. DDAVP nasal dose 5 μg in the morning and 10 μg at night). The polyuria in nephrogenic diabetes insipidus is improved by thiazide diuretics (e.g. bendroflumethiazide 5–10 mg/day), amiloride (5–10 mg/day) and NSAIDs (e.g. indometacin 15 mg 3 times daily), although the last of these carries a risk of reducing glomerular filtration rate. Disorders affecting multiple endocrine glands Multiple endocrine neoplasia Multiple endocrine neoplasias (MEN) are rare autosomal dominant syndromes characterised by hyperplasia and formation of adenomas or malignant tumours in multiple glands. They fall into four groups, as shown in Box 18.63. Some other genetic diseases also have an increased risk of endocrine tumours; for example, phaeochromocytoma is associated with von Hippel–Lindau syndrome (p. 1132) and neurofibromatosis type 1 (p. 1131). The MEN syndromes should be considered in all patients with two or more endocrine tumours and in patients with solitary tumours who report other endocrine tumours in their family. Inactivating mutations in MEN 1 (MENIN), a tumour suppressor gene on chromosome 11, cause MEN 1, whereas MEN 2 and 3 (also known as MEN 2a and 2b, respectively) are caused by gain-of-function mutations in the RET proto-oncogene on chromosome 10. These cause constitutive activation of the membrane-associated tyrosine kinase RET, which controls the development of cells that migrate from the neural crest. In contrast, loss-of-function mutations of the RET kinase cause Hirschsprung’s disease (p. 834). MEN 4 is extremely rare and is associated with loss-of-function mutations in the CDNK1B gene on chromosome 12; this gene codes for the protein p27, which has putative tumour suppressor activity. Predictive genetic testing can be performed on relatives of individuals with MEN syndromes, after appropriate counselling (p. 59). Individuals who carry mutations associated with MEN should be entered into a surveillance programme. In MEN 1, this typically involves annual history, examination and measurements of serum calcium and prolactin, and MRI of the pituitary and pancreas every 2 years; some centres also perform regular CT or MRI scans Investigations Diabetes insipidus can be confirmed if serum vasopressin is undetectable (although the assay for this is not widely available) or the urine is not maximally concentrated (i.e. < 600 mmol/kg) in the presence of increased plasma osmolality (i.e. > 300 mOsmol/kg). Sometimes, the diagnosis can be confirmed or refuted by random simultaneous samples of blood and urine, but more often a dynamic test is required. The water deprivation test described in Box 18.61 is widely used, but an alternative is to infuse hypertonic (5%) saline and measure vasopressin secretion in response to increasing plasma osmolality. Thirst can also be assessed during these tests on a visual analogue scale. Anterior pituitary function and suprasellar anatomy should be assessed in patients with cranial diabetes insipidus (see Box 18.53). In primary polydipsia, the urine may be excessively dilute because of chronic diuresis, which ‘washes out’ the solute gradient across the loop of Henle, but plasma osmolality is low rather than high. DDAVP (see below) should not be administered to patients with primary polydipsia, since it will prevent excretion of water and there is a risk of severe water intoxication if the patient continues to drink fluid to excess. In nephrogenic diabetes insipidus, appropriate further tests may include plasma electrolytes, calcium, ultrasound of the kidneys and urinalysis. Management Treatment of cranial diabetes insipidus is with des-amino-desaspartate-arginine vasopressin (desmopressin, DDAVP), an analogue of vasopressin that has a longer half-life. For chronic replacement therapy DDAVP may be administered intranasally and orally, although the latter formulation has variable bioavailability. In sick patients, DDAVP should be given by intramuscular injection. The dose of DDAVP should be adjusted on the basis 18.61 How and when to do a water deprivation test Use • To establish a diagnosis of diabetes insipidus and to differentiate cranial from nephrogenic causes Protocol • No coffee, tea or smoking on the test day • Free fluids until 0730 hrs on the morning of the test, but discourage patients from ‘stocking up’ with extra fluid in anticipation of fluid deprivation • No fluids from 0730 hrs • Attend at 0830 hrs for measurement of body weight and plasma and urine osmolality • Record body weight, urine volume, urine and plasma osmolality and thirst score on a visual analogue scale every 2 hrs for up to 8 hrs • Stop the test if the patient loses 3% of body weight • If plasma osmolality reaches > 300 mOsmol/kg and urine osmolality < 600 mOsmol/kg, then administer DDAVP (see text) 2 μg IM Interpretation • Diabetes insipidus is confirmed by a plasma osmolality

300 mOsmol/kg with a urine osmolality < 600 mOsmol/kg • Cranial diabetes insipidus is confirmed if urine osmolality rises by at least 50% after DDAVP • Nephrogenic diabetes insipidus is confirmed if DDAVP does not concentrate the urine • Primary polydipsia is suggested by low plasma osmolality at the start of the test 18.62 The pituitary and hypothalamus in old age • Late presentation: often with large tumours causing visual disturbance, because early symptoms such as amenorrhoea and sexual dysfunction do not occur or are not recognised. • Coincidentally discovered pituitary tumours: may not require surgical intervention if the visual apparatus is not involved, because of slow growth. • Hyperprolactinaemia: less impact in post-menopausal women who are already ‘physiologically’ hypogonadal. Macroprolactinomas, however, require treatment because of their potential to cause mass effects.

Further information • 689

of the chest. In individuals with MEN 2 and 3, annual history, examination and measurement of serum calcium, calcitonin and urinary or plasma catecholamine metabolites should be performed. Because the penetrance of medullary carcinoma of the thyroid approaches 100% in individuals with a RET mutation, prophylactic thyroidectomy should be performed in early childhood in most patients. The precise timing of surgery in childhood should be guided by the specific mutation in the RET gene. Autoimmune polyendocrine syndromes Two distinct autoimmune polyendocrine syndromes are known: APS types 1 and 2. The most common is APS type 2 (Schmidt’s syndrome), which typically presents in women between the ages of 20 and 60. It is usually defined as the occurrence in the same individual of two or more autoimmune endocrine disorders, some of which are listed in Box 18.64. The mode of inheritance is autosomal dominant with incomplete penetrance and there is a strong association with HLA-DR3 and CTLA-4. Much less common is APS type 1, which is also termed autoimmune poly-endocrinopathy-candidiasis-ectodermal 18.63 Multiple endocrine neoplasia (MEN) syndromes MEN 1 (Wermer’s syndrome) • Primary hyperparathyroidism • Pituitary tumours • Pancreatic neuro-endocrine tumours (e.g. non-functioning, insulinoma, gastrinoma) • Bronchial and thymic carcinoids • Adrenal tumours • Cutaneous lesions (e.g. lipomas, collagenomas, angiofibromas) MEN 2 (also known as MEN 2a or Sipple’s syndrome) • Primary hyperparathyroidism • Medullary carcinoma of thyroid • Phaeochromocytoma MEN 3 (also known as MEN 2b) • As for MEN 2 above (though medullary thyroid cancer occurs earlier, even within the first year of life) • Marfanoid habitus • Skeletal abnormalities (e.g. craniosynostosis) • Abnormal dental enamel • Multiple mucosal neuromas MEN 4 • Primary hyperparathyroidism • Pituitary tumours • Possible tumours in the adrenals, reproductive organs, kidneys • Possible pancreatic, gastric, bronchial and cervical neuro-endocrine tumours 18.64 Autoimmune polyendocrine syndromes (APS)* Type 1 (APECED) • Addison’s disease • Hypoparathyroidism • Type 1 diabetes • Primary hypothyroidism • Chronic mucocutaneous candidiasis • Nail dystrophy • Dental enamel hypoplasia Type 2 (Schmidt’s syndrome) • Addison’s disease • Primary hypothyroidism • Graves’ disease • Pernicious anaemia • Primary hypogonadism • Type 1 diabetes • Vitiligo • Coeliac disease • Myasthenia gravis *In both types of APS, the precise pattern of disease varies between affected individuals. (APECED = autoimmune poly-endocrinopathy-candidiasis-ectodermal dystrophy) dystrophy (APECED). This is inherited in an autosomal recessive fashion and is caused by loss-of-function mutations in the autoimmune regulator gene AIRE, which is responsible for the presentation of self-antigens to thymocytes in utero. This is essential for the deletion of thymocyte clones that react against self-antigens and hence for the development of immune tolerance (p. 82). The most common clinical features are described in Box 18.64, although the pattern of presentation is variable and other autoimmune disorders are often observed. Late effects of childhood cancer therapy The therapies used to treat cancers in children and adolescents, including radiotherapy and chemotherapy, may cause long-term endocrine dysfunction (p. 1298). Further information Websites british-thyroid-association.org British Thyroid Association: provider of guidelines, e.g. treatment of hypothyroidism and the investigation and management of thyroid cancer. btf-thyroid.org British Thyroid Foundation: a resource for patient leaflets and support for patients with thyroid disorders. endocrinology.org British Society for Endocrinology: useful online education resources and links to patient support group. endo-society.org American Endocrine Society: provider of clinical practice guidelines. pituitary.org.uk Pituitary Foundation: a resource for patient and general practitioner leaflets and further information. thyroid.org American Thyroid Association: provider of clinical practice guidelines.

7KLVSDJHLQWHQWLRQDOO\OHIWEODQN

Ch04-3 Clinical Medicine

09-19 Nutritional factors in disease

19 Nutritional factors in disease

Nutritional factors in disease AG Shand JPH Wilding Clinical examination in nutritional disorders 692 Clinical assessment and investigation of nutritional status 693 Nutritional factors and disease 694 Physiology of nutrition 694 Disorders of altered energy balance 698 Obesity 698 Under-nutrition 704 Micronutrients, minerals and their diseases 711 Vitamins 711 Inorganic micronutrients 716

692 • NUTRITIONAL FACTORS IN DISEASE Insets (Scaphoid abdomen) From Chandra A, Quinones-Baldrich WJ. Chronic mesenteric ischemia: How to select patients for invasive treatment. Sem Vasc Surg 2010; 23:21–28; (Koilonychia) Habif TP. Clinical Dermatology, 6th edn. Philadelphia: Saunders, Elsevier Inc.; 2016; (Gingivitis) Newman MG, Takei H, Klokkevold PR, et al. Carranza’s Clinical Periodontology, 12th edn. Philadelphia: Saunders, Elsevier Inc.; 2015; (Corkscrew hairs) Bolognia JL, Jorizzo JL, Schaffer JV, et al. Dermatology, 3rd edn. Philadelphia: Saunders, Elsevier Inc.; 2012. Eyes Sunken eyes Pallor Jaundice Bitot spots (↓vitamin A; see Fig. 19.12) Hands Muscle wasting (dorsal interossei, thenar eminences) Finger clubbing Leukonychia (low albumin) Koilonychia (iron deficiency) Simple anthropometrics (see right) Body mass index Triceps skin fold thickness Waist circumference Legs Pitting oedema Ulcers Affect Fatigue Depression Dementia Mouth Pallor Angular stomatitis (↓B12, folate, iron) Glossitis (↓B12, folate, iron) Gingivitis, bleeding gums (↓vitamin C; see Fig. 19.14) Poorly fitting dentures Corkscrew hairs Gingivitis Koilonychia Scaphoid abdomen Clinical effects of short bowel syndrome after multiple resection in Crohn’s disease

Skin Dry, flaky skin or dermatitis (see Fig. 19.13) Hair loss Specific abnormalities: Petechiae, corkscrew hairs (↓vitamin C) Dermatitis of pellegra (↓niacin)

Observation Signs of weight loss: Prominent ribs Muscle wasting ↓Skin turgor

Clinical examination in nutritional disorders

Clinical assessment and investigation of nutritional status • 693

Clinical assessment and investigation of nutritional status Important elements of the diet history Ask about weight • Current weight • Weight 2 weeks, 1 month and 6 months ago • Assessment of degree of change Ask about current food intake • Quantity of food and if any change • Quality of food taken • Whether normal food is being eaten • Avoidance of specific food types (e.g. solids) • Any nutritional supplements • Reliance on supplements/tube feeding • Any change in appetite or interest in food • Any taste disturbance Ask about symptoms that interfere with eating • Oral ulcers or oral pain • Difficulties swallowing • Nausea/vomiting • Early satiety • Alteration in bowel habit • Abdominal (or other) pain Ask about activity levels/performance status • Normal activity • Slightly reduced activity • Inactive < 50% of the time • Inactive most of the time Under-nutrition can go unnoticed in patients with multiple comorbidities. It is vital to be aware of under-nutrition as a potential reason for any acute medical presentation or as a modifier of it. Early nutritional assessment is crucial and a dietary history provides useful information (especially when taken by a dietitian). Points to note include past medical and surgical history (e.g. abdominal or intestinal surgery), a drug history and a specific diet history. Evidence of recent weight loss and muscle wasting should be sought. Simple, validated tools are available to screen patients for nutritional problems. Body composition reflects energy balance and is assessed by clinical anthropomorphic measurements. More sophisticated techniques may be used to assess body composition or functional capacity if required. 2 Body mass index (BMI) BMI wt kg ht m

( ) ( )2 Example: an adult of 70 kg with a height of 1.75 m has a BMI of 70/1.752 = 22.9 kg/m2 • BMI is a useful way of identifying under- or over-nutrition but cannot discriminate between lean body or muscle mass and fat mass • Fat mass is also subject to ethnic variation; for the same BMI, Asians tend to have more body fat than Europeans • If height cannot be determined (e.g. in older people or those unable to stand), measurement of the femoral length or ‘knee height’ is a good surrogate Measurement of knee height. 2 Measures of body composition and nutritional status Body composition • Anthropometry (see below) • Bioelectrical impedance • Dual X-ray absorptiometry (DXA) Muscle function and global nutritional status • Hand grip strength (dynamometer test) – poor grip associated with increased mortality Obesity and fat distribution (android vs gynoid) • Waist:hip ratio (circumferences measured midway between superior iliac crest and lower border of rib cage, and at greater trochanters, respectively) Body fat content and muscle mass • Triceps skinfold thickness (when combined with mid-/upper arm circumference estimates muscle mass) Triceps skinfold thickness. Lean patients 6–12 mm; obese patients 40–50 mm. Screening hospitalised patients for risk of malnutrition. Acute illnesses include decompensated liver disease, cancer cachexia or being kept ‘nil by mouth’. Adapted from the British Association of Parenteral and Enteral Nutrition Malnutrition Universal Screening Tool (www.bapen.org.uk). Weight loss score Unplanned loss in 6 months < 5% 5 – 10%

10% = 0 = 1 = 2 BMI score 20 18.5 – 20 < 18.5 = 0 = 1 = 2 Acute disease score Acute illness with no nutritional intake for 5 days = 2 Total = 1 – Medium risk Total = 0 – Low risk Total ≥ 2 – High risk Total score • Routine clinical care • Repeat screen weekly • Document dietary intake for 3 days • Repeat screen weekly • Refer to dietitian/nutrition support team • Review plan weekly

694 • NUTRITIONAL FACTORS IN DISEASE energy is also required for thermal regulation, and expenditure is higher in cold or hot environments. The energy required for digestion of food (diet-induced thermogenesis; Fig. 19.2D) accounts for approximately 10% of total energy expenditure, with protein requiring more energy than other macronutrients. Another component of energy expenditure is governed by the level of muscular activity, which can vary considerably with occupation and lifestyle (Fig. 19.2C). Physical activity levels are usually defined as multiples of BMR. Energy intake is determined by the ‘macronutrient’ content of food. Carbohydrates, fat, protein and alcohol provide fuel for oxidation in the mitochondria to generate energy (as adenosine triphosphate (ATP); p. 49). The energy provided by each of these elements differs: • carbohydrates (16 kJ/g) • fat (37 kJ/g) • protein (17 kJ/g) • alcohol (29 kJ/g). Regulation of energy balance Energy intake and expenditure are highly regulated (Fig. 19.3). A link with reproductive function ensures that pregnancy is most likely to occur during times of nutritional plenty, when both mother and baby have a better chance of survival. Improved nutrition is thought to be the reason for the increasingly early onset of puberty in many societies. At the other extreme, anorexia nervosa and excessive exercise can lead to amenorrhoea (p. 654). Regulation of energy balance is coordinated in the hypothalamus, which receives afferent signals that indicate nutritional status in the short term (e.g. the stomach hormone ghrelin, which falls immediately after eating and rises gradually thereafter, to suppress satiety and signal that it is time for the next meal) and the long term (e.g. the adipose hormone leptin, which increases with growing fat mass and may also link fat mass to reproductive function). The hypothalamus responds with changes in many local neurotransmitters that alter activity in a number of pathways that influence energy balance (Fig. 19.3), including hormones acting on the pituitary gland (see Fig. 18.2, p. 633), and neural control circuits that connect with the cerebral cortex and autonomic nervous system. Responses to under- and over-nutrition These complex regulatory pathways allow adaptation to variations in nutrition. In response to starvation, reproductive function is suppressed, BMR is reduced, and there are profound psychological effects, including energy conservation through lethargy. These adjustments can ‘defend’ body weight within certain limits. In the low-insulin state of starvation (see Fig. 20.5, p. 725), however, fuels are liberated from stores initially in glycogen (in liver and muscle), then in triglyceride (lipolysis in adipose tissue, with excess free fatty acid supply to the liver leading to ketosis) and finally in protein (proteolysis in muscle). In those with a high glucose requirement, such as neonates and women who are pregnant or breastfeeding, starvation can result in ketoacidosis associated with normal or low blood glucose (p. 365). In response to over-nutrition, BMR is increased, and extra energy is consumed in the work of carrying increased fat stores, so that body weight is again ‘defended’ within certain limits. In the high-insulin state of over-nutrition, excess energy is invested in fatty acids and stored as triglycerides; these are deposited principally in adipose tissue but they may also accumulate in the liver (non-alcoholic fatty liver disease; p. 882) and skeletal muscle. If hypothalamic function is abnormal (e.g. in those with Nutritional factors and disease Obtaining adequate nutrition is a fundamental requirement for the survival of every individual and species. The politics of food provision for humans are complex and constitute a prominent factor in wars, natural disasters and the global economy. In recent decades, economic success has been rewarded by plentiful nutrition unknown to previous generations, which has led to a pandemic of obesity and its consequences for health, yet in many parts of the world, famine and under-nutrition still represent a huge burden. Quality, as well as quantity, of food influences health, with governmental advice on healthy diets maximising fruit and vegetable intakes (Fig. 19.1). Inappropriate diets have been linked to diseases such as coronary heart disease and cancer. Deficiencies of vitamins or minerals lead to avoidable conditions, such as anaemia due to iron deficiency or blindness due to severe vitamin A deficiency. A proper understanding of nutrition is therefore essential in dealing with the needs of individual patients and in informing the planning of public policy. Physiology of nutrition Nutrients in the diet can be classified into ‘macronutrients’, which are eaten in relatively large amounts to provide fuel for energy, and ‘micronutrients’ (e.g. vitamins and minerals), which do not contribute to energy balance but are required in small amounts because they are not synthesised in the body. Energy balance The laws of thermodynamics dictate that energy balance is achieved when energy intake = energy expenditure (Fig. 19.2). Energy expenditure has several components. The basal metabolic rate (BMR) describes the obligatory energy expenditure required to maintain metabolic functions in tissues and hence sustain life. It is most closely predicted by fat-free mass (i.e. total body mass minus fat mass), which is lower in females and older people (Fig. 19.2B). Extra metabolic energy is consumed during growth, pregnancy and lactation, and when febrile. Metabolic Fig. 19.1 Proportion of key food groups recommended for a healthy, well-balanced diet. Crown copyright. Department of Health in association with the Welsh Government, the Scottish Government and the Food Standards Agency in Northern Ireland. Fruit and vegetables Food and drinks high in fat and/or sugar Milk and dairy foods Bread, rice, potatoes, pasta and other starchy foods Meat, fish, eggs, beans and other non-dairy sources of protein

Nutritional factors and disease • 695

are broken down to monosaccharides before absorption from the gut (p. 768), and supply over half the energy in a normal, well-balanced diet (see Fig. 19.2A). No individual carbohydrate is an essential nutrient, as carbohydrates can be synthesised de novo from glycerol or protein. If the available carbohydrate intake is less than 100 g per day, however, increased lipolysis leads to ketosis (see Fig. 20.7, p. 730). Dietary guidelines do not restrict the intake of intrinsic sugars in fruit and vegetables or the sugars in milk. However, intake of non-milk extrinsic sugars (sucrose, maltose, fructose), which increase the risk of dental caries and diabetes mellitus, should craniopharyngioma; see Fig. 18.31, p. 687) or in rare patients with mutations in relevant genes (e.g. in leptin or melanocortin-4 receptors), loss of response to satiety signals, together with loss of adaptive changes in energy expenditure, result in relentless weight gain. Macronutrients (energy-yielding nutrients) Carbohydrates Types of carbohydrate and their dietary sources are listed in Box 19.1. The ‘available’ carbohydrates (starches and sugars) Fig. 19.2 Determinants of energy balance. A Energy intake is shown as national averages, highlighting the differences in sources of energy in different countries (but obscuring substantial regional variations). The targets are recommendations as a percentage of food energy only (Source: Dept of Health 1991). For WHO targets, see Box 19.4. In the UK, it is assumed that 5% of energy intake will be derived from alcohol. B Data for normal basal metabolic rate (BMR) were obtained from healthy men and women in various countries. BMR declines from middle age and is lower in women, even after adjustment for body size because of differences in fat-free mass. C Energy is required for movement and activity. Physical activity level (PAL) is the multiple of BMR by which total energy expenditure is increased by activity. D Energy is consumed in order to digest food. Leisure or sport activity increases PAL by ~0.3 for each 30–60 minutes of moderate exercise performed 4–5 times per week. The UK population median for PAL is 1.6, with estimates of 1.5 for the ‘less active’ and 1.8 for the ‘more active’. Immobile Sedentary work Standing work Active leisure/ sport Strenuous work Soldier Athlete 0.0 1.0 2.0 3.0 Physical activity level (PAL) Total energy expenditure Basal metabolic rate Male Female Energy expenditure = B Basal metabolic rate D Diet-induced thermogenesis C Physical activity A Dietary intake = food + alcohol 17% Protein 35% Fat 48% Carbohydrate 10% Protein 15% Fat 75% Carbohydrate 17% Protein 33% Fat 50% Carbohydrate UK target food intakes Current food intakes Energy intake Energy expenditure India UK 1 megajoule (MJ) = 239 kilocalorie (kcal) = energy stored in ~ 34 g fat 18 – 29 30 – 39 40 – 64 Age (years) • Higher with greater fat-free mass • Lower with ageing • Increases with cold, heat, fever • Higher in smokers

Energy expenditure (MJ/day)

696 • NUTRITIONAL FACTORS IN DISEASE Fig. 19.3 Regulation of energy balance and its link with reproduction. Պ indicates factors that are stimulated by eating and induce satiety. Ջ indicates factors that are suppressed by eating and inhibit satiety. Eating behaviour Habit Hedonic response to food Satiety Muscle Adipose tissue Energy expenditure/storage Fertility Neuro-endocrine responses (growth hormone, cortisol, thyroxine) Autonomic nervous system Reproductive hormones Adipose tissue Hypothalamus Stomach Pancreas Small bowel Ghrelin Leptin Insulin Peptide YY Oxyntomodulin Glucagon-like peptide-1 Pancreatic polypeptide 19.1 Dietary carbohydrates Class Components Examples Source Free sugars Monosaccharides Disaccharides Glucose, fructose Sucrose, lactose, maltose Intrinsic: fruits, milks, vegetables Extrinsic (extracted, refined): beet or cane sucrose, high-fructose corn syrup Short-chain carbohydrates Oligosaccharides Maltodextrins, fructo-oligosaccharides Starch polysaccharides Rapidly digestible Slowly digestible Resistant Cereals (wheat, rice), root vegetables (potato), legumes (lentils, beans, peas) Non-starch polysaccharides (NSPs; dietary fibre) Fibrous Viscous Cellulose Hemicellulose Pectins Gums Plants Sugar alcohols Sorbitol, xylitol Sorbitol: stone fruits (apples, peaches, prunes) Xylitol: maize, berry fruits Both used as low-calorie sugar alternatives be limited. Individuals who do not produce lactase (‘lactoseintolerant’) are advised to avoid or limit dairy products and foods with added lactose. Starches in cereal foods, root foods and legumes provide the largest proportion of energy in most diets around the world. All starches are polymers of glucose, linked by the same 1–4 glycosidic linkages. Some starches are digested promptly by salivary and then pancreatic amylase, however, producing rapid delivery of glucose to the blood. Other starches are digested more slowly, either because they are protected in the structure of the food, or because of their crystal structure, or because the molecule is unbranched (amylose). These differences are the basis for the ‘glycaemic index’ of foods. This is the area under the curve of the rise in blood glucose concentration in the 2 hours following ingestion of 50 g carbohydrate, expressed as a percentage of the response to 50 g anhydrous glucose. There is evidence linking high glycaemic index foods, particularly foods containing large amounts of sugars such as glucose, sucrose or fructose (e.g. in soft drinks) with obesity and type 2 diabetes

Nutritional factors and disease • 697

fat (i.e. from animal sources: butter, ghee or lard) with PUFA in the diet can lower the concentration of circulating low-density lipoprotein (LDL) cholesterol and may help prevent coronary heart disease. High intakes of trans fatty acids (TFAs; isomers of the natural cis fatty acids) reflect the use of oils that have been partially hydrogenated in the food industry. It is recommended that TFAs are limited to less than 2% of the dietary fat intake, as they are associated with cardiovascular disease. Changes in industrial practice in the UK and US have meant that TFA intake is now below 1%, with the residual amounts coming from milk as a result of ruminant digestion. Cholesterol is also absorbed directly from food in chylomicrons and is an important substrate for steroid and sterol synthesis, but not an important source of energy. Proteins Proteins are made up of some 20 different amino acids, of which nine are ‘essential’ (Box 19.2), i.e. they cannot be synthesised in humans but are required for synthesis of important proteins. Another group of five amino acids are termed ‘conditionally essential’, meaning that they can be synthesised from other amino acids, provided there is an adequate dietary supply. The remaining amino acids can be synthesised in the body by transamination, provided there is a sufficient supply of amino groups. The nutritive or ‘biological’ value of different proteins depends on the relative proportions of essential amino acids they contain. Proteins of animal origin, particularly from eggs, milk and meat, are generally of higher biological value than proteins of vegetable origin, which are low in one or more of the essential amino acids. When two different vegetable proteins are eaten together (e.g. a cereal and a legume), however, their amino acid contents are complementary and produce an adequate mix, an important principle in vegan diets. Dietary recommendations for macronutrients Recommendations for energy intake (Box 19.3) and proportions of macronutrients (Box 19.4) have been calculated to provide a balance of essential nutrients and minimise the risks of excessive refined sugar (dental caries, high glycaemic index/diabetes mellitus), saturated fat or trans fat (obesity, coronary heart disease). Recommended dietary fibre intake is based on avoiding risks of colonic disease. The usual recommended protein intake for a healthy man doing light work is 65–100 g/day. The minimum requirement is around 40 g of protein with a high proportion of essential amino acids or a high biological value. (p. 932). Sugar alcohols (e.g. sorbitol) that are not absorbed form the gut and are used as replacement sweeteners can cause diarrhoea if eaten in large amounts. Dietary fibre Dietary fibre is plant food that is not digested by human enzymes in the gastrointestinal tract. Most dietary fibre is known as ‘non-starch polysaccharides’ (NSPs) (see Box 19.1). A small percentage of ‘resistant’ dietary starch may also pass unchanged into the large intestine. Dietary fibre can be broken down by the resident bacteria in the colon to produce short-chain fatty acids. This is essential fuel for the enterocytes and contributes to bowel health. The extent of flatus formed is dependent on the food source. Some types of NSP, notably the hemicellulose of wheat, increase the water-holding capacity of colonic contents and the bulk of faeces. They relieve simple constipation, appear to prevent diverticulosis and may reduce the risk of cancer of the colon. Other viscous, indigestible polysaccharides like pectin and guar gum are important in the upper gastrointestinal tract, where they slow gastric emptying, contribute to satiety, and reduce bile salt absorption and hence plasma cholesterol concentration. Fats Fat has the highest energy density of the macronutrients (37 kJ/g) and excessive consumption may be an insidious cause of obesity (see Fig. 19.2A). Free fatty acids are absorbed in chylomicrons (pp. 371 and 372; see Fig. 21.5, p. 768), allowing access of complex molecules into the circulation. Fatty acid structures are shown in Figure 19.4. The principal polyunsaturated fatty acid (PUFA) in plant seed oils is linoleic acid (18 : 2 ω6). This and α-linolenic acid (18 : 3 ω3) are the ‘essential’ fatty acids, which humans cannot synthesise de novo. They undergo further desaturation and elongation, to produce, for example, γ-linolenic acid (18 : 3 ω6) and arachidonic acid (20 : 4 ω6). These are precursors of prostaglandins and eicosanoids, and form part of the structure of lipid membranes in all cells. Fish oils are rich in ω3 PUFA (e.g. eicosapentaenoic (20 : 5 ω3) and docosahexaenoic (22 : 6 ω3), which promote the anti-inflammatory cascade of prostaglandin production and occur in the lipids of the human brain and retina. They inhibit thrombosis by competitively antagonising thromboxane A2 formation. Replacing saturated Fig. 19.4 Schematic representation of fatty acids. Standard nomenclature specifies the number of carbon atoms and indicates the number and position of the double bond(s) relative to the methyl (−CH3, ω) end of the molecule after a colon. CH3 COOH Polyunsaturated fatty acid, e.g. linoleic acid (18:2 ω6) CH3 COOH Monounsaturated fatty acid, e.g. oleic acid (18:1 ω9) CH3 COOH Saturated fatty acid, e.g. myristic acid (14:0 )

CH2 CH 19.2 Amino acids Essential amino acids • Tryptophan • Histidine • Methionine • Threonine • Isoleucine • Valine • Phenylalanine • Lysine • Leucine Conditionally essential amino acids and their precursors • Cysteine: methionine, serine • Tyrosine: phenylalanine • Arginine: glutamine/glutamate, aspartate • Proline: glutamate • Glycine: serine, choline

698 • NUTRITIONAL FACTORS IN DISEASE Disorders of altered energy balance Obesity Obesity is regarded as a pandemic, with potentially disastrous consequences for human health. Over 25% of adults in the UK were obese (i.e. BMI ≥ 30 kg/m2) in 2015, compared with 7% in 1980 and 16% in 1995. Moreover, almost 66% of the UK adult population are overweight (BMI ≥ 25 kg/m2), although there is considerable regional and age group variation. In developing countries, average national rates of obesity are low, but these figures may disguise high rates of obesity in urban communities; for example, nearly 25% of women in urban India are overweight. There is increasing public awareness of the health implications of obesity. Many will seek medical help for their obesity, others will present with complications of obesity, and increasing numbers are being identified during health screening examinations. Complications Obesity has adverse effects on both mortality and morbidity (Fig. 19.5). Changes in mortality are difficult to analyse due to the confounding effects of lower body weight in cigarette smokers and those with other illnesses (such as cancer). It is clear, however, that the lowest mortality rates are seen in Europeans in the BMI range 18.5–24 kg/m2 (and at lower BMI in Asians). It is suggested that obesity at age 40 years can reduce life expectancy by up to 7 years for non-smokers and by 13 years for smokers. Coronary heart disease (Fig. 19.6) is the major cause of death but cancer rates are also increased in the overweight, especially colorectal cancer in males and cancer of the gallbladder, biliary tract, breast, endometrium and cervix in females. Obesity has little effect on life expectancy above 70 years of age, but the obese do spend a greater proportion of their active life disabled. The Fig. 19.5 Complications of obesity. Pulmonary Exercise intolerance Obstructive sleep apnoea Asthma Gastrointestinal Gallstones Gastro-oesophageal reflux Non-alcoholic fatty liver disease Colon cancer Renal Glomerulosclerosis Renal cancer Musculoskeletal Ankle sprains Flat feet Tibia vara Osteoarthritis Back pain Psychosocial Eating disorders Poor self-esteem Body image disorder Social isolation and stigmatisation Depression Neurological Pseudotumour cerebri (idiopathic intracranial hypertension) Cardiovascular Hypertension Dyslipidaemia Coagulopathy Chronic inflammation Endothelial dysfunction Endocrine Insulin resistance Impaired fasting glucose or glucose intolerance Type 2 diabetes Precocious puberty Menstrual irregularities Polycystic ovary syndrome (females) Hormone-related cancers (breast, endometrium, prostate) 19.4 WHO recommended population macronutrient goals Nutrient (% of total energy unless indicated) Target limits for average population intakes Lower Upper Total fat

Saturated fatty acids

Polyunsaturated fatty acids

Trans fatty acids

Dietary cholesterol (mg/day)

Total carbohydrate

Free sugars

Complex carbohydrate

Dietary fibre (g/day): As non-starch polysaccharides

As total dietary fibre

Protein

19.3 Daily adult energy requirements in health Circumstances Daily requirements* Females Males At rest (basal metabolic rate) 5.4 MJ (1300 kcal) 6.7 MJ (1600 kcal) Less active 8.0 MJ (1900 kcal) 9.9 MJ (2400 kcal) Population median 8.8 MJ (2100 kcal) 10.8 MJ (2600 kcal) More active 9.6 MJ (2300 kcal) 11.8 MJ (2800 kcal) *These are based on a healthy target body mass index (BMI) of 22.5 kg/m2. For a female, height is 162 cm and weight 59.0 kg; for a male, height is 175 cm and weight 68.8 kg. Previous average recommendations of 8.1 MJ (1950 kcal, usually rounded up to 2000 kcal) for females and 10.7 MJ (2500 kcal) for males should continue to be used, as these fall within experimental error.

Disorders of altered energy balance • 699

in the liver and muscle, and hence induce insulin resistance and promote type 2 diabetes. Recent research has also highlighted the importance of fat deposition within specific organs, especially the liver, as an important determinant of metabolic risk in the obese. Aetiology Accumulation of fat results from a discrepancy between energy consumption and energy expenditure that is too large to be defended by the hypothalamic regulation of BMR. A continuous small daily positive energy balance of only 0.2–0.8 MJ (50–200 kcal; < 10% of intake) would lead to weight gain of 2–20 kg over a period of 4–10 years. Given the cumulative effects of subtle energy excess, body fat content shows ‘tracking’ with age, such that obese children usually become obese adults. Weight tends to increase throughout adult life, as BMR and physical activity decrease (see Fig. 19.2). The pandemic of obesity reflects changes in both energy intake and expenditure (Box 19.5), although both are difficult to measure reliably. The estimated average global daily supply of food energy per person increased from approximately 9.8 MJ (2350 kcal) in the 1960s to approximately 11.7 MJ (2800 kcal) in the 1990s, but its delivery is unequal. For example, in India it is estimated that 5% of the population receives 40% of the available food energy, leading to obesity in the urban population in parallel with under-nutrition in some rural communities. In affluent societies, a significant proportion of this food supply is discarded. In the USA, men’s average daily energy intake reportedly rose from 10.2 MJ (2450 kcal) in 1971 to 11.0 MJ (2618 kcal) in 2000. Portion sizes, particularly of energy-dense foods such as drinks with highly refined sugar content and salty snacks, have increased. However, UK data suggest that energy intakes have declined (which may in part be due to deliberate restriction or ‘dieting’), but this is apparently insufficient to compensate for the decrease in physical activity in recent years. Obesity is correlated positively with the number of hours spent watching television, and inversely with levels of physical activity (e.g. stair climbing). It is suggested that minor activities such as fidgeting, also termed non-exercise activity thermogenesis (NEAT), may contribute to energy expenditure and protect against obesity. Susceptibility to obesity Susceptibility to obesity and its adverse consequences undoubtedly varies between individuals. It is not true that obese subjects have a ‘slow metabolism’, since their BMR is higher than that of lean subjects. Twin and adoption studies confirm a genetic influence on obesity. The pattern of inheritance suggests a polygenic disorder, with small contributions from a number of different genes, together accounting for 25–70% of variation in weight. Recent results from ‘genome-wide’ association studies of polymorphisms in large numbers of people (p. 45) have rise in obesity has been accompanied by an epidemic of type 2 diabetes (p. 732) and osteoarthritis, particularly of the knee. Although an increased body size results in greater bone density through increased mechanical stress, it is not certain whether this translates to a lower incidence of osteoporotic fractures (p. 1044). Obesity may have profound psychological consequences, compounded by stigmatisation of the obese in many societies. Body fat distribution For some complications of obesity, the distribution rather than the absolute amount of excess adipose tissue appears to be important. Increased intra-abdominal fat causes ‘central’ (‘abdominal’, ‘visceral’, ‘android’ or ‘apple-shaped’) obesity, which contrasts with subcutaneous fat accumulation causing ‘generalised’ (‘gynoid’ or ‘pear-shaped’) obesity; the former is more common in men and is more closely associated with type 2 diabetes, the metabolic syndrome and cardiovascular disease (see Fig. 19.5). The key difference between these depots of fat may lie in their vascular anatomy, with intra-abdominal fat draining into the portal vein and thence directly to the liver. Thus many factors that are released from adipose tissue (including free fatty acids; ‘adipokines’, such as tumour necrosis factor alpha, adiponectin and resistin) may be at higher concentration Fig. 19.6 Risks of diabetes and cardiovascular disease in overweight and obese women. Data are from the Nurses’ Health Study in the USA, and mostly relate to Caucasian women. In some ethnic groups (e.g. South Asians, Native Americans) and in people with higher waist circumference, the metabolic complications are even more severe at a given level of body mass index.

Relative risk for cardiovascular disease < 21 21– 22.9 23– 24.9 25– 28.9

29

Relative risk for type 2 diabetes < 25 25 – 30

30 Normal weight Overweight Obese Body mass index (kg/m2)

19.5 Some reasons for the increasing prevalence of obesity – the ‘obesogenic’ environment Increasing energy intake • ↑ Portion sizes • ↑ Snacking and loss of regular meals • ↑ Energy-dense food (fat and sugars) • ↑ Affluence Decreasing energy expenditure • ↑ Car ownership • ↓ Walking to school/work • ↑ Automation; ↓ manual labour • ↓ Sports in schools • ↑ Time spent on computer games and watching TV • ↑ Central heating

700 • NUTRITIONAL FACTORS IN DISEASE Severity of obesity can be quantified using the BMI and waist circumference. The risk of metabolic and cardiovascular complications of obesity is higher in those with a high waist circumference; lower levels of BMI and waist circumference indicate higher risk in Asian populations (Box 19.7). A dietary history may be helpful in guiding dietary advice (p. 693) but is notoriously susceptible to under-reporting of food consumption. It is important to consider ‘pathological’ eating behaviour (such as binge eating, nocturnal eating or bulimia; p. 1204), which may be the most important issue to address in some patients. Alcohol is an important source of energy intake and should be considered in detail. The history of weight gain may help diagnose underlying causes. A patient who has recently gained substantial weight or has gained weight at a faster rate than previously, and is not taking relevant drugs (see Box 19.6), is more likely to have an underlying disorder such as hypothyroidism (p. 639) or Cushing’s syndrome (p. 666). All obese patients should have thyroid function tests performed on one occasion, and an overnight dexamethasone suppression test or 24-hour urine free cortisol if Cushing’s syndrome is suspected. Monogenic and ‘syndromic’ causes of obesity are usually relevant only in children presenting with severe obesity. Assessment of the diverse complications of obesity (see Fig. 19.5) requires a thorough history, examination and screening investigations. The impact of obesity on the patient’s life and work is a major consideration. Assessment of other cardiovascular risk factors is important. Blood pressure should be measured with a large cuff, if required (p. 510). Associated type 2 diabetes and dyslipidaemia are detected by measurement of blood glucose or HbA1c and a serum lipid profile, ideally in a fasting morning sample. Elevated serum transaminases occur in patients with non-alcoholic fatty liver disease (p. 884). Management The health risks of obesity are largely reversible if identified and treated early. Interventions proven to reduce weight in obese patients also ameliorate cardiovascular risk factors. Lifestyle advice that lowers body weight and increases physical exercise reduces the incidence of type 2 diabetes (p. 743). Given the high prevalence of obesity and the large magnitude of its risks, population strategies to prevent and reverse obesity are high on the public health priority list for many countries. Initiatives include promoting healthy eating in schools, enhancing walking identified a handful of genes that influence obesity, some of which encode proteins known to be involved in the control of appetite or metabolism and some of which have an unknown function. These genes account for less than 5% of the variation in body weight, however. Genes also influence fat distribution and therefore the risk of the metabolic consequences of obesity, such as type 2 diabetes and fatty liver disease. A few rare single-gene disorders have been identified that lead to severe childhood obesity. These include mutations of the melanocortin-4 receptor (MC4R), which account for approximately 5% of severe early-onset obesity; defects in the enzymes processing propiomelanocortin (POMC, the precursor for adrenocorticotrophic hormone (ACTH)) in the hypothalamus; and mutations in the leptin gene (see Fig. 19.3). The latter can be treated by leptin injections. Additional genetic conditions in which obesity is a feature include Prader–Willi (see Box 3.8, p. 51) and Lawrence–Moon–Biedl syndromes. Reversible causes of obesity and weight gain In a small minority of patients presenting with obesity, specific causal factors can be identified and treated (Box 19.6). These patients are distinguished from those with idiopathic obesity by their short history, with a recent marked change in the trajectory of their adult weight gain. Clinical features and investigations In assessing an individual presenting with obesity, the aims are to: • quantify the problem • exclude an underlying cause • identify complications • reach a management plan. 19.6 Potentially reversible causes of weight gain Endocrine factors • Hypothyroidism • Cushing’s syndrome • Insulinoma • Hypothalamic tumours or injury Drug treatments • Atypical antipsychotics (e.g. olanzapine) • Sulphonylureas, thiazolidinediones, insulin • Pizotifen • Glucocorticoids • Sodium valproate • β-blockers 19.7 Quantifying obesity with BMI and waist circumference for risk of type 2 diabetes and cardiovascular disease BMI (weight in kg/height in m2) Classification1 Waist circumference2 Men < 94 cm Women < 80 cm Men 94–102 cm Women 80–88 cm Men > 102 cm Women > 88 cm 18.5–24.9 Reference range Negligible Mildly increased Moderate 25.0–29.9 Overweight Negligible Moderate Severe

30.0 Obese 30.0–34.9 Class I Moderate Severe Very severe 35.0–39.9 Class II – Very severe Very severe 40.0 Class III – Very severe Very severe 1Classification of the World Health Organisation (WHO) and International Obesity Task Force. The Western Pacific Region Office of WHO recommends that, among Asians, BMI > 23.0 is overweight and > 25.0 is obese. Lower cut-offs for waist circumference have also been proposed for Asians but have not been validated. 2When BMI is 35 kg/m2 , waist circumference does not add to the increased risk.

Disorders of altered energy balance • 701

snacking, regular meals to encourage satiety, and substitution of sugar with artificial sweeteners) should be discussed. Regular support from a dietitian or attendance at a weight loss group may be helpful. Weight loss diets In overweight people, adherence to the lifestyle advice given above may gradually induce weight loss. In obese patients, more active intervention is usually required to lose weight before conversion to the ‘weight maintenance’ advice given above. A significant industry has developed in marketing diets for weight loss. These vary substantially in their balance of macronutrients (Box 19.8) but there is little evidence that they vary in their medium-term (1-year) efficacy. Most involve recommending a reduction of daily total energy intake of −2.5 MJ (600 kcal) from the patient’s normal consumption. Modelling data that take into account the reduced energy expenditure as weight is lost suggest that a reduction of energy intake of 100 kJ per day will lead to an eventual body weight change of about 1 kg, with half of the weight change being achieved in about 1 year and 95% of the weight change in about 3 years. Weight loss is highly variable and patient adherence is the major determinant of success. There is some evidence that weight loss diets are most effective in their early weeks and that adherence is improved by novelty of the diet; this provides some justification for switching to a different dietary regimen when weight loss slows on the first diet. Vitamin and cycling options for commuters, and liaising with the food industry to reduce energy, sugar and fat content and to label foods appropriately; taxes on high-sugar drinks have also been introduced in some countries. Unfortunately, ‘low-fat’ foods are often still energy-dense, and current lifestyles with labour-saving devices, sedentary work and passive leisure activities have much lower energy requirements than the manual labour and household duties of previous generations. Most patients seeking assistance with obesity are motivated to lose weight but have attempted to do so previously without long-term success. Often weight will have oscillated between periods of successful weight loss and then regain of weight. These patients may hold misconceptions that they have an underlying disease, inaccurate perceptions of their energy intake and expenditure, and an unrealistic view of the target weight that they would regard as a ‘success’. An empathetic explanation of energy balance, which recognises that some individuals are more susceptible to obesity than others and may find it more difficult to lose body weight and sustain this loss, is important. Exclusion of underlying ‘hormone imbalance’ with simple tests is reassuring and shifts the focus on to consideration of energy balance. Appropriate goals for weight loss should be agreed, recognising that the slope of the relationship between obesity and many of its complications becomes steeper with increasing BMI, so that a given amount of weight loss achieves greater risk reduction at higher levels of BMI. A reasonable goal for most patients is to lose 5–10% of body weight. The management plan will vary according to the severity of the obesity (see Box 19.7) and the associated risk factors and complications. It will also be influenced by availability of resources; health-care providers and regulators have generally been careful not to recommend expensive interventions (especially long-term drug therapy and surgery) for everyone who is overweight. Instead, most guidelines focus resources on short-term interventions in those who have high health risks and comorbidities associated with their obesity, and who have demonstrated their capacity to alter their lifestyle to achieve weight loss (Fig. 19.7). Lifestyle advice Behavioural modification to avoid some of the effects of the ‘obesogenic’ environment (see Box 19.5) is the cornerstone of long-term control of weight. Adopting regular eating patterns and maximising physical activity are advised, with reference to the modest extra activity required to increase physical activity level (PAL) ratios (see Fig. 19.2C). Where possible, this should be incorporated in the daily routine (e.g. walking rather than driving to work), as this is more likely to be sustained. Alternative exercise (e.g. swimming) may be considered if musculoskeletal complications prevent walking. Changes in eating behaviour (including food selection, portion size control, avoidance of Fig. 19.7 Therapeutic options for obesity. Relevant comorbidities include type 2 diabetes, hypertension, cardiovascular disease, sleep apnoea, and waist circumference of > 102 cm in men or 88 cm in women. This is an approximate consensus of the numerous national guidelines, which vary slightly in their recommendations and are revised every few years. ↑Exercise Eating behaviour modification Treat cardiovascular risk factors Supervised low-calorie diet Drugs Surgery BMI cut-offs in absence of comorbidity

BMI cut-offs in presence of comorbidity 19.8 Low-calorie diet therapy for obesity Diet % Carbohydrate % Fat % Protein Comments Normal (typical developed country)

Moderate fat (e.g. Weight Watchers)

Maintains balance in macronutrients and micronutrients while reducing energy-dense fats Low carbohydrate (e.g. Atkins)

Induction of ketosis may suppress hunger High protein (e.g. Zone)

Protein has greater satiety effect than other macronutrients Low fat (e.g. Ornish)

702 • NUTRITIONAL FACTORS IN DISEASE rimonabant (psychiatric side-effects) in recent years. Orlistat has been available for many years, and four drugs or drug combinations have recently been approved in the USA and two of these in Europe. There is no role for diuretics, or for thyroxine therapy without biochemical evidence of hypothyroidism. Drug therapy should always be used as an adjunct to lifestyle advice and support, which should be continued throughout treatment. Orlistat inhibits pancreatic and gastric lipases and thereby decreases the hydrolysis of ingested triglycerides, reducing dietary fat absorption by approximately 30%. The drug is not absorbed and adverse side-effects relate to the effect of the resultant fat malabsorption on the gut: namely, loose stools, oily spotting, faecal urgency, flatus and the potential for malabsorption of fat-soluble vitamins. Orlistat at the standard dose of 120 mg is taken with each of the three main meals of the day; a lower dose (60 mg) is available without prescription in some countries. Its efficacy is shown in Figure 19.8; these effects may be explained because patients taking orlistat adhere better to low-fat diets in order to avoid unpleasant gastrointestinal side-effects. The combination of low-dose phentermine and topiramate extended release has been approved in the USA; this results in weight loss of approximately 6% greater than placebo and benefits lipids and glucose concentrations. Concerns over teratogenicity of topiramate and cardiovascular effects of phentermine have so far supplementation is wise in those diets in which macronutrient balance is markedly disturbed. In some patients, more rapid weight loss is required, e.g. in preparation for surgery. There is no role for starvation diets, which risk profound loss of muscle mass and the development of arrhythmias (and even sudden death) secondary to elevated free fatty acids, ketosis and deranged electrolytes. Very-lowcalorie diets (VLCDs) can be considered for short-term rapid weight loss, producing losses of 1.5–2.5 kg/week, compared to 0.5 kg/week on conventional regimens, but require the supervision of an experienced physician and nutritionist. The composition of the diet should ensure a minimum of 50 g of protein each day for men and 40 g for women to minimise muscle degradation. Energy content should be a minimum of 1.65 MJ (400 kcal) for women of height < 1.73 m, and 2.1 MJ (500 kcal) for all men and for women taller than 1.73 m. Side-effects are a problem in the early stages and include orthostatic hypotension, headache, diarrhoea and nausea. Drugs A huge investment has been made by the pharmaceutical industry in finding drugs for obesity. The side-effect profile has limited the use of many agents, with notable withdrawals from clinical use of sibutramine (increased cardiovascular events) and Fig. 19.8 Effects of orlistat (A), liraglutide (B) and bariatric surgery (C) on weight loss. For the bariatric surgery data, each obese subject undergoing surgery was matched with a control subject whose obesity was managed according to the standard of care for non-operative interventions. Note that the maximum weight loss achieved with orlistat and liraglutide was approximately 10 kg, and that the follow-up period is relatively short; surgery achieves much more substantial and prolonged weight loss. A, Data from Torgerson JS Hauptman J, Boldrin MS, et al. A randomized study of orlistat as an adjunct to lifestyle changes for the prevention of type 2 diabetes in obese patients. Diabetes Care 2004; 27:155–161. B, Data from le Roux CW, Astrup A, Fujioka K, et al. 3 years of liraglutide versus placebo for type 2 diabetes risk reduction and weight management in individuals with prediabetes: a randomised, double-blind trial. Lancet; published online 22 Feb 2017. C, Data from Sjöström L, Narbro K, Sjöström D, et al. Effects of bariatric surgery on mortality in Swedish obese subjects. N Engl J Med 2007; 357:741–752. Change in body weight (%) Control Banding Vertical banded gastroplasty Gastric bypass -2% -13% -18% -27% Placebo

-40 -35 -30 -25 -20 -15 -10 -5 -40 -35 -30 -25 -20 -15 -10 -5

Change in body weight (%) -40 -35 -30 -25 -20 -15 -10 -5

A Change in body weight (%)

B

Years of follow-up Years of follow-up Years of follow-up C

Disorders of altered energy balance • 703

recent-onset diabetes and a BMI > 30 kg/m2. Only experienced specialist surgeons should undertake these procedures, in collaboration with a multidisciplinary team. Several approaches are used (Fig. 19.9) and all can be performed laparoscopically. The mechanism of weight loss may not simply relate to limiting the stomach or absorptive capacity, but rather in disrupting the release of ghrelin from the stomach or promoting the release of other peptides from the small bowel, thereby enhancing satiety signalling in the hypothalamus. Diabetes may improve rapidly precluded its approval in Europe. The 5-HT2c inhibitor lorcaserin is also approved in the USA; it is moderately effective and has a relatively low rate of adverse effects. The combination of the opioid antagonist naltrexone and the noradrenaline (norepinephrine)/ dopamine re-uptake inhibitor bupropion is also effective. The main adverse effects are dry mouth and constipation. Finally, a higher dose of the injectable glucagon-like peptide-1 (GLP-1) receptor agonist liraglutide (3 mg) is also approved for use and has been shown to reduce the risk of diabetes in patients with pre-diabetes. Drug therapy is usually reserved for patients with high risk of complications from obesity (see Fig. 19.7), and its optimum timing and duration are controversial. There is evidence that those patients who demonstrate early weight loss (usually defined as 5% after 12 weeks on the optimum dose) achieve greater and longer-term weight loss, and this is reflected in most guidelines for the use of drugs for obesity. Treatment can be stopped in non-responders at this point and an alternative treatment considered. Although life-long therapy is advocated for many drugs that reduce risk on the basis of relatively short-term research trials (e.g. drugs for hypertension and osteoporosis), some patients who continue to take anti-obesity drugs tend to regain weight with time; this may partly reflect age-related weight gain, but significant weight gain should prompt reinforcement of lifestyle advice and, if this is unsuccessful, drug therapy should be discontinued (see Fig. 19.8). Surgery ‘Bariatric’ surgery is by far the most effective long-term treatment for obesity (see Fig. 19.8 and Box 19.9) and is the only anti-obesity intervention that has been associated with reduced mortality. Bariatric surgery should be contemplated in motivated patients who have very high risks of complications of obesity (see Fig. 19.7), when extensive dietary and drug therapy has been insufficiently effective. It is usually reserved for those with severe obesity (BMI

40 kg/m2), or those with a BMI > 35 kg/m2 and significant complications, such as type 2 diabetes or obstructive sleep apnoea, although some evidence-based guidelines now suggest surgery can be considered at a lower weight in people with 19.9 Effectiveness and adverse effects of laparoscopic bariatric surgical procedures Procedure Expected weight loss (% excess weight) Adverse effects Gastric banding 50–60% Band slippage, erosion, stricture Port site infection Mortality < 0.2% in experienced centres Sleeve gastrectomy 50–60% Iron deficiency Vitamin B12 deficiency Mortality < 0.2% in experienced centres Roux-en-Y gastric bypass 70–80% Internal hernia Stomal ulcer Dumping syndrome Hypoglycaemia Iron deficiency Vitamin B12 deficiency Vitamin D deficiency Mortality 0.5% Duodenal switch Up to 100% Steatorrhoea Protein-calorie malnutrition Iron deficiency Vitamin B12 deficiency Calcium, zinc, copper deficiency Mortality 1% Fig. 19.9 Bariatric surgical procedures. A Laparoscopic banding, with the option of a reservoir band and subcutaneous access to restrict the stomach further after compensatory expansion has occurred. B Sleeve gastrectomy. C Roux-en-Y gastric bypass. D Biliopancreatic diversion with duodenal switch. A B C D Access port Oesophagus Gastric band Gastric sleeve Pylorus Resected stomach The small intestine is connected to the stomach pouch Unused portion of the small intestine Removed portion of stomach Biliopancreatic loop Digestive loop Duodenal switch 75–100 cm common loop

704 • NUTRITIONAL FACTORS IN DISEASE Clinical features In starvation, the severity of malnutrition can be assessed by anthropometric measurements, such as BMI (see p. 693 and Box 19.10). Demispan and mid-arm circumference measurements are most useful in monitoring progress during treatment. The clinical features of severe under-nutrition in adults are listed in Box 19.12. Under-nutrition often leads to vitamin deficiencies, especially of thiamin, folate and vitamin C (see below). Diarrhoea can lead to depletion of sodium, potassium and magnesium. The high mortality rate in famine situations is often due to outbreaks of infection, such as typhus or cholera, but the usual signs of infection may not be apparent. In advanced starvation, patients become completely inactive and may assume a flexed, fetal position. In the last stage of starvation, death comes quietly and often quite suddenly. The very old are most vulnerable. All organs are atrophied at necropsy, except the brain, which tends to maintain its weight. Investigations In a famine, laboratory investigations may be impractical but will show that plasma free fatty acids are increased and there is ketosis and a mild metabolic acidosis. Plasma glucose is low after surgery, particularly after gastric bypass, and although this may be attributed to severe energy restriction in the perioperative period, it is possible that increased release of incretin hormones such as GLP-1 may contribute to the improvement in glucose control. Complications depend on the approach. Mortality is low in experienced centres but post-operative respiratory problems, wound infection and dehiscence, staple leaks, stomal stenosis, marginal ulcers and venous thrombosis may occur. Additional problems may arise at a later stage, such as pouch and distal oesophageal dilatation, persistent vomiting, ‘dumping’ (p. 801), hypoglycaemia and micronutrient deficiencies, particularly of folate, vitamin B12 and iron, which are of special concern to women contemplating pregnancy; this should be delayed for at least 2 years following surgery. Cosmetic surgical procedures may be considered in obese patients after successful weight loss. Apronectomy is usually advocated to remove an overhang of abdominal skin, especially if infected or ulcerated. This operation is of no value for long-term weight reduction if food intake remains unrestricted. Treatment of additional risk factors Obesity must not be treated in isolation and other risk factors must be addressed, including smoking, excess alcohol consumption, diabetes mellitus, hyperlipidaemia, hypertension and obstructive sleep apnoea. Treatment of these is discussed in the relevant chapters. Under-nutrition Starvation and famine There remain regions of the world, particularly rural Africa, where under-nutrition due to famine is endemic, the prevalence of BMI of less than 18.5 kg/m2 (Box 19.10) in adults is as high as 20%, and growth retardation due to under-nutrition affects 50% of children. The World Health Organisation (WHO) reports that chronic under-nutrition is responsible for more than half of all childhood deaths worldwide. Starvation is manifest as marasmus (malnutrition with marked muscle wasting) or, when additive complications such as oxidative stress come into play, malnourished children can develop kwashiorkor (malnutrition with oedema). Growth retardation is due to deficiencies of key nutrients (protein, zinc, potassium, phosphate and sulphur). Treatment of these childhood conditions is not discussed in this adult medical textbook. In adults, starvation is the result of chronic sustained negative energy (calorie) balance. Causes are shown in Box 19.11. Causes of weight loss are considered further on page 785. 19.12 Clinical features of severe under-nutrition in adults • Weight loss • Thirst, craving for food, weakness and feeling cold • Nocturia, amenorrhoea or impotence • Lax, pale, dry skin with loss of turgor and, occasionally, pigmented patches • Cold and cyanosed extremities, pressure sores • Hair thinning or loss (except in adolescents) • Muscle-wasting, best demonstrated by the loss of the temporalis and periscapular muscles and reduced mid-arm circumference • Loss of subcutaneous fat, reflected in reduced skinfold thickness and mid-arm circumference • Hypothermia, bradycardia, hypotension and small heart • Oedema, which may be present without hypoalbuminaemia (‘famine oedema’) • Distended abdomen with diarrhoea • Diminished tendon jerks • Apathy, loss of initiative, depression, introversion, aggression if food is nearby • Susceptibility to infections (Box 19.13) 19.11 Causes of under-nutrition and weight loss in adults Decreased energy intake • Famine • Persistent regurgitation or vomiting • Anorexia, including depression and anorexia nervosa • Malabsorption (e.g. small intestinal disease) • Maldigestion (e.g. pancreatic exocrine insufficiency) Increased energy expenditure • Increased basal metabolic rate (thyrotoxicosis, trauma, fever, cancer, cachexia) • Excessive physical activity (e.g. marathon runners) • Energy loss (e.g. glycosuria in diabetes) • Impaired energy storage (e.g. Addison’s disease, phaeochromocytoma) 19.10 Classification of under-nutrition in adults by body mass index (weight/height2) BMI (kg/m2) Classification

20 Adequate nutrition 18.5–20 Marginal < 18.5 Under-nutrition 17–18.4 Mild 16–17 Moderate < 16 Severe

Disorders of altered energy balance • 705

average of 5% of their total body weight during that admission. In the older population, levels of under-nutrition and vitamin deficiencies parallel levels of independent living. In Scotland, 33% of those aged over 65 who are living in their own home are deficient in folic acid and 10% are deficient in vitamin C. The prevalence of vitamin deficiencies rises further in less independent groups in residential or nursing homes. Under-nutrition is poorly recognised in hospitals and has serious consequences. Physical effects include impaired immunity and muscle weakness, which in turn affect cardiac and respiratory function, and delayed wound healing after surgery with increased risks of post-operative infection. The under-nourished patient is often withdrawn and this may be mistaken for depressive illness. Engagement with treatment and rehabilitation can be adversely affected. Much of this can be avoided through better awareness of the prevalence of under-nutrition, prompt nutritional assessment and monitoring with appropriate intervention. Scoring systems, such as the MUST tool (p. 693), raise awareness across multidisciplinary teams, and encourage staff to assess and monitor food intake and weigh patients regularly. Causes are often complex (see Box 19.11). Social issues impact on food choices and may cause or exacerbate disease. Social isolation, low levels of disposable income and a lack of knowledge or interest in healthy eating may increase reliance on calorie-dense convenience foods of poor nutritional quality. In turn, the non-specific effects of chronic inflammation, infection or malignancy, as well as specific gastrointestinal disorders, may adversely affect appetite, reducing food intake. Patients may report avoidance of certain foods that exacerbate their symptoms (often fibre-rich, otherwise healthy foods). A loss of appetite is not specific to gastrointestinal disease and may be seen as a non-specific response to myriad other conditions or their treatments. The most common reported side-effects but albumin concentration is often maintained because the liver still functions normally. Insulin secretion is diminished, glucagon and cortisol tend to increase, and reverse T3 replaces normal triiodothyronine (p. 634). The resting metabolic rate falls, partly because of reduced lean body mass and partly because of hypothalamic compensation (see Fig. 19.2). The urine has a fixed specific gravity and creatinine excretion becomes low. There may be mild anaemia, leucopenia and thrombocytopenia. The erythrocyte sedimentation rate is normal unless there is infection. Tests of delayed skin hypersensitivity, e.g. to tuberculin, are falsely negative. The electrocardiogram shows sinus bradycardia and low voltage. Management Whether in a famine or in wasting secondary to disease, the severity of under-nutrition is graded according to BMI (see Box 19.10). People with mild starvation are in no danger; those with moderate starvation need extra feeding; and those who are severely underweight need hospital care. In severe starvation, there is atrophy of the intestinal epithelium and of the exocrine pancreas, and the bile is dilute. It is critical for the condition to be managed by experts. When food becomes available, it should be given by mouth in small, frequent amounts at first, using a suitable formula preparation (Box 19.14). Individual energy requirements can vary by 30%. During rehabilitation, more concentrated formula can be given with additional food that is palatable and similar to the usual staple meal. Salt should be restricted and micronutrient supplements (e.g. potassium, magnesium, zinc and multivitamins) may be essential. Between 6.3 and 8.4 MJ/day (1500–2000 kcal/day) will arrest progressive under-nutrition but additional energy may be required for regain of weight. During refeeding, a weight gain of 5% body weight per month indicates satisfactory progress. Other care is supportive and includes attention to the skin, adequate hydration, treatment of infections and careful monitoring of body temperature, since thermoregulation may be impaired. Circumstances and resources are different in every famine but many problems are non-medical and concern organisation, infrastructure, liaison, politics, procurement, security and ensuring that food is distributed on the basis of need. Lastly, plans must be made for the future for prevention and/or earlier intervention if similar circumstances prevail. Under-nutrition in hospital It is a paradox that, in spite of record levels of access to food in the developed economies of the world, under-nutrition remains a serious issue in many sectors of society, particularly the elderly and less independent. While the scale of the problem does not match that seen in the developing world, the issues pertaining to poor or impaired health are similar. In the general UK population, 30% of those requiring acute admission to hospital show evidence of serious under-nutrition and 65% of those admitted will lose an 19.13 Infections associated with starvation • Gastroenteritis and Gram-negative sepsis • Respiratory infections, especially bronchopneumonia • Certain viral diseases, especially measles and herpes simplex • Tuberculosis • Streptococcal and staphylococcal skin infections • Helminthic infestations 19.14 WHO recommended diets for refeeding Nutrient (per 100 mL) F-75 diet1 F-100 diet2 Energy 315 kJ (75 kcal) 420 kJ (100 kcal) Protein (g) 0.9 2.9 Lactose (g) 1.3 4.2 Potassium (mmol) 3.6 5.9 Sodium (mmol) 0.9 1.9 Magnesium (mmol) 0.43 0.73 Zinc (mg) 2.0 2.3 Copper (mg) 0.25 0.25 Percentage of energy from: Protein

Fat

Osmolality (mOsmol/kg)

Dose 170 kJ/kg (40 kcal/kg) 630–920 kJ/kg (150–220 kcal/kg) Rate of feeding by mouth 2.2 (mL/kg/hr) Gradual increase in volume, 6 times daily 1F-75 is prepared from milk powder (25 g), sugar (70 g), cereal flour (35 g), vegetable oil (27 g) and vitamin and mineral supplements, made up to 1 L with water. 2F-100 (1 L) contains milk powder (80 g), sugar (50 g), vegetable oil (60 g) and vitamin and mineral supplements (no cereal).

706 • NUTRITIONAL FACTORS IN DISEASE for small intestinal bacterial overgrowth (malabsorption of iron, folic acid and vitamin B12). Ileal resection Ileal resection (p. 810) may give rise to vitamin B12 deficiency and, rarely, to steatorrhoea and malabsorption of fat-soluble vitamins. Massive small bowel resection This may cause short bowel syndrome and intestinal failure, with impaired ability to absorb fluids, electrolytes and macronutrients adequately without parenteral support. An approach to assisted nutrition in hospital patients Once the problems leading to under-nutrition have been recognised, it is important to make an individualised plan to address these issues specifically. In most cases, this means a decision to intervene to tackle and reverse nutritional difficulties. This may involve simply ensuring that adequate supplies of food are delivered and prepared regularly or that dentures fit properly, but may require an assessment of a patient’s ability to swallow or of the intestine’s ability to digest foods. This must include consideration of the potential for disruption of the normal physiology of absorption and digestion in the context of the patient’s medical and surgical history. Whenever possible, it is best to use the most physiological means of feeding, reserving more invasive interventions for when normal physiological mechanisms of swallowing and digestion are impaired or absent. Enteral feeding is preferred to parenteral, provided the intestine is accessible and functioning. Refeeding syndrome In severely malnourished individuals, attempts at rapid correction of malnutrition switch the body from a reliance on fat to carbohydrate metabolism. Release of insulin is triggered, shifting potassium, phosphate and magnesium into cells (with water following the osmotic gradient) and causing potentially fatal shifts of fluids and electrolytes from the extracellular to the intracellular compartment. Rapid depletion of (already low) thiamin exacerbates the condition. Clinical features include nausea, vomiting, muscle weakness, seizures, respiratory depression, cardiac arrest and sudden death. The risks of refeeding are greatest in those who are most malnourished (especially chronic alcoholics), but even those who have gone without food for 5 days can be at risk and restitution of feeding should always be done slowly, with careful monitoring of serum potassium, phosphate and magnesium in the first 3–5 days. Oral nutritional supplements Poor appetite, immobility, poor dentition or even being kept ‘nil by mouth’ for hospital procedures all contribute to weight loss. As a first step, patients should be encouraged and helped to eat an adequate amount of normal food. Where swallow and intestinal function remain intact, the simplest form of assisted nutrition is the use of oral nutritional supplements. Most branded products are nutritionally complete (fortified with the daily requirements of vitamins, minerals and trace elements). They most often come in the form of liquid drinks but various formulations and textures exist, including ‘shakes’ and ‘puddings’ with a thicker consistency. They are cost-effective and very useful for people who may require just a small number of additional calories each day to maintain or gain weight in the short or longer term. However, in spite of their nutritional value, small volume and range of flavours, many people find them unpalatable or difficult to tolerate. of many prescription drugs are nausea and gastrointestinal disturbance. Surgical resection of the gastrointestinal tract can have major nutritional sequelae in the years following, ranging from intolerance of normal volumes of food to intestinal failure (where there is partial or complete failure of the intestine to perform its vital functions). There may be no single problem impacting on the intake of adequate nutrition but it helps to consider systematically where the problem(s) might lie (Box 19.15). Specific issues arising after intestinal surgery Gastrectomy or partial gastrectomy There may be a loss of gastric capacity, leading to intolerance of larger volumes of food and early satiety or vomiting. Vagotomy and gastroenterostomy may cause symptoms of dumping syndrome (p. 801), which can lead to food avoidance and weight loss. Many patients who have had gastric surgery will develop iron deficiency (and, less commonly, vitamin D and vitamin B12 deficiency) unless adequately supplemented post-operatively. Proximal small bowel surgery Those who have had roux-en-Y reconstruction or have blindending or excluded loops of small bowel are prone to small intestinal bacterial overgrowth. This may impair absorption of iron, folic acid and vitamin B12. Very rarely, it can cause hyperammonaemia and metabolic coma, in which bacterial metabolism of amino acids leads to a lack of citrulline and impairment of the urea cycle. Pancreatic resection/Whipple’s operation Without adequate post-operative supplementation, this can be a very serious insult to the digestive tract. There is loss of pancreatic exocrine function (causing steatorrhoea and malabsorption of protein, fats and fat-soluble vitamins), as well as the potential 19.15 Factors affecting adequacy of nutritional intake in hospitalised patients Factors affecting appetite • Altered taste • Nausea and/or vomiting • Non-specific effects of illness and/or drugs Issues of quantity • Is there enough food on the plate? • Social, cultural, financial, general and mental health issues may all be relevant, individually or in combination Getting the food from the plate to the mouth • Generalised reduced mobility • Reduced manual dexterity • Loss of limb function Difficulties chewing the food • Poorly fitting dentures • Pain in the oral cavity Specific problems with the gastrointestinal tract • Obstruction • Ischaemia • Inflammation • Malabsorption Cultural issues • Is the food provided appropriate to the patient’s beliefs? More general evidence of self-neglect • Evidence of chronic coexisting illness • Evidence of mental health problems – low mood may be ‘cause’ or ‘effect’ in under-nutrition

Disorders of altered energy balance • 707

device, which fixes the tube around the nasal septum. Although these devices are very effective, there is a risk of damage to the nasal septum (especially bleeding) if a patient persists in pulling forcibly on the tube. Gastrostomy feeding Gastrostomy is a more invasive insertion technique with higher costs initially. It is most suitable for when longer-term feeding (more than 4 weeks) is required. Gastrostomies are less liable to displacement than nasogastric tubes and the presence of the gastrostomy in the stomach allows for fewer feed interruptions, meaning that more of the prescribed feeds can be administered. Tubes were placed at the time of open surgery until the 1980s, when an endoscopic, minimally invasive technique was developed. A variety of techniques for radiological insertion have also been introduced subsequently. Both endoscopic and radiological gastrostomy insertion involve inflating the stomach, thus apposing it to the anterior abdominal wall. The stomach is then punctured percutaneously and a suitable tube placed (Fig. 19.10). Tubes vary in design but each has an internal retainer device (plastic ‘bumper’ or balloon) that sits snugly against the gastric mucosa, and an external retainer that limits movement. These retainers hold the gastric wall against the abdominal wall, effectively creating a controlled gastrocutaneous fistula that matures over 2–4 weeks. Radiological gastrostomy placement also utilises percutaneous ‘stay sutures’, which provide further temporary anchorage and assist in placement. There is no evidence to recommend one technique over another, although the radiological method has advantages in patients with cancers of the head and neck undergoing potentially curative therapy (less chance of tumour ‘seeding’) and in those with poor respiratory reserve (such as motor neuron disease) since there is no endoscope to compress the upper airways. Reported outcomes are broadly similar for both and the choice of technique should be based on indications and contraindications, operator experience and facilities available. Most important is rigorous patient assessment and selection prior to gastrostomy placement, which should be done by a multidisciplinary nutrition support team, and avoided when the procedure may be too hazardous or the benefits are outweighed by the risks (see Boxes 19.18 and Box 19.27 below). Post-pyloric feeding In patients with a high risk of pulmonary aspiration or gastroparesis, it may be preferable to feed into the jejunum (via a nasojejunal tube, gastrostomy with jejunal extension or direct placement into jejunum by radiological, endoscopic or laparoscopic means). Parenteral nutrition This is usually reserved for clinical situations where the absorptive functioning of the intestine is severely impaired. In parenteral feeding, nutrition is delivered directly into a large-diameter systemic vein, completely bypassing the intestine and portal venous system. As well as being more invasive, more expensive and Enteral feeding Where swallowing or food ingestion is impaired but intestinal function remains intact, more invasive forms of assisted feeding may be necessary. Enteral tube feeding is usually the intervention of choice. In enteral feeding, nutrition is delivered to and absorbed by the functioning intestine. Delivery usually means bypassing the mouth and oesophagus (or sometimes the stomach and proximal small bowel) by means of a feeding tube (naso-enteral, gastrostomy or jejunostomy feeding). There are a number of theoretical advantages to enteral, as opposed to parenteral, feeding, which have achieved almost mythical status. These include: • preservation of intestinal mucosal architecture, gutassociated lymphoid tissue, and hepatic and pulmonary immune function • reduced levels of systemic inflammation and hyperglycaemia • interference with pathogenicity of gut micro-organisms. However, the areas in which advantage has been consistently proven are: • fewer episodes of infection • reduced cost • earlier return to intestinal function • reduced length of hospital stay. Complications The risks of enteral feeding are those related to tube insertion (Box 19.16) and diarrhoea (Box 19.17). Route of access Nasogastric tube feeding This is simple, readily available, comparatively low-cost and most suitable for short-term feeding (up to 4 weeks). Insertion of a nasogastric tube requires care and training (see Box 21.41, p. 805), as potentially serious complications can arise (Box 19.16). Patients with reduced conscious level may pull at tubes and displace them. This can be minimised in the short term by the use of a nasal ‘bridle’ 19.16 Complications of nasogastric tube feeding • Tube misplacement, e.g. tracheal or bronchial placement (rarely, intracranial placement) • Reflux of gastric contents and pulmonary aspiration • Interrupted feeding or inadequate feed volumes • Refeeding syndrome 19.17 Diarrhoea related to enteral feeding Factors contributing to diarrhoea • Fibre-free feed may reduce short-chain fatty acid production in colon • Fat malabsorption • Inappropriate osmotic load • Pre-existing primary gut problem (e.g. lactose intolerance) • Infection Management • Often responds well to a fibre-containing feed or a switch to an alternative feed • Simple antidiarrhoeal agents (e.g. loperamide) can be very effective 19.18 Complications of gastrostomy tube feeding • Reflux of gastric contents and pulmonary aspiration (same as nasogastric tube) • Risks of insertion (pain, damage to intra-abdominal structures, intestinal perforation, pulmonary aspiration, infection, death) • Risk of tumour ‘seeding’ if an endoscopic ‘pull-through’ technique is used in head and neck or oesophageal cancer patients • Refeeding syndrome

708 • NUTRITIONAL FACTORS IN DISEASE impair gastrointestinal function, such that oral or enteral feeding is not possible for at least 7 days. Intestinal failure (‘short bowel syndrome’) Intestinal failure (IF) is defined as a reduction in the function of the gut below the minimum necessary for the absorption of macronutrients and/or water and electrolytes such that intravenous supplementation is required to support health and/or growth. The term can be used only when there is both: • a major reduction in absorptive capacity and • an absolute need for intravenous fluid support. IF can be further classified according to its onset, metabolic consequences and expected outcome. • Type 1 IF: an acute-onset, usually self-limiting condition with few long-term sequelae. It is most often seen following abdominal surgery or in the context of critical illness. Intravenous support may be required for a few days to weeks. less physiological than the enteral route, parenteral nutrition is associated with many more complications (Box 19.19), mainly infective and metabolic (disturbances of electrolytes, hyperglycaemia). Strict adherence to aseptic practice in handling catheters and careful monitoring of clinical (pulse, blood pressure and temperature) and biochemical (urea, electrolytes, glucose and liver function tests) parameters are necessary to minimise risk to the patient (Box 19.20). The parenteral route may be indicated for patients who are malnourished or at risk of becoming so, and who have an inadequate or unsafe oral intake and a poorly functioning or non-functioning or perforated intestine or an intestine that cannot be accessed by tube feeding. In practice, it is most often required in acutely ill patients with multi-organ failure or in severely under-nourished patients undergoing surgery. It may offer a benefit over oral or enteral feeding prior to surgery in those who are severely malnourished when other routes of feeding have been inadequate. Parenteral nutrition following surgery should be reserved for when enteral nutrition is not tolerated or feasible or where complications (especially sepsis) Fig. 19.10 Percutaneous endoscopic gastrostomy (PEG) placement. A Finger pressure on the anterior abdominal wall is noted by the endoscopist. B Following insertion of a cannula through the anterior abdominal wall into the stomach, a guidewire is threaded through the cannula and grasped by the endoscopic forceps or snare. C The endoscope is withdrawn with the guidewire. The gastrostomy tube is then attached to the guidewire. D The guidewire and tube are pulled back through the mouth, oesophagus and stomach to exit on the anterior abdominal wall, and the endoscope is repassed to confirm the site of placement of the retention device. The latter closely abuts the gastric mucosa; its position is maintained by an external fixation device (see inset). It is also possible to place PEG tubes using fluoroscopic guidance when endoscopy is difficult (radiologically inserted gastrostomy). A B C D 19.20 Parameters for monitoring parenteral nutrition in hospital Parameter Monitoring requirement Electrolytes (sodium, potassium, magnesium) Bone profile (calcium, phosphate) Liver function tests (bilirubin, alanine aminotransferase, alkaline phosphatase, γ-glutamyl transferase) Markers of inflammation (C-reactive protein, leucocyte count) Daily until stable and then 2–3 times per week Blood glucose At least twice daily until stable and then daily Cholesterol and triglycerides Weekly initially, reducing to every 3 months when stable 19.19 Complications of parenteral nutrition Intravenous catheter complications • Insertion (pneumothorax, haemothorax, arterial puncture) • Catheter infection (sepsis, discitis, pulmonary or cerebral abscess) • Central venous thrombosis Metabolic complications • Refeeding syndrome • Electrolyte imbalance • Hyperglycaemia • Hyperalimentation • Fluid overload • Hepatic steatosis/fibrosis/cirrhosis

Disorders of altered energy balance • 709

following the acute insult but develop protein-energy malnutrition and significant weight loss, becoming seriously under-nourished over weeks to months. Stool volume is determined by oral intake, with higher intakes causing more diarrhoea and the potential for dehydration, sodium and magnesium depletion and acute renal failure. The absence of the ileum leads to deficiencies of vitamin B12 and fat-soluble vitamins. The absorption of various drugs, including thyroxine, digoxin and warfarin, can be reduced. Approximately 45% of patients will develop gallstones due to disruption of the enterohepatic circulation of bile acids, and 25% may develop calcium oxalate renal stones due to increased colonic absorption of oxalate (see Fig. 21.43, p. 810). Jejunostomy patients Patients left with a stoma (usually a jejunostomy) behave very differently, although stool volumes are again determined by oral intake. The jejunum is intrinsically highly permeable, and in the absence of the ileum and its net absorptive role, high losses of fluid, sodium and magnesium dominate the clinical picture from the outset. Dehydration, hyponatraemia, hypomagnesaemia and acute renal failure are the most immediate problems but protein-energy malnutrition will also develop. The jejunum has no real potential for adaptation in terms of absorption, so it is essential to recognise and address the issues of dehydration and electrolyte disturbance early and not expect the problems to improve with time (Box 19.23). • Type 2 IF: far less common. The onset is also usually acute, following some intra-abdominal catastrophic event (ischaemia, volvulus, trauma or perioperative complication). Septic and metabolic problems are seen, along with complex nutritional issues. It requires multidisciplinary input (nursing, dietetic, medical, biochemical, surgical, radiological and microbiological) and support may be necessary for weeks to months. • Type 3 IF: a chronic condition in which patients are metabolically stable but intravenous support is required over months to years. It may or may not be reversible. Management IF is a complex clinical problem with profound and wide-ranging physiological and psychological effects, which is best cared for by a dedicated multidisciplinary team. The majority of IF results from short bowel syndrome (Box 19.21), with chronic intestinal dysmotility and chronic intestinal pseudo-obstruction accounting for most of the remainder. The severity of the physiological upset correlates well with how much functioning intestine remains (rather than how much has been removed). Measurement of the remaining small bowel (from the duodeno-jejunal flexure) at the time of surgery is essential for planning future therapy (Box 19.22). The aims of treatment are to: • provide nutrition, water and electrolytes to maintain health with normal body weight (and allow normal growth in affected children) • utilise the enteral or oral routes as much as possible • minimise the burden of complications of the underlying disease, as well as the IF and its treatment • allow a good quality of life. If the ileum and especially the ileum and colon remain intact, long-term nutritional support can usually be avoided. Unlike the jejunum, the ileum can adapt to increase absorption of water and electrolytes over time. The presence of the colon (part or wholly intact) further improves fluid absorption and can generate energy through production of short-chain fatty acids. It is therefore useful to classify patients with a short gut according to whether or not they have any residual colon. Jejunum–colon patients Those with an anastomosis between jejunum and residual colon (jejunum–colon patients) may look well in the days or initial weeks 19.21 Causes of short bowel syndrome in adults • Mesenteric ischaemia • Post-operative complications • Crohn’s disease • Trauma • Neoplasia • Radiation enteritis 19.22 Likely requirements for support according to length of intact residual small bowel Residual length of jejunum (cm) Oral fluid restriction Oral glucose/electrolyte solution Intravenous fluids Parenteral nutrition < 200 Yes Yes May avoid May avoid < 100 Yes Yes Yes May avoid < 75 Yes Yes Yes Yes 19.23 Management of short bowel patients (and ‘high-output’ stoma) Accurate charting of fluid intake and losses • Vital: oral intake determines stool volume and should be restricted rather than encouraged Dehydration and hyponatraemia • Must first be corrected intravenously to restore circulating volume and reduce thirst • Stool volume should be minimised and any ongoing fluid imbalance between oral intake and stool losses replenished intravenously Measures to reduce stool volume losses • Restrict oral fluid intake to ≤ 500 mL/24 hrs • Give a further 1000 mL oral fluid as oral rehydration solution containing 90–120 mmol Na/L (St Mark’s solution or Glucodrate, Nestlé) • Slow intestinal transit (to maximise opportunities for absorption): Loperamide, codeine phosphate • Reduce volume of intestinal secretions: Gastric acid: omeprazole 20 mg/day orally Other secretions: octreotide 50–100 μg 3 times daily by subcutaneous injection Measures to increase absorption • Teduglutide (a recombinant glucagon-like peptide 2) significantly reduces requirements for intravenous fluid and nutritional support

710 • NUTRITIONAL FACTORS IN DISEASE 19.27 Ethical and legal considerations in the management of artificial nutritional support • Care of the sick involves the duty of providing adequate fluid and nutrients • Food and fluid should not be withheld from a patient who expresses a desire to eat and drink, unless there is a medical contraindication (e.g. risk of aspiration) • A treatment plan should include consideration of nutritional issues and should be agreed by all members of the health-care team • In the situation of palliative care, tube feeding should be instituted only if it is needed to relieve symptoms • Tube feeding is usually regarded in law as a medical treatment. Like other treatments, the need for such support should be reviewed on a regular basis and changes made in the light of clinical circumstances • A competent adult patient must give consent for any invasive procedures, including passage of a nasogastric tube or insertion of a central venous cannula • If a patient is unable to give consent, the health-care team should act in that person’s best interests, taking into account any wishes previously expressed by the patient and the views of family • Under certain specified circumstances (e.g. anorexia nervosa), it is appropriate to provide artificial nutritional support to the unwilling patient Adapted from British Association for Parenteral and Enteral Nutrition guidelines (www.bapen.org.uk). include abdominal cramps and distension (seen in 50%), peristomal swelling, pain, nausea, vomiting and local injection site reactions. Since teduglutide stimulates proliferation of the intestinal epithelium, it should be avoided in those with a history of gastrointestinal malignancy in the past 5 years or a current malignancy. In those patients with a colon, a pre-treatment screening colonoscopy should be undertaken to detect and remove any polyps. Use of teduglutide is currently limited by high costs. Artificial nutrition at the end of life Rarely, assisted nutrition may not result in the expected outcomes of reversal of weight loss or improved quality and duration of life. It very seldom reverses other underlying health issues, although it may be used as a short term ‘bridge’ to help through a patient through a particular crisis. Such scenarios may present when someone is approaching the end of life, or in the face of weight loss due to advanced Small bowel and multivisceral transplantation Long-term intravenous nutritional support remains the mainstay of therapy for chronic IF but has its own morbidity and mortality. The 10-year survival for patients on long-term home parenteral nutrition is approximately 90%. The majority of deaths are due to the underlying disease process but 5–11% will die from direct complications of parenteral nutrition itself (especially catheterrelated sepsis). A minority of patients with chronic IF, for whom the safe administration of parenteral nutrition has become difficult or impossible, may benefit from small bowel transplantation (Box 19.24). The first successful small bowel transplant was carried out in 1988. The introduction of tacrolimus allowed a satisfactory balance of immunosuppression, avoiding rejection while minimising sepsis. Since then, over 2000 transplants have been performed worldwide. Survival rates continue to improve, for both isolated small bowel and multivisceral transplantation (small bowel along with a combination of liver and/or kidney and/ or pancreas), although major complications are still frequent (Box 19.25). Current 5-year survival rates are 50–80%, with better outcomes for younger patients and those receiving isolated small bowel procedures. Further developments in treatment of intestinal failure Teduglutide is a long-acting recombinant human GLP-2. It enhances intestinal absorption by: • increasing intestinal blood flow to the intestine • increasing portal blood flow away from the intestine • slowing intestinal transit times • reducing gastric acid secretion. In patients with short bowel syndrome and IF, the increased intestinal absorptive function induced by teduglutide can significantly reduce the volumes of parenteral fluids and nutrition required, and may allow some patients to regain independence of parenteral support. Recognised side-effects 19.26 Energy balance in old age • Body composition: muscle mass is decreased and percentage of body fat increased. • Energy expenditure: with the fall in lean body mass, basal metabolic rate is decreased and energy requirements are reduced. • Weight loss: after weight gain throughout adult life, weight often falls beyond the age of 80 years. This may reflect decreased appetite, loss of smell and taste, and decreased interest in and financial resources for food preparation, especially after loss of a partner. • BMI: less reliable in old age as height is lost (due to kyphosis, osteoporotic crush fractures, loss of intervertebral disc spaces). Alternative measurements include arm demispan and knee height (p. 693), which can be extrapolated to estimate height. 19.25 Complications of small bowel/multivisceral transplantation • Sepsis: Enteric bacterial species Staphylococci Fungal species • Cytomegalovirus infection • Post-transplantation lymphoproliferative disease (PTLD) • Graft-versus-host disease • Acute and chronic rejection • Chronic renal impairment 19.24 Potential indications for small bowel transplantation Complications of central venous catheters • Central venous thrombosis leading to loss of two or more intravenous access points • Severe or recurrent line sepsis • Recurrent severe acute kidney injury related to dehydration Metabolic complications of parenteral nutrition • Parenteral nutrition-related liver fibrosis, cirrhosis and liver failure

Micronutrients, minerals and their diseases • 711

Micronutrients, minerals and their diseases Vitamins Vitamins are organic substances with key roles in certain metabolic pathways, and are categorised into those that are fat-soluble (vitamins A, D, E and K) and those that are water-soluble (vitamins of the B complex group and vitamin C). Recommended daily intakes of micronutrients (Box 19.28) vary between countries and the nomenclature has become potentially confusing. In the UK, the ‘reference nutrient intake’ (RNI) has been calculated as the mean plus two standard deviations (SD) of daily intake in the population, which therefore describes normal intake for 97.5% of the population. The lower reference Fig. 19.11 Malnutrition in dementia – a vicious circle. From Volkert D, Chourdakis M, Faxen-Irving G, et al. ESPEN guidelines on nutrition in dementia. Clin Nutr 2015; 34:1052–1073. Intake↓ Cognitive impairment↑ Dementia Cognitive impairment Age-related changes and diseases Frailty Sarcopenia Weight loss Nutritional deficiencies 19.28 Summary of clinically important vitamins Vitamin Sources* Reference nutrient intake (RNI) Rich Important Fat-soluble A (retinol) Liver Milk and milk products, eggs, fish oils 700 μg men 600 μg women D (cholecalciferol) Fish oils Ultraviolet exposure to skin Egg yolks, margarine, fortified cereals 10 μg if > 65 years or no sunlight exposure E (tocopherol) Sunflower oil Vegetables, nuts, seed oils No RNI. Safe intake: 4 mg men 3 mg women K (phylloquinone, menaquinone) Soya oil, menaquinones produced by intestinal bacteria Green vegetables No RNI. Safe intake: 1 μg/kg Water-soluble B1 (thiamin) Pork Cereals, grains, beans 0.8 mg per 9.68 MJ (2000 kcal) energy intake B2 (riboflavin) Milk Milk and milk products, breakfast cereals, bread 1.3 mg men 1.1 mg women B3 (niacin, nicotinic acid, nicotinamide) Meat, cereals 17 mg men 13 mg women B6 (pyridoxine) Meat, fish, potatoes, bananas Vegetables, intestinal microflora synthesis 1.4 mg men 1.2 mg women Folate Liver Green leafy vegetables, fortified breakfast cereals 200 μg B12 (cobalamin) Animal products Bacterial colonisation 1.5 μg Biotin Egg yolk Intestinal flora No RNI. Safe intake: 10–200 μg C (ascorbic acid) Citrus fruit Fresh fruit, fresh and frozen vegetables 40 mg *Rich sources contain the nutrient in high concentration but are not generally eaten in large amounts; important sources contain less but contribute most because larger amounts are eaten. respiratory or cardiac failure, malignancy or dementia. In selected cases, a decision not to intervene may be appropriate. An intervention that merely prolongs life without preserving or adding to its quality is seldom justified, particularly if the intervention is not without risk itself. Such decisions are not taken lightly and careful scrutiny of each case is necessary. There should be a thoughtful and sensitive discussion explaining what artificial nutrition can and cannot achieve involving the multidisciplinary team looking after the patient as well as next of kin and, in some cases, legal representatives (Box 19.27). Nutrition and dementia Weight loss is seen commonly in people with dementia, and nutritional and eating problems are a significant source of concern for those caring for them. It is appropriate to: • screen for malnutrition (e.g. MUST, see above) • assess specific eating difficulties (e.g. Edinburgh Feeding Evaluation in Dementia questionnaire) • monitor and document body weight • encourage adequate intake of food • use oral nutritional supplements. However, the evidence that artificial nutritional support beyond oral supplementation improves overall functioning or prolongs life in dementia is absent or weak. There may be specific circumstances where a trial of such feeding can be justified (see Box 19.27). Success is more likely in those with mild to moderate dementia, when a temporary and reversible crisis has been precipitated by some acute event. It is important to remember that there is strong evidence to avoid tube feeding in those with advanced dementia because this improves neither the quality nor the duration of life (Fig. 19.11).

712 • NUTRITIONAL FACTORS IN DISEASE Some vitamins also have pharmacological actions when given at supraphysiological doses, such as the use of vitamin A for acne (p. 1242). Taking vitamin supplements is fashionable in many countries, although there is no evidence of benefit. Toxic effects are most serious with high dosages of vitamins A, B6 and D. Investigation of suspected vitamin deficiency or excess may involve biochemical assessment of body stores (Box 19.32). Measurements in blood should be interpreted carefully, however, in conjunction with the clinical presentation. Fat-soluble vitamins Vitamin A (retinol) Pre-formed retinol is found only in foods of animal origin. Vitamin A can also be derived from carotenes, which are present in green and coloured vegetables and some fruits. Carotenes provide most of the total vitamin A in the UK and constitute the only supply in vegans. Retinol is converted to several other important molecules: • 11-cis-retinaldehyde is part of the photoreceptor complex in rods of the retina. nutrient intake (LRNI) is the mean minus 2 SD, below which would be considered deficient in most of the population. These dietary reference values (DRV) have superseded the terms RDI (recommended daily intake) and RDA (recommended daily amount). Other countries use different terminology. Additional amounts of some micronutrients may be required in pregnancy and lactation (Box 19.29). Vitamin deficiency diseases are most prevalent in developing countries but still occur in developed countries. Older people (Box 19.30) and alcoholics are at risk of deficiencies in B vitamins and in vitamins D and C. Nutritional deficiencies in pregnancy can affect either the mother or the developing fetus, and extra increments of vitamins are recommended in the UK (see Box 19.29). Darker-skinned individuals living at higher latitude, and those who cover up or do not go outside are at increased risk of vitamin D deficiency due to inadequate sunlight exposure. Dietary supplements are recommended for these ‘at-risk’ groups. Some nutrient deficiencies are induced by diseases or drugs. Deficiencies of fat-soluble vitamins are seen in conditions of fat malabsorption (Box 19.31). 19.31 Gastrointestinal disorders that may be associated with malabsorption of fat-soluble vitamins • Biliary obstruction • Pancreatic exocrine insufficiency • Coeliac disease • Ileal inflammation or resection 19.30 Vitamin deficiency in old age • Requirements: although requirements for energy fall with age, those for micronutrients do not. If dietary intake falls, a vitamin-rich diet is required to compensate. • Vitamin D: levels are commonly low due to reduced dietary intake, decreased sun exposure and less efficient skin conversion. This leads to bone loss and fractures. Supplements should be given to those at risk of falls in institutional care – the group at highest risk and most likely to benefit. • Vitamin B12 deficiency: a causal relationship with dementia has not been identified, but it does produce neuropsychiatric effects and should be checked in all those with declining cognitive function. 19.29 Nutrition in pregnancy and lactation • Energy requirements: increased in both mother and fetus but can be met through reduced maternal energy expenditure. • Micronutrient requirements: adaptive mechanisms ensure increased uptake of minerals in pregnancy, but extra increments of some are required during lactation (see Box 19.32). Additional increments of some vitamins are recommended during pregnancy and lactation: Vitamin A: for growth and maintenance of the fetus, and to provide some reserve (important in some countries to prevent blindness associated with vitamin A deficiency). Teratogenic in excessive amounts. Vitamin D: to ensure bone and dental development in the infant. Higher incidences of hypocalcaemia, hypoparathyroidisim and defective dental enamel have been seen in infants of women not taking vitamin D supplements at > 50° latitude. Folate: taken pre-conceptually and during the first trimester, reduces the incidence of neural tube defects by 70%. Vitamin B12: in lactation only. Thiamin: to meet increased fetal energy demands. Riboflavin: to meet extra demands. Niacin: in lactation only. Vitamin C: for the last trimester to maintain maternal stores as fetal demands increase. Iodine: in countries with high consumption of staple foods (e.g. brassicas, maize, bamboo shoots) that contain goitrogens (thiocyanates or perchlorates) that interfere with iodine uptake, supplements prevent infants being born with cretinism. 19.32 Biochemical assessment of vitamin status Nutrient Biochemical assessments of deficiency or excess Vitamin A Serum retinol may be low in deficiency Serum retinyl esters: when vitamin A toxicity is suspected Vitamin D Plasma/serum 25-hydroxyvitamin D (25(OH)D): reflects body stores (liver and adipose tissue) Plasma/serum 1,25(OH)2D: difficult to interpret Vitamin E Serum tocopherol:cholesterol ratio Vitamin K Coagulation assays (e.g. prothrombin time) Plasma vitamin K Vitamin B1 (thiamin) Red blood cell transketolase activity or whole-blood vitamin B1 Vitamin B2 (riboflavin) Red blood cell glutathione reductase activity or whole-blood vitamin B2 Vitamin B3 (niacin) Urinary metabolites: 1-methyl-2-pyridone-5carboxamide, 1-methylnicotinamide Vitamin B6 Plasma pyridoxal phosphate or erythrocyte transaminase activation coefficient Vitamin B12 Plasma B12: poor measure of overall vitamin B12 status but will detect severe deficiency Alternatives (methylmalonic acid and holotranscobalamin) are not used routinely Folate Red blood cell folate Plasma folate: reflects recent intake but also detects unmetabolised folic acid from foods and supplements Vitamin C Leucocyte ascorbic acid: assesses vitamin C tissue stores Plasma ascorbic acid: reflects recent (daily) intake

Micronutrients, minerals and their diseases • 713

is according high priority to prevention in communities where xerophthalmia occurs, giving single prophylactic oral doses of 60 mg retinyl palmitate (providing 200 000 U retinol) to pre-school children. This also reduces mortality from gastroenteritis and respiratory infections. Repeated moderate or high doses of retinol can cause liver damage, hyperostosis and teratogenicity. Women in countries where deficiency is not endemic are therefore advised not to take vitamin A supplements in pregnancy. Retinol intake may also be restricted in those at risk of osteoporosis. Acute overdose leads to nausea and headache, increased intracranial pressure and skin desquamation. Excessive intake of carotene can cause pigmentation of the skin (hypercarotenosis); this gradually fades when intake is reduced. Vitamin D The natural form of vitamin D, cholecalciferol or vitamin D3, is formed in the skin by the action of ultraviolet (UV) light on 7-dehydrocholesterol, a metabolite of cholesterol. Few foods contain vitamin D naturally and skin exposure to sunlight is the main source. Moving away from the equator, the intensity of UV light decreases, so that at a latitude above 50° (including northern Europe) vitamin D is not synthesised in winter, and even above 30° there is seasonal variation. The body store accumulated during the summer is consumed during the winter. Vitamin D is converted in the liver to 25-hydroxyvitamin D (25(OH)D), which is further hydroxylated in the kidneys to 1,25-dihydroxyvitamin D (1,25(OH)2D), the active form of the vitamin (see Fig. 24.61, p. 1051). This 1,25(OH)2D activates specific intracellular receptors that influence calcium metabolism, bone mineralisation and tissue differentiation. The synthetic form, ergocalciferol or vitamin D2, is considered to be less potent than endogenous D3. Recommended dietary intakes aim to improve musculoskeletal health, preventing rickets and osteomalacia, enhancing muscle strength and reducing the risks of falls in the elderly. Adequate levels of vitamin D may also be important in non-musculoskeletal conditions and may improve immune function (p. 1309). Margarines are fortified with vitamin D in the UK, and milk is fortified in some parts of Europe and in North America. However, the combination of low dietary intake and limited sunlight exposure in the UK has led to recommendations that everyone over the age of 5 should take 10 μg of vitamin D daily. The individuals at highest risk of vitamin D deficiency are those who have limited exposure to sunshine. People who are confined indoors, those who habitually cover up their skin when outdoors and those with darker skins should take 10 μg of vitamin D per day all year round. Other groups may require such supplementation only in the winter months of October to March. The effects of vitamin D deficiency (calcium deficiency, rickets and osteomalacia) are described on page 1049. An analogue of vitamin D (calcipotriol) is used for treatment of skin conditions such as psoriasis. Excessive doses of cholecalciferol, ergocalciferol or the hydroxylated metabolites cause hypercalcaemia (p. 661). Vitamin E There are eight related fat-soluble substances with vitamin E activity. The most important dietary form is α-tocopherol. Vitamin E has many direct metabolic actions: • It prevents oxidation of polyunsaturated fatty acids in cell membranes by free radicals. • It helps maintain cell membrane structure. • It affects DNA synthesis and cell signalling. • It is involved in the anti-inflammatory and immune systems. • Retinoic acid induces differentiation of epithelial cells by binding to specific nuclear receptors, which induce responsive genes. In vitamin A deficiency, mucus-secreting cells are replaced by keratin-producing cells. • Retinoids are necessary for normal growth, fetal development, fertility, haematopoiesis and immune function. Globally, the most important consequence of vitamin A deficiency is irreversible blindness in young children. Asia is most notably affected and the problem is being addressed through widespread vitamin A supplementation programmes. Adults are not usually at risk because liver stores can supply vitamin A when foods containing vitamin A are unavailable. Early deficiency causes impaired adaptation to the dark (night blindness). Keratinisation of the cornea (xerophthalmia) gives rise to characteristic Bitot’s spots and progresses to keratomalacia, with corneal ulceration, scarring and irreversible blindness (Fig. 19.12). In countries where vitamin A deficiency is endemic, pregnant women should be advised to eat dark green, leafy vegetables and yellow fruits (to build up stores of retinol in the fetal liver), and infants should be fed the same. The WHO Fig. 19.12 Eye signs of vitamin A deficiency. A Bitot’s spots in xerophthalmia, showing the white triangular plaques (arrows). B Keratomalacia in a 14-month-old child. There is liquefactive necrosis affecting the greater part of the cornea, with typical sparing of the superior aspect. A, Courtesy of Institute of Ophthalmology, Moorfields Eye Hospital, London. B, From WHO. Report of a joint WHO/USAID meeting, vitamin A deficiency and xerophthalmia (WHO technical report series no. 5 W); 1976. A B

714 • NUTRITIONAL FACTORS IN DISEASE • Wet (or cardiac) beri-beri causes generalised oedema due to biventricular heart failure with pulmonary congestion. In dry beri-beri, response to thiamin administration is not uniformly good. Multivitamin therapy seems to produce some improvement, however, suggesting that other vitamin deficiencies may be involved. Wernicke’s encephalopathy and wet beri-beri should be treated without delay with intravenous vitamin B and C mixture (Pabrinex, p. 1195). Korsakoff’s psychosis is irreversible and does not respond to thiamin treatment. Riboflavin (vitamin B2) Riboflavin is required for the flavin co-factors involved in oxidation–reduction reactions. It is widely distributed in animal and vegetable foods. Levels are low in staple cereals but germination increases its content. It is destroyed under alkaline conditions by heat and by exposure to sunlight. Deficiency is rare in developed countries. It mainly affects the tongue and lips and manifests as glossitis, angular stomatitis and cheilosis. The genitals may be involved, as well as the skin areas rich in sebaceous glands, causing nasolabial or facial dyssebacea. Rapid recovery usually follows administration of riboflavin 10 mg daily by mouth. Niacin (vitamin B3) Niacin encompasses nicotinic acid and nicotinamide. Nicotinamide is an essential part of the two pyridine nucleotides, nicotinamide adenine dinucleotide (NAD) and nicotinamide adenine dinucleotide phosphate (NADP), which play a key role as hydrogen acceptors and donors for many enzymes. Niacin can be synthesised in the body in limited amounts from the amino acid tryptophan. Deficiency – pellagra Pellagra was formerly endemic among poor people who subsisted chiefly on maize, which contains niacytin, a form of niacin that the body is unable to utilise. Pellagra can develop in only 8 weeks in individuals eating diets that are very deficient in niacin and tryptophan. It remains a problem in parts of Africa, and is occasionally seen in alcoholics and in patients with chronic small intestinal disease in developed countries. Pellagra can occur in Hartnup’s disease, a genetic disorder characterised by impaired absorption of several amino acids, including tryptophan. It is also seen occasionally in carcinoid syndrome (p. 678), when tryptophan is consumed in the excessive production of 5-hydroxytryptamine (5-HT, serotonin). Pellagra has been called the disease of the three Ds: • Dermatitis. Characteristically, there is erythema resembling severe sunburn, appearing symmetrically over the parts of the body exposed to sunlight, particularly the limbs and especially on the neck but not the face (Casal’s necklace, Fig. 19.13). The skin lesions may progress to vesiculation, cracking, exudation and secondary infection. • Diarrhoea. This is often associated with anorexia, nausea, glossitis and dysphagia, reflecting the presence of a non-infective inflammation that extends throughout the gastrointestinal tract. • Dementia. In severe deficiency, delirium occurs acutely and dementia develops in chronic cases. Treatment is with nicotinamide, given in a dose of 100 mg 3 times daily orally or parenterally. The response is usually rapid. Within 24 hours the erythema diminishes, the diarrhoea ceases and a striking improvement occurs in the patient’s mental state. Human deficiency is rare and has been described only in premature infants and in malabsorption. It can cause a mild haemolytic anaemia, ataxia and visual scotomas. Vitamin E intakes of up to 3200 mg/day (1000-fold greater than recommended intakes) are considered safe. Diets rich in vitamin E are consumed in countries with lower rates of coronary heart disease, although randomised controlled trials have not demonstrated cardioprotective effects of vitamin E or other antioxidants. Vitamin K Vitamin K is supplied in the diet mainly as vitamin K1 (phylloquinone) in the UK, or as vitamin K2 (menaquinone) from fermented products in parts of Asia. Vitamin K2 is also synthesised by bacteria in the colon. Vitamin K is a co-factor for carboxylation reactions: in particular, the production of γ-carboxyglutamate (gla). Gla residues are found in four of the coagulation factor proteins (II, VII, IX and X; p. 918), conferring their capacity to bind to phospholipid surfaces in the presence of calcium. Other important gla proteins are osteocalcin and matrix gla protein, which are important in bone mineralisation. Vitamin K deficiency leads to delayed coagulation and bleeding. In obstructive jaundice, dietary vitamin K is not absorbed and it is essential to administer the vitamin in parenteral form before surgery. Warfarin and related anticoagulants (p. 939) act by antagonising vitamin K. Vitamin K is given routinely to newborn babies to prevent haemorrhagic disease. Symptoms of excess have been reported only in infants, with synthetic preparations linked to haemolysis and liver damage. Water-soluble vitamins Thiamin (vitamin B1) Thiamin is widely distributed in foods of both vegetable and animal origin. Thiamin pyrophosphate (TPP) is a co-factor for enzyme reactions involved in the metabolism of macronutrients (carbohydrate, fat and alcohol), including: • decarboxylation of pyruvate to acetyl-co-enzyme A, which bridges between glycolysis and the tricarboxylic acid (Krebs) cycle • transketolase activity in the hexose monophosphate shunt pathway • decarboxylation of α-ketoglutarate to succinate in the Krebs cycle. In thiamin deficiency, cells cannot metabolise glucose aerobically to generate energy as ATP. Neuronal cells are most vulnerable because they depend almost exclusively on glucose for energy requirements. Impaired glucose oxidation also causes an accumulation of pyruvic and lactic acids, which produce vasodilatation and increased cardiac output. Deficiency – beri-beri In the developed world, thiamin deficiency is mainly encountered in chronic alcoholics. Poor diet, impaired absorption, storage and phosphorylation of thiamin in the liver, and the increased requirements for thiamin to metabolise ethanol all contribute. In the developing world, deficiency usually arises as a consequence of a diet based on polished rice. The body has very limited stores of thiamin, so deficiency is manifest after only 1 month on a thiamin-free diet. There are two forms of the disease in adults: • Dry (or neurological) beri-beri manifests with chronic peripheral neuropathy and with wrist and/or foot drop, and may cause Korsakoff’s psychosis and Wernicke’s encephalopathy (p. 1195).

Micronutrients, minerals and their diseases • 715

Folic acid is the stable synthetic form. Folate works as a methyl donor for cellular methylation and protein synthesis. It is directly involved in DNA and RNA synthesis, and requirements increase during embryonic development. Folate deficiency may cause three major birth defects (spina bifida, anencephaly and encephalocele) resulting from imperfect closure of the neural tube, which takes place 3–4 weeks after conception. The UK Department of Health advises that women who have experienced a pregnancy affected by a neural tube defect should take 5 mg of folic acid daily from before conception and throughout the first trimester; this reduces the incidence of these defects by 70%. All women planning a pregnancy are advised to include good sources of folate in their diet, and to take folate supplements throughout the first trimester. Liver is the richest source of folate but an alternative source (e.g. leafy vegetables) is advised in early pregnancy because of the high vitamin A content of liver (p. 712). Folate deficiency has also been associated with heart disease, dementia and cancer. There is mandatory fortification of flour with folic acid in the USA and voluntary fortification of many foods across Europe. There are now concerns that this may contribute to the increased incidence of colon cancer through promotion of the growth of polyps. Hydroxycobalamin (vitamin B12) Vitamin B12 is a co-factor in folate co-enzyme recycling and nerve myelination. Vitamin B12 and folate are particularly important in DNA synthesis in red blood cells (p. 943). The haematological disorders (macrocytic or megaloblastic anaemias) caused by their deficiency are discussed on pages 943–945. Vitamin B12, but not folate, is needed for the integrity of myelin, so that vitamin B12 deficiency is also associated with neurological disease (see Box 23.33, p. 944). Neurological consequences of vitamin B12 deficiency In older people and chronic alcoholics, vitamin B12 deficiency arises from insufficient intake and/or from malabsorption. Several drugs, including neomycin, can render vitamin B12 inactive. Adequate intake of folate maintains erythropoiesis and there is a concern that fortification of foods with folate may mask underlying vitamin B12 deficiency. In severe deficiency there is insidious, diffuse and uneven demyelination. It may be clinically manifest as peripheral neuropathy or spinal cord degeneration affecting both posterior and lateral columns (‘subacute combined degeneration of the spinal cord’; p. 1138), or there may be cerebral manifestations (resembling dementia) or optic atrophy. Vitamin B12 therapy improves symptoms in most cases. Vitamin C (ascorbic acid) Ascorbic acid is the most active reducing agent in the aqueous phase of living tissues and is involved in intracellular electron transfer. It takes part in the hydroxylation of proline and lysine in protocollagen to hydroxyproline and hydroxylysine in mature collagen. It is very easily destroyed by heat, increased pH and light, and is very soluble in water; hence many traditional cooking methods reduce or eliminate it. Claims that high-dose vitamin C improves immune function (including resistance to the common cold) and cholesterol turnover remain unsubstantiated. Deficiency – scurvy Vitamin C deficiency causes defective formation of collagen with impaired healing of wounds, capillary haemorrhage and reduced platelet adhesiveness (normal platelets are rich in ascorbate) (Fig. 19.14). Precipitants and clinical features of scurvy are shown Toxicity Excessive intakes of niacin may lead to reversible hepatotoxicity. Nicotinic acid is a lipid-lowering agent but at doses above 200 mg a day gives rise to vasodilatory symptoms (‘flushing’ and/or hypotension). Pyridoxine (vitamin B6) Pyridoxine, pyridoxal and pyridoxamine are different forms of vitamin B6 that undergo phosphorylation to produce pyridoxal 5-phosphate (PLP). PLP is the co-factor for a large number of enzymes involved in the metabolism of amino acids. Vitamin B6 is available in most foods. Deficiency is rare, although certain drugs, such as isoniazid and penicillamine, act as chemical antagonists to pyridoxine. Pyridoxine administration is effective in isoniazid-induced peripheral neuropathy and some cases of sideroblastic anaemia. Large doses of vitamin B6 have an antiemetic effect in radiotherapy-induced nausea. Although vitamin B6 supplements have become popular in the treatment of nausea in pregnancy, carpal tunnel syndrome and pre-menstrual syndrome, there is no convincing evidence of benefit. Very high doses of vitamin B6 taken for several months can cause a sensory polyneuropathy. Biotin Biotin is a co-enzyme in the synthesis of fatty acids, isoleucine and valine, and is also involved in gluconeogenesis. Deficiency results from consuming very large quantities of raw egg whites (> 30% energy intake) because the avidin they contain binds to and inactivates biotin in the intestine. It may also be seen after long periods of total parenteral nutrition. The clinical features of deficiency include scaly dermatitis, alopecia and paraesthesia. Folate (folic acid) Folates exist in many forms. The main circulating form is 5-methyltetrahydrofolate. The natural forms are prone to oxidation. Fig. 19.13 Dermatitis due to pellagra (niacin deficiency). The lesions appear on those parts of the body exposed to sunlight. The classic ‘Casal’s necklace’ can be seen around the neck and upper chest. From Karthikeyan K, Thappa DM. Pellagra and skin. Int J Dermatol 2002; 41:476–481.

716 • NUTRITIONAL FACTORS IN DISEASE inadequate dietary intake of minerals or excessive loss from the body. Toxic effects have also been observed from selfmedication and disordered absorption or excretion. Examples of clinical toxicity include excess of iron (haemochromatosis or haemosiderosis), fluoride (fluorosis; p. 149), copper (Wilson’s disease) and selenium (selenosis, seen in parts of China). For most minerals, the available biochemical markers do not accurately reflect dietary intake and dietary assessment is required. Calcium and phosphorus Calcium is the most abundant cation in the body and powerful homeostatic mechanisms control circulating ionised calcium levels (pp. 661 and 1050). The WHO’s dietary guidelines for calcium differ between countries, with higher intakes usually recommended in places with higher fracture prevalence. Between 20% and 30% of calcium in the diet is absorbed, depending on vitamin D status and food source. Calcium requirements depend on phosphorus intakes, with an optimum molar ratio (Ca:P) of 1 : 1. Excessive phosphorus intakes (e.g. 1–1.5 g/day) with a Ca:P of 1 : 3 have been shown to cause hypocalcaemia and secondary hyperparathyroidism (p. 662). Calcium absorption may be impaired in vitamin D deficiency (pp. 661 and 1050) and in malabsorption secondary to small intestinal disease. Calcium deficiency causes impaired bone mineralisation and can lead to osteomalacia in adults. The potential benefits of high calcium intake in osteoporosis are discussed on page 1048. Too much calcium can lead to constipation, and toxicity has been observed in ‘milk-alkali syndrome’ (p. 662). Dietary deficiency of phosphorus is rare (except in older people with limited diets) because it is present in nearly all foods and phosphates are added to a number of processed foods. Phosphate deficiency in adults occurs: • in patients with renal tubular phosphate loss (p. 405) • in patients receiving a prolonged high dosage of aluminium hydroxide (p. 419) • in alcoholics sometimes when they are fed with highcarbohydrate foods • in patients receiving parenteral nutrition if inadequate phosphate is provided. Deficiency causes hypophosphataemia (p. 368) and muscle weakness secondary to ATP deficiency. Iron Iron is involved in the synthesis of haemoglobin and is required for the transport of electrons within cells and for a number of enzyme reactions. Non-haem iron in cereals and vegetables is in Box 19.33. A dose of 250 mg vitamin C 3 times daily by mouth should saturate the tissues quickly. The deficiencies of the patient’s diet also need to be corrected and other vitamin supplements given if necessary. Daily intakes of more than 1 g/day have been reported to cause diarrhoea and the formation of renal oxalate stones. Other dietary organic compounds There are a number of non-essential organic compounds with purported health benefits, such as reducing risk of heart disease or cancer. Groups of compounds such as the flavonoids and phytoestrogens show bioactivity through their respective antioxidant and oestrogenic or anti-oestrogenic activities. Flavonoids (of which there are a number of different classes of compound) are found in fruit and vegetables, tea and wine; phytoestrogens are found in soy products (with higher intakes in parts of Asia compared to Europe and the USA) and pulses. Caffeine from tea and coffee and carbonated beverages affects the nervous system and can improve mental performance in the short term, with adverse effects seen at higher intakes. Intake of non-carbonic organic acids (which are not metabolised to carbon dioxide), e.g. oxalates, may be restricted in individuals prone to kidney stones. Inorganic micronutrients A number of inorganic elements are essential dietary constituents for humans (Box 19.34). Deficiency is seen when there is Fig. 19.14 Scurvy. A Gingival swelling and bleeding. B Perifollicular hyperkeratosis. A and B, From Ho V, Prinsloo P, Ombiga J. Persistent anaemia due to scurvy. J New Zeal Med Assoc 2007; 120:62. Reproduced with permission. A B 19.33 Scurvy – vitamin C deficiency Precipitants Increased requirement Dietary deficiency • Trauma, surgery, burns, infections • Smoking • Drugs (glucocorticoids, aspirin, indometacin, tetracycline) • Lack of dietary fruit and vegetables for > 2 months • Infants fed exclusively on boiled milk Clinical features • Swollen gums that bleed easily • Perifollicular and petechial haemorrhages • Ecchymoses • Haemarthrosis • Gastrointestinal bleeding • Anaemia • Poor wound healing

Micronutrients, minerals and their diseases • 717

disorder. Goitre is the most common manifestation, affecting about 200 million people (p. 648). In those areas where most women have endemic goitre, 1% or more of babies are born with cretinism (characterised by mental and physical retardation). There is a higher than usual prevalence of deafness, slowed reflexes and poor learning in the remaining population. The best way of preventing neonatal cretinism is to ensure adequate levels of iodine during pregnancy. This can be achieved by intramuscular injections with 1–2 mL of iodised poppy seed oil (475–950 mg iodine) to women of child-bearing age every 3–5 years, by administration of iodised oil orally at 6-monthly or yearly intervals to adults and children, or by provision of iodised salt for cooking. Zinc Zinc is present in most foods of vegetable and animal origin. It is an essential component of many enzymes, including carbonic anhydrase, alcohol dehydrogenase and alkaline phosphatase. Acute zinc deficiency has been reported in patients receiving prolonged zinc-free parenteral nutrition and causes diarrhoea, mental apathy, a moist, eczematoid dermatitis, especially around the mouth, and loss of hair. Chronic zinc deficiency occurs in dietary deficiency, malabsorption syndromes, alcoholism and its associated hepatic cirrhosis. It causes the clinical features seen in the very rare congenital disorder known as acrodermatitis enteropathica (growth retardation, hair loss and chronic diarrhoea). Zinc deficiency is thought to be responsible for one-third of the world’s population not reaching their optimal height. In the Middle East, chronic deficiency has been associated with dwarfism and hypogonadism. In starvation, zinc deficiency causes thymic atrophy; zinc supplements may accelerate the healing of skin lesions, promote general well-being, improve appetite and reduce the morbidity associated with the under-nourished state, and lower the mortality associated with diarrhoea and pneumonia in children. poorly absorbed but makes the greater contribution to overall intake, compared to the well-absorbed haem iron from animal products. Fruits and vegetables containing vitamin C enhance iron absorption, while the tannins in tea reduce it. Dietary calcium reduces iron uptake from the same meal, which may precipitate iron deficiency in those with borderline iron stores. There is no physiological mechanism for excretion of iron, so homeostasis depends on the regulation of iron absorption (see Fig. 23.18, p. 942). This is regulated at the level of duodenal enterocytes by hepcidin (a peptide secreted by hepatocytes in the duodenum). The expression of hepcidin is suppressed when body iron is low, leading to enhanced efflux of iron into the circulation. The normal daily loss of iron is 1 mg, arising from desquamated surface cells and intestinal losses. A regular loss of only 2 mL of blood per day doubles the iron requirement. On average, an additional 20 mg of iron is lost during menstruation, so pre-menopausal women require about twice as much iron as men (and more if menstrual losses are heavy). The major consequence of iron deficiency is anaemia (p. 940). This is one of the most important nutritional causes of ill health in all parts of the world. In the UK, it is estimated that 10% women are iron-deficient. Dietary iron overload is occasionally observed and results in iron accumulation in the liver and, rarely, cirrhosis. Haemochromatosis results from an inherited increase in iron absorption (p. 895). Iodine Iodine is required for synthesis of thyroid hormones (p. 634). It is present in sea fish, seaweed and most plant foods grown near the sea. The amount of iodine in soil and water influences the iodine content of most foods. Iodine is lacking in the highest mountainous areas of the world (e.g. the Alps and the Himalayas) and in the soil of frequently flooded plains (e.g. Bangladesh). About a billion people in the world are estimated to have an inadequate iodine intake and hence are at risk of iodine deficiency 19.34 Summary of clinically important minerals Mineral Sources1 Reference nutrient intake (RNI) Rich Important Calcium Milk and milk products, tofu Milk, boned fish, green vegetables, beans 700 mg2 Phosphorus Most foods contain phosphorus 550 mg2 Marmite and dry-roasted peanuts Milk, cereal products, bread and meat Magnesium Whole grains, nuts Unprocessed and wholegrain foods 300 mg men 270 mg women2 Iron Liver, red meat (haem iron) Non-haem iron from vegetables, wholemeal bread 8.7 mg 14.8 mg women < 50 years Zinc Red meat, seafood Dairy produce, wholemeal bread 9.5 mg men 7 mg women2 Iodine Edible seaweeds Milk and dairy products 140 μg Selenium Fish, wheat grown in selenium-rich soils Fish 75 μg men 60 μg women2 Copper Shellfish, liver Bread, cereal products, vegetables 1.2 mg2 Fluoride Drinking water, tea No RNI. Safe intake: 0.5 mg/kg Potassium Dried fruit, potatoes, coffee Fresh fruit, vegetables, milk 3500 mg Sodium Table salt, anchovies Processed foods, bread, bacon 1600 mg 1Rich sources contain the nutrient in high concentration but are not generally eaten in large amounts; important sources contain less but contribute most because larger amounts are eaten. 2Increased amounts are required in women during lactation.

718 • NUTRITIONAL FACTORS IN DISEASE that daily salt intakes are kept well below 6 g. The roles of sodium, potassium and magnesium, along with the disease states associated with abnormal intakes or disordered metabolism, are discussed in Chapter 14. Other essential inorganic nutrients These include chloride (a counter-ion to sodium and potassium), cobalt (required for vitamin B12), sulphur (a constituent of methionine and cysteine), manganese (needed for or activates many enzymes) and chromium (necessary for insulin action). Deficiency of chromium presents as hyperglycaemia and has been reported in adults as a rare complication of prolonged parenteral nutrition. Copper metabolism is abnormal in Wilson’s disease (p. 896). Deficiency occasionally occurs but only in young children, causing microcytic hypochromic anaemia, neutropenia, retarded growth, skeletal rarefaction and dermatosis. Further information Websites bapen.org.uk British Society for Parenteral and Enteral Nutrition; includes the MUST tool. bsg.org.uk British Society of Gastroenterology: guidelines on management of patients with a short bowel, enteral feeding for adult hospital patients and the provision of a percutaneously placed enteral tube feeding service. espen.org European Society for Parenteral and Enteral Nutrition: guidelines for adult parenteral nutrition; perioperative care in elective colonic and rectal/pelvic surgery; nutrition in dementia; acute and chronic intestinal failure in adults; and nutrition in cancer patients. nice.org.uk National Institute for Health and Care Excellence: guidance for nutritional support in adults. Selenium The family of seleno-enzymes includes glutathione peroxidase, which helps prevent free radical damage to cells, and monodeiodinase, which converts thyroxine to triiodothyronine (p. 634). North American soil has a higher selenium content than European and Asian soil, and the decreasing reliance of Europe on imported American food in recent decades has resulted in a decline in dietary selenium intake. Selenium deficiency can cause hypothyroidism, cardiomyopathy in children (Keshan’s disease) and myopathy in adults. Excess selenium can cause heart disease. Fluoride Fluoride helps prevent dental caries because it increases the resistance of the enamel to acid attack. It is a component of bone mineral and some studies have shown anti-fracture effects at low doses, but excessive intakes may compromise bone structure. If the local water supply contains more than 1 part per million (ppm) of fluoride, the incidence of dental caries is low. Soft waters usually contain no fluoride, while very hard waters may contain over 10 ppm. The benefit of fluoride is greatest when it is taken before the permanent teeth erupt, while their enamel is being laid down. The addition of traces of fluoride (at 1 ppm) to public water supplies is now a widespread practice. Chronic fluoride poisoning is occasionally seen where the water supply contains > 10 ppm fluoride. It can also occur in workers handling cryolite (aluminium sodium fluoride), used in smelting aluminium. Fluoride poisoning is described on page 149. Pitting of teeth is a result of too much fluoride as a child. Sodium, potassium and magnesium Western diets are high in sodium due to the sodium chloride (salt) that is added to processed food. In the UK, it is suggested

Ch04-3 Clinical Medicine

10-20 Diabetes mellitus

20 Diabetes mellitus

Diabetes mellitus ER Pearson RJ McCrimmon Clinical examination of the patient with diabetes 720 Functional anatomy and physiology 723 Investigations 725 Establishing the diagnosis of diabetes 727 Aetiology and pathogenesis of diabetes 728 Presenting problems in diabetes mellitus 734 Hyperglycaemia 734 Presentation with the complications of diabetes 735 Diabetes emergencies 735 Diabetic ketoacidosis 735 Hyperglycaemic hyperosmolar state 738 Hypoglycaemia 738 Management of diabetes 741 Patient education, diet and lifestyle 743 Drugs to reduce hyperglycaemia 745 Insulin therapy 748 Transplantation 752 Management of diabetes in special situations 752 Complications of diabetes 755 Diabetic retinopathy 757 Diabetic nephropathy 757 Diabetic neuropathy 758 The diabetic foot 761

720 • DIABETES MELLITUS Clinical examination of the patient with diabetes Insets (Acanthosis nigricans) From Lim E (ed.). Medicine and surgery: an integrated textbook. Edinburgh: Elsevier Ltd; 2007. ( Exudative maculopathy) Courtesy of Dr A.W. Patrick and Dr I.W. Campbell. Blood pressure Skin Bullae Pigmentation Granuloma annulare Vitiligo Axillae Neck Carotid pulse Bruits Thyroid enlargement Eyes (see opposite) Visual acuity Cataract/lens opacity Fundoscopy Insulin injection sites (see opposite) Hands (see opposite) Feet (see opposite) Inspection Peripheral pulses Sensation Abdomen Hepatomegaly (fatty infiltration of liver) Legs Muscle-wasting Sensory abnormality Hair loss Tendon reflexes Exudative maculopathy Necrobiosis lipoidica Charcot neuroarthropathy Neuropathic foot ulcer Head Xanthelasma Cranial nerve palsy/eye movements/ptosis Observation • Weight loss in insulin deficiency • Obesity in type 2 diabetes • Mucosal candidiasis • Dehydration– dry mouth, ↓tissue turgor • Air hunger– Kussmaul breathing in ketoacidosis

Acanthosis nigricans in insulin resistance ‘Prayer sign’

Clinical examination of the patient with diabetes • 721

Diabetes can affect every system in the body. In routine clinical practice, examination of the patient with diabetes is focused on hands, blood pressure, axillae, neck, eyes, insulin injection sites and feet. 1 Examination of the hands Several abnormalities are more common in diabetes: • Limited joint mobility (‘cheiroarthropathy’) causes painless stiffness. The inability to extend (to 180°) the metacarpophalangeal or interphalangeal joints of at least one finger bilaterally can be demonstrated in the ‘prayer sign’ • Dupuytren’s contracture (p. 1059) causes nodules or thickening of the skin and knuckle pads • Carpal tunnel syndrome (p. 1139) presents with wrist pain radiating into the hand • Trigger finger (flexor tenosynovitis) may be present • Muscle-wasting/sensory changes may be present in peripheral sensorimotor neuropathy, although this is more common in the lower limbs Background retinopathy. Courtesy of Dr A.W. Patrick and Dr I.W. Campbell. Proliferative retinopathy. Courtesy of Dr A.W. Patrick and Dr I.W. Campbell. 7 Examination of the eyes Visual acuity • Check distance vision using Snellen chart at 6 m • Check near vision using standard reading chart • Note that visual acuity can alter reversibly with acute hyperglycaemia due to osmotic changes affecting the lens. Most patients with retinopathy do not have altered visual acuity, except after a vitreous haemorrhage or in some cases of maculopathy Lens opacification • Look for the red reflex using the ophthalmoscope held 30 cm from the eye Fundal examination • Either use a three-field retinal camera or dilate pupils with a mydriatic (e.g. tropicamide) and examine with an ophthalmoscope in a darkened room • Note features of diabetic retinopathy (p. 1174), including photocoagulation scars from previous laser treatment 8 Insulin injection sites Main areas used • Anterior abdominal wall • Upper thighs/buttocks • Upper outer arms Inspection • Bruising • Subcutaneous fat deposition (lipohypertrophy) • Subcutaneous fat loss (lipoatrophy; associated with injection of unpurified animal insulins – now rare) • Erythema, infection (rare) Lipohypertrophy of the upper arm. 11 Examination of the feet Inspection • Look for evidence of callus formation on weight-bearing areas, clawing of the toes (in neuropathy), loss of the plantar arch, discoloration of the skin (ischaemia), localised infection and ulcers • Deformity may be present, especially in Charcot neuroarthropathy • Fungal infection may affect skin between toes, and nails Circulation • Peripheral pulses, skin temperature and capillary refill may be abnormal Sensation • This is abnormal in stocking distribution in typical peripheral sensorimotor neuropathy • Testing light touch with monofilaments is sufficient for risk assessment; test other sensation modalities (vibration, pain, proprioception) only when neuropathy is being evaluated Reflexes • Ankle reflexes are lost in typical sensorimotor neuropathy • Test plantar and ankle reflexes Monofilaments. The monofilament is applied gently until slightly deformed at five points on each foot. Callus should be avoided as sensation is reduced. If the patient feels fewer than 8 out of 10 touches, the risk of foot ulceration is increased 5–10-fold.

722 • DIABETES MELLITUS The incidence of diabetes is rising. Globally, it is estimated that 415 million people had diabetes in 2015 (10% of the world adult population), and this figure is expected to reach 642 million by 2040. This global pandemic principally involves type 2 diabetes; prevalence varies considerably around the world (Fig. 20.1), being associated with differences in genetic factors, as well as environmental ones such as greater longevity, obesity, unsatisfactory diet, sedentary lifestyle, increasing urbanisation and economic development. A pronounced rise in the prevalence of type 2 diabetes occurs in migrant populations to industrialised countries, as in Asian and Afro-Caribbean immigrants to the UK or USA. Type 2 diabetes is now seen in children and adolescents, particularly in some ethnic groups such as Hispanics, non-Hispanic blacks and Asian Indians. The incidence of type 1 diabetes is also increasing: between 1960 and 1996, 3% more children were diagnosed worldwide each year. It is generally more common in countries closer to the polar regions. Finland, for instance, has the highest rate of type 1 diagnosis per year at > 60 per 100 000 of the population, whereas in China, India and Venezuela the incidence is only 0.1 per 100 000. Type 1 diabetes is most common in Caucasians, and more people are diagnosed in the winter months. Diabetes is a major burden on health-care facilities in all countries. Globally, in 2015, diabetes caused 5 million deaths in those aged 20–79 years, and health-care expenditure attributed to diabetes was estimated to be at least 673 billion US dollars, or 12% of total health-care expenditure. Fig. 20.1 Prevalence (%) of diabetes in those aged 20–79 years, 2015. Based on estimates from the International Diabetes Federation. IDF Diabetes Atlas, 7th edn. Brussels, Belgium: International Diabetes Federation, 2015. http://www.diabetesatlas.org. <4% 4–5% 5–7% 7–9% 9–12%

12% Diabetes mellitus is a clinical syndrome characterised by an increase in plasma blood glucose (hyperglycaemia). It has many causes (see Box 20.9), most commonly type 1 or type 2 diabetes. Type 1 diabetes is generally considered to result from autoimmune destruction of insulin-producing cells (β cells) in the pancreas, leading to marked insulin deficiency, whereas type 2 diabetes is characterised by reduced sensitivity to the action of insulin and an inability to produce sufficient insulin to overcome this ‘insulin resistance’. Hyperglycaemia causes both acute and long-term problems. Acutely, high glucose and lack of insulin can result in marked symptoms, metabolic decompensation and hospitalisation. Chronic hyperglycaemia is responsible for diabetes-specific ‘microvascular’ complications affecting the eyes (retinopathy), kidneys (nephropathy) and feet (neuropathy). There is a continuous distribution of blood glucose in the population, with no clear division between people with normal values and those with abnormal ones. The diagnostic criteria for diabetes (a fasting plasma glucose of ≥ 7.0 mmol/L (126 mg/ dL) or glucose 2 hours after an oral glucose challenge of ≥ 11.1 mmol/L (200 mg/dL); p. 726) have been selected to identify a degree of hyperglycaemia that, if untreated, carries a significant risk of microvascular disease, and in particular diabetic retinopathy. Less severe hyperglycaemia is called ‘impaired glucose tolerance’. This is not associated with a substantial risk of microvascular disease, but is connected with an increased risk of large-vessel disease (e.g. atheroma leading to myocardial infarction) and with a greater risk of developing diabetes in future.

Functional anatomy and physiology • 723

down its concentration gradient through cell membrane glucose transporters (GLUTs). Glucose is then metabolised by glycolysis and oxidative phosphorylation. The first step of the glycolytic pathway, the conversion of glucose to glucose-6-phosphate, is catalysed by the enzyme glucokinase (GK). Glucokinase has a low affinity for glucose and so its activity under normal physiological conditions varies markedly, according to the concentration of glucose. This makes it a very effective glucose sensor in the β cell. In what is considered a classical direct or triggering pathway, glucose metabolism results in increased intracellular adenosine triphosphate (ATP) and reduced adenosine diphosphate Functional anatomy and physiology Regulation of insulin secretion Insulin is the primary regulator of glucose metabolism and storage (Box 20.1), and is secreted from pancreatic β cells into the portal circulation (Fig. 20.2). The pancreatic β cell is designed to regulate blood glucose concentrations tightly by coupling glucose and other nutrient stimulus with insulin secretion (Fig. 20.2). Entry of glucose into the pancreatic β cell is by facilitated diffusion 20.1 Metabolic actions of insulin Increase Decrease Carbohydrate metabolism Glucose transport (muscle, adipose tissue) Glucose phosphorylation Glycogen synthesis Glycolysis Pyruvate dehydrogenase activity Pentose phosphate shunt Gluconeogenesis Glycogenolysis Lipid metabolism Triglyceride synthesis Fatty acid synthesis (liver) Lipoprotein lipase activity (adipose tissue) Lipolysis Lipoprotein lipase (muscle) Ketogenesis Fatty acid oxidation (liver) Protein metabolism Amino acid transport Protein synthesis Protein degradation Fig. 20.2 Pancreatic structure and endocrine function. A The normal adult pancreas contains about 1 million islets, which are scattered throughout the exocrine parenchyma. Histology is shown in Figure 20.6. B The core of each islet consists of β cells that produce insulin, and is surrounded by a cortex of endocrine cells that produce other hormones, including glucagon (α cells), somatostatin (δ cells) and pancreatic polypeptide (PP cells). C Schematic representation of the pancreatic β cell. (1) Glucose enters the cell via a glucose transporter (GLUT1 or GLUT2). (2) Glucose then enters glycolysis, and subsequent oxidative phosphorylation in the mitochondria results in a rise in intracellular adenosine triphosphate (ATP). (3) This ATP acts to close the KATP channel (which consists of four KIR6.2 subunits and four SUR1 subunits). This leads to membrane depolarisation. (4) The rise in membrane potential results in calcium influx due to opening of a voltage-gated calcium channel. This rise in intracellular calcium causes insulin secretory vesicles to fuse with the cell membrane, leading to insulin secretion. (5) Other stimuli, such as glucagon-like peptide-1 (GLP-1) or gastric inhibitory polypeptide (GIP), act on G-protein-coupled receptors to increase cyclic adenosine monophosphate (cAMP) and amplify the insulin secretion. Genetic defects in the β cell result in diabetes. The primary genes are glucokinase (the initial step in glycolysis) and HNF1α, HNF4α and HNF1β (nuclear transcription factors). Two groups of drugs act on the β cell to promote insulin secretion. Sulphonylureas act to close the KATP channel, causing membrane depolarisation, calcium influx and insulin secretion. Incretin-acting drugs either increase the concentration of endogenous GLP-1 and GIP (the dipeptidyl peptidase 4, or DPP-4, inhibitors) or act as directly on the GLP-1 receptor (GLP-1 receptor agonists). Both of these drug groups act to augment insulin secretion but only following an initial stimulus to insulin secretion through closure of β cell KATP channels by glucose (or sulphonylureas). Accessory ampulla Ampulla of Vater Duodenum Islet core (β cells) Arteriole Other islet cells Venule Glucose GLUT

Glucose Nucleus HNF1α HNF4α HNF1β Glucokinase Glycolysis Incretin-acting drugs Insulin KIR6.2 SUR1 ATP GLP-1 Ca2+ K+ Mitochondria Sulphonylureas A B C Oxidative phosphorylation

724 • DIABETES MELLITUS classically occurs in two phases (see Fig. 20.3). The rapid first phase represents the secretion of pre-formed insulin from granules within the β cells, while the more prolonged second phase is a consequence of newly synthesised insulin. Regulation of glucagon secretion Pancreatic islets also contain other endocrine cells such as α cells that secrete the peptide hormone glucagon, and δ cells that produce somatostatin (see Fig. 20.2B). Alpha cells make up about 20% of the human islet cell population. Glucagon has opposite effects to insulin and acts on the liver (and kidney) to stimulate glycogenolysis, leading to increased hepatic glucose production. Regulation of glucagon secretion by the α cell is complex, but β-cell insulin secretion, co-secreted zinc and γ-aminobutyric acid (GABA), as well as somatostatin from δ cells, are thought to have major regulatory roles. This means that insulin and glucagon are tightly, and reciprocally, regulated, such that the ratio of insulin to glucagon in the portal vein is a major determinant of hepatic glucose production. Glucagon is also critically important to the body’s defence against hypoglycaemia (p. 738). Blood glucose homeostasis Blood glucose is tightly regulated and maintained within a narrow range. This is essential for ensuring a continuous supply of glucose to the central nervous system. The brain has little capacity to store energy in the form of glycogen or triglyceride, and the blood–brain barrier is largely impermeable to fatty acids, so the brain depends on the liver for a constant supply of glucose for oxidation and hence generation of ATP. Glucose homeostasis is achieved through the coordinated actions of multiple organs, but mainly reflects a balance between the entry of glucose into the circulation from the liver, supplemented by intestinal absorption of glucose after meals, and the uptake of glucose by peripheral tissues, particularly skeletal muscle and brain. After ingestion of a meal containing carbohydrate, normal blood glucose levels are maintained by: • suppression of hepatic glucose production • stimulation of hepatic glucose uptake • stimulation of glucose uptake by peripheral tissues (Fig. 20.5). The post-prandial rise in portal vein insulin and glucose, together with a fall in portal glucagon concentrations, suppresses hepatic glucose production and results in net hepatic glucose uptake. Depending on the size of the carbohydrate load, around one-quarter to one-third of ingested glucose is taken up in the liver. In addition, insulin stimulates glucose uptake in skeletal muscle and fat, mediated by the glucose transporter GLUT4. Fig. 20.3 Insulin secretion in response to intravenous or oral glucose. A An acute first phase of insulin secretion occurs in response to an elevated blood glucose, followed by a sustained second phase. B The incretin effect describes the observation that insulin secretion is greater when glucose is given by mouth than when glucose is administered intravenously to achieve the same rise in blood glucose concentrations. The additional stimulus to insulin secretion is mediated by release of peptides from the gut and these actions are exploited in incretin-based therapies (p. 747). 1st phase 2nd phase Basal secretion Insulin secretion The incretin effect Glucose stimulus 0–5 mins Time Time After oral glucose After intravenous glucose Insulin A B Fig. 20.4 Processing of pro-insulin into insulin and C-peptide. Pro-insulin in the pancreatic β cell is cleaved to release insulin and equimolar amounts of inert C-peptide (connecting peptide). Measurement of C-peptide can be used to assess endogenous insulin secretory capacity. Pro-insulin Pancreatic β cell C-peptide Insulin (ADP), which causes closure of an ATP-sensitive potassium channel (KATP). The resulting membrane depolarisation of the β cell results in insulin secretion due to triggering of calcium release by voltage-sensitive calcium channels. In addition to this pathway, the amount of insulin released can be amplified or potentiated by the background blood glucose, other nutrients and peptides, and by neuronal control via the sympathetic and parasympathetic nervous system. A good example of this potentiation of insulin release is seen with the secretion of two gut peptides following ingestion of food. Glucagon-like peptide-1 (GLP-1) and gastric inhibitory polypeptide (GIP) are released from gastrointestinal L cells and K cells, respectively, following a meal, and act via receptors on the pancreatic β cells to augment insulin secretion. Thus, for a given glucose stimulus to the β cell, there is greater insulin secretion with oral glucose administration (where the gut peptides are released) compared to intravenous glucose administration (which does not stimulate gut peptide release). This enhanced insulin secretion following oral administration of glucose is termed the ‘incretin’ effect (Fig. 20.3), and GLP-1 and GIP are known as incretin hormones. Insulin is synthesised as a pro-hormone (pro-insulin) that consists of an α and a β chain, which are linked by C-peptide (Fig. 20.4). The C-peptide is cleaved by β-cell peptidases to create insulin (which now consists of the α and β chains) and free C-peptide. Insulin secretion in response to a glucose stimulus

Investigations • 725

utilisation of ketone bodies by peripheral tissues is limited, and when the rate of production by the liver exceeds their removal, hyperketonaemia results. This occurs physiologically during starvation, when low insulin levels and high catecholamine levels increase lipolysis and delivery of FFAs to the liver. Investigations Urine glucose Testing the urine for glucose with dipsticks is a common screening procedure for detecting diabetes. If possible, testing should be performed on urine passed 1–2 hours after a meal to maximise sensitivity. Glycosuria always warrants further assessment by blood testing (see below). The greatest disadvantage of urine glucose measurement is the individual variation in renal threshold for glucose. The most frequent cause of glycosuria is a low renal threshold, which is common during pregnancy and in young people; the resulting ‘renal glycosuria’ is a benign condition unrelated to diabetes. Another disadvantage is that some drugs (such as β-lactam antibiotics, levodopa and salicylates) may interfere with urine glucose tests. When intestinal glucose absorption declines between meals, portal vein insulin and glucose concentrations fall while glucagon levels rise. This leads to increased hepatic glucose output via gluconeogenesis and glycogen breakdown. The liver now resumes net glucose production and glucose homeostasis is maintained. The main substrates for gluconeogenesis are glycerol and amino acids, as shown in Figure 20.5. Fat metabolism Adipocytes (and the liver) synthesise triglyceride from nonesterified (‘free’) fatty acids (FFAs) and glycerol. Insulin is the major regulator not only of glucose metabolism but also of fatty acid metabolism. High insulin levels after meals promote triglyceride accumulation. In contrast, in the fasting state, low insulin levels permit lipolysis and the release into the circulation of FFAs (and glycerol), which can be oxidised by many tissues. Their partial oxidation in the liver provides energy to drive gluconeogenesis and also produces ketone bodies (acetoacetate, which can be reduced to 3-hydroxybutyrate or decarboxylated to acetone), which are generated in hepatocyte mitochondria. Ketone bodies are organic acids that, when formed in small amounts, are oxidised and utilised as metabolic fuel. However, the rate of Fig. 20.5 Major metabolic pathways of fuel metabolism and the actions of insulin. Պ indicates stimulation and Ջ indicates suppression by insulin. In response to a rise in blood glucose, e.g. after a meal, insulin is released, suppressing gluconeogenesis and promoting glycogen synthesis and storage. Insulin promotes the peripheral uptake of glucose, particularly in skeletal muscle, and encourages storage (as muscle glycogen). It also promotes protein synthesis and lipogenesis, and suppresses lipolysis. The release of intermediate metabolites, including amino acids (glutamine, alanine), 3-carbon intermediates in oxidation (lactate, pyruvate) and free fatty acids (FFAs), is controlled by insulin. In the absence of insulin, e.g. during fasting, these processes are reversed and favour gluconeogenesis in liver from glycogen, glycerol, amino acids and other 3-carbon precursors. Liver Adipose tissue Muscle Gut Gluconeogenesis FFAs Amino acids Lactate Pyruvate Proteolysis Glucose GLUT4 GLUT4 Ketone bodies Oxidation Glucose Glycogen Oxidation FFAs Triglycerides Food Glucose Glycogen Ketogenesis Oxidation Glycerol FFAs Glucose Glycerol +

726 • DIABETES MELLITUS Interstitial glucose A relatively new approach to measuring glucose levels in diabetes is through the use of interstitial continuous glucose monitoring (CGM). CGM systems use a tiny sensor inserted under the skin to check glucose levels in interstitial fluid. The sensor can stay in place for up to 2 weeks before being replaced and provides real-time measurements of glucose levels every 1 or 5 minutes (see Fig. 20.16, p. 751). These devices are not as accurate as blood glucose testing, particularly when levels are low or changing rapidly, so users must still check blood glucose with a glucose meter before driving or changing therapy. CGM provides useful information on daily glucose profiles and, in particular, night-time glucose levels. In addition, alarms can be incorporated into the CGM device to warn individuals about hypoglycaemia. Urine and blood ketones Acetoacetate can be identified in urine by the nitroprusside reaction, using either tablets or dipsticks. Ketonuria may be found in normal people who have been fasting or exercising strenuously for long periods, vomiting repeatedly, or eating a diet high in fat and low in carbohydrate. Ketonuria is therefore not pathognomonic of diabetes but, if it is associated with glycosuria, the diagnosis of diabetes is highly likely. Urine ketone measurements are semi-quantitative, awkward to perform and retrospective (i.e. the urine has accumulated over several hours). Also, they do not measure the major ketone found in blood during diabetic ketoacidosis (DKA), beta-hydroxybutyrate (β-OHB). Beta-OHB can be measured in blood in the laboratory and also in a fingerprick specimen of capillary blood with a test stick and electronic meter. Whole-blood β-OHB monitoring is useful in assisting with insulin adjustment during intercurrent illness or sustained hyperglycaemia to prevent or detect DKA. Blood β-OHB monitoring is also useful in monitoring resolution of DKA in hospitalised patients (Box 20.4). Glycated haemoglobin Glycated haemoglobin provides an accurate and objective measure of glycaemic control over a period of weeks to months. In diabetes, the slow non-enzymatic covalent attachment of glucose to haemoglobin (glycation) increases the amount in the HbA1 (HbA1c) fraction relative to non-glycated adult haemoglobin (HbA0). These fractions can be separated by chromatography; Blood glucose Laboratory glucose testing in blood relies on an enzymatic reaction (glucose oxidase) and is cheap, usually automated and highly reliable. However, blood glucose levels depend on whether the patient has eaten recently, so it is important to consider the circumstances in which the blood sample was taken. Blood glucose can also be measured with testing sticks that are read with a portable electronic meter. These are used for capillary (fingerprick) testing to monitor diabetes treatment (p. 742). There is some debate as to whether self-monitoring in people with type 2 diabetes improves glycaemic control. Many countries now offer self-monitoring only to people with type 2 diabetes taking sulphonylurea or insulin therapy because of the risk of hypoglycaemia. To make the diagnosis of diabetes, the blood glucose concentration should be estimated using an accurate laboratory method rather than a portable technique. Glucose concentrations are lower in venous than arterial or capillary (fingerprick) blood. Whole-blood glucose concentrations are lower than plasma concentrations because red blood cells contain relatively little glucose. Venous plasma values are usually the most reliable for diagnostic purposes (Boxes 20.2 and 20.3). 20.4 Interpretation of capillary blood ketone measurements Measurement* Interpretation < 0.6 mmol/L Normal; no action required 0.6–1.5 mmol/L Suggests metabolic control may be deteriorating; the patient should continue to monitor and seek medical advice if sustained/progressive 1.5–3.0 mmol/L With high blood glucose (> 10 mmol/L), there is a high risk of diabetic ketoacidosis; seek medical advice

3.0 mmol/L Severe ketosis; in the presence of high glucose (> 10 mmol/L) suggests presence of diabetic ketoacidosis; seek urgent medical help *To convert to mg/dL, multiply values by 18. 20.3 How to perform an oral glucose tolerance test (OGTT) Preparation before the test • Unrestricted carbohydrate diet for 3 days • Fasted overnight for at least 8 hrs • Rest for 30 mins • Remain seated for the duration of the test, with no smoking Sampling • Measure plasma glucose before and 2 hrs after a 75 g oral glucose drink 20.2 Diagnosis of diabetes and pre-diabetes Diabetes is confirmed by: • either plasma glucose in random sample or 2 hrs after a 75 g glucose load ≥ 11.1 mmol/L (200 mg/dL) or • fasting plasma glucose ≥ 7.0 mmol/L (126 mg/dL) or • HbA1c ≥ 48 mmol/mol In asymptomatic patients, two diagnostic tests are required to confirm diabetes; the second test should be the same as the first test to avoid confusion ‘Pre-diabetes’ is classified as: • impaired fasting glucose = fasting plasma glucose ≥ 6.1 mmol/L (110 mg/dL) and < 7.0 mmol/L (126 mg/dL) • impaired glucose tolerance = fasting plasma glucose < 7.0 mmol/L (126 mg/dL) and 2-hr glucose after 75 g oral glucose drink 7.8–11.1 mmol/L (140–200 mg/dL) HbA1c criteria for pre-diabetes vary. The National Institute for Health and Care Excellence (NICE) guidelines (UK) recommend considering an HbA1c range of 42–47 mmol/mol to be indicative of pre-diabetes; the American Diabetes Association (ADA) guidelines suggest a range of 39–47 mmol/mol. The ADA also suggests a lower fasting plasma glucose limit of ≥ 5.6 mmol/L (100 mg/dL) for impaired fasting glucose.

Investigations • 727

approximately 85% of newly diagnosed type 1 diabetes. Some laboratories now include anti-ZnT8 antibodies in their panel of tests, which increases sensitivity for type 1 diabetes to 92%. C-peptide C-peptide is the connecting peptide that is cleaved in the production of insulin from pro-insulin (see Fig. 20.4). It can be readily measured in blood and urine by sensitive immunoassays. Serum C-peptide is a marker of endogenous insulin secretion (a synthetic insulin does not contain C-peptide) and is particularly useful if a patient is on exogenous (injected) insulin treatment, when insulin assays would simply detect the injected insulin. Serum C-peptide can help clarify the differential diagnosis of diabetes, as it is usually very low in long-standing type 1 diabetes and very high in severe insulin resistance. It is also useful in the diagnosis of spontaneous hypoglycaemia (p. 676). Urine protein Standard urine dipstick testing for albumin detects urinary albumin at concentrations above 300 mg/L, but smaller amounts (microalbuminuria; see Box 15.9, p. 394) can only be measured using specific albumin dipsticks or quantitative biochemical laboratory tests. Microalbuminuria or proteinuria, in the absence of urinary tract infection, is an important indicator of diabetic nephropathy and/or increased risk of macrovascular disease (p. 757). Establishing the diagnosis of diabetes Glycaemia can be classified into three categories: normal, impaired (pre-diabetes) and diabetes (see Box 20.2). The glycaemia cut-off that defines diabetes is based on the level above which there is a significant risk of microvascular complications (retinopathy, nephropathy and neuropathy). People categorised as having pre-diabetes have blood glucose levels that carry a negligible risk of microvascular complications but are at increased risk of developing diabetes. Also, because there is a continuous risk of macrovascular disease (atheroma of large conduit blood vessels) with increasing glycaemia in the population, people with pre-diabetes have an increased risk of cardiovascular disease (myocardial infarction, stroke and peripheral vascular disease). The traditional way to diagnose diabetes or pre-diabetes has been by using random or fasting plasma glucose and/or an oral glucose tolerance test (OGTT). In 2011, the World Health Organisation (WHO) advocated the use of glycated haemoglobin (HbA1c, see above) to diagnose diabetes and this has been adopted in some regions. When a person has symptoms of diabetes, the diagnosis can be confirmed with either a fasting glucose of ≥ 7.0 mmol/L (126 mg/dL) or a random glucose of ≥ 11.1 mmol/L (200 mg/dL) (see Box 20.2). Asymptomatic individuals should have a second confirmatory test. Diabetes should not be diagnosed on capillary blood glucose results. Alternatively, an HbA1c of ≥ 48 mmol/mol is also diagnostic of diabetes. As HbA1c reflects the last 2–3 months of glycaemia, it should not be used to diagnose diabetes where the duration of onset is short, i.e. in someone with suspected type 1 diabetes or severe symptomatic hyperglycaemia (p. 734). If there is a high clinical suspicion of diabetes with an HbA1c of less than 48 mmol/ mol, then a fasting glucose measurement is required to rule out diabetes. It should be noted that the two populations identified using blood glucose and using HbA1c will not be identical, some laboratories may report glycated haemoglobin as total glycated haemoglobin (GHb), HbA1 or HbA1c. In most countries, HbA1c is the preferred measurement. The rate of formation of HbA1c is directly proportional to the ambient blood glucose concentration; a rise of 11 mmol/mol in HbA1c corresponds to an approximate average increase of 2 mmol/L (36 mg/dL) in blood glucose. Although HbA1c concentration reflects the integrated blood glucose control over the lifespan of erythrocytes (120 days), HbA1c is most sensitive to changes in glycaemic control occurring in the month before measurement. Various assay methods are used to measure HbA1c, but most laboratories have been reporting HbA1c values (as %) aligned with the reference range that was used in the Diabetes Control and Complications Trial (DCCT). To allow worldwide comparisons of HbA1c values, the International Federation of Clinical Chemistry and Laboratory Medicine (IFCC) has developed a standard method; IFCC-standardised HbA1c values are reported in mmol/mol. In 2011, many countries adopted the IFCC reference method (Box 20.5) and this is used throughout this textbook. HbA1c estimates may be erroneously diminished in anaemia or during pregnancy, and may be difficult to interpret with some assay methods in patients who have uraemia or a haemoglobinopathy. It is particularly important to be aware of this in some developing countries where nutritional deficiency is common, especially when an absolute cut-off point is used, e.g. in the diagnosis of diabetes. Islet autoantibodies As type 1 diabetes is a characterised by autoimmune destruction of the pancreatic β cells, it can be useful in the differential diagnosis of diabetes (see below) to establish evidence of such an autoimmune process. If islet autoantibodies are present at high titre, this can be supportive of a diagnosis of type 1 diabetes. The antibodies that are measured are directed against components of the islet and consist of antibodies to insulin, glutamic acid decarboxylase (GAD), protein tyrosine phosphatase-related proteins (IA-2) and the zinc transporter ZnT8. These antibodies can be detected in the general population; the level at which they are called positive does vary by laboratory but is usually at concentrations greater than the 95th centile or 97.5th centile of the general population. This means that pancreatic autoantibodies can be weakly positive in people who do not have type 1 diabetes. However, if anti-GAD and anti-IA-2 antibodies are measured together, they will be ‘positive’ (alone or in combination) in 20.5 Conversion between DCCT and IFCC units for HbA1c DCCT units (%) IFCC units (mmol/mol)

IFCC HbA1c (mmol/mol) = [DCCT HbA1c(%)−2.15] × 10.929 (DCCT = Diabetes Control and Complications Trial; IFCC = International Federation of Clinical Chemistry and Laboratory Medicine)

728 • DIABETES MELLITUS insulin-secreting β cells in the pancreatic islets. The natural history of type 1 diabetes is based on the model proposed by Eisenbarth in 1986, which proposed that genetically susceptible individuals with a given β-cell mass who were subsequently exposed to an environmental trigger then developed β-cell autoimmunity that led to progressive loss of β cells. This process was seen to take place over a prolonged period (months to years). Marked hyperglycaemia, accompanied by the classical symptoms of diabetes, occurs only when 80–90% of the functional capacity of β cells has been lost. More recent data have led to modifications of this model. For example, it is now recognised that pancreatic β cells can persist in some individuals with very long-standing diabetes and may never reach zero. On the contrary, some individuals present with much higher levels of β-cell viability (40–50%) and that may reflect lower levels of physical activity or increased body mass. Despite this uncertainty, in the natural history of type 1 diabetes there is initially a loss of first-phase insulin secretion, followed by a period of glucose intolerance and clinically undiagnosed diabetes. The pathology in the pre-diabetic pancreas is characterised by an inflammatory lesion within islets, ‘insulitis’ (Fig. 20.6), with infiltration of the islets by mononuclear cells containing activated macrophages, helper cytotoxic and suppressor T lymphocytes, natural killer cells and B lymphocytes. Initially, these lesions are patchy and, until a very late stage, lobules containing heavily infiltrated islets are seen adjacent to unaffected lobules. The destructive process is β-cell-specific. It is unclear why other hormone-secreting cells in the islets, such as α and δ cells, remain intact. In addition, while a number of theories such as molecular mimicry, oxidative stress and viral infections have been proposed, the specific mechanisms for inducing autoimmunity in type 1 diabetes are unknown. Autoimmunity in type 1 diabetes is identified by the presence of autoantibodies to islet and/or β-cell antigens. Islet cell antibodies can be present long before the clinical presentation of type 1 diabetes, and their detection can be useful in confirming a diagnosis of type 1 diabetes, but they are poorly predictive of disease progression and disappear over time (Fig. 20.6). Autoantibodies are typically present in 70–80% of newly diagnosed type 1 diabetes, but this can vary depending on age, gender and ethnicity, as well as quality of the assay employed. Autoantibodies can also be used to predict disease with a 5-year risk of type 1 diabetes of about 20–25% in people with a single positive autoantibody, 50–60% in those with two positive autoantibodies, and 70% in those with three autoantibodies. Type 1 diabetes is associated with other autoimmune disorders (Ch. 4), including thyroid disease (p. 638), coeliac disease (p. 805), Addison’s disease (p. 671), pernicious anaemia (p. 944) and vitiligo (p. 1257). The association between type 1 diabetes and coeliac disease is particularly strong; it is estimated that around 1 in 20 people with type 1 diabetes (especially when diagnosed in childhood) will have biopsy-proven coeliac disease and so many countries advocate routine screening for this condition. Genetic predisposition Although not showing a simple pattern of inheritance, type 1 diabetes is strongly influenced by genetic factors. The relationship is complex and, as indicated, multifactorial. Monozygotic twins have a disease concordance rate of 30–50%, while dizygotic twins have a concordance of 6–10%. In the USA, the risk of developing type 1 diabetes is 1 : 20 for those with a first-degree relative, compared with a 1 : 300 risk in the general population. Children of mothers with type 1 diabetes have a 1–4% risk of being diagnosed with diabetes using one criterion but not the other. When a person is asymptomatic and repeat testing is required, the same method should be used for the confirmatory test to avoid diagnostic confusion. Pre-diabetes can be subclassified as ‘impaired fasting glucose’ (IFG), based on a fasting plasma glucose result, or ‘impaired glucose tolerance’ (IGT), based on the fasting and 2-hour OGTT results (see Box 20.3). Patients with pre-diabetes should be advised of their risk of progression to diabetes, given advice about lifestyle modification to reduce this risk (as for type 2 diabetes, p. 743), and have aggressive management of cardiovascular risk factors such as hypertension and dyslipidaemia. The HbA1c criteria for pre-diabetes are less clear. The NICE guidelines (UK) suggest a range of 42–47 mmol/mol, whereas the American Diabetes Association guidelines recommend a range of 39–47 mmol/mol. In some people (especially those with pre-existing insulin resistance or low β-cell mass/function), an abnormal blood glucose result is observed during acute severe illness, such as infection or myocardial infarction. This ‘stress hyperglycaemia’ is a consequence of hormones, such as cortisol and catecholamines, antagonising the action of insulin and thereby increasing insulin resistance. It usually disappears after the acute illness has resolved, but affected individuals have a significantly increased risk of type 2 diabetes in subsequent years. A similar mechanism explains the occurrence of diabetes in some people treated with glucocorticoids (steroid-induced diabetes). The diagnostic criteria recommended for diabetes in pregnancy are more stringent than those for non-pregnant patients (see Box 20.31). Pregnant women with abnormal glucose tolerance should be referred urgently to a specialist unit for full evaluation. Due to the increased red cell turnover that occurs in pregnancy, an HbA1c test should not be used to diagnose diabetes in pregnancy When a diagnosis of diabetes is confirmed, other investigations should include plasma urea, creatinine and electrolytes, lipids, liver and thyroid function tests, blood or urine ketones, and urine protein. Aetiology and pathogenesis of diabetes In both of the common types of diabetes, environmental factors interact with genetic susceptibility to determine which people develop the clinical syndrome, and the timing of its onset. However, the underlying genes, precipitating environmental factors and pathophysiology differ substantially between type 1 and type 2 diabetes. Type 1 diabetes was previously termed ‘insulin-dependent diabetes mellitus’ (IDDM) and is invariably associated with insulin deficiency requiring replacement therapy. Type 2 diabetes was previously termed ‘non-insulin-dependent diabetes mellitus’ (NIDDM) because patients retain the capacity to secrete insulin, and measured insulin levels are often higher than those seen in people without diabetes. In type 2 diabetes, though, there is an impaired sensitivity to insulin (insulin resistance) and, initially, affected individuals can usually be treated without insulin replacement therapy. However, 20% or more of patients with type 2 diabetes will ultimately develop insulin deficiency requiring replacement therapy, so IDDM and NIDDM were misnomers. Type 1 diabetes Pathology Type 1 diabetes is generally considered a T-cell-mediated autoimmune disease (p. 81) involving destruction of the

Aetiology and pathogenesis of diabetes • 729

Environmental predisposition The wide geographical and seasonal variations in incidence, and the rapid acquisition of local disease incidence rates in migrants from low- to high-incidence countries suggest that environmental factors have an important role in precipitating disease. Although hypotheses abound, the nature of these environmental factors is unknown. They may trigger type 1 diabetes through direct toxicity to β cells or by stimulating an autoimmune reaction directed against β cells. Potential candidates fall into three main categories: viruses, specific drugs or chemicals, and dietary constituents. Viruses implicated in the aetiology of type 1 diabetes include mumps, Coxsackie B4, retroviruses, rubella (in utero), cytomegalovirus and Epstein–Barr virus. Various dietary nitrosamines (found in smoked and cured meats) and coffee have been proposed as potentially diabetogenic toxins. Bovine serum albumin (BSA), a major constituent of cow’s milk, has been implicated, since children who are given cow’s milk early in infancy are more likely to develop type 1 diabetes than those who are breastfed. BSA may cross the neonatal gut and raise antibodies that cross-react with a heat-shock protein expressed by β cells. It has also been proposed that reduced exposure to microorganisms in early childhood limits maturation of the immune system and increases susceptibility to autoimmune disease (the ‘hygiene hypothesis’). In addition, the high incidence rates in northern Europe have led to the suggestion that low levels of vitamin D may be important, but to date no clear cause–effect relationship has been identified. Metabolic disturbances in type 1 diabetes Patients with type 1 diabetes present when progressive β-cell destruction has crossed a threshold at which adequate insulin secretion and normal blood glucose levels can no longer be sustained. Above a certain level, high glucose levels may be toxic to the remaining β cells, so that profound insulin deficiency rapidly ensues, causing the metabolic sequelae shown in Figure 20.7. Hyperglycaemia leads to glycosuria and dehydration, causing fatigue, polyuria, nocturia, thirst and polydipsia, susceptibility to urinary and genital tract infections, and later tachycardia and hypotension. Unrestrained lipolysis and proteolysis result in developing type 1 diabetes, but children of fathers with type 1 diabetes have a 10% risk. Despite this genetic influence, 80–85% of new cases present in individuals with no known family history of the disease. The inheritance of type 1 diabetes is polygenic (Box 20.6), with over 20 different regions of the human genome showing an association with type 1 diabetes risk. Most interest has focused on the human leucocyte antigen (HLA) region within the major histocompatibility complex on the short arm of chromosome 6. The HLA haplotypes DR3 and/or DR4 are associated with increased susceptibility to type 1 diabetes in Caucasians and are in ‘linkage disequilibrium’, i.e. they tend to be transmitted together, with the neighbouring alleles of the HLA-DQA1 and DQB1 genes. The latter may be the main determinants of genetic susceptibility, since these HLA class II genes code for proteins on the surface of cells that present foreign and self-antigens to T lymphocytes (p. 82). Candidate gene and genome-wide association studies have also implicated other genes in type 1 diabetes, e.g. CD25, PTPN22, SH2B3, IL2RA and IL-10. Interestingly, the majority of these disease risk loci are involved in immune responsiveness, such as recognition of pancreatic islet antigens, T-cell development and immune regulation. The genes associated with type 1 diabetes overlap with those for other autoimmune disorders, such as coeliac disease and thyroid disease, consistent with clustering of these conditions in individuals or families. Fig. 20.6 Pathogenesis of type 1 diabetes. Proposed sequence of events in the development of type 1 diabetes. Environmental triggers are described in the text. Insets (normal islet, β-cell destruction) Courtesy of Dr A. Foulis, Dept of Pathology, University of Glasgow. Normal islet β-cell mass Environmental triggers Genetic susceptibility to immune dysfunction Inflammatory cell infiltration of islet Antibody-mediated β-cell destruction Autoantibodies present in blood Overt diabetes Loss of first-phase insulin secretion Impaired glucose tolerance Insulitis β-cell destruction Time 20.6 Risk of type 1 diabetes among first-degree relatives of patients with type 1 diabetes Relative with type 1 diabetes % overall risk Identical twin 30–50 Non-identical twin 6–10 HLA-identical sibling

Non-HLA-identical sibling

Father

Mother 1–4 Both parents Up to 30

730 • DIABETES MELLITUS Type 2 diabetes Pathology Type 2 diabetes is a diagnosis of exclusion, i.e. it is made when type 1 diabetes and other types of diabetes (see Box 20.9) are ruled out; it is highly heterogeneous. The natural history of typical type 2 diabetes is shown in Figure 20.8. Initially, insulin resistance leads to elevated insulin secretion in order to maintain normal blood glucose levels. However, in susceptible individuals, the pancreatic β cells are unable to sustain the increased demand for insulin and a slowly progressive insulin deficiency develops. Some patients develop diabetes at a young age, usually driven by insulin resistance due to obesity and ethnicity; others, particularly older patients, develop diabetes despite being non-obese and may have more pronounced β-cell failure. The key feature is a ‘relative’ insulin deficiency, such that there is insufficient insulin production to overcome the resistance to insulin action. This contrasts with type 1 diabetes, in which there is rapid loss of insulin production, resulting in ketoacidosis and death if the insulin is not replaced. Insulin resistance and the metabolic syndrome Type 2 diabetes and its pre-diabetes antecedents belong to a cluster of conditions thought to be caused by resistance to insulin action. Thus, people with type 2 diabetes often have associated disorders including hypertension, dyslipidaemia (characterised by elevated levels of small dense low-density lipoprotein (LDL) weight loss. Ketoacidosis occurs when generation of ketones exceeds the capacity for their metabolism. Elevated blood H+ ions drive K+ out of the intracellular compartment, while secondary hyperaldosteronism encourages urinary loss of K+. Thus patients usually present with a short history (typically a few weeks) of hyperglycaemic symptoms (thirst, polyuria, nocturia and fatigue), infections and weight loss, and may have developed ketoacidosis (p. 735). Type 1 diabetes in adults While type 1 diabetes is classically thought of as a disease of children and young adults (most commonly presenting between 5 and 7 years of age and at or near puberty), it can manifest at any age, with as much as half of cases thought to develop in adults. It is also possible for patients who have a more insidious onset of diabetes to have an autoimmune aetiology; these people are sometimes described as having slow-onset type 1 diabetes or latent autoimmune diabetes of adulthood (LADA). LADA is defined as the presence of islet autoantibodies in high titre (usually GAD antibodies), without rapid progression to insulin therapy (which would usually signify type 1 diabetes). Patients with LADA can often present and be managed similarly to those with type 2 diabetes, but they do progress more rapidly to requiring insulin treatment for glucose control. Not all expert committees recognise LADA as a diagnostic category, however, and consider LADA to be just a subset of autoimmune type 1 diabetes developing in adulthood. Fig. 20.7 Acute metabolic complications of insulin deficiency. (FFA = free fatty acid) ↓Glucose uptake and utilisation ↑Glycogenolysis Hyperglycaemia Glycosuria Osmotic diuresis Dehydration Hyperosmolarity Secondary hyperaldosteronism K+ deficiency ↑Gluconeogenesis ↑Lipolysis ↑Proteolysis ↑FFA and glycerol to liver ↓Renal function ↑Lactate ↑Ketogenesis Metabolic acidosis Insufficient insulin

Aetiology and pathogenesis of diabetes • 731

treatment of the diabetes but, despite this, some patients progress to non-alcoholic steatohepatitis (NASH, p. 882) and cirrhosis. Pancreatic β-cell failure In the early stages of type 2 diabetes, reduction in the total mass of pancreatic islet tissue is modest. At the time of diagnosis, around 50% of β-cell function has been lost and this declines progressively (Fig. 20.8B). Some pathological changes are typical of type 2 diabetes, the most consistent of which is deposition of amyloid in the islets. In addition, elevated plasma glucose and FFAs exert toxic effects on pancreatic β cells to impair insulin secretion. However, while β-cell numbers are reduced, β-cell mass is unchanged and glucagon secretion is increased, which may contribute to hyperglycaemia. Genetic predisposition Genetic factors are important in type 2 diabetes, as shown by marked differences in susceptibility in different ethnic groups and by studies in monozygotic twins where concordance rates for type 2 diabetes approach 100%. However, many genes are involved and the chance of developing diabetes is also influenced very powerfully by environmental factors (Box 20.7). Genome-wide association studies have identified over 70 genes cholesterol and triglycerides, and a low level of high-density lipoprotein (HDL) cholesterol), non-alcoholic fatty liver disease (p. 882) and, in women, polycystic ovarian syndrome. This cluster has been termed the ‘insulin resistance syndrome’ or ‘metabolic syndrome’, and is much more common in individuals who are obese. The primary cause of insulin resistance remains unclear; it is likely that there are multiple defects in insulin signalling, affecting several tissues. One theory is centred around the adipocyte; this is particularly appealing, as obesity is a major cause of increased insulin resistance. Intra-abdominal ‘central’ adipose tissue is metabolically active and releases large quantities of FFAs, which may induce insulin resistance because they compete with glucose as a fuel supply for oxidation in peripheral tissues such as muscle. In addition, adipose tissue releases a number of hormones (including a variety of peptides, called ‘adipokines’ because they are structurally similar to immunological ‘cytokines’) that act on specific receptors to influence sensitivity to insulin in other tissues. Because the venous drainage of visceral adipose tissue is into the portal vein, central obesity may have a particularly potent influence on insulin sensitivity in the liver, and thereby adversely affect gluconeogenesis and hepatic lipid metabolism. Physical activity is another important determinant of insulin sensitivity. Inactivity is associated with down-regulation of insulin-sensitive kinases and may promote accumulation of FFAs within skeletal muscle. Sedentary people are therefore more insulin-resistant than active people with the same degree of obesity. Moreover, physical activity allows non-insulin-dependent glucose uptake into muscle, reducing the ‘demand’ on the pancreatic β cells to produce insulin. Deposition of fat in the liver is a common association with central obesity and is exacerbated by insulin resistance and/or deficiency. Many people with type 2 diabetes have evidence of fatty infiltration of the liver (non-alcoholic fatty liver disease, NAFLD). This condition may improve with effective Fig. 20.8 Natural history of type 2 diabetes. A In the early stage of the disorder, the response to progressive insulin resistance is an increase in insulin secretion by the pancreatic cells, causing hyperinsulinaemia. Eventually, the β cells are unable to compensate adequately and blood glucose rises, producing hyperglycaemia. With further β-cell failure, glycaemic control deteriorates and treatment requirements escalate. B Progressive pancreatic β-cell failure in patients with type 2 diabetes in the United Kingdom Prospective Diabetes Study (UKPDS). Beta-cell function was estimated using the homeostasis model assessment (HOMA) and was already below 50% at the time of diagnosis. Thereafter, long-term incremental increases in fasting plasma glucose were accompanied by progressive β-cell dysfunction. If the slope of this progression is extrapolated, it appears that pancreatic dysfunction may have been developing for many years before diagnosis of diabetes. B, Adapted from Holman RR. Diabetes Res Clin Pract 1998; 40 (Suppl.):S21–S25. Impaired glucose tolerance Type 2 diabetes Hyperinsulinaemia Normal Time Plasma glucose

β-cell function (%)

−10 −8 −6 −4 −2 Start of treatment Years

Plasma insulin Deteriorating β-cell function Increasing insulin resistance with age, obesity etc. Euglycaemia Dietcontrolled Antidiabetic drugs Insulin A B 20.7 Risk of developing type 2 diabetes for siblings of individuals with type 2 diabetes Age at onset of type 2 diabetes in proband (years) Age-corrected risk of type 2 diabetes for siblings (%) 25–44

45–54

55–64

65–80

732 • DIABETES MELLITUS Ethnicity Ethnic origin is a major risk factor for development of diabetes. For example, within the USA, the prevalence of diabetes is lowest in Alaskan Natives at 5.5%, moderate for non-Hispanic whites at 7.1%, high for non-Hispanic blacks at 13% and highest in Native Americans at 33%. This considerable variation in prevalence reflects a number of different factors, including a higher BMI and lower socioeconomic class in high-risk groups in the USA; differences in health behaviour, e.g. decreased physical activity and increased smoking; and differences in genetic risk. Studies in high-risk ethnic groups largely demonstrate increased insulin resistance and more central/visceral adiposity than in the lower-risk groups. Metabolic disturbances in type 2 diabetes Patients with type 2 diabetes have a slow onset of ‘relative’ insulin deficiency. Relatively small amounts of insulin are required to suppress lipolysis, and some glucose uptake is maintained in muscle so that, in contrast to type 1 diabetes, lipolysis and proteolysis are not unrestrained and weight loss and ketoacidosis seldom occur. In type 2 diabetes, hyperglycaemia tends to develop slowly over months or years; because of this insidious onset many cases of type 2 diabetes are discovered coincidentally and a large number are undetected. At diagnosis, patients are often asymptomatic or give a long history (typically many months) of fatigue, with or without ‘osmotic symptoms’ (thirst and polyuria). However, there are some people with type 2 diabetes who present acutely with marked osmotic symptoms and weight loss. These may be presenting late, such that they have already developed β-cell failure, but more usually this decompensation reflects a vicious spiral of decline. As hyperglycaemia worsens, patients often crave sugar and will consume large volumes of sugary drinks to try to quench their thirst; worsening hyperglycaemia is also associated with increasing lipolysis, and the high circulating glucose and FFAs are toxic to the β cell, resulting in ‘glucolipotoxicity’ and reduced β-cell function. In these patients, ketosis and even DKA can occur; this is classically described in the African American population, where up to half of patients who present with DKA have type 2 diabetes and not type 1 diabetes. The presentation of DKA in type 2 diabetes is referred to as ‘ketosis-prone’ diabetes or ‘Flatbush syndrome’, named after the Flatbush neighbourhood of New York, which had a large Caribbean population and where presentation with DKA was common. Importantly in these patients, insulin treatment is required initially but, as the glucose and lipids are controlled, the β cells recover, and they can usually transfer off insulin and on to oral treatments such as metformin after 3 months of insulin treatment. Intercurrent illness, e.g. with infections, increases the production of stress hormones that oppose insulin action, such as cortisol, growth hormone and catecholamines. This can precipitate an acute exacerbation of insulin resistance and insulin deficiency, and result in more severe hyperglycaemia and dehydration (p. 738). Other forms of diabetes Other causes of diabetes are shown in Box 20.9. These can broadly be broken down into genetic disorders including monogenic diabetes (diabetes due to a mutation in or deletion of a single gene) or diabetes as part of a genetic syndrome; endocrine disorders due to excess in hormones that oppose or gene regions that are associated with type 2 diabetes, each exerting a small effect. Most of the genes known to contribute to risk of type 2 diabetes are involved in β-cell function or in regulation of cell cycling and turnover, suggesting that altered regulation of β-cell mass is a key factor. The largest population genetic effect described to date is seen with variation in TCF7L2; the 10% of the population with two copies of the risk variant for this gene have a nearly twofold increase in risk of developing type 2 diabetes. In general, other common variants explain much lower risk than this, many explaining less than a 10% increase in risk only; as only about 10% of the genetic variance in type 2 diabetes is explained by these common genetic variants, this has led some to question the relevance of finding diabetes genes. However, it should be noted that, within a population, the distribution of risk variants will vary, with some patients having inherited a high genetic burden (e.g. more than 40 risk variants) and others having inherited very few. When studies compare those in the top 20% of this risk band with the lowest 20%, those at highest risk are over 2.5 times more likely to develop diabetes. More recent insights into the genetics of type 2 diabetes have highlighted how some genetic variants may be rare and therefore affect only a small proportion of the population, but have large clinical effects. For example, in a Greenlandic population, 3% of people carry a homozygous variant in an insulin signalling gene, TBC1D4, that results in muscle insulin resistance; these individuals are over 10 times more likely to develop type 2 diabetes. Environmental and other risk factors Diet and obesity Epidemiological studies show that type 2 diabetes is associated with overeating, especially when combined with obesity and under-activity. Middle-aged people with diabetes eat significantly more and are fatter and less active than their non-diabetic siblings. The risk of developing type 2 diabetes increases 10-fold in people with a body mass index (BMI) of more than 30 kg/m2 (p. 698). However, although the majority of individuals with type 2 diabetes are obese, only a minority of obese people develop diabetes, as most obese people are able to increase insulin secretion to compensate for the increased demand resulting from obesity and insulin resistance. Those who develop diabetes may have genetically impaired β-cell function, reduced β-cell mass, or a susceptibility of β cells to attack by toxic substances such as FFAs or inflammatory cytokines. Age Type 2 diabetes is more common in middle-aged and older individuals (Box 20.8). In the UK, it affects 10% of the population over 65, and over 70% of all cases of diabetes occur after the age of 50 years. 20.8 Diagnosis of diabetes mellitus in old age • Prevalence: increases with age, affecting ~10% of people over 65 years. Half of these are undiagnosed. Impaired β-cell function and exaggerated insulin resistance with ageing both contribute. • Glycosuria: the renal threshold for glucose rises with age, so glycosuria may not develop until the blood glucose concentration is markedly raised. • Pancreatic carcinoma: may present in old age with the development of diabetes, in association with weight loss and diminished appetite.

Aetiology and pathogenesis of diabetes • 733

Monogenic diabetes Monogenic diabetes accounts for approximately 4% of diabetes in those diagnosed under the age of 30 in the UK. While there are a number of monogenic disorders of insulin action, the most common monogenic forms of diabetes are caused by defects in insulin secretion, in part because insulin resistance alone is not sufficient to cause diabetes. Monogenic disorders of the β cell cause two diabetes subtypes: maturity-onset diabetes of the young (MODY; Box 20.10) and neonatal diabetes. The common genes involved in MODY and neonatal diabetes are shown in Figure 20.2C. MODY is defined as non-insulin-requiring diabetes that develops under the age of 25 years in one family member. MODY is dominantly inherited (p. 46), which means that the diabetes runs in families, many having a family history of diabetes spanning three generations or more. MODY itself is a heterogeneous condition, with multiple subtypes. One form is caused by mutations in glucokinase (see Fig. 20.2B); this is the pancreatic glucose sensor and patients with glucokinase mutations have an altered set-point for glucose. This results in a high fasting glucose (usually

5.5 mmol/L (99 mg/dL)) but a normal post-prandial response. As a result, patients with glucokinase MODY have stable, mild hyperglycaemia, with only a slightly elevated HbA1c; they do not require treatment and do not develop diabetes complications. It is therefore important to identify these patients, to avoid unnecessary diabetes treatment and monitoring. The other forms of MODY are mostly caused by defective transcription factors that play a key role in pancreatic β-cell development and function (hepatocyte nuclear factor (HNF) 1α, 1β and 4α). Patients with transcription factor MODY develop diabetes in adolescence or early adulthood and the diabetes is progressive, requiring oral diabetes treatment before eventually needing insulin. Patients with HNF1α and 4α MODY are extremely sensitive to sulphonylureas and this is the treatment of choice for these individuals. HNF1β is a critical transcription factor not only in pancreatic development but also in renal and genital tract development in utero. Patients with HNF1β mutations usually have renal abnormalities, including renal cystic disease and genital tract malformation, such as absent or bicornuate uterus or hypospadias and infertility; about 50% of individuals with the gene mutation have young-onset diabetes. 20.10 Monogenic diabetes mellitus: maturity-onset diabetes of the young (MODY) Functional defect Main type* Gene mutated* β-cell glucose sensing MODY2 GCK The set point for basal insulin release is altered, causing a high fasting glucose, but sufficient insulin is released after meals. As a result, the HbA1c is often normal and microvascular complications are rare. Treatment is rarely required β-cell transcriptional regulation MODY3 HNF1α MODY5 HNF1β MODY1 HNF4α Diabetes develops during adolescence/early adulthood and can be managed with diet and tablets for many years, but ultimately, insulin treatment is required. The HNF1α and 4α forms respond particularly well to sulphonylurea drugs. All types are associated with microvascular complications. HNF1β mutations also cause renal cysts and renal failure *Other gene mutations have been found in rare cases. For further information, see diabetesgenes.org. 20.9 Aetiological classification of diabetes mellitus Type 1 diabetes • Immune-mediated • Idiopathic Type 2 diabetes Other specific types • Genetic defects of β-cell function (see Box 20.10) • Genetic defects of insulin action (e.g. leprechaunism, lipodystrophies) • Pancreatic disease (e.g. pancreatitis, pancreatectomy, neoplastic disease, cystic fibrosis, haemochromatosis, fibrocalculous pancreatopathy) • Excess endogenous production of hormonal antagonists to insulin, e.g.: Growth hormone – acromegaly Glucocorticoids – Cushing’s syndrome Glucagon – glucagonoma Catecholamines – phaeochromocytoma Thyroid hormones – thyrotoxicosis • Drug-induced (e.g. glucocorticoids, thiazide diuretics, phenytoin) • Uncommon forms of immune-mediated diabetes (e.g. IPEX syndrome) • Associated with genetic syndromes (e.g. Down’s syndrome, Klinefelter’s syndrome, Turner’s syndrome, DIDMOAD (Wolfram’s syndrome), Friedreich’s ataxia, myotonic dystrophy) Gestational diabetes (DIDMOAD = diabetes insipidus, diabetes mellitus, optic atrophy, nerve deafness; IPEX = immunodysregulation polyendocrinopathy X) the effects of insulin (Ch. 18); and more generalised diseases of the pancreas. Pancreatic disease Pancreatic disease is a relatively common but often unrecognised cause of diabetes, largely related to alcohol excess. Alcohol excess can cause recurrent bouts of acute pancreatitis, with progressive destruction of the pancreas and subsequent diabetes. However, more commonly, chronic alcohol excess can be linked to chronic pancreatitis, which is then termed alcoholic chronic pancreatitis. Although this is associated with recurrent abdominal pain, it is asymptomatic in many patients, resulting in both pancreatic exocrine failure and endocrine failure. While diabetes due to pancreatic insufficiency secondary to alcohol excess can be managed with oral therapy, the insulin deficiency usually requires insulin replacement therapy. In some geographical regions, there is a form of chronic calcific pancreatitis that is not caused by alcohol excess and causes diabetes to present in adolescence or early adulthood; this condition is called fibrocalculous pancreatic diabetes (FCPD). It is characteristically a disease of the tropics, with variable prevalence across these regions. The aetiology of FCPD is poorly understood. While there is thought to be a genetic predisposition, with mutations in SPINK1 being described, it is usually seen in malnourished individuals, but it is not clear whether this is a cause or consequence of the disease. FCPD usually presents with recurrent severe abdominal pain in childhood, diabetes developing 10–20 years later; there is a 100-fold increased risk of pancreatic cancer in later life. Insulin treatment is usually required at or soon after diagnosis.

734 • DIABETES MELLITUS Presenting problems in diabetes mellitus Hyperglycaemia The diagnosis of diabetes is simple: it is based on confirmation of hyperglycaemia using either fasting or random glucose, an OGTT or HbA1c (p. 727). Diabetes, however, results from a variety of pathological processes, meaning that within this broad category are many aetiological subtypes. Following the identification of hyperglycaemia and subsequent diagnosis of diabetes, the initial management involves a careful clinical assessment of the patient to decide whether immediate treatment is required and, with appropriate investigation, to establish the aetiology of the diabetes, as this will determine subsequent diabetes treatment (Fig. 20.9). The main differential diagnosis to consider is that of type 1 or type 2 diabetes; making a diagnosis of type 1 diabetes is important, as a failure to initiate insulin treatment can result in Neonatal diabetes is variably defined as diabetes that presents in the neonatal period, although this is usually extended to the first 6 months of life. The presentation is usually that of profound insulin deficiency with marked hyperglycaemia and DKA. Approximately half of patients with neonatal diabetes have a transient form that remits by about 1 year of age, with diabetes recurring in adolescence or early adulthood; the remaining patients have permanent neonatal diabetes. In recent years, the genetics of neonatal diabetes have been unravelled, having a major positive impact for people with this condition. Approximately two-thirds of patients with permanent neonatal diabetes have an activating mutation in the genes encoding the KIR6.2 and SUR1 subunits of the KATP channel (see Fig. 20.2C). These mutations cause the KATP channel to be insensitive to the glucose-mediated rise in intracellular ATP; as a result, the pancreatic β cells do not secrete insulin and patients require insulin treatment from soon after birth. It has been shown, however, that these individuals do respond to sulphonylureas; this finding has transformed their care, over 90% being managed with oral sulphonylurea treatment. Fig. 20.9 New-onset hyperglycaemia. (DKA = diabetic ketoacidosis; GAD = glutamic acid decarboxylase; HHS = hyperosmotic hyperglycaemic state; IA-2 = islet antigen 2; IV = intravenous; SC = subcutaneous) New-onset hyperglycaemia Confirm diagnosis of diabetes (Box 20.2) Patient unwell and/or Marked symptoms of hyperglycaemia and/or Blood ketones elevated Intercurrent illness; dehydration HHS Box 20.17 DKA Box 20.16 Commence IV insulin and fluids Continue on SC insulin Continue on insulin Evaluate aetiology of diabetes* Likely type 1 diabetes Typical type 1 diabetes? Not overweight No family history of diabetes GAD/IA-2 antibody-positive Low C-peptide Other types? Chronic pancreatitis/abdominal pain – consider alcohol-related or pancreatic malignancy Features of endocrine disease? Abnormal liver function – consider haemochromatosis Three-generation family history – consider monogenic diabetes Renal and urinary tract abnormalities – consider HNF1β Typical type 2 diabetes? Obese or overweight Aged over 40 Family history of diabetes Ethnicity high diabetes risk GAD/IA-2 antibody-negative Elevated C-peptide No other cause Consider introducing oral agents and weaning insulin (careful monitoring required) Likely type 2 diabetes No underlying cause Patient well Commence SC insulin Refer for immediate assessment Evaluate for DKA/HHS and intercurrent illness – see emergency management Probable type 2 diabetes? Possible type 1 diabetes? Self-monitoring of blood glucose and ketones Low threshold to start SC insulin Evaluate aetiology of diabetes* *Evaluation of diabetes aetiology Manage according to diabetes aetiology Diet and lifestyle modification Early initiation of metformin Patient not unwell and Mild or no symptoms of hyperglycaemia and Blood ketones not elevated

Presenting problems in diabetes mellitus • 735

Sometimes the definitive classification of the type of diabetes is only made later, once the natural history or responsiveness to different therapies becomes apparent. Physical signs in patients with type 2 diabetes at diagnosis depend on the mode of presentation. In Western populations, more than 80% are overweight and the obesity is often central (truncal or abdominal). Obesity is much less evident in Asians. Hypertension is present in at least 50% of patients with type 2 diabetes. Although dyslipidaemia is also common, skin lesions such as xanthelasma and eruptive xanthomas are rare. Presentation with the complications of diabetes Patients with long-standing diabetes are at risk of developing a variety of complications (see Box 20.35, p. 756) and as many as 25% of people with type 2 diabetes have evidence of diabetic complications at the time of diagnosis. Thus, diabetes may be first suspected when a patient visits an optometrist or podiatrist, or presents with hypertension or a vascular event such as an acute myocardial infarction or stroke. Blood glucose should therefore be checked in all patients presenting with such pathology. The detailed investigation and management of diabetic complications are described on page 755. Diabetes emergencies Diabetic ketoacidosis Diabetic ketoacidosis (DKA) is a medical emergency and remains a serious cause of morbidity, principally in people with type 1 diabetes. Mortality is low in the UK (approximately 2%) but remains high in developing countries and among non-hospitalised patients. Mortality in DKA is most commonly caused in children and adolescents by cerebral oedema, and in adults by hypokalaemia, acute respiratory distress syndrome and comorbid conditions such as acute myocardial infarction, sepsis or pneumonia. DKA is characteristic of type 1 diabetes (see Box 20.12) and is often the presenting problem in newly diagnosed patients. However, an increasing number of patients presenting with DKA have underlying type 2 diabetes. This appears to be particularly prevalent in black and non-Hispanic populations. In established type 1 diabetes, DKA may be precipitated by an intercurrent illness because of failure to increase insulin dose appropriately to compensate for the stress response. Sometimes, there is no evidence of a precipitating infection and DKA develops because of errors in self-management. In young patients with recurrent episodes of DKA, up to 20% may have psychological problems complicated by eating disorders. Pathogenesis A clear understanding of the biochemical basis and pathophysiology of DKA is essential for its efficient treatment (see Fig. 20.7). The cardinal biochemical features are: • hyperketonaemia (≥ 3.0 mmol/L) or ketonuria (more than 2+ on standard urine sticks) • hyperglycaemia (blood glucose ≥ 11 mmol/L (approximately 200 mg/dL)) • metabolic acidosis (venous bicarbonate < 15 mmol/L and/ or venous pH < 7.3 (H+ > 50 nmol/L)). The hyperglycaemia causes a profound osmotic diuresis leading to dehydration and electrolyte loss, particularly of the development of DKA and death. If the aetiological diagnosis is in doubt, it is important not to delay insulin treatment, which can be withdrawn subsequently if necessary. Hyperglycaemia causes a wide variety of symptoms (Box 20.11). The classical clinical features of type 1 and type 2 diabetes are compared in Box 20.12. Symptoms of polydipsia, polyuria, nocturia and rapid weight loss are prominent in type 1 diabetes but are often absent in patients with type 2 diabetes, many of whom are asymptomatic or have non-specific complaints such as chronic fatigue and malaise. Uncontrolled diabetes is associated with an increased susceptibility to infection and patients may present with skin sepsis (boils) or genital candidiasis, and complain of pruritus vulvae or balanitis. While the distinction between type 1 and type 2 diabetes is usually obvious, overlap occurs, particularly in age at onset, duration of symptoms and family history. There are many patients in whom the type of diabetes is not immediately apparent. For example, patients with type 2 diabetes may present with marked and rapid weight loss and even DKA (10–15% of all cases of DKA), and type 2 diabetes is increasingly diagnosed in children and young adults. Type 1 diabetes can occur at any age, not just in younger people, and may develop more insidiously; the presence of pancreatic autoantibodies confirms the diagnosis of slow-onset type 1 diabetes or LADA. Islet autoantibodies are detectable at high titre in many patients with type 1 diabetes, so a negative result should prompt consideration of other aetiologies. Other causes of diabetes (see Box 20.9), such as MODY, should not be forgotten, particularly in those presenting in childhood or as young adults. A history of pancreatic disease, particularly in patients with a history of alcohol excess, makes insulin deficiency more likely. 20.12 Classical features of type 1 and type 2 diabetes Type 1 Type 2 Typical age at onset < 40 years

50 years Duration of symptoms Weeks Months to years Body weight Normal or low Obese Ketonuria Yes No Rapid death without treatment with insulin Yes No Autoantibodies Positive in 80–90% Negative Diabetic complications at diagnosis No 25% Family history of diabetes Uncommon Common Other autoimmune disease Common Uncommon 20.11 Symptoms of hyperglycaemia • Thirst, dry mouth • Polyuria • Nocturia • Tiredness, fatigue, lethargy • Change in weight (usually weight loss) • Blurring of vision • Pruritus vulvae, balanitis (genital candidiasis) • Nausea • Headache • Hyperphagia; predilection for sweet foods • Mood change, irritability, difficulty in concentrating, apathy

736 • DIABETES MELLITUS water depletion, with loss of skin turgor, furred tongue and cracked lips, tachycardia, hypotension and reduced intra-ocular pressure. Breathing may be deep and sighing (Kussmaul’s sign), the breath is usually fetid, and the sickly-sweet smell of acetone may be apparent. Mental apathy, delirium or a reduced conscious level may be present, although coma is uncommon. Indeed, a patient with dangerous ketoacidosis requiring urgent treatment may walk into the consulting room. For this reason, the term ‘diabetic ketoacidosis’ is to be preferred to ‘diabetic coma’, which implies that there is no urgency until unconsciousness supervenes. In fact, it is imperative that energetic treatment is started at the earliest possible stage. Abdominal pain is sometimes a feature of DKA, particularly in children, and vomiting is common. Serum amylase may be elevated but rarely indicates coexisting pancreatitis. In infected patients, pyrexia may not be present initially because of vasodilatation secondary to acidosis. Investigations The following investigations are important but should not delay the institution of intravenous fluid and insulin replacement: • Venous blood: for urea and electrolytes, glucose, bicarbonate and acid–base status (venous blood can be used in portable and fixed blood gas analysers, and differences between venous and arterial pH and bicarbonate are minor). • Urine or blood analysis for ketones (p. 726). • Electrocardiogram (ECG). • Infection screen: full blood count, blood and urine culture, C-reactive protein, chest X-ray. Although leucocytosis invariably occurs in DKA, this represents a stress response and does not necessarily indicate infection. Assessment of severity The presence of one or more of the features listed in Box 20.15 is indicative of severe DKA. Management DKA is a medical emergency that should be treated in hospital, preferably in a high-dependency area. If available, the diabetes specialist team should be involved. Regular clinical and biochemical review is essential, particularly during the first 24 hours of treatment. Guidelines for the management of DKA are shown in Box 20.16. Early specialist involvement is recommended for high-risk groups such as older people, young adults (18–25 years), pregnant women, and those with heart or kidney failure or other serious comorbidities. sodium and potassium. Potassium loss is exacerbated by secondary hyperaldosteronism as a result of reduced renal perfusion. Ketosis stems from insulin deficiency, exacerbated by elevated catecholamines and other stress hormones, leading to unrestrained lipolysis and supply of FFAs for hepatic ketogenesis. When this exceeds the capacity to metabolise acidic ketones, these accumulate in blood. The resulting metabolic acidosis forces hydrogen ions into cells, displacing potassium ions. The average loss of fluid and electrolytes in moderately severe DKA in an adult is shown in Box 20.13. About half the deficit of total body water is derived from the intracellular compartment and occurs comparatively early in the development of acidosis with relatively few clinical features; the remainder represents loss of extracellular fluid sustained largely in the later stages, when marked contraction of extracellular fluid volume occurs, with haemoconcentration, a decreased blood volume, and finally a fall in blood pressure with associated renal ischaemia and oliguria. Every patient in DKA is potassium-depleted but the plasma concentration of potassium gives very little indication of the total body deficit. Plasma potassium may even be raised initially due to disproportionate loss of water, catabolism of protein and glycogen, and displacement of potassium from the intracellular compartment by H+ ions. However, soon after treatment is started, there is likely to be a precipitous fall in the plasma potassium due to dilution of extracellular potassium by administration of intravenous fluids, the movement of potassium into cells induced by insulin, and the continuing renal loss of potassium. The magnitude of the hyperglycaemia does not correlate with the severity of the metabolic acidosis; moderate elevation of blood glucose may be associated with life-threatening ketoacidosis. Type 1 diabetes in pregnancy is one situation where DKA can occur with blood glucose levels that are not especially high. Conversely, in other situations, hyperglycaemia predominates and acidosis is minimal, with patients presenting in a hyperosmolar state (p. 738). Clinical assessment The clinical features of ketoacidosis are listed in Box 20.14. In the fulminating case, the striking features are those of salt and 20.14 Clinical features of diabetic ketoacidosis Symptoms • Polyuria, thirst • Weight loss • Weakness • Nausea, vomiting • Leg cramps • Blurred vision • Abdominal pain Signs • Dehydration • Hypotension (postural or supine) • Cold extremities/peripheral cyanosis • Tachycardia • Air hunger (Kussmaul breathing) • Smell of acetone • Hypothermia • Delirium, drowsiness, coma (10%) 20.13 Average loss of fluid and electrolytes in adult diabetic ketoacidosis of moderate severity • Water: 6 L 3 L extracellular • Sodium: 500 mmol – replace with saline • Chloride: 400 mmol 3 L intracellular • Potassium: 350 mmol – replace with dextrose } 20.15 Indicators of severe diabetic ketoacidosis • Blood ketones > 6 mmol/L • Bicarbonate < 5 mmol/L • Venous/arterial pH < 7.0 (H+ > 100 nmol/L) • Hypokalaemia on admission (< 3.5 mmol/L) • Glasgow Coma Scale score < 12 (p. 194) or abnormal AVPU scale score (p. 188) • O2 saturation < 92% on air • Systolic blood pressure < 90 mmHg • Heart rate > 100 or < 60 beats per minute • Anion gap > 16 mmol/L

Presenting problems in diabetes mellitus • 737

Insulin A fixed-rate intravenous insulin infusion of 0.1 U/kg body weight/ hr is recommended (Box 20.16). Exceptionally, if intravenous administration is not feasible, soluble insulin can be given by intramuscular injection (loading dose of 10–20 U, followed by 5 U hourly), or a fast-acting insulin analogue can be given hourly by subcutaneous injection (initially 0.3 U/kg body weight, then 0.1 U/kg hourly). The blood glucose concentration should fall by 3–6 mmol/L (approximately 55–110 mg/dL) per hour, or blood ketone concentrations fall by at least 0.5 mmol/L/hr. A more rapid decrease in blood glucose should be avoided, as this might precipitate hypoglycaemia and the serious complication of cerebral oedema, particularly in children. Failure of blood glucose to fall within 1 hour of commencing insulin infusion should lead to a re-assessment of insulin dose. Ketosis, dehydration, acidaemia, infection and stress combine to produce severe insulin resistance in some cases, but most will respond to a low-dose insulin regimen. When the blood glucose has fallen, 10% dextrose infusion is introduced and insulin infusion continued to encourage glucose uptake into cells and restoration of normal metabolism. In recent years, it has also become increasingly common to continue with the use of long-acting insulin analogues administered subcutaneously during the initial management of DKA; this provides background insulin for when the intravenous insulin is discontinued, to reduce the risk of in-hospital DKA. Restoration of the usual insulin regimen, by subcutaneous injection, should not be instituted until the patient is both biochemically stable and able to eat and drink normally. Fluid replacement In adults, rapid fluid replacement in the first few hours is usually recommended (Box 20.16). Caution is advised in children and young adults because of the risk of cerebral oedema. Most guidelines favour correction of the extracellular fluid deficit with isotonic saline (0.9% sodium chloride). If the plasma sodium is greater than 155 mmol/L, 0.45% saline may be used initially. Introduction of 10% glucose is recommended when the blood glucose falls below 14 mmol/L (252 mg/dL). The 0.9% saline infusion should be continued to correct circulating volume so both glucose and saline infusions are used concurrently. Time: 0–60 mins • Establish IV access, assess patient and perform initial investigations • Commence 0.9% sodium chloride: If systolic BP > 90 mmHg, give 1 L over 60 mins If systolic BP < 90 mmHg, give 500 mL over 10–15 mins, then re-assess; if BP remains < 90 mmHg, repeat and seek senior review • Commence insulin treatment: 50 U human soluble insulin in 50 mL 0.9% sodium chloride infused intravenously at 0.1 U/kg body weight/hr Continue with SC basal insulin analogue if usually taken by patient • Perform further investigations: see text • Establish monitoring schedule: Hourly capillary blood glucose and ketone testing Venous bicarbonate and potassium after 1 and 2 hrs, then every 2 hrs for first 6 hrs Plasma electrolytes every 4 hrs Clinical monitoring of O2 saturation, pulse, BP, respiratory rate and urine output every hour • Treat any precipitating cause Time: 60 mins to 6 hrs • IV infusion of 0.9% sodium chloride with potassium chloride added as indicated below: 1 L over 2 hrs 1 L over 2 hrs 1 L over 4 hrs 1 L over 4 hrs 1 L over 6 hrs • Add 10% glucose 125 mL/hr IV when glucose < 14 mmol/L (252 mg/dL) • Be more cautious with fluid replacement in older or young people, pregnant patients and those with renal or heart failure; if plasma sodium is > 155 mmol/L, 0.45% sodium chloride may be used • Adjust potassium chloride infusion: Plasma potassium (mmol/L) Potassium replacement (mmol/L of infusion)

5.5 Nil 3.5–5.5

< 3.5 Senior review – additional potassium required Time: 6–12 hrs • Clinical status, glucose, ketonaemia and acidosis should be improving; request senior review if not • Continue IV fluid replacement • Continue insulin administration • Assess for complications of treatment (fluid overload, cerebral oedema) • Avoid hypoglycaemia Time: 12–24 hrs • By 24 hrs, ketonaemia and acidosis should have resolved (blood ketones < 0.3 mmol/L, venous bicarbonate > 18 mmol/L) • If patient is not eating and drinking: Continue IV insulin infusion at lower rate of 2–3 U/hr Continue IV fluid replacement and biochemical monitoring • If ketoacidosis has resolved and patient is able to eat and drink: Re-initiate SC insulin with advice from diabetes team; do not discontinue IV insulin until 30 mins after SC short-acting insulin injection Additional procedures • Consider urinary catheterisation if anuric after 3 hrs or incontinent • Insert nasogastric tube if obtunded or there is persistent vomiting • Insert central venous line if cardiovascular system is compromised, to allow fluid replacement to be adjusted accurately; also consider in older patients, pregnant women, renal or cardiac failure, other serious comorbidities and severe DKA • Measure arterial blood gases; repeat chest X-ray if O2 saturation < 92% • Institute ECG monitoring in severe cases • Give thromboprophylaxis with low-molecular-weight heparin Adapted from Joint British Diabetes Societies Inpatient Care Group. The Management of Diabetic Ketoacidosis in Adults, 2nd edn; September 2013; abcd.care. (BP = blood pressure; ECG = electrocardiogram; IV = intravenous; SC = subcutaneous) 20.16 Emergency management of diabetic ketoacidosis

738 • DIABETES MELLITUS Potassium Careful monitoring of potassium is essential to the management of DKA because both hypo- and hyperkalaemia can occur and are potentially life-threatening. Potassium replacement is not usually recommended with the initial litre of fluid because pre-renal failure may be present secondary to dehydration. Treatment with 0.9% sodium chloride with potassium chloride 40 mmol/L is recommended if the serum potassium is below 5.5 mmol/L and the patient is passing urine (Box 20.16). If the potassium falls below 3.5 mmol/L, the potassium replacement regimen needs to be reviewed. Aim to maintain potassium between 4.0 and 5.5 mmol/L. Cardiac rhythm should be monitored in severe DKA because of the risk of electrolyte-induced cardiac arrhythmia. Bicarbonate Adequate fluid and insulin replacement should resolve the acidosis. The use of intravenous bicarbonate therapy is not recommended. Acidosis may reflect an adaptive response, improving oxygen delivery to the tissues, and so excessive bicarbonate may induce a paradoxical increase in cerebrospinal fluid acidosis and has been implicated in the pathogenesis of cerebral oedema in children and young adults. Phosphate There is no evidence of benefit with phosphate replacement unless low levels are detected in the presence of respiratory or muscle weakness. Ongoing management Where possible, refer the patient to the diabetes specialist team within 24 hours of admission. It is important to review the precipitating factors that led to DKA, glycaemic control and insulin injection technique, as well as to discuss prevention of recurrence and to provide blood ketone meters where available. There is a significant mortality associated with recurrent DKA and so early educational assessment and treatment review are critical. Hyperglycaemic hyperosmolar state Hyperglycaemic hyperosmolar state (HHS) is a medical emergency that is different from DKA and so treatment requires a different approach. There is no precise definition of HHS but it is characterised by hypovolaemia, severe hyperglycaemia (> 30 mmol/L (600 mg/dL)) and hyperosmolality (serum osmolality > 320 mOsmol/kg), without significant ketonaemia (< 3 mmol/L) or acidosis (pH > 7.3 (H+ < 50 nmol/L), bicarbonate

15 mmol/L). As with DKA, there is glycosuria, leading to an osmotic diuresis with loss of water, sodium, potassium and other electrolytes. However, in HHS, hyperglycaemia usually develops over a longer period (a few days to weeks), causing more profound hyperglycaemia and dehydration (fluid loss may be 10–12 L in a person weighing 100 kg). The reason that patients with HHS do not develop significant ketoacidosis is unclear, although it has been speculated that insulin levels may be too low to stimulate glucose uptake in insulin-sensitive tissues, but are still sufficient to prevent lipolysis and subsequent ketogenesis. A mixed picture of HHS and DKA can occur. Although typically occurring in older patients, HHS is increasingly seen in younger adults. Common precipitating factors include infection, myocardial infarction, cerebrovascular events or drug therapy (e.g. glucocorticoids). Poor prognostic signs include hypothermia, hypotension (systolic blood pressure < 90 mmHg), tachy- or bradycardia, severe hypernatraemia (sodium > 160 mmol/L), serum osmolality > 360 mOsmol/kg, and the presence of other serious comorbidities. Mortality rates are higher than in DKA – up to 20% in the USA – reflecting the age and frailty of the population and the more frequent presence of comorbidities. The principles of therapy are shown in Box 20.17. The aims are to normalise osmolality, replace fluid and electrolyte losses, and normalise blood glucose, at the same time as preventing complications such as arterial or venous thrombosis, cerebral oedema and central pontine demyelinosis (Ch. 14). Comorbidities also need to be taken into account; for example, rapid fluid replacement may precipitate cardiac failure in patients with coronary artery disease. Historically, management of HHS has followed DKA guidelines, but increasing recognition of the differences between HHS and DKA has led to new approaches in HHS. In particular, rapid shifts in osmolality should be avoided through more measured fluid replacement regimens that are guided by serial calculations of serum osmolality. Key recommendations are that 0.9% sodium chloride solution alone is used for initial treatment, and that insulin is introduced only when the rate of fall in blood glucose has plateaued. If osmolality cannot be measured frequently, osmolarity can be calculated as follows and used as a surrogate (based on plasma values in mmol/L): Plasma osmolarity Na glucose urea =

2[ ] [ ] [ ] The normal value is 280–296 mOsmol/L and consciousness is impaired when it is high (> 340 mOsmol/L), as commonly occurs in HHS. A limitation of this approach is that hyperglycaemia, by increasing serum osmolality, causes the movement of water out of cells, therefore reducing measured Na+ levels by dilution. In hyperglycaemic patients, the corrected [Na+] should be taken into account. This is calculated by adding 1.6 mmol/L to the measured [Na+] for every 5.55 mmol/L (100 mg/dL) increment of serum glucose above normal. Hypoglycaemia Hypoglycaemia is uncommon in people without diabetes but relatively frequent in people with diabetes, mainly due to insulin therapy, and less frequently to use of oral insulin secretagogues such as sulphonylurea drugs, and rarely with other antidiabetic drugs. In people with diabetes, hypoglycaemia is defined as a blood glucose of less than 3.9 mmol/L (70 mg/dL). Severe hypoglycaemia – the need for external assistance to provide glucose, glucagon or other corrective action actively – is greatly feared by people with diabetes and has a major impact on their willingness and ability to achieve target glucose levels. When hypoglycaemia develops in non-diabetic people, it is called ‘spontaneous’ hypoglycaemia; its definition, causes and investigation are described on page 676. The critical importance of glucose as a fuel source for the brain means that, in health, a number of mechanisms are in place to ensure that glucose homeostasis is maintained. If blood glucose falls, three primary physiological defence mechanisms operate: • endogenous insulin release from pancreatic β cells is suppressed • release of glucagon from pancreatic α cells is increased • the autonomic nervous system is activated, with release of catecholamines both systemically and within the tissues.

Presenting problems in diabetes mellitus • 739

Circumstances of hypoglycaemia Risk factors and causes of hypoglycaemia in patients taking insulin or sulphonylurea drugs are listed in Box 20.19. Severe hypoglycaemia can have serious morbidity (e.g. convulsions, coma, focal neurological lesions) and has a mortality of up to In addition, stress hormones, such as cortisol and growth hormone, are increased in the blood. These actions reduce whole-body glucose uptake and increase hepatic glucose production, maintaining a glucose supply to the brain. People with type 1 diabetes cannot regulate insulin once it is injected subcutaneously, and so it continues to act, despite the development of hypoglycaemia. In addition, within 5 years of diagnosis, most patients will have lost their ability to release glucagon specifically during hypoglycaemia. The reasons for this are unknown, but may result from loss of α-cell regulation by insulin or other products of the β cell. These two primary defects mean that hypoglycaemia occurs much more frequently in people with type 1 and longer-duration type 2 diabetes. Clinical assessment Symptoms of hypoglycaemia (Box 20.18) comprise two main groups: those related to acute activation of the autonomic nervous system and those secondary to glucose deprivation of the brain (neuroglycopenia). Symptoms of hypoglycaemia are idiosyncratic, differing with age and duration of diabetes, and also depending on the circumstances in which hypoglycaemia occurs. Hypoglycaemia also affects mood, inducing a state of increased tension and low energy. Learning to recognise the early onset of hypoglycaemia is an important aspect of the education of people with diabetes treated with insulin. 20.18 Most common symptoms of hypoglycaemia Autonomic • Sweating • Trembling • Pounding heart • Hunger • Anxiety Neuroglycopenic • Delirium • Drowsiness • Speech difficulty • Inability to concentrate • Incoordination • Irritability, anger Non-specific • Nausea • Tiredness • Headache N.B. Symptoms differ with age; children exhibit behavioural changes (such as naughtiness or irritability), while older people experience more prominent neurological symptoms (such as visual disturbance and ataxia). Time 0–60 mins • Commence IV 0.9% sodium chloride 1 L over 1 hr • Commence insulin infusion (0.05 U/kg/hr) only if there is significant ketonaemia (3-hydroxybutyrate > 1.0 mmol/L) • Perform initial investigations • Perform clinical assessment to assess degree of dehydration, mental status and any source of potential sepsis • Assess foot risk score • Establish monitoring regimen – generally hourly glucose and calculated osmolality (2Na+ + glucose + urea) for first 6 hrs then 2-hourly if responding • Insert urinary catheter to monitor hourly urine output and calculate fluid balance • Commence LMWH in a prophylactic dose • Consider antibiotic therapy if sepsis suspected Time 60 mins to 6 hrs • Continue with 0.9% sodium chloride infusion 0.5–1.0 L/hr, depending on clinical assessment and response (target positive balance of 2–3 L by 6 hrs) • Calculate osmolality hourly and aim for gradual decline (3–8 mOsmol/kg/hr); if osmolality is increasing and fluid balance adequate, consider 0.45% sodium chloride • If blood glucose is falling at less than 5 mmol/L/hr, check fluid balance and, if adequate, commence low-dose IV insulin (0.05 U/ kg/hr); if insulin is already running, increase rate to 0.1 U/kg/hr • Maintain potassium in the reference range (3.6–5.0 mmol/L), as with DKA (see Box 20.16) • Avoid hypoglycaemia – aim to keep blood glucose at 10–15 mmol/L (180–270 mg/dL) in the first 24 hrs. If blood glucose falls below 14 mmol/L (252 mg/dL), commence 5% or 10% glucose infusion in addition to 0.9% saline • Monitor fluid balance Time 6–12 hrs • Ensure clinical and biochemical parameters are improving • Assess for complications of treatment • Continue IV fluid replacement to target 3–6 L positive balance by 12 hrs • Continue treatment of underlying precipitant • Avoid hypoglycaemia Time 12–24 hrs • Ensure clinical and biochemical parameters are improving; measurement can be reduced to 4-hourly; biochemistry does not usually normalise by 24 hrs • Assess for complications of treatment • Continue IV fluid replacement to target remaining estimated fluid loss by 24 hrs • Continue IV insulin with or without 5% or 10% glucose to maintain blood glucose at 10–15 mmol/L (180–270 mg/dL) • Continue treatment of underlying precipitant • Avoid hypoglycaemia Time 24 hrs to day 3 • Ensure clinical and biochemical parameters are improving or normalised; continue IV fluids until eating and drinking; variable-rate insulin and fluids may be required if not • Convert to appropriate SC insulin regimen when stable • Assess for signs of fluid overload • Encourage early mobilisation • Carry out daily foot checks • Continue LMWH until discharge • Ensure review by diabetes team Adapted from Joint British Diabetes Societies Inpatient Care Group. The Management of the Hyperosmolar Hyperglycaemic State (HHS) in Adults with Diabetes; 2012; abcd.care. (DKA = diabetic ketoacidosis; IV = intravenous; LMWH = low-molecular-weight heparin; SC = subcutaneous) 20.17 Emergency management of hyperglycaemic hyperosmolar state

740 • DIABETES MELLITUS 4% in insulin-treated patients. Rarely, sudden death during sleep occurs in otherwise healthy young patients with type 1 diabetes (‘dead-in-bed syndrome’) and may result from hypoglycaemiainduced cardiac arrhythmia. Severe hypoglycaemia is very disruptive and impinges on many aspects of the patient’s life, including employment, driving (see Box 20.24), travel, sport and personal relationships. Nocturnal hypoglycaemia in patients with type 1 diabetes is common but often undetected, as hypoglycaemia does not usually waken a person from sleep. Patients may describe poor quality of sleep, morning headaches and vivid dreams or nightmares, or a partner may observe profuse sweating, restlessness, twitching or even seizures. The only reliable way to identify this problem is to measure blood glucose during the night. High glucose levels in the morning are not, as commonly perceived, an indicator of nocturnal hypoglycaemia. Exercise-induced hypoglycaemia occurs in people with wellcontrolled, insulin-treated diabetes because of hyperinsulinaemia. Suppression of endogenous insulin secretion to allow increased hepatic glucose production to meet the increased metabolic demand is key to the normal physiological response to exercise. In insulin-treated diabetes, insulin levels may actually increase with exercise because of improved blood flow at the site of injection, and this increases the risk of hypoglycaemia. This means that both insulin and muscle contraction will increase glucose uptake, causing a fall in blood glucose. This occurs most commonly with prolonged and/or aerobic exercise. In addition, the ‘double hit’ of hypoglycaemia with exercise reflects the additional increased risk of nocturnal hypoglycaemia that can occur after exercise, possibly as a result of glycogen depletion. In contrast, high-intensity exercise because of the marked stimulation to adrenaline (epinephrine) production may actually cause blood glucose to rise significantly. Education is key to preventing exercise-induced hypoglycaemia. Hypoglycaemia may also occur within the hospital setting. This may result from errors in insulin dose or type of insulin prescribed, infusion of IV insulin without glucose, changes in meal timings or content and failure to provide usual snacks, reduced carbohydrate intake because of vomiting or reduced appetite, or factors related to the hospital admission, e.g. concurrent illness or discontinuation of long-term glucocorticoid therapy. Awareness of hypoglycaemia For most individuals, the glucose level (threshold) at which they first become aware of hypoglycaemia is not constant but varies according to the circumstances in which hypoglycaemia arises (e.g. during the night or during exercise). In addition, with longer duration of disease, and particularly in response to frequent hypoglycaemia, the threshold for generation of symptom responses to hypoglycaemia shifts to a lower glucose concentration. This cerebral adaptation has a similar effect on the counter-regulatory hormonal response to hypoglycaemia. Taken together, this means that individuals with type 1 diabetes may have reduced (impaired) awareness of hypoglycaemia. Symptoms can be experienced less intensely, or even be absent, despite blood glucose concentrations below 3.0 mmol/L (55 mg/dL). Such individuals are at an especially high risk of severe hypoglycaemia. The prevalence of impaired awareness of hypoglycaemia increases with time; overall, it affects around 20–25% of people with type 1 diabetes and under 10% with insulin-treated type 2 diabetes. Management Acute treatment of hypoglycaemia Treatment of hypoglycaemia depends on its severity and on whether the patient is conscious and able to swallow (Box 20.20). Oral carbohydrate usually suffices if hypoglycaemia is recognised early. If parenteral therapy is required, then as soon as the patient is able to swallow, glucose should be given orally. Full recovery may not occur immediately and reversal of cognitive impairment may not be complete until 60 minutes after normoglycaemia is restored. When hypoglycaemia has occurred in a patient treated with a long- or intermediate-acting insulin or a long-acting sulphonylurea, such as glibenclamide, the possibility of recurrence should be anticipated; to prevent this, infusion of 10% dextrose, titrated to the patient’s blood glucose, or provision of additional carbohydrate may be necessary. If the patient fails to regain consciousness after blood glucose is restored to normal, then cerebral oedema and other causes of impaired consciousness – such as alcohol intoxication, a post-ictal state or cerebral haemorrhage – should be considered. Cerebral oedema has a high mortality and morbidity. Following recovery, it is important to try to identify a cause and make appropriate adjustments to the patient’s therapy. Unless the reason for a hypoglycaemic episode is clear, the patient should reduce the next dose of insulin by 10–20% and seek medical advice about further adjustments in dose. The management of self-poisoning with oral antidiabetic agents is described on page 141. Prevention of hypoglycaemia Patient education is fundamental to the prevention of hypoglycaemia. Risk factors for, and treatment of, hypoglycaemia should be discussed. The importance of regular blood glucose monitoring and the need to have glucose (and glucagon) readily available should be stressed. A review of insulin and carbohydrate 20.19 Hypoglycaemia in diabetes: common causes and risk factors Medical issues • Rapid improvement in and/or strict glycaemic control • Previous severe hypoglycaemia • Impaired awareness of hypoglycaemia • Long-duration type 1 diabetes • Duration of insulin therapy in type 2 diabetes • Lipohypertrophy at injection sites causing variable insulin absorption • Severe hepatic dysfunction • Impaired renal function • Inadequate treatment of previous hypoglycaemia • Terminal illness • Bariatric surgery involving bowel resection • Unrecognised other endocrine disorder, e.g. Addison’s disease Reduced carbohydrate intake • Gastroparesis due to autonomic neuropathy causing variable carbohydrate absorption • Malabsorption, e.g. coeliac disease • Eating disorder Lifestyle issues • Exercise • Irregular lifestyle • Increasing age • Alcohol • Early pregnancy • Breastfeeding • No or inadequate glucose monitoring • Factitious (deliberately induced)

Management of diabetes • 741

20.20 Emergency treatment of hypoglycaemia Biochemical or symptomatic hypoglycaemia (self-treated) In the UK, it is recommended that all glucose levels < 4.0 mmol/L (72 mg/dL) are treated (‘4 is the floor’). People with diabetes who recognise developing hypoglycaemia are encouraged to treat immediately. Options available include: • Oral fast-acting carbohydrate (10–15 g) is taken as glucose drink or tablets or confectionery, e.g. 5–7 Dextrosol tablets (or 4–5 Glucotabs), 90–120 mL original Lucozade, 150–200 mL pure fruit juice, 3–4 heaped teaspoons of sugar dissolved in water) • Repeat capillary glucose measurement 1–15 mins later. If still < 4.0 mmol/L, repeat above treatment • If blood glucose remains < 4.0 mmol/L after three cycles (30–45 mins), contact a doctor. Consider glucagon 1 mg IM or 150–200 mL 10% glucose over 15 mins IV • Once blood glucose is > 4.0 mmol/L, take additional long-acting carbohydrate of choice • Do not omit insulin injection if due but review regimen Severe (external help required) This means individuals are either unconscious or unable to treat hypoglycaemia themselves. Treatment is usually by a relative or by paramedical or medical staff. Immediate treatment as below is needed. • If patient is semiconscious or unconscious, parenteral treatment is required: IV 75–100 mL 20% dextrose over 15 mins (= 15 g; give 0.2 g/kg in children)* Or IV 150–200 mL 10% dextrose over 15 mins Or IM glucagon (1 mg; 0.5 mg in children) – may be less effective in patients on sulphonylurea/under the influence of alcohol • If patient is conscious and able to swallow: Give oral refined glucose as drink or sweets (= 25 g) or 1.5–2 tubes of Glucogel/Dextrogel Or Apply glucose gel or jam or honey to buccal mucosa • Repeat blood glucose measurement after 10–15 mins and manage as per biochemical hypoglycaemia Adapted from Joint British Diabetes Societies. The hospital management of hypoglycaemia in adults with diabetes mellitus (2013). Available at: abcd.care. *Use of 50% dextrose is no longer recommended. management during exercise is particularly useful. Advice for patients when travelling is summarised in Box 20.21. Relatives and friends also need to be familiar with the symptoms and signs of hypoglycaemia and should be instructed in how to help (including how to inject glucagon). It is important to recognise that all current insulin replacement regimens are suboptimal and do not accurately replicate normal physiological insulin profiles. Understanding the pharmacokinetics and pharmacodynamics of the insulin regimen in use by the patient will help prevent further hypoglycaemia (p. 748). For example, an individual experiencing regular nocturnal hypoglycaemia between midnight and 0200 hrs may be found to be taking twice-daily soluble and intermediate-acting insulins before breakfast and before the main evening meal between 1700 and 1900 hrs. In this case, the peak action of the isophane insulin will coincide with the period of maximum sensitivity to insulin – namely, 2300–0200 hrs – and increase the risk of nocturnal hypoglycaemia. To address this, the evening dose of depot intermediate-acting insulin should 20.21 Avoidance and treatment of hypoglycaemia during travel • Carry a supply of fast-acting carbohydrate (non-perishable, in suitable containers): Screwtop plastic bottles for glucose drinks Packets of powdered glucose (for use in hot, humid climates) Confectionery (foil-wrapped in hot climates) • Ask companions to carry additional oral carbohydrate, and glucagon • Perform frequent blood glucose testing (carry spare meter and/or visually read strips) • Use fast-acting insulin analogues for long-distance air travel be deferred until bedtime (after 2300 hrs), shifting its peak action period to 0500–0700 hrs. It is also a sensible precaution for patients to measure their blood glucose before they retire to bed and to have a carbohydrate snack if the reading is less than 6.0 mmol/L (approximately 110 mg/dL). Management of diabetes The aims are to improve symptoms of hyperglycaemia and minimise the risks of long-term microvascular and macrovascular complications. Treatment methods for diabetes include dietary/ lifestyle modification, oral antidiabetic drugs and injected therapies. Initial investigation and management is outlined in Figure 20.10. In patients with suspected type 1 diabetes, urgent treatment with insulin is required and prompt referral to a specialist is usually needed. In patients with suspected type 2 diabetes, the first approach to management involves advice about dietary and lifestyle modification. Oral antidiabetic drugs are usually added in those who do not achieve glycaemic targets, or who have symptomatic hyperglycaemia at diagnosis and a high HbA1c. However, the guidelines in some countries are to introduce medication immediately on diagnosis of diabetes without waiting to assess the impact of diet and lifestyle changes. Patients with type 2 diabetes who present with marked symptomatic hyperglycaemia or DKA will require initial management with insulin treatment. For most people, types 1 and 2 diabetes are chronic conditions that will impact on their day-to-day activities and require sustained changes to lifestyle. Education is key to achieving and maintaining a healthy lifestyle and to managing diabetes. Early educational intervention at diagnosis and repeated education are essential if these goals are to be successfully achieved. Management of people with diabetes should be individualised where possible, taking into account personal and cultural beliefs, individual circumstances, comorbidities and other factors. Diabetes is a complex disorder that progresses in severity with time, so people with diabetes should be seen at regular intervals for the remainder of their lives, either at a specialist diabetic clinic or in primary care where facilities are available and staff are trained in diabetes care. A checklist for follow-up visits is given in Box 20.22. The frequency of visits is variable, ranging from weekly during pregnancy to annually in the case of patients with well-controlled type 2 diabetes. In parallel with treatment of hyperglycaemia, other risk factors for complications of diabetes need to be addressed, including treatment of hypertension (p. 510) and dyslipidaemia (p. 373), and advice on smoking cessation (p. 94).

742 • DIABETES MELLITUS have been developed that allow for a more detailed examination of daily glucose profiles. These can be used continuously as part of day-to-day diabetes management or intermittently as an educational tool. Urine testing for glucose is not recommended because variability in renal threshold means that some patients with inadequate glycaemic control will not find glucose in their urine. Therapeutic goals The target HbA1c depends on the individual patient. Early on in diabetes (i.e. patients managed by diet or one or two oral agents), a target of 48 mmol/mol or less may be appropriate. However, a higher target of 58 mmol/mol may be more appropriate in older patients with pre-existing cardiovascular disease, or those treated with insulin and therefore at risk of hypoglycaemia. In general, the benefits of lower target HbA1c (primarily, a lower risk of microvascular disease) need to be weighed against any increased risks (primarily, hypoglycaemia in insulin-treated patients). Type 2 diabetes is usually a progressive condition Self-assessment of glycaemic control In people with type 2 diabetes, there is not usually a need for regular self-assessment of blood glucose, unless they are treated with insulin, or at risk of hypoglycaemia while taking sulphonylureas. Blood glucose testing can be used for selfeducation (i.e. demonstrating how different food and exercise regimes affect blood glucose) and may be useful in acute illness. Blood glucose targets vary according to individual circumstances but, in general, fasting glucose levels of 5–7 mmol/L (90– 126 mg/dL), pre-meal values of 4–7 mmol/L (72–126 mg/dL) and 2-hour post-meal values of 4–8 mmol/L (72–144 mg/dL) represent optimal control. Insulin-treated patients should be taught how to monitor their own blood glucose using capillary blood glucose meters. Immediate knowledge of blood glucose levels can be used by patients to guide their insulin dosing and to manage exercise and illness. This can be supplemented with blood testing for ketones when blood glucose is high and/or during intercurrent illness. More recently, continuous glucose monitoring systems (CGMS) Fig. 20.10 The recommended approach for the management of type 2 diabetes. First-line drug treatment should be metformin. Second- and third-line treatment should be chosen based on the efficacy, hypoglycaemia risk, weight effects and other side-effects, and costs of the therapy in discussion with the patient. (DPP-4-i = dipeptidyl peptidase 4 inhibitor; fxs = fractures; GI = gastrointestinal; GLP-1-RA = glucagon-like peptide 1 receptor agonist; GU = genitourinary; HF, heart failure; SGLT2-i = sodium and glucose transporter 2 inhibitor; SU, sulphonylurea; TZD = thiazolidinedione) Adapted from the American Diabetes Association/European Association for the Study of Diabetes joint position statement, 2015. Diabetes Care 2015; 38:140–149. Healthy eating, weight control, increased physical activity and diabetes education If HbA1c target not achieved after ∼3 months of monotherapy, proceed to two-drug combination (order not meant to denote any specific preference – choice dependent on a variety of patient- and disease-specific factors) If HbA1c target not achieved after ∼3 months of dual therapy, proceed to three-drug combination (order not meant to denote any specific preference – choice dependent on a variety of patient- and disease-specific factors) If HbA1c target not achieved after ∼3 months of triple therapy and patient (1) on oral combination, move to injectables; (2) on GLP-1-RA, add basal insulin; or (3) on optimally titrated basal insulin, add GLP-1-RA or mealtime insulin. In refractory patients consider adding TDZ or SGLT2-1 Monotherapy Triple therapy Combination injectable therapy Efficacy Hypoglycaemia risk Weight Side-effects Costs Dual therapy Efficacy Hypoglycaemia risk Weight Side-effects Costs Thiazolidinedione Sulphonylurea DPP-4 inhibitor SGLT2 inhibitor GLP-1 receptor agonist Insulin (basal) Metformin + Metformin + Metformin + Metformin + Metformin + Metformin + high moderate risk gain hypoglycaemia low high low risk gain oedema,HF, fxs low intermediate low risk neutral rare high intermediate low risk loss GU, dehydration high high low risk loss GI high highest high risk gain hypoglycaemia variable Thiazolidinedione + Sulphonylurea + TZD DPP-4-i or SGLT2-i or GLP-1-RA or Insulin or SU TZD DPP-4-i DPP-4-i DPP-4-i or SGLT2-i SU SGLT2-i SGLT2-i or GLP-1-RA or GLP-1-RA GLP-1-RA or or or or Insulin Insulin TZD SU TZD TZD SU or or or or or or or Insulin Insulin or DPP-4 inhibitor + SGLT2 inhibitor + GLP-1 receptor agonist + Insulin (basal) + Metformin + Metformin + Metformin + Metformin + Basal insulin + Mealtime insulin or Metformin + Metformin + Metformin + Metformin high low risk neutral/loss GI/lactic acidosis low

Management of diabetes • 743

alcohol consumption, should not be under-estimated in improving glycaemic control for people with both type 1 and type 2 diabetes. Many people find this difficult to sustain and constant reinforcement of the benefits of lifestyle change will usually be required. Patients should be encouraged to stop smoking. Healthy eating All people with diabetes need to pay special attention to their diet (Box 20.23; see also p. 694). They should have access to a dietitian at diagnosis, at review and at times of treatment change. Nutritional advice should be tailored to individuals and take account of their age, lifestyle, culture and personal circumstances. Structured education programmes are available for both common types of diabetes and, if possible, a clear referral mechanism for diabetes education should be in place. Between 80% and 90% of people with type 2 diabetes are overweight and so the majority require dietary advice for achieving weight loss, to include caloric restriction. There is, however, limited evidence for the ideal macronutrient composition of the diet in type 2 diabetes. In general, high fat intake (especially saturated fats) is associated with a raised HbA1c, but it is unclear how the type and amount of fat influence post-prandial glucose control. Reduction of caloric intake and weight loss should be the major goals. Some evidence for the Mediterranean diet, low-carbohydrate diets and meal replacements is emerging. Whichever approach is taken, weight loss in overweight and obese individuals with diabetes markedly improves glycaemic control and slows diabetes progression. Carbohydrate While it is recognised that the total amount of carbohydrate is the major determinant of post-prandial glucose (p. 694), there is little evidence to support specific strategies for carbohydrate intake in type 2 diabetes or to identify the ideal amount of carbohydrate in their diet. Current UK government Food Standards Agency recommendations are that the total carbohydrate intake should be no more than 50% of energy, and of this non-milk extrinsic sugars (e.g. table sugar, honey, (Fig. 20.11) unless there are major diet and lifestyle changes, so that there is usually a need to increase diabetes medication over time to achieve the individualised target HbA1c. In people with type 2 diabetes, treatment of coexisting hypertension and dyslipidaemia is usually required. This can be decided by assessing absolute risk of a cardiovascular disease event (p. 510) and adjusting targets to individual circumstances. The target for blood pressure is usually below 140/80 mmHg, although some guidelines suggest 130/80 mmHg. For lipid-lowering, there is a reduction in cardiovascular risk even with normal cholesterol levels, but statin therapy is usually recommended when the 10-year cardiovascular event risk is at least 20%. As a rule, anyone with type 2 diabetes who is over the age of 40 years should receive a statin, irrespective of baseline cholesterol levels. Some guidelines do not propose a target level once the patient is started on a statin but others suggest a total cholesterol of less than 4.0 mmol/L (approximately 150 mg/dL) and an LDL cholesterol of less than 2.0 mmol/L (approximately 75 mg/dL). Similar targets are appropriate in type 1 diabetes, although there is a shortage of data from clinical trials. Patient education, diet and lifestyle The importance of lifestyle changes, such as undertaking regular physical activity, observing a healthy diet and reducing Fig. 20.11 Time course of changes in HbA1c during the United Kingdom Prospective Diabetes Study (UKPDS). In the UKPDS there was loss of glycaemic control with time in patients receiving monotherapy, independently of their randomisation to conventional or intensive glycaemic control, consistent with progressive decline in β-cell function (see Fig. 20.8). Adapted from UK Prospective Diabetes Study Group. UKPDS 33. Lancet 1998; 352:837–853.

Conventional Upper limit of normal Years from randomisation Intensive

HbA1c(%)

20.22 How to review a patient in the diabetes clinic Lifestyle issues • General health • Work or school • Smoking • Alcohol intake • Stress or depression • Sexual health • Exercise Body weight and BMI Blood pressure • Individualised target of 130–140/70–80 mmHg, depending on risk factors and presence of nephropathy Urinalysis • Analyse fasting specimen for glucose, ketones, albumin (both macro- and micro-albuminuria) Biochemistry • Renal, liver and thyroid function • Lipid profile and estimated 10-year cardiovascular risk to guide need for lipid-lowering therapy (p. 487) Glycaemic control • Glycated haemoglobin (HbA1c); individualised target between 48 and 58 mmol/mol • Inspection of home blood glucose monitoring record (if carried out by patient) Hypoglycaemic episodes • Number and cause of severe (requiring assistance for treatment) events and frequency of mild (self-treated) episodes and biochemical hypoglycaemia • Awareness of hypoglycaemia • Driving advice Assessment of injection sites if insulin-treated Eye examination • Visual acuities (near and distance) • Ophthalmoscopy (with pupils dilated) or digital photography Examination of lower limbs and feet • Assessment of foot risk (p. 721)

744 • DIABETES MELLITUS Weight management In patients with diabetes, weight management is important, as a high percentage of people with type 2 diabetes are overweight or obese, and many antidiabetic drugs, including insulin, encourage weight gain. Obesity, particularly central obesity with increased waist circumference, also predicts insulin resistance and cardiovascular risk. Management of obesity is described on page 700. Weight loss can be achieved through a reduction in energy intake and an increase in energy expenditure through physical activity. Lifestyle interventions or pharmacotherapy for obesity, when associated with weight reduction, have beneficial effects on HbA1c, but long-term benefits in terms of glycaemic control and microvascular disease have not been adequately assessed. More recently, bariatric surgery (p. 703) has been shown to induce marked weight loss in obese individuals with type 2 diabetes and this is often associated with significant improvements in HbA1c and withdrawal of or reduction in diabetes medications. Exercise All patients with diabetes should be advised to achieve a significant level of physical activity and to maintain this in the long term. This can include activities such as walking, gardening, swimming or cycling. Supervised and structured exercise programmes may be of particular benefit in type 2 diabetes. Various guidelines exist for physical activity in the general population. The American Diabetes Association recommends that all adults with diabetes are encouraged to reduce sedentary time, and suggest that adults over 18 years of age should do either 150 minutes per week of moderate-intensity exercise or 75 minutes per week of vigorous-intensity exercise, or a combination thereof. Musclestrengthening (resistance) exercise is recommended on 2 or more days of the week. Adults over 65 years or those with disabilities should follow the recommended guidelines if possible or be as physically active as they are able. Recent evidence also indicates that extended sedentary time (> 90 mins) should be avoided. People with type 1 diabetes appear to exercise less frequently than the general population, perhaps because of perceived concerns about hypoglycaemia and difficulties in insulin management around exercise. However, the health benefits of exercise are equally important in type 1 diabetes, so this should be addressed in the clinic and specialist advice sought on insulin and carbohydrate management before, during and after exercise. Alcohol Alcohol is recognised as having both beneficial and harmful effects on cardiovascular disease and this also appears to apply in patients with diabetes. Alcohol can therefore be taken in moderation in diabetes, with the aim of keeping within national guidelines relating to recommendations for people without diabetes (e.g. in the UK, the weekly recommended maximum is 14 units for women and men). However, alcohol can reduce hypoglycaemia awareness and, by suppressing gluconeogenesis, increase hypoglycaemia risk. The latter occurs when individuals are in the fasted state and so people with diabetes who drink should be advised to eat at the same time. In addition, all patients with diabetes should be made aware of the high calorie glucose and fructose sugars) should not be more than 11%. Low glycaemic index (GI) diets have, in some short-term trials, been shown to improve HbA1c, but the literature concerning GI and glycaemic control is mixed. The GI of a carbohydrate-containing food is a measure of the change in blood glucose following its ingestion relative to the rise in blood glucose observed following a liquid OGTT. Different foods can be ranked by their effect on post-prandial glycaemia. Low-GI foods, such as starchy foods (e.g. basmati rice, spaghetti, porridge, noodles, granary bread, and beans and lentils), may reduce post-prandial glucose excursions. However, different methods of food processing and preparation can influence the GI of foods, and this may limit their benefit. Low-carbohydrate diets may lead to significant reductions in body weight and improved glycaemic control in the short term, although high dropout rates and poor adherence have limited widespread application of this approach. Increased consumption of whole grains has not been shown to improve glycaemic control. Fat There is limited evidence on the ideal fat content in the diet of people with diabetes. Current UK government Food Standards Agency recommendations are that intake of total fat should be not more than 35% of energy intake, of which not more than 11% should consist of polyunsaturated fats. The type of fatty acids consumed may be more important when looking at glycaemic targets and risk of cardiovascular disease. Mediterranean diets rich in monounsaturated fats appear more beneficial (Box 20.23). The influence of dietary fats on plasma lipid profile and cardiovascular disease is discussed on page 697. Salt People with diabetes should follow the advice given to the general population: namely, adults should limit their sodium intake to no more than 6 g daily. 20.23 Dietary management of diabetes Aims of dietary management • Achieve good glycaemic control • Reduce hyperglycaemia and avoid hypoglycaemia • Assist with weight management: Weight maintenance for type 1 diabetes and non-obese type 2 diabetes Weight loss for overweight and obese type 2 diabetes • Reduce the risk of micro- and macrovascular complications • Ensure adequate nutritional intake • Avoid ‘atherogenic’ diets or those that aggravate complications, e.g. high protein intake in nephropathy Dietary constituents and recommended % of energy intake • Carbohydrate: 50%: Sucrose: up to 10% • Fat (total): < 35%: n-6 Polyunsaturated: < 10% n-3 Polyunsaturated: eat 1 portion (140 g) oily fish once or twice weekly Monounsaturated: 10–20% Saturated: < 10% • Protein: 10–15% (do not exceed 1 g/kg body weight/day) • Fruit/vegetables: 5 portions daily

Management of diabetes • 745

sulphonylureas and insulin (particularly older people or those with renal failure); such individuals need careful blood glucose monitoring and, if necessary their treatment regimens may need to be adjusted (Box 20.25). Diabetes therapies that do not cause hypoglycaemia may prove safest during Ramadan if glycaemic control permits. DPP-4 inhibitors or GLP-1 receptor agonists may be especially useful because their effect on insulin secretion is glucose-dependent. Drugs to reduce hyperglycaemia Patients whose glycaemic control deteriorates after a period of satisfactory control need their therapy to be adjusted. However, this is not a homogeneous group; it includes some patients with late-onset type 1 diabetes who develop an absolute deficiency of insulin, some with type 2 diabetes whose β-cell failure is advanced, and others who are not adhering to the recommended lifestyle changes or medication. Weight loss suggests worsening β-cell function. During continuing follow-up, the majority of patients will require combinations of antidiabetic drugs, often with additional insulin replacement, to obtain satisfactory glycaemic control. For many years, only a few choices of drug were available for type 2 diabetes – the biguanide metformin, the sulphonylureas and insulin. Insulin is the only treatment for type 1 diabetes, although sometimes metformin is used with insulin in type 1 diabetes. Acarbose is also available but is little used in most countries. Since the late 1990s, however, several new classes of agent have been approved for use in type 2 diabetes, with more in development. These include thiazolidinediones, dipeptidyl peptidase 4 (DPP-4) inhibitors, glucagon-like peptide 1 (GLP-1) receptor agonists, and sodium and glucose transporter 2 (SGLT2) inhibitors. The effects of these drugs are compared in Box 20.26. This makes for an exciting time in diabetes pharmacotherapy but exactly how, when and in what order these agents should be used remains uncertain. The older drugs are cheaper and have established benefits for reducing microvascular disease; they are therefore usually recommended as first-line therapy. Use of the newer drugs is not supported by evidence for reduction in microvascular disease (because the trials have not yet been done) and they are much more expensive, so are often reserved for later therapy after failure of metformin and sulphonylureas. The American Diabetes Association/European Association for the Study of Diabetes (ADA/EASD) consensus content of some alcohols and the implications for body weight management, which are often overlooked. Driving European legislation on driving has had a major impact on people with diabetes. Legislation will vary from country to country and so individuals should contact their nurse or doctor to find out if their treatment means they need to inform the licensing authority (Box 20.24). To drive a car or ride a motorcycle in the UK, people with diabetes who take insulin replacement therapy must notify the Driver and Vehicle Licensing Agency (DVLA). They must have adequate awareness of hypoglycaemia, have had no more than one episode of severe hypoglycaemia in the preceding 12 months, meet the standards for visual acuity and visual fields, and not be regarded as a likely risk to the public while driving. In addition, blood glucose testing is required to be performed no more than 2 hours before the start of a journey and every 2 hours while driving. Blood glucose levels should be over 5 mmol/L (90 mg/dL) before driving; if they are below 4.0 mmol/L (72 mg/dL) or there are symptoms of hypoglycaemia, the person should not drive. Legislative requirements for people on insulin therapy who drive larger vehicles such as buses or lorries require, in addition, an annual examination by a diabetes specialist, along with review of 3 months of glucose meter readings. Legislation differs between countries and patients and health-care specialists need to be aware of current requirements. 20.24 Diabetes and driving • Licensing regulations vary considerably between countries. In the UK, diabetes requiring insulin therapy or any complication that could affect driving should be declared to the Driver and Vehicle Licensing Agency; ordinary driving licences are ‘period-restricted’ for insulin-treated drivers; and vocational licences (large goods vehicles and public service vehicles) may be granted but require very strict criteria to be met • The main risk to driving performance is hypoglycaemia. Visual impairment and other complications may occasionally cause problems • Insulin-treated diabetic drivers should: Check blood glucose before driving and 2-hourly during long journeys Keep an accessible supply of fast-acting carbohydrate in the vehicle Take regular snacks or meals during long journeys Stop driving if hypoglycaemia develops Refrain from driving until at least 45 mins after treatment of hypoglycaemia (delayed recovery of cognitive function) Carry identification in case of injury 20.25 Recommendations for management of diabetes during Ramadan • Monitor blood glucose: depending on treatment regimen, glucose levels should be checked daily or several times a day. Patients treated with insulin and insulin secretagogues should measure glucose before, during and after fasting (2–4 times daily) • Consult diabetes team for medication adjustment at least 1 month prior to Ramadan. Treatment should be evaluated and modified according to risk of hypoglycaemia. Avoid or reduce sulphonylureas and/or insulin daily dosage • Avoid skipping pre-dawn meals • Avoid strenuous physical activity during fasting period • Adjust medication dose and eat a snack in the presence of hypoglycaemia. Break the fast if there is severe or recurrent hypoglycaemia Ramadan The Qur’an requires Muslims to fast during the month of Ramadan from sunrise to sunset. While people with diabetes are a recognised exception to this and are not required to fast, many will choose to do so. In this context, patient education, regular glucose monitoring and adjustment of treatment regimens are essential and should occur weeks prior to Ramadan. The highest risk of hypoglycaemia is in patients treated with

746 • DIABETES MELLITUS At the molecular level, metformin acts as a weak inhibitor of mitochondrial respiration, which increases intracellular adenosine monophosphate (AMP) and reduces adenosine triphosphate (ATP). This has direct effects on the flux through gluconeogenesis, and activates the intracellular energy sensor, AMP-activated protein kinase (AMPK), leading to multiple beneficial metabolic effects. However, metformin is still effective in mice lacking AMPK, and a number of AMPK-independent mechanisms have been proposed. Clinical use Metformin is a potent blood glucose-lowering treatment that is weight-neutral or causes weight loss, does not cause hypoglycaemia and has established benefits in microvascular disease. It is employed as first-line therapy in all patients who tolerate it, and its use is maintained when additional agents are added as glycaemia deteriorates (see Fig. 20.10). Metformin is usually introduced at low dose (500 mg twice daily) to minimise the risk of gastrointestinal side-effects. The usual maintenance dose is 1 g twice daily. There is a modified-release formulation of metformin, which may be better tolerated by patients with gastrointestinal side-effects. Metformin can increase susceptibility to lactic acidosis, although this is much less common than was previously thought. As metformin is cleared by the kidneys, it can accumulate in renal impairment, so the dose should be halved when estimated glomerular filtration rate (eGFR) is 30–45 mL/min/1.73 m2, and it should not be used below an eGFR of 30 mL/min/1.73 m2. It should be omitted temporarily during any acute illness where acute kidney injury is possible, as this greatly increases the risk of lactic acidosis; insulin treatment may be required while metformin is withheld. Its use is also contraindicated in patients with significantly impaired hepatic function and in those who drink alcohol in excess, in whom the risk of lactic acidosis is significantly increased. Sulphonylureas Sulphonylureas are ‘insulin secretagogues’, i.e. they promote pancreatic β-cell insulin secretion. Similar to metformin, the long-term benefits of sulphonylureas in lowering microvascular guidelines are shown in Figure 20.10. These position metformin in the first line, and then aim to encourage choice of second-line treatment to be personalised for each patient. This personalisation is largely based on the adverse risk profile of the drug – in particular, risk of hypoglycaemia (avoid where hypoglycaemia would be a problem, e.g. in drivers of heavy goods vehicles) and weight gain. There is little evidence to guide the clinician and patient in choosing the second- or third-line treatment, and until biomarkers are identified that predict who will respond best and/or experience the fewest side-effects with one drug rather than another, this individualisation of treatment needs to be largely empirical. A trial-and-error approach may be best: stop a drug that does not work or that causes side-effects and trial the next drug. At the time of writing, the ADA/EASD guidelines were already out of date; in 2015/16, the SGLT2 inhibitor empagliflozin and the GLP-1 receptor agonist liraglutide were shown to reduce adverse cardiovascular outcomes and mortality. It is likely that the guidelines will change to take these exciting results into account and we will probably see these newer, more expensive drugs used earlier in the diabetes trajectory. Biguanides Metformin is the only biguanide available. Its long-term benefits were shown in the UK Prospective Diabetes Study (UKPDS, p. 756) and it is now widely used as first-line therapy for type 2 diabetes, irrespective of body weight. It is also given as an adjunct to insulin therapy in obese patients with type 1 diabetes. Approximately 25% of patients develop mild gastrointestinal side-effects with metformin, but only 5% are unable to tolerate it even at low dose. The main side-effects are diarrhoea, abdominal cramps, bloating and nausea. Mechanism of action The mechanism of action of metformin has not been precisely defined. While classically considered an ‘insulin sensitiser’ because it lowers insulin levels, its main effects are on fasting glucose and are insulin-independent. Metformin reduces hepatic glucose production, may also increase insulin-mediated glucose uptake, and has effects on gut glucose uptake and utilisation. 20.26 Effects of drugs used in the treatment of type 2 diabetes Insulin Sulphonylureas and meglitinides Metformin Alphaglucosidase inhibitors Thiazolidinediones (glitazones) DPP-4 inhibitors (gliptins) GLP-1 receptor agonists SGLT2 inhibitors Fasting blood glucose ↓ ↓ ↓ ѭ ↓ ↓ ↓ ↓ Post-prandial blood glucose ↓ ↓ ↓ ↓ ↓ ↓ ↓ ↓ Plasma insulin ↑ ↑ ↓ ↓ ↓ ↑ ↑ ↓ Body weight ↑ ↑ → → ↑ → ↓ ↓ Cardiovascular benefit? No No Possible No Probable (pioglitazone) No Yes Yes Risk of hypoglycaemia ++ + – – – – – – Tolerability Good Good Moderate Moderate Moderate Good Moderate Limited experience (ѭ = small reduction; DPP-4 = dipeptidyl peptidase 4; GLP-1 = glucagon-like peptide 1; SGLT2 = sodium and glucose transporter 2)

Management of diabetes • 747

bladder cancer. These observations have led to a dramatic reduction in the use of pioglitazone. Pioglitazone can be very effective at lowering blood glucose in some patients and appears more effective in insulin-resistant patients. In addition, it has a beneficial effect in reducing fatty liver and NASH (p. 882). Pioglitazone is usually added to metformin with or without sulphonylurea therapy (see Fig. 20.10). It may be given with insulin therapy, when it can be very effective, but the combination of insulin and TZDs markedly increases fluid retention and risk of cardiac failure, so should be used with caution. Incretin-based therapies: DPP-4 inhibitors and GLP-1 receptor agonists The incretin effect is the augmentation of insulin secretion seen when a glucose stimulus is given orally rather than intravenously, and reflects the release of incretin peptides from the gut (see Fig. 20.3). The incretin hormones are primarily glucagon-like peptide 1 (GLP-1) and gastric inhibitory polypeptide (GIP), which act to potentiate insulin secretion (see Fig. 20.2). These are rapidly broken down by dipeptidyl peptidase 4 (DPP-4). The incretin effect is diminished in type 2 diabetes, and this has stimulated the development of two incretin-based therapeutic approaches. The ‘gliptins’, or DPP-4 inhibitors, prevent breakdown and therefore enhance concentrations of endogenous GLP-1 and GIP. The first DPP-4 inhibitor to market was sitagliptin; others now available include vildagliptin, saxagliptin, linagliptin and alogliptin. These drugs are very well tolerated and are weight-neutral (see Box 20.26). Recent cardiovascular outcome studies have shown mixed results with the DPP-4 inhibitors. The Trial to Evaluate Cardiovascular Outcomes after Treatment with Sitagliptin (TECOS) study reported no adverse cardiovascular outcomes for sitagliptin, but the Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus – Thrombolysis in Myocardial Infarction (SAVOR-TIMI) study found an increased risk of heart failure in patients treated with saxagliptin. The GLP-1 receptor agonists have a similar structure to GLP-1 but have been modified to resist breakdown by DPP-4. These agents are not orally active and have to be given by subcutaneous injection. However, they have a key advantage over the DPP-4 inhibitors: because the GLP-1 activity achieved is supra-physiological, it delays gastric emptying and, at the level of the hypothalamus, decreases appetite. Thus, injectable GLP-1 receptor agonists lower blood glucose and result in weight loss – an appealing therapy, as the majority of patients with type 2 diabetes are obese. Currently available GLP-1 receptor agonists include exenatide (twice daily), exenatide modified-release (once weekly), liraglutide (once daily), lixisenatide (once daily) and albiglutide (once weekly). Recently, GLP-1 receptor agonists and long-acting insulin analogue have been combined, enabling co-administration of insulin and GLP-1 receptor agonists with one injection. The GLP-1 receptor agonists vary in their side-effect profile, depending on whether they are administered daily or weekly, but the main side-effect that often limits use is nausea. The Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results (LEADER) study has recently demonstrated that liraglutide, when added to usual therapy, results in improved cardiovascular outcomes over placebo in patients at high risk for cardiovascular disease; this contrasts with the Evaluation of Lixisenatide in Acute Coronary Syndrome (ELIXA) study, which showed that lixisenatide was neutral with respect to cardiovascular disease. complications of diabetes were established in the UKPDS (p. 756). Mechanism of action Sulphonylureas act by closing the pancreatic β-cell ATP-sensitive potassium (KATP) channel, decreasing K+ efflux, which ultimately triggers insulin secretion (see Fig. 20.2C). Meglitinides (e.g. repaglinide and nateglinide) also work in this way and, although short-acting, are essentially sulphonylurea-like drugs. Clinical use Sulphonylureas are an effective therapy for lowering blood glucose and are often used as an add-on to metformin, if glycaemia is inadequately controlled on metformin alone (see Fig. 20.10). The main adverse effects of sulphonylureas are weight gain and hypoglycaemia. The weight gain is not ideal in patients with diabetes who are already overweight or obese, although sulphonylureas are effective treatments in this group. Hypoglycaemia occurs because the closure of KATP channels brings about unregulated insulin secretion, even with normal or low blood glucose levels. There are a number of sulphonylureas. In the UK, gliclazide is the most commonly used; in contrast, in the USA, glibenclamide (also known as glyburide) is widely used. Glibenclamide, however, is long-acting and prone to inducing hypoglycaemia, so should be avoided in older patients. Other sulphonylureas include glimepiride and glipizide. The dose–response of all sulphonylureas is steepest at low doses; little additional benefit is obtained when the dose is increased above half-maximal doses. Alpha-glucosidase inhibitors The α-glucosidase inhibitors delay carbohydrate absorption in the gut by inhibiting disaccharidases. Acarbose and miglitol are available and are taken with each meal. Both lower post-prandial blood glucose and modestly improve overall glycaemic control. They can be combined with a sulphonylurea. The main side-effects are flatulence, abdominal bloating and diarrhoea. They are used widely in the Far East but infrequently in the UK. Thiazolidinediones Mechanism of action These drugs (also called TZDs, ‘glitazones’ or PPARγ agonists) bind and activate peroxisome proliferator-activated receptor-γ, a nuclear receptor present mainly in adipose tissue, which regulates the expression of several genes involved in metabolism. TZDs enhance the actions of endogenous insulin, both directly (in the adipose cells) and indirectly (by altering release of ‘adipokines’, such as adiponectin, which alter insulin sensitivity in the liver). Plasma insulin concentrations are not increased and hypoglycaemia does not occur. TZDs increase preadipocyte differentiation, resulting in an increase in fat mass and body weight. Clinical use TZDs have been prescribed widely since the late 1990s but a number of adverse effects have become apparent and their use has declined. One popular TZD, rosiglitazone, was reported to increase the risk of myocardial infarction and was withdrawn in 2010. The other TZD in common use, pioglitazone, does not appear to increase the risk of myocardial infarction but may exacerbate cardiac failure by causing fluid retention, and recent data show that it increases the risk of bone fracture and possibly

748 • DIABETES MELLITUS Insulin therapy Manufacture and formulation Insulin was discovered in 1921 and transformed the management of type 1 diabetes, which was a fatal disorder until then. Up to the 1980s, insulin was obtained by extraction and purification from pancreases of cows and pigs (bovine and porcine insulins), and some patients still prefer to use animal insulins. Recombinant DNA technology enabled large-scale production of human insulin. Unmodified (‘soluble’ or ‘regular’) insulin aggregates into hexamers in subcutaneous tissues; these must dissociate before systemic absorption can occur and this process helps extend the duration of action to nearly 8 hours. The amino acid sequence of insulin can be altered to produce analogues of insulin, which differ in their rate of absorption from the site of injection. For example, in insulin lispro, the penultimate lysine and proline residues on the C-terminal end of the β chain are reversed (Fig. 20.13). This prevents the insulin molecules from aggregating as hexamers in subcutaneous tissues after injection and so speeds absorption, leading to a more rapid onset and shorter duration of action than soluble insulin (Box 20.27). The onset of action of insulin analogues may be further hastened by the addition of excipients to the formulation (e.g. nicotinamide and arginine to insulin aspart). Conversely, in insulin glargine, a substitution of glycine for asparagine in the α chain and the addition of two additional arginine residues to the C-terminal end of the β chain serves to prolong the duration of action of the insulin to over 24 hours. The amino acid modifications shift the isoelectric point from a pH of 5.4 to 6.7, making the molecule less soluble at a physiological pH (see Fig. 20.13). Duration of action can also be extended by adding chemicals to soluble insulin solution or by adding other molecules to the insulin structure. Chemical additives include protamine and zinc at neutral pH (isophane or NPH insulin) or excess zinc ions (lente insulins). In insulin detemir and degludec, the duration of action is extended by adding fatty acids to a slightly truncated C-terminal end of the β chain (Fig. 20.13). Following subcutaneous injection, these bind to albumin in the All the incretin-acting drugs have been reported to be associated with an increased risk of pancreatitis, although this risk is small: between 1 and 10 cases per 1000 patients treated. Unlike sulphonylureas, both incretin-based therapies promote insulin secretion only when there is a glucose ‘trigger’ for it. Thus, when the blood glucose is normal, the insulin secretion is not augmented and so these agents do not cause hypoglycaemia when used as monotherapy or with other drugs that do not cause hypoglycaemia. SGLT2 inhibitors The sodium and glucose transporter 2 (SGLT2) inhibitor, dapagliflozin, was licensed for use in 2012. Subsequently, canagliflozin and empagliflozin have also been licensed. Glucose is filtered freely in the renal glomeruli and reabsorbed in the proximal tubules. SGLT2 is involved in reabsorption of glucose (Fig. 20.12). Inhibition results in approximately 25% of the filtered glucose not being reabsorbed, with consequent glycosuria. Although this helps to lower blood glucose and results in calorie loss and subsequent weight loss, the glycosuria does also lead to genital fungal infections. There has been increasing use of these agents over the last few years; however, the recent announcement of the Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes (EMPA-REG Outcomes) trial has the potential to change dramatically the way these drugs are now used. Empagliflozin therapy resulted in a 35% reduction in cardiovascular mortality and a similar reduction in admissions to hospital with heart failure. This result was much greater than anticipated and the mechanism behind it is still being investigated, but this landmark study was the first to show such striking benefits in mortality reduction from a glucose-lowering agent; as such, these drugs should now, at the very least, be used in all patients who fulfil the inclusion criteria of the trial – prior myocardial infarction, coronary artery disease, stroke, unstable angina or occlusive peripheral arterial disease. Euglycaemic diabetic ketoacidosis (i.e. DKA not associated with marked hyperglycaemia) has been recognised as a rare complication of this class of drugs. Fig. 20.12 Glucose filtration and reabsorption by the nephron. Some 90% of filtered glucose is reabsorbed by sodium and glucose transporter 2 (SGLT2) and 10% by SGLT1. SGLT2 inhibitors reduce net reabsorbed glucose by 25%. For a mean plasma glucose of 8 mmol/L (144 mg/dL), this results in a glucose loss of approximately 80 g per day in the urine, which in turn reduces plasma glucose. This equates to 320 kcal per day and subsequent weight loss. S1 segment Proximal tubule Distal S2/S3 segment -90% reabsorption ˜ 90% reabsorption ˜ 10% reabsorption Glucose Collecting duct No glucose SGLT2 -10% reabsorption SGLT1

Management of diabetes • 749

discomfort of injecting bigger volumes and also to reduce variability in insulin delivery from the subcutaneous depot. Therefore, U 200, U 300 and U 500 formulations of insulin are available, which are, respectively, two, three and five times more concentrated than standard insulin. Expert advice should be sought before using concentrated insulin because errors in prescribing can cause severe hypoglycaemia. Subcutaneous multiple dose insulin therapy In most patients, insulin is injected subcutaneously several times a day into the anterior abdominal wall, upper arms, outer thighs and buttocks (Box 20.28). Accidental intramuscular injection often occurs in children and thin adults. The rate of absorption of insulin may be influenced by many factors other than the insulin formulation, including the site, depth and volume of injection, skin temperature (warming), local massage and exercise. Absorption is delayed from areas of lipohypertrophy at injection sites (p. 721), which results from the local trophic action of insulin, so repeated injection at the same site should be avoided. Other routes of administration (intravenous and intraperitoneal) are reserved for specific circumstances. Once absorbed into the blood, insulin has a half-life of just a few minutes. It is removed mainly by the liver and also the kidneys, so plasma insulin concentrations are elevated in patients with liver disease or renal failure. Rarely, the rate of clearance can be affected by binding to insulin antibodies. blood, from which the insulin slowly disassociates. The duration of action of insulin degludec may also be extended as the fatty acid moiety promotes the formation of multi-hexamers of insulin in the subcutaneous tissues (Box 20.27). Isophane and lente insulins are cloudy preparations and have to be resuspended prior to injection to ensure adequate mixing of the components. The more modern, structurally modified, long-acting insulins (e.g. glargine, detemir and degludec) are clear and do not require resuspension. Pre-mixed formulations containing short-acting and isophane insulins in various proportions are available. In most countries, the insulin concentration in available formulations has been standardised at 100 U/mL. Increasing levels of obesity, which are associated with increased daily insulin requirements, have stimulated pharmaceutical companies to develop more concentrated insulin formulations to reduce the Fig. 20.13 Amino acid structure of insulin and insulin analogues. The areas in the shaded colours show the modifications made to the normal structure of insulin. These are important in altering the pharmocokinetic properties of the analogues. Gly Ile Val Glu Gln CysCys S S S S S S Cys Thr Ser Ser Leu Leu Tyr Gln Glu Asn Asn Tyr Cys Ile Phe Val Val Val Arg Gln His Leu Cys Cys Gly Gly Glu

Gly Gly Lys Ser His Leu Leu Leu Glu Glu Ala Thr Arg Phe Phe Tyr Thr Pro Pro Lys Asp Lys Thr Arg Arg Gly Arg Phe Phe Tyr Thr Pro Lys Fast-acting analogues Lispro Aspart Glulisine Glargine Detemir/Degludec Long-acting analogues 20.27 Duration of action (in hours) of insulin preparations Insulin Onset Peak Duration Rapid-acting (insulin analogues: lispro, aspart, glulisine) < 0.5 0.5–2.5 3–4.5 Short-acting (soluble (regular)) 0.5–1 1–4 4–8 Intermediate-acting (isophane (NPH), lente) 1–3 3–8 7–14 Long-acting (bovine ultralente) 2–4 6–12 12–30 Long-acting (insulin analogues: glargine, detemir, degludec) 1–2 None 18–26 20.28 How to inject insulin subcutaneously • Needle sited at right angle to the skin • Subcutaneous (not intramuscular) injection • Delivery devices: glass syringe (requires resterilisation), plastic syringe (disposable), pen device (reusable, some disposable), infusion pump

750 • DIABETES MELLITUS vial several times before administration. Fixed-mixture insulins also have altered pharmacodynamic profiles, such that the peak insulin action and time to peak effect are significantly reduced compared with separately injecting the same insulins. This increases the risk of hypoglycaemia. Multiple injection regimens (intensive insulin therapy) are popular, with short-acting insulin being taken before each meal, and intermediate- or long-acting insulin being injected once or twice daily (basal-bolus regimen, Box 20.30). This type of regimen is more physiological and allows greater freedom with regard to meal timing, as well more variable day-to-day physical activity. Insulin can be administered using a disposable plastic syringe with a fine needle (which can be re-used several times), but this has largely been replaced by pen injectors containing insulin in cartridges sufficient for multiple dosing. These are also available as pre-loaded disposable pens. For the most part, insulin analogues have replaced soluble and isophane insulins, especially for people with type 1 diabetes, because they allow greater flexibility and convenience and reduce risk of hypoglycaemia (see Box 20.26). Unlike soluble insulin, which should be injected 30–60 minutes before eating, rapid-acting insulin analogues can be administered immediately before, during or even after meals, although are better injected 15 minutes before eating. Long-acting insulin analogues are also better able than isophane insulin to maintain ‘basal’ insulin levels for up to 24 hours. Despite these pharmacokinetic benefits, the impact of insulin analogues on overall glycaemic control is minor, but studies consistently show a significant reduction in frequency of hypoglycaemia, particularly overnight. The complications of insulin therapy are listed in Box 20.29; the most important of these is hypoglycaemia (p. 738). A common problem is fasting hyperglycaemia (‘the dawn phenomenon’), which arises through a combination of the normal circadian rhythm and release of hormones such as growth hormone and cortisol during the later part of the night, as well as diminishing levels of overnight isophane insulin. The dawn phenomenon is not a consequence of prior nocturnal hypoglycaemia. Insulin dosing regimens The choice of regimen depends on the desired degree of glycaemic control, the severity of underlying insulin deficiency, the patient’s lifestyle, and his or her ability to adjust the insulin dose. The time–action profile of different insulin regimens, compared to the secretory pattern of insulin in the non-diabetic state, is shown in Figure 20.14. People with type 1 diabetes are best managed by multiple daily insulin injections or an insulin pump. In type 2 diabetes, insulin is usually initiated as a once-daily long-acting insulin, either alone or in combination with oral antidiabetic agents. However, in time, more frequent insulin injections are usually required. Twice-daily administration of a short-acting and intermediateacting insulin (usually soluble and isophane insulins), given in combination before breakfast and the evening meal, is the simplest regimen and is still commonly used in many countries. Initially, two-thirds of the total daily requirement of insulin is given in the morning in a ratio of short-acting to intermediate-acting of 1 : 2, and the remaining third is given in the evening. Pre-mixed formulations are available that contain different proportions of soluble and isophane insulins (e.g. 30 : 70 and 50 : 50). These are useful as they avoid the need for directly mixing insulins, but are inflexible as the individual components cannot be adjusted independently. They need to be resuspended by shaking the 20.29 Side-effects of insulin therapy • Hypoglycaemia • Weight gain • Peripheral oedema (insulin treatment causes salt and water retention in the short term) • Insulin antibodies • Local allergy (rare) • Lipohypertrophy or lipoatrophy at injection sites Fig. 20.14 Profiles of plasma insulin associated with different insulin regimens. The schematic profiles are compared with the insulin responses (mean ± 1 standard deviation) observed in non-diabetic adults shown in the top panel (shaded area). These are theoretical patterns of plasma insulin and may differ considerably in magnitude and duration of action between individuals. Plasma insulin Soluble before meals, long-acting insulin late evening

Clock time (hrs) Soluble before meals, isophane late evening Soluble and isophane, twice daily Non-diabetic state Injection of insulin Soluble or fast-acting analogue Isophane Long -acting analogue Meal Key

Management of diabetes • 751

clinical trials in children and adults in the hospital or free-living setting aim to determine how effective this approach will be in optimising management of type 1 diabetes. Widespread use may, however, be limited by cost. Alternative routes of insulin delivery have also been investigated. Clinical trials with intrapulmonary (inhalation), transdermal and oral insulins are ongoing but as yet none has proven commercially viable. Inhaled insulin has been approved for use in the USA as a mealtime insulin, but experience with this is very limited. Subcutaneous continuous insulin therapy Subcutaneous continuous insulin therapy, commonly know as the insulin pump, is a system of insulin delivery that uses a battery-operated medical device to deliver insulin continuously to the individual with type 1 diabetes. Device configurations vary between manufacturers but will include the pump with controls, processing module and batteries, a disposable insulin reservoir, and a disposable insulin set including cannula for subcutaneous insertion and a tubing system to deliver insulin from the reservoir to the cannula. Some recent versions are disposable or semi-disposable and eliminate tubing from the infusion set (patch pumps). Insulin pumps allow the individual more flexibility with bolus insulin injections in both timing and shape (e.g. using an extended bolus when covering high-fat/protein meals such as steak, or when diabetes is complicated by gastroparesis), and also in changing basal insulin infusion rates. This is especially useful overnight when basal rates can be reduced to prevent low glucose, but increased pre-dawn to prevent high glucose. In addition, the temporary basal rates can be used to lessen the risk of hypoglycaemia with exercise. Determining an individual’s basal rate on the pump requires help from a specialist, but in essence is determined by fasting for periods of at least 4 hours while periodically evaluating the blood glucose levels and adjusting the pump infusion rate to maintain glucose in the normal range. Basal rates will change and can be influenced by factors such as increasing duration of disease, puberty, weight gain or loss, drugs that affect insulin sensitivity (e.g. glucocorticoids), and a change in fitness levels with exercise on overall glycaemic control. An example of an insulin pump is shown in Figure 20.15. Closed loop insulin therapy A further iteration in insulin pump therapy in recent years is the development of a ‘closed loop’ system, also known as the artificial pancreas (Fig. 20.16). These systems aim to integrate insulin pumps with continuous glucose monitoring systems (CGMS). In a closed loop system, the CGMS device communicates with the insulin pump via a computerised program. This means that real-time glucose data obtained through the CGMS can be used to calculate an insulin dosage to be dispensed through the insulin pump (Fig. 20.17). Features might include a ‘low-glucose suspend’ function, where detection of hypoglycaemia or a glucose level falling below a pre-set threshold (e.g. 4.0 mmol/L (72 mg/ dL)) signals the pump to stop dispensing insulin until the wearer can treat the hypoglycaemia with food or glucose tabs. Current 20.30 Example of a meal bolus calculation RL has type 1 diabetes treated with an insulin pump. His pre-breakfast glucose (G) is 12 mmol/L (216 mg/dL). He is having a breakfast meal of cereal with milk containing 30 g of carbohydrate (CHO) in total. His insulin:carbohydrate ratio (ICR) is 10 (1 U of insulin for every 10 g of CHO) and his insulin sensitivity factor (ISF) is 2 (1 U of insulin to bring down blood glucose by 2 mmol/L (36 mg/dL)). He wants to achieve a glucose target (GT) of 8 mmol/L (144 mg/dL) after eating. Calculation of estimated bolus dose: Bolus dose CHO ICR G G ISF U of T

÷ + − ÷

÷ + − ÷

( ) (( ) ) ( ) (( ) )

insulin Fig. 20.15 Insulin pump. An insulin pump is an alternative means of delivering insulin in type 1 diabetes. Different types are available and include the pump device itself (with controls, processing module and batteries), a disposable reservoir for insulin (inside the pump) and a disposable infusion set (with tubing and a cannula for subcutaneous insertion). Alternative configurations include disposable or semi-disposable pumps, and pumps without infusion tubing. Insulin pumps deliver rapid-acting insulin continuously, and can be adjusted by the user, based on regular glucose monitoring and carbohydrate counting. Electronic device containing a plastic cartridge of insulin, battery and internal computer to program insulin delivery Insulin infusion set containing flexible tubing and cannula for insertion Fig. 20.16 Artificial pancreas. The artificial pancreas (AP) can vary in its set up and the different components employed in its delivery but core to an AP system are: (1) a continuous glucose monitor (CGM) measuring interstitial glucose levels every 5–15 minutes; (2) a smartphone (or personal glucose monitor) with an app that uses the glucose information from the CGM along with modifications inserted by the user to calculate how much insulin should be delivered. This is communicated wirelessly to (3) the insulin pump that delivers insulin subcutaneously as directed.

752 • DIABETES MELLITUS donor pancreas into a person with type 1 diabetes. The isolated pancreatic islets are usually infused into the patient’s liver via the portal vein. This approach has now been successfully adopted in a number of centres around the world (Fig. 20.18). At present, islet transplantation is usually suitable only for patients with unstable glycaemic control characterised by recurrent severe hypoglycaemia that cannot be corrected by standard conventional and intensive insulin therapies. Progress is being made towards meeting the needs of supply, purification and storage of islets, but problems remain relating to transplant rejection, and destruction by the patient’s autoantibodies against β cells. Nevertheless, the development of methods of inducing tolerance to transplanted islets and the potential use of stem cells (p. 58) mean that this may still prove the most promising approach in the long term. Adoption of newer immunosuppressive protocols has resulted in far better outcomes and now nearly 50% of transplanted patients will be insulin-independent at 3 years post transplantation. Management of diabetes in special situations Diabetes in pregnancy The management of women with pre-existing diabetes who are pregnant or who have developed diabetes in pregnancy (gestational diabetes) is discussed in detail on page 1278 and summarised in Box 20.31. This is a highly specialised area and requires careful and attentive management, as elevated maternal Transplantation Whole-pancreas transplantation is carried out in a small number of patients with diabetes each year, but it presents problems relating to exocrine pancreatic secretions and long-term immunosuppression is necessary. There are currently four main types of whole-pancreas transplantation: • pancreas transplant alone • simultaneous pancreas–kidney (SPK) transplant, when pancreas and kidney are transplanted simultaneously from the same deceased donor • pancreas-after-kidney (PAK) transplant, when a cadaveric, or deceased, donor pancreas transplant is performed after a previous, and different, living or deceased donor kidney transplant • simultaneous deceased donor pancreas and live donor kidney (SPLK) transplant. The principal complications occurring immediately after surgery include thrombosis, pancreatitis, infection, bleeding and rejection. Prognosis is improving: 1 year after transplantation more than 95% of all patients are still alive and 80–85% of all pancreases are still functional. After transplantation, patients will need life-long immunosuppression, which carries with it an increased risk of infection and cancer. An alternative form of transplantation is allogenic islet transplantation, which involves the transplantation of islets from a Fig. 20.17 Continuous glucose monitoring (CGM) profiles: sensor data. A CGM profile from an individual without diabetes. B CGM profile from an individual with type 1 diabetes. The green box shows the reference range. CGM devices may be worn for 7–14 days and the glucose profile of each day illustrated by a different colour. Based on this, the person with diabetes and their health-care team can review overall profiles and adjust treatment as necessary to improve control and avoid hypoglycaemia.

5.6 7.8 3.9 3.3 3.9 3.3 11.1 16.7 Glucose (mmol/L) Glucose (mmol/L) 12:00 a.m.

5.6 7.8 11.1 16.7 2.00 a.m. 4:00 a.m. 6:00 a.m. 8:00 a.m. 10:00 a.m. 12:00 p.m. Time through the day 2:00 p.m. 4:00 p.m. 6:00 p.m. 8:00 p.m. 10:00 p.m. 12:00 a.m. 12:00 a.m. 2.00 a.m. 4:00 a.m. 6:00 a.m. 8:00 a.m. 10:00 a.m. 12:00 p.m. Time through the day 2:00 p.m. 4:00 p.m. 6:00 p.m. 8:00 p.m. 10:00 p.m. 12:00 a.m. B A

Management of diabetes • 753

blood glucose in pregnancy is associated with significant maternal and fetal morbidity. Children, adolescents and young adults with diabetes Most type 1 diabetes is diagnosed in children below 18 years of age, with peak incidence rates between 5 and 7 years of age and at puberty. The management of diabetes in children and adolescents presents particular challenges, which should be addressed in specialised clinics with multidisciplinary input (Box 20.32). Some of the unique aspects of childhood type 1 Fig. 20.18 Transplanting islet cells. (1) Pancreas obtained from suitable human donor. (2) Pancreatic islets containing insulin-producing β cells are isolated first in a Ricordi chamber. (3) Islets, once separated and purified, are infused into the hepatic portal vein. (4) Once embedded in the liver, pancreatic islets secrete insulin in response to changes in portal vein glucose.

Box 20.31 Diabetes in pregnancy • Control of established diabetes before and during pregnancy: must be meticulous, to reduce the risk of complications such as pre-eclampsia, congenital malformations and stillbirth. • Gestational diabetes: most commonly an inability to increase insulin secretion adequately to compensate for pregnancy-induced insulin resistance. • Screening for gestational diabetes: all women at high risk should have an oral glucose tolerance test at 24–28 weeks. Measurement of HbA1c and/or blood glucose at booking visit is usually recommended. • Management of gestational diabetes: reduce intake of refined carbohydrate, and add metformin, glibenclamide and/or insulin if necessary to optimise glycaemic control. • Self-monitoring of glucose: targets are a pre-prandial level of < 5.3 mmol/L (95 mg/dL) and a 1-hour or 2-hour post-prandial level of < 7.8 mmol/L (140 mg/dL) and < 6.4 mmol/L (114 mg/dL), respectively. 20.32 Diabetes in adolescence • Type of diabetes: type 1 diabetes is predominant in children and adolescents, but type 2 diabetes is now presenting in unprecedented numbers of obese, inactive teenagers. Monogenic diabetes (MODY) should also be considered (see Box 20.10, p. 733). • Physiological changes: hormonal, physical and lifestyle changes in puberty affect dietary intake, exercise patterns and sensitivity to insulin, necessitating alterations in insulin regimen. • Emotional changes: adolescence is a phase of transition into independence (principally from parental care). Periods of rebellion against parental control, experimentation (e.g. with alcohol) and a more chaotic lifestyle are common, and often impact adversely on control of diabetes. • Glycaemic control: a temporary deterioration in control is common, although not universal. It is sometimes more important to maintain contact and engagement with a young person than to insist on tight glycaemic control. • Diabetic ketoacidosis: a few adolescents and young adults present with frequent episodes of DKA, often because of non-adherence to insulin therapy. This is more common in females. Motivating factors may include weight loss, rebellion, and manipulation of family or schooling circumstances. • Adolescent diabetes clinics: these challenges are best tackled with support from a specialised multidisciplinary team, including paediatricians, physicians, nurses and psychologists. Support is required for the patient and parents. diabetes management include changing insulin sensitivity related to sexual maturity and physical growth, unique vulnerability to hypoglycaemia (especially in children below 6 years of age) and possibly hyperglycaemia, as well as DKA. In addition, family dynamics, child care and schooling, developmental stages and

754 • DIABETES MELLITUS 20.33 Recommended therapeutic targets in childhood and adolescence Plasma glucose levels • Before meals 4.0–7.0 mmol/L (72–126 mg/dL) • After meals 5.0–9.0 mmol/L (90–160 mg/dL) HbA1c • < 53 mmol/mol (7.0%) with a target of 48 mmol/L Recommended screening • HbA1c up to four times per year • Thyroid disease at diagnosis and annually thereafter • Diabetic retinopathy annually from 12 years • Albuminuria (albumin:creatinine ratio (ACR) 3–30 mg/mmol; ‘microalbuminuria’) to detect diabetic kidney disease, annually from 12 years • Hypertension annually from 12 years Adapted from National Institute for Health and Care Excellence NG18 – Diabetes (type 1 and type 2) in children and young people: diagnosis and management; 2015. 20.34 How to carry out pre-operative assessment of patients with diabetes • Assess glycaemic control: Consider delaying surgery and refer to the diabetes team if HbA1c

75 mmol/mol; this should be weighed against the need for surgery • Assess cardiovascular status Optimise blood pressure Perform an ECG for evidence of (possibly silent) ischaemic heart disease and to assess QTc (p. 448) • Assess foot risk (p. 761) Patients with high-risk feet should have suitable pressure relief provided during post-operative nursing • For minor/moderate operations where only one meal will be omitted, plan for the patient to be first on the list and 180 mg/dL) seems appropriate. Achieving such a target may require the use of intravenous insulin and dextrose in some individuals. Surgery and diabetes Patients with diabetes are reported to have up to 50% higher perioperative mortality than patients without diabetes. Surgery causes catabolic stress and secretion of counter-regulatory hormones (including catecholamines and cortisol) in both normal and diabetic individuals. This results in increased glycogenolysis, gluconeogenesis, lipolysis, proteolysis and insulin resistance. Starvation exacerbates this process by increasing lipolysis. In the non-diabetic person, these metabolic effects lead to a secondary increase in the secretion of insulin, which exerts a controlling influence. In diabetic patients, either there is absolute deficiency of insulin (type 1 diabetes) or insulin secretion is delayed and impaired (type 2 diabetes), so that in untreated or poorly controlled diabetes, the uptake of metabolic substrate into tissues is significantly reduced, catabolism is increased and, ultimately, metabolic decompensation in the form of DKA may develop in both types of diabetes. In addition, hyperglycaemia impairs wound healing and innate immunity, leading to increased risk of infection. Patients with diabetes are also more likely to have underlying pre-operative morbidity, especially cardiovascular disease. Finally, management errors in diabetes may cause dangerous hyperglycaemia or hypoglycaemia. Careful preoperative assessment and perioperative management are therefore essential, ideally with support from the diabetes specialist team. Pre-operative assessment Unless a surgical intervention is an emergency, patients with diabetes should be assessed well in advance of surgery so that poor glycaemic control and other risk factors can be addressed (Box 20.34). There is good evidence that a higher HbA1c is associated with adverse perioperative outcome. In general, an upper limit for an acceptable HbA1c should be between 64 and 75 mmol/mol (8% and 9%). However, since optimisation of care may take weeks or months to achieve, the benefits need to be weighed against the need for early surgical intervention. Perioperative management Figure 20.19 outlines a general approach to perioperative management of diabetes, although this may need to be adapted according to the patient, the surgical procedure and local guidelines. Patients with diabetes who are considered low-risk can attend as day cases or be admitted on the day of surgery. ability to self-care all have to be considered in the management plan, as well as, in older children and adolescents, issues of body image, eating disorders and recreational drug and alcohol use. It is also notable that there is very limited clinical research in children with diabetes and so most recommendations are based on expert opinion. The prevalence of type 2 diabetes in those below 20 years has been increasing and is estimated to increase fourfold in the next 40 years. Management of these children and young adults is difficult. Coeliac disease and thyroid disease are much more common in children with type 1 diabetes than in the general population and so it is currently recommended that these conditions are screened for. Current recommendations for screening in type 1 diabetes are shown in Box 20.33. Hyperglycaemia in acute medical illness Hyperglycaemia is often found in patients who are admitted to hospital as an emergency. In most people this occurs in the context of a known diagnosis of diabetes; in some individuals, however, it is a consequence of stress hyperglycaemia (p. 728), while in others it is due to undiagnosed diabetes. Hyperglycaemia on admission to hospital is associated with increased length of stay and increased mortality in a wide variety of acute medical emergencies, including acute coronary syndrome and acute stroke. Intuitively, intensive glycaemic control with intravenous insulin should improve outcomes during acute illness. However, recent studies have shown that strategies aiming for near-normal blood glucose levels in acutely ill patients are associated with either increased mortality or no overall benefit. The reasons for the adverse outcomes are not established, but intensive glycaemic control is inevitably associated with an increased risk of hypoglycaemia because of the inherent limitations of modern insulins, the restricted frequency of glucose monitoring in a ward environment and the relative imprecision of near-patient blood glucose meters. The activation of the sympathetic nervous system and release of counter-regulatory hormones during acute hypoglycaemia could have deleterious consequences for the acutely ill patient. There is no consensus on the optimum glucose targets in acutely ill patients but extremes of blood glucose should be avoided, and so a target of between 6 and 12 mmol/L (105

Complications of diabetes • 755

Fig. 20.19 Management of diabetic patients undergoing surgery and general anaesthesia. (eGFR = estimated glomerular filtration rate; GLP-1 = glucagon-like peptide 1; IV = intravenous; U&Es = urea and electrolytes) Minor operation/ only one meal omitted HbA1c ≤ 64 mmol/mol? Yes No Aim for ‘first on list’ Omit any oral antidiabetic drugs and GLP-1 analogues on morning of operation Omit quick- or medium-acting insulins prior to missed meal. Continue long-acting insulin (e.g. glargine or detemir) but consider reducing dose if surgical list is in afternoon No need for IV insulin unless unable to eat post-operatively, blood glucose > 14 mmol/L (250 mg/dL), or ketones present in urine or blood Resume usual medication with first meal; if it is lunch for patient using mixed insulin, give half of usual morning dose Major operation/ prolonged fast Omit any oral antidiabetic drugs and GLP-1 analogues on morning of operation Omit quick- or medium-acting insulins prior to missed meal. Continue long-acting insulin (e.g. glargine or detemir) Start IV insulin infusion and IV fluids early on morning of operation and maintain on IV insulin until eating and drinking Once patient is eating, prescribe usual oral or injectable treatment with a meal and discontinue insulin infusion 1 hr later Withhold metformin if eGFR < 30 mL/min/1.73 m2 Check U&Es at least daily while on IV insulin and fluids; ensure adequate potassium replacement and avoid hyponatraemia from dextrose infusion Occasionally, patients may be admitted the night before to ensure optimal management. Post-operative management Patients who need to continue fasting after surgery should be maintained on intravenous insulin and fluids until they are able to eat and drink (Fig. 20.19). During this time, care must be taken with fluid balance and electrolyte levels. Insulin infusion necessitates dextrose infusion to maintain a supply of glucose but this combination drives down plasma potassium (p. 360) and can result in hyponatraemia. Intravenous fluids during prolonged insulin infusion should therefore include saline and potassium supplementation. UK guidelines recommend the use of dextrose/ saline (0.45% saline with 5% dextrose and 0.15% potassium chloride). Once a patient’s usual treatment has been reinstated, care must be taken to continue to control the blood glucose, ideally between 6 and 10 mmol/L (105–180 mg/dL), in order to optimise wound healing and recovery. Patients normally controlled on tablets may require temporary subcutaneous insulin treatment until the increased ‘stress’ of surgery, wound healing or infection has resolved. Complications of diabetes Despite all the treatments now available, the outcome for patients with diabetes remains disappointing. Long-term complications of diabetes still cause significant morbidity and mortality (Boxes 20.35 and 20.36). Excess mortality in diabetes is caused mainly by large blood vessel disease, particularly myocardial infarction and stroke. Macrovascular disease also causes substantial morbidity from myocardial infarction, stroke, angina, cardiac failure and intermittent claudication. The pathological changes of atherosclerosis in diabetic patients are similar to those in the non-diabetic population but occur earlier in life and are more extensive and severe. Diabetes amplifies the effects of the other major cardiovascular risk factors: smoking, hypertension and dyslipidaemia (Fig. 20.20). Moreover, patients with type 2 diabetes are more likely to have additional cardiovascular risk factors, which co-segregate with insulin resistance in the metabolic syndrome (p. 730). Mortality statistics from the USA indicate that cardiovascular death rates are 1.7 times higher in adults with diabetes aged 20 years or older compared to adults in the same age group who do not have diabetes, while similar figures for myocardial infarction show a 1.8 times greater rate. Hospitalisation rates for stroke were 1.5 times higher in adults with diabetes than in those without diabetes. In addition, 60% of non-traumatic amputations among people aged 20 years or older were reported to be in people with diabetes. Type 1 diabetes is also associated with increased cardiovascular risk. Recent data from Scotland show that the age-adjusted incidence rate ratio for first cardiovascular event was 3 times higher in women and 2.3 times higher in men with type 1 diabetes compared to those without diabetes.

756 • DIABETES MELLITUS body. The development of the characteristic clinical syndromes of diabetic retinopathy, nephropathy, neuropathy and accelerated atherosclerosis is thought to result from the local response to generalised vascular injury. For example, in the wall of large vessels, increased permeability of arterial endothelium, particularly when combined with hyperinsulinaemia and hypertension, may increase the deposition of atherogenic lipoproteins. The mechanisms linking hyperglycaemia to these pathological changes are, however, poorly characterised. Preventing diabetes complications Glycaemic control The evidence that improved glycaemic control decreases the risk of developing microvascular complications of diabetes was established by the DCCT in type 1 diabetes and the UKPDS in type 2 diabetes. The DCCT was a large study that lasted 9 years; it randomised patients with type 1 diabetes to intensive treatment (mean HbA1c 53 mmol/mol) and conventional treatment (mean HbA1c 75 mmol/mol). There was a 60% overall reduction in the risk of developing diabetic complications in patients with type 1 diabetes on intensive therapy with strict glycaemic control, compared with those on conventional therapy. No single factor other than glycaemic control had a significant effect on outcome. However, the group that was intensively treated to lower blood glucose had three times the rate of severe hypoglycaemia. The UKPDS randomised patients to intensive treatment (mean HbA1c 53 mmol/mol) versus conventional treatment (mean HbA1c 64 mmol/mol). This study showed that, in type 2 diabetes, the frequency of diabetic complications is lower and progression is slower with good glycaemic control and effective treatment of hypertension, irrespective of the type of therapy used. Extrapolation from the UKPDS suggests that, for every 11 mmol/mol Disease of small blood vessels is a specific complication of diabetes and is termed diabetic microangiopathy. It contributes to mortality through renal failure caused by diabetic nephropathy, and is responsible for substantial morbidity and disability: for example, blindness from diabetic retinopathy, difficulty in walking, chronic ulceration of the feet from peripheral neuropathy, and bowel and bladder dysfunction from autonomic neuropathy. The risk of microvascular disease is positively correlated with the duration and degree of sustained hyperglycaemia, however it is caused and at whatever age it develops. Pathophysiology The histopathological hallmark of diabetic microangiopathy is thickening of the capillary basement membrane, with associated increased vascular permeability, which occurs throughout the Fig. 20.20 Association between HbA1c and risk of microvascular and macrovascular diabetes complications. These data were obtained amongst participants in the UK Prospective Diabetes Study and were adjusted for effects of age, sex and ethnicity; the incidences show what could be expected amongst white men aged 50–54 years at diagnosis of type 2 diabetes, followed up for 10 years. Microvascular disease included retinopathy requiring photocoagulation, vitreous haemorrhage and renal failure. Macrovascular disease included fatal and non-fatal myocardial infarction and sudden death. A 1% change in HbA1c is equivalent to a reduction of 11 mmol/mol. < 6 6–7 7–8 8–9 9–10

10 HbA1c (%)

Incidence per 1000 patient-years Microvascular disease Macrovascular disease (myocardial infarction) Risk versus non-diabetic controls (mortality ratio) • Overall 2.6 • Coronary heart disease

Cerebrovascular disease

Peripheral vascular disease 2.8 • All other causes, including renal failure 2.7 Causes of death in diabetes (approximate proportion) • Cardiovascular disease 70% • Renal failure 10% • Cancer 10% • Infections 6% • Diabetic ketoacidosis 1% • Other 3% Risk factors for increased morbidity and mortality in diabetes • Duration of diabetes • Early age at onset of disease • High glycated haemoglobin (HbA1c) • Raised blood pressure • Proteinuria; microalbuminuria • Dyslipidaemla • Obesity } 20.36 Mortality in diabetes 20.35 Complications of diabetes Microvascular/neuropathic Retinopathy, cataract • Impaired vision Nephropathy • Renal failure Peripheral neuropathy • Sensory loss • Pain • Motor weakness Autonomic neuropathy • Gastrointestinal problems (gastroparesis; altered bowel habit) • Postural hypotension Foot disease • Ulceration • Arthropathy Macrovascular Coronary circulation • Myocardial ischaemia/infarction Cerebral circulation • Transient ischaemic attack • Stroke Peripheral circulation • Claudication • Ischaemia

Complications of diabetes • 757

and accounts for between 20% and 50% of patients starting renal replacement therapy. About 30% of patients with type 1 diabetes have developed diabetic nephropathy 20 years after diagnosis, but the risk after this time falls to less than 1% per year, and from the outset the risk is not equal in all patients (Box 20.38). The risk of nephropathy in Caucasian populations with type 2 diabetes is similar to those with type 1 diabetes but the rate of progression may be exacerbated by concomitant obesity and other risk factors. The risk of nephropathy is much greater in some ethnic groups, with epigenetic and genetic factors thought to influence this increased risk. Some patients do not develop nephropathy, however, despite having long-standing, poorly controlled diabetes, suggesting that they do not have a genetic predisposition. While variants in a few genes have been implicated in diabetic nephropathy, the major differences in individual risk remain unexplained. With improved standards of care focusing on glycaemic control and blood pressure lowering, the proportion of patients with overt nephropathy is reducing; however, due to the global rise in the incidence of type 2 diabetes, the prevalent number of people with diabetes and end-stage renal failure continues to rise. The pathophysiology is not fully understood and there are several postulated mechanisms by which hyperglycaemia causes the pathological changes seen in diabetic nephropathy. The central features are activation of the renin–angiotensin system, leading to both intrarenal and systemic effects, as well as direct toxic effects of prolonged hyperglycaemia, leading to renal inflammation and fibrosis. The pattern of progression of renal abnormalities in diabetes is shown schematically in Figure 20.21. Pathologically, the first changes coincide with the onset of microalbuminuria and include thickening of the glomerular basement membrane and accumulation of matrix material in the mesangium. Subsequently, nodular deposits (Fig. 20.22) are characteristic, and glomerulosclerosis worsens as heavy proteinuria develops, until glomeruli are progressively lost and renal function deteriorates. Diagnosis and screening Microalbuminuria (Box 20.39) is the presence in the urine of small amounts of albumin, at a concentration below that detectable using a standard urine dipstick. Overt nephropathy is defined as the presence of macroalbuminuria (urinary albumin

300 mg/24 hrs, detectable on urine dipstick). Microalbuminuria is a good predictor of progression to nephropathy in type 1 diabetes. It is a less reliable predictor of nephropathy in older patients with type 2 diabetes, in whom it may be accounted for by other diseases (p. 394), although it is a potentially useful marker of an increased risk of macrovascular disease. Management The presence of established microalbuminuria or overt nephropathy should prompt vigorous efforts to reduce the 20.37 Diabetes management in old age • Glycaemic control: the optimal target for glycaemic control in older people has yet to be determined. Strict glycaemic control should be avoided in frail patients with comorbidities and in older patients with long duration of diabetes. • Cognitive function and affect: may benefit from improved glycaemic control but it is important to avoid hypoglycaemia. • Hypoglycaemia: older people have reduced symptomatic awareness of hypoglycaemia and limited knowledge of symptoms, and are at greater risk of, and from, hypoglycaemia. • Mortality: the mortality rate of older people with diabetes is more than double that of age-matched non-diabetic people, largely because of increased deaths from cardiovascular disease. reduction in HbA1c, there is a 21% reduction in death related to diabetes, a 14% reduction in myocardial infarction and 30–40% reduction in risk of microvascular complications (Fig. 20.20). These landmark trials demonstrated that diabetic complications are preventable and that the aim of treatment should be ‘nearnormal’ glycaemia. More recent studies, however, such as the Action to Control Cardiovascular Risk in Diabetes (ACCORD), showed increased mortality in a subgroup of patients who were aggressively treated to lower HbA1c to a target of less than 48 mmol/mol. The patients in this study had poor glycaemic control at baseline, a long duration of diabetes and a high prevalence of cardiovascular disease. It appears that, while a low target HbA1c is appropriate in younger patients with earlier diabetes who do not have underlying cardiovascular disease, aggressive glucose-lowering is not beneficial in older patients with long duration of diabetes and multiple comorbidities (Box 20.37). Control of other risk factors Randomised controlled trials have shown that aggressive management of blood pressure minimises the microvascular and macrovascular complications of diabetes. Angiotensin-converting enzyme (ACE) inhibitors are valuable in improving outcome in heart disease and in treating diabetic nephropathy (see below). The management of dyslipidaemia with a statin limits macrovascular disease in people with diabetes (p. 375). This often results in the necessary use of multiple medications, which exacerbates the problem of adherence to therapy by patients; it is not unusual for a patient to be taking two or more diabetes therapies, two or more blood pressure drugs and a statin. Diabetic retinopathy Diabetic retinopathy (DR) is one of the most common causes of blindness in adults between 30 and 65 years of age in developed countries. The prevalence of DR increases with duration of diabetes, and almost all individuals with type 1 diabetes and the majority of those with type 2 diabetes will have some degree of DR after 20 years. The pathogenesis, clinical features and management of diabetic retinopathy, as well as screening and prevention, are described on page 1174. Other causes of visual loss in type 2 diabetes are also covered in Chapter 27. Diabetic nephropathy Diabetic nephropathy is an important cause of morbidity and mortality in both type 1 and type 2 diabetes. It is now the most common cause of end-stage renal failure in developed countries 20.38 Risk factors for diabetic nephropathy • Poor glycaemic control • Long duration of diabetes • Presence of other microvascular complications • Ethnicity (e.g. Asians, Pima Indians) • Pre-existing hypertension • Family history of diabetic nephropathy • Family history of hypertension

758 • DIABETES MELLITUS Blockade of the renin–angiotensin system using either ACE inhibitors or angiotensin 2 receptor blockers (ARBs) has been shown to have an additional benefit over similar levels of blood pressure control achieved with other antihypertensive agents and is recommended as first-line therapy. The addition of a diuretic and/or salt restriction increase both the anti-proteinuric and antihypertensive effect of angiotensin blockade and therefore constitute an ideal second-line treatment. The benefit from blockade of the renin–angiotensin system arises from a reduction in the angiotensin II-mediated vasoconstriction of efferent arterioles in glomeruli (see Fig. 15.1D, p. 385). The resulting dilatation of these vessels decreases glomerular filtration pressure and, therefore, the hyperfiltration and protein leak. Both ACE inhibitors and ARBs increase risk of hyperkalaemia (p. 362) and, in the presence of renal artery stenosis (p. 406), may induce marked deterioration in renal function. Therefore, electrolytes and renal function should be checked after initiation or each dose increase. If blockade of the renin–angiotensin system is not possible, blood pressure should managed with standard treatment, such as calcium channel blockers and diuretics. There may be a role for spironolactone (an aldosterone antagonist) but this is limited by hyperkalaemia. Halving the amount of albuminuria with an ACE inhibitor or ARB results in a nearly 50% reduction in long-term risk of progression to end-stage renal disease. Some patients do progress, however, with worsening renal function. Renal replacement therapy (p. 420) is often required at a higher eGFR than in other causes of renal failure, due to fluid overload or symptomatic uraemia. Renal transplantation dramatically improves the life of many, and any recurrence of diabetic nephropathy in the allograft is usually too slow to be a serious problem; associated macrovascular and microvascular disease elsewhere may still progress, however. Pancreatic transplantation (generally carried out at the same time as renal transplantation) can produce insulin independence and delay or reverse microvascular disease, but the supply of organs is limited and this option is available to few. For further information on management, see Chapter 15. Diabetic neuropathy Diabetic neuropathy causes substantial morbidity and increases mortality. It is diagnosed on the basis of symptoms and signs, after the exclusion of other causes of neuropathy (p. 1138). Depending on the criteria used for diagnosis, it affects between 50% and 90% of patients with diabetes, and of these, 15–30% will have painful diabetic neuropathy (PDN). Like retinopathy, neuropathy occurs secondary to metabolic disturbance, and prevalence is related to the duration of diabetes and the degree of metabolic control. Pathological features can occur in any peripheral nerves. They include axonal degeneration of both myelinated and unmyelinated fibres, with thickening of the Schwann cell basal lamina, patchy segmental demyelination and abnormal intraneural capillaries (with basement membrane thickening and microthrombi). Various classifications of diabetic neuropathy have been proposed. One is shown in Box 20.40 but motor, sensory and autonomic nerves may be involved in varying combinations, so that clinically mixed syndromes usually occur. Clinical features Symmetrical sensory polyneuropathy This is frequently asymptomatic. The most common clinical signs are diminished perception of vibration sensation distally, ‘glove 20.39 Screening for microalbuminuria • Screening identifies incipient nephropathy in type 1 and type 2 diabetes; is an independent predictor of macrovascular disease in type 2 diabetes • Risk factors include high blood pressure, poor glycaemic control and smoking • Early morning urine is measured for the albumin:creatinine ratio (ACR). Microalbuminuria is present if: Male ACR 2.5–30 mg/mmol creatinine Female ACR 3.5–30 mg/mmol creatinine • An elevated ACR should be followed by a repeat test: There is established microalbuminuria if 2 out of 3 tests are positive An ACR > 30 mg/mmol creatinine is consistent with overt nephropathy Fig. 20.22 Nodular diabetic glomerulosclerosis. There is thickening of basement membranes, mesangial expansion and a Kimmelstiel–Wilson nodule (arrow), which is pathognomonic of diabetic kidney disease. Fig. 20.21 Natural history of diabetic nephropathy. In the first few years of type 1 diabetes mellitus, there is hyperfiltration, which declines fairly steadily to return to a normal value at approximately 10 years (blue line). In susceptible patients (about 30%), after about 10 years, there is sustained proteinuria, and by approximately 14 years it has reached the nephrotic range (red line). Renal function continues to decline, with the end stage being reached at approximately 16 years. Microalbuminuria Sustained proteinuria Nephrotic range proteinuria

GFR (mL / min) Proteinuria (g / 24 hrs) Years Hyperfiltration Hypertension Renal failure risk of progression of nephropathy and of cardiovascular disease by: • aggressive reduction of blood pressure • aggressive reduction of cardiovascular risk factors • optimisation of glycaemic control

Complications of diabetes • 759

pressure on the plantar aspects of the metatarsal heads, with the development of callus skin at these and other pressure points. Electrophysiological tests (p. 1074) demonstrate slowing of both motor and sensory conduction, and tests of vibration sensitivity and thermal thresholds are abnormal. A diffuse small-fibre neuropathy causes altered perception of pain and temperature, and is associated with symptomatic autonomic neuropathy; characteristic features include foot ulcers and Charcot neuroarthropathy. Asymmetrical motor diabetic neuropathy Sometimes called diabetic amyotrophy, this presents as severe and progressive weakness and wasting of the proximal muscles of the lower (and occasionally the upper) limbs. It is commonly accompanied by severe pain, felt mainly on the anterior aspect of the leg, and hyperaesthesia and paraesthesiae. Sometimes there may also be marked loss of weight (‘neuropathic cachexia’). The patient may look extremely ill and be unable to get out of bed. Tendon reflexes may be absent on the affected side(s). Sometimes there are extensor plantar responses and the cerebrospinal fluid protein is often raised. This condition is thought to involve acute infarction of the lower motor neurons of the lumbosacral plexus. Other lesions involving this plexus, such as neoplasms and lumbar disc disease, must be excluded. Although recovery usually occurs within 12 months, some deficits are permanent. Management is mainly supportive. and stocking’ impairment of all other modalities of sensation (Fig. 20.23), and loss of tendon reflexes in the lower limbs. In symptomatic patients, sensory abnormalities are predominant. Symptoms include paraesthesiae in the feet (and, rarely, in the hands), pain in the lower limbs (dull, aching and/or lancinating, worse at night, and felt mainly on the anterior aspect of the legs), burning sensations in the soles of the feet, cutaneous hyperaesthesia and, when severe, an abnormal gait (commonly wide-based), often associated with a sense of numbness in the feet. Weakness and atrophy, in particular of the interosseous muscles, develops, leading to structural changes in the foot with loss of lateral and transverse arches, clawing of the toes and exposure of the metatarsal heads. This results in increased 20.40 Classification of diabetic neuropathy Somatic • Polyneuropathy: Symmetrical, mainly sensory and distal Asymmetrical, mainly motor and proximal (including amyotrophy) • Mononeuropathy (including mononeuritis multiplex) Visceral (autonomic) • Cardiovascular • Gastrointestinal • Genitourinary • Sudomotor • Vasomotor • Pupillary Fig. 20.23 Diabetic foot disease. Patients with diabetes can have neuropathy, peripheral vascular disease or both. Clawing of the toes is thought to be caused by intrinsic muscle atrophy and subsequent imbalance of muscle function, and causes greater pressure on the metatarsal heads and pressure on flexed toes, leading to increased callus and risk of ulceration. A Charcot foot occurs only in the presence of neuropathy, and results in bony destruction and ultimately deformity (this X-ray shows a resulting ‘rocker bottom foot’). The angiogram reveals disease of the superficial femoral arteries (occlusion of the left and stenosis of the right). Insets (Proximal arterial occlusion) From http://emedicine.medscape.com/article/460178-overview#a0104; (Toe clawing) Bowker JH, Pfeifer MA. Levin and O’Neal’s The diabetic foot, 7th edn. Philadelphia: Mosby, Elsevier Inc.; 2008; (Neuropathic foot ulcer) Levy MJ, Valabhji J. Vascular II: The diabetic foot. Surgery 2008; 26:25–28; (Digital gangrene) Swartz MH. Textbook of physical diagnosis, 5th edn. Philadelphia: WB Saunders, Elsevier Inc.; 2006. Glove and stocking neuropathy Clawing of toes Digital gangrene Neuropathic ulcer Dry, cracked skin Callus Loss of leg hair Peripheral vascular disease Peripheral neuropathy Charcot foot Proximal arterial occlusion Absent pulses Cold feet

760 • DIABETES MELLITUS Gastroparesis Gastroparesis is diagnosed when there is an objectively measured delay in gastric emptying in the absence of mechanical obstruction. It is most commonly a manifestation of autonomic neuropathy in diabetes, but can occur with eating disorders such as anorexia nervosa or bulimia that are also associated with diabetes. Prevalence rates are estimated to be approximately 5% in type 1 diabetes and 1% in type 2 diabetes. The main symptoms are chronic nausea, vomiting (especially of undigested food), abdominal pain and a feeling of fullness/early satiety. Diagnosis is most commonly made by 99m-technetium scintigraphy following a solid-phase meal with standard imaging over 4 hours. In this test it is important to recognise that high glucose levels can delay gastric emptying and so every attempt should be made to conduct the test when glucose levels are below 15 mmol/L (270 mg/dL). Other tests include upper gastrointestinal endoscopy, wireless motility capsules and breath testing (pp. 774, 776 and 777). Management is difficult, with glucose levels directly impacting on gastric motility and, conversely, gastroparesis affecting absorption of ingested carbohydrate. Insulin pump therapy may be especially useful in this context; patients on conventional injection therapy may benefit from injecting rapid-acting insulin after a meal rather than before. Recommended dietary changes include following low-fibre and low-residue diets, as well as eating smaller amounts more frequently. Enteral nutrition is rarely required unless gastroparesis is very severe. Recommended pharmacological and interventional therapy is shown in Box 20.43. Erectile dysfunction Erectile failure (impotence) affects 30% of diabetic males and is often multifactorial. Although neuropathy and vascular causes are common, psychological factors, including depression, anxiety and reduced libido, may be partly responsible. Alcohol and antihypertensive drugs, such as thiazide diuretics and β-adrenoceptor antagonists (β-blockers), may cause sexual dysfunction and in some patients there may be an endocrine 20.41 Clinical features of autonomic neuropathy Cardiovascular • Postural hypotension • Resting tachycardia • Fixed heart rate Gastrointestinal • Dysphagia, due to oesophageal atony • Abdominal fullness, nausea and vomiting, unstable glycaemia, due to delayed gastric emptying (‘gastroparesis’) • Nocturnal diarrhoea ± faecal incontinence • Constipation, due to colonic atony Genitourinary • Difficulty in micturition, urinary incontinence, recurrent infection, due to atonic bladder • Erectile dysfunction and retrograde ejaculation Sudomotor • Nocturnal sweats without hypoglycaemia • Gustatory sweating • Anhidrosis; fissures in the feet Vasomotor • Feet feel cold, due to loss of skin vasomotor responses • Dependent oedema, due to loss of vasomotor tone and increased vascular permeability • Bulla formation Pupillary • Decreased pupil size • Resistance to mydriatics • Delayed or absent reflexes to light Mononeuropathy Either motor or sensory function can be affected within a single peripheral or cranial nerve. Unlike the gradual progression of distal symmetrical and autonomic neuropathies, mononeuropathies are severe and of rapid onset, but they eventually recover. The nerves most commonly affected are the 3rd and 6th cranial nerves (resulting in diplopia), and the femoral and sciatic nerves. Rarely, involvement of other single nerves results in paresis and paraesthesiae in the thorax and trunk (truncal radiculopathies). Nerve compression palsies are more common in diabetes, frequently affecting the median nerve and giving the clinical picture of carpal tunnel syndrome, and less commonly the ulnar nerve. Lateral popliteal nerve compression occasionally causes foot drop. Compression palsies may be more common because of glycosylation and thickening of connective tissue and/or because of increased susceptibility of nerves affected by diabetic microangiopathy. Autonomic neuropathy This is not necessarily associated with peripheral somatic neuropathy. Parasympathetic or sympathetic nerves may be predominantly affected in one or more visceral systems. The resulting symptoms and signs are listed in Box 20.41 and tests of autonomic function in Box 20.42. The development of autonomic neuropathy is related to poor metabolic control less clearly than to somatic neuropathy, and improved control rarely results in improved symptoms. Within 10 years of developing overt symptoms of autonomic neuropathy, 30–50% of patients are dead, many from sudden cardiorespiratory arrest. Patients with postural hypotension (a drop in systolic pressure of 30 mmHg or more on standing from the supine position) have the highest subsequent mortality. 20.42 How to test cardiovascular autonomic function Simple reflex tests Normal Borderline Abnormal Heart rate responses To Valsalva manœuvre (15 secs)1: ratio of longest to shortest R–R interval ≥ 1.21 ≤ 1.20 To deep breathing (6 breaths over 1 min): maximum– minimum heart rate ≥ 15 11–14 ≤ 10 To standing after lying: ratio of R–R interval of 30th to 15th beats ≥ 1.04 1.01–1.03 ≤ 1.00 Blood pressure response2 To standing: systolic blood pressure fall (mmHg) ≤ 10 11–29 ≥ 30 Specialised tests • Heart rate and blood pressure responses to sustained handgrip • Heart rate variability using power spectral analysis of ECG monitoring • Heart rate and blood pressure variability using time–domain analysis of ambulatory monitoring • MIBG (meta-iodobenzylguanidine) scan of the heart 1Omit in patients with previous laser therapy for proliferative retinopathy. 2Avoid arm with arteriovenous fistula in dialysed patients.

Complications of diabetes • 761

(p. 502 and Fig. 20.23); with infection is a secondary phenomenon following disruption of the protective epidermis. Most ulcers develop at the site of a plaque of callus skin, beneath which tissue necrosis occurs and eventually breaks through to the surface. In many cases, multiple components are involved but sometimes neuropathy or ischaemia predominates (Box 20.44). Ischaemia alone accounts for a minority of foot ulcers in diabetic patients, with most being either neuropathic or neuro-ischaemic. Charcot neuroarthropathy is a progressive condition affecting the bones and joints of the foot; it is characterised by early inflammation and then joint dislocation, subluxation and pathological fractures of the foot of neuropathic patients, often resulting in debilitating deformity (Fig. 20.23 and p. 720). Charcot neuroarthropathy can arise in any condition that causes neuropathy (including syphilis, spinal cord injury, syringomyelia etc.) but diabetes is the most common cause. The pathophysiological mechanisms remain poorly understood but may involve unperceived trauma, leading to progressive destruction (the ‘neurotraumatic’ theory) and/or increased blood flow that results in a mismatch of bone destruction and synthesis (the ‘neurovascular’ theory). More recent evidence points to disordered inflammation mediated via the nuclear factor kappa B (NFκB)/receptor activator of NFκB ligand (RANKL) pathway, opening the way for trials of the RANKL inhibitor denosumab (p. 1048). Management Management can be divided into primary prevention and treatment of an active problem. All patients should be educated in preventative measures (Box 20.45). The feet of people with diabetes should be screened annually, following the steps listed on page 721. Two simple tests are required to grade risk: a 10 g monofilament should be used to assess sensation at five points on each foot, and foot pulses should be palpated (dorsalis pedis and/or posterior tibial). Combined with the clinical scenario, these tests guide appropriate referral and monitoring (Fig. 20.24). Removal of callus skin with a scalpel is best done by a podiatrist who has specialist training and experience in diabetic foot problems. Foot ulcer Once a foot ulcer develops, patients should ideally be referred to a multidisciplinary foot team, involving a diabetes specialist, a podiatrist, a vascular surgeon and an orthotist. Treatment involves: débridement of dead tissue; prompt, often prolonged, treatment with antibiotics if required, as infection can accelerate tissue necrosis and lead to gangrene; and pressure relief using customised insoles, specialised orthotic footwear and sometimes total contact plaster cast or an irremovable aircast boot. If an ulcer cause, such as testosterone deficiency or hyperprolactinaemia. For further information, see page 440. Management Management of neuropathies is outlined in Box 20.43. The diabetic foot The foot is a frequent site of complications in patients with diabetes and for this reason foot care is particularly important. Tissue necrosis in the feet is a common reason for hospital admission in diabetic patients. Treatment of the foot complications of diabetes accounts for more inpatient days than any other diabetes-related complication. Aetiology Foot ulceration occurs as a result of trauma (often trivial) in the presence of neuropathy and/or peripheral vascular disease 20.44 Clinical features of the diabetic foot Neuropathy Ischaemia Symptoms None Paraesthesiae Pain Numbness None Claudication Rest pain Structural damage Ulcer Sepsis Abscess Osteomyelitis Digital gangrene Charcot joint Ulcer Sepsis Gangrene Gastroparesis • Dopamine antagonists (metoclopramide, domperidone) • Erythromycin • Botulinum toxin • α-adrenoceptor agonist (midodrine) • Gastric pacemaker; percutaneous enteral (jejunal) feeding (see Fig. 19.10, p. 708) • Clonidine • Octreotide Diarrhoea (p. 783) • Loperamide • Broad-spectrum antibiotics Constipation • Stimulant laxatives (senna) Atonic bladder • Intermittent self-catheterisation (p. 1093) Excessive sweating • Anticholinergic drugs (propantheline, poldine, oxybutinin) • Clonidine • Topical antimuscarinic agent (glycopyrrolate cream) Erectile dysfunction (p. 440) • Phosphodiesterase type 5 inhibitors (sildenafil, vardenafil, tadalafil) – oral • Dopamine agonist (apomorphine) – sublingual • Prostaglandin E1 (alprostadil) – injected into corpus cavernosum or intra-urethral administration of pellets • Vacuum tumescence devices • Implanted penile prosthesis • Psychological counselling; psychosexual therapy (NSAIDs = non-steroidal anti-inflammatory drugs) 20.43 Management options for peripheral sensorimotor and autonomic neuropathies Pain and paraesthesiae from peripheral somatic neuropathies • Intensive insulin therapy (strict glycaemic control) • Anticonvulsants (gabapentin, pregabalin, carbamazepine, phenytoin) • Tricyclic antidepressants (amitriptyline, imipramine) • Other antidepressants (duloxetine) • Substance P depleter (capsaicin – topical) • Opiates (tramadol, oxycodone) • Membrane stabilisers (mexiletine, IV lidocaine) • Antioxidant (α-lipoic acid) Postural hypotension • Support stockings • Fludrocortisone • NSAIDs

762 • DIABETES MELLITUS of weight-bearing on the affected foot. The rationale is that if no pressure is applied through the foot, the destructive process involving the bones will not result in significant deformity when the acute inflammatory process subsides. Immobilisation is often achieved by a total contact plaster cast or ‘aircast’ boot. The acute phase frequently lasts 3–6 months and sometimes longer. In the post-acute phase, there is consolidation and remodelling of fracture fragments, eventually resulting in a stable foot. Further information Books and journal articles Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med 1993; 329:977–986. Nathan DM, Cleary PA, Backlud JY, et al. Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Study Research Group. Intensive diabetes treatment and cardiovascular disease in patients with type 1 diabetes. N Engl J Med 2005; 353:2643–2653. UK Prospective Diabetes Study (UKPDS) Group. Intensive bloodglucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 1998; 352:837–853, 854–865. Websites cdc.gov/diabetes/ Diabetes Public Health Resource. Useful American site with resources for patients and health-care professionals. diabetes.org American Diabetes Association. Includes information on research and advocacy issues. diabetes.org.uk Diabetes UK. Includes information for patients and leaflets. idf.org International Diabetes Federation. Useful information on international aspects of care and education. joslin.org Joslin Diabetes Center. Well-written resource for patients and health-care professionals, and information on diabetes research. mydiabetesmyway.scot.nhs.uk An interactive diabetes website for patients with diabetes and their carers. ndei.org National Diabetes Education Initiative. Web-based education for health-care professionals, including case studies and slides. is neuro-ischaemic, a vascular assessment is often carried out, by ultrasound or angiography, as revascularisation by angioplasty or surgery may be required to allow the ulcer to heal. In cases of severe secondary infection or gangrene, an amputation may be required. This can be limited to the affected toe or involve more extensive limb amputation. Charcot neuroarthropathy Acute Charcot neuroarthropathy almost always presents with signs of inflammation – a hot, red, swollen foot. The initial X-ray may show bony destruction but is often normal. As about 40% of patients with a Charcot joint also have a foot ulcer, it can be difficult to differentiate from osteomyelitis. Magnetic resonance imaging (MRI) of the foot is often helpful. The mainstay of treatment for an active Charcot foot is immobilisation and, ideally, avoidance Fig. 20.24 Risk assessment and management of foot problems in diabetes. Adapted from Scottish Intercollegiate Guidelines Network (SIGN) guideline number 116. Moderate Low High Active Urgent referral to specialist team Current foot ulcer, infection, critical ischaemia, gangrene or unexplained hot, red swollen foot Previous foot ulcer or amputation Sensation impaired and foot pulses absent Skin callus or foot deformity? Yes No Inability to selfcare for feet Sensation impaired or foot pulses absent Sensation unimpaired and foot pulses present Annual assessment by specialist podiatrist Annual assessment by podiatrist Annual screening by health-care professional Management Screening • Check footwear for foreign bodies • Wear suitable, well-fitting shoes • Cover minor cuts with sterile dressings • Do not burst blisters • Avoid over-the-counter corn/ callus remedies Moderate- and high-risk patients As above plus: • Do not attempt corn removal • Avoid high and low temperatures Podiatric care • A podiatrist is an integral part of the diabetes team to ensure regular and effective podiatry and to educate patients in care of the feet Orthotic footwear • Specially manufactured and fitted orthotic footwear is required to prevent recurrence of ulceration and to protect the feet of patients with Charcot neuroarthropathy 20.45 Care of the feet in patients with diabetes Preventative advice All diabetic patients • Inspect feet every day • Wash feet every day • Moisturise skin if dry • Cut or file toenails regularly • Change socks or stockings every day • Avoid walking barefoot

Ch04-3 Clinical Medicine

11-21 Gastroenterology

21 Gastroenterology

Gastroenterology E El-Omar MH McLean Clinical examination of the gastrointestinal tract 764 Functional anatomy and physiology 766 Oesophagus, stomach and duodenum 766 Small intestine 767 Pancreas 770 Colon 770 Intestinal microbiota 771 Control of gastrointestinal function 771 Gut hormones 772 Investigation of gastrointestinal disease 772 Imaging 772 Tests of infection 777 Tests of function 777 Radioisotope tests 778 Gut hormone testing 778 Presenting problems in gastrointestinal disease 778 Dysphagia 778 Dyspepsia 779 Heartburn and regurgitation 779 Vomiting 780 Gastrointestinal bleeding 780 Diarrhoea 783 Malabsorption 783 Weight loss 785 Constipation 786 Abdominal pain 787 Diseases of the mouth and salivary glands 790 Diseases of the oesophagus 791 Gastro-oesophageal reflux disease 791 Motility disorders 794 Tumours of the oesophagus 796 Perforation of the oesophagus 797 Diseases of the stomach and duodenum 797 Gastritis 797 Peptic ulcer disease 798 Functional disorders 802 Tumours of the stomach 803 Diseases of the small intestine 805 Disorders causing malabsorption 805 Motility disorders 810 Miscellaneous disorders of the small intestine 811 Adverse food reactions 812 Infections of the small intestine 812 Tumours of the small intestine 813 Inflammatory bowel disease 813 Irritable bowel syndrome 824 HIV/AIDS and the gastrointestinal tract 826 Ischaemic gut injury 827 Disorders of the colon and rectum 827 Tumours of the colon and rectum 827 Diverticulosis 833 Constipation and disorders of defecation 834 Anorectal disorders 835 Diseases of the peritoneal cavity 836 Other disorders 837 Diseases of the pancreas 837 Acute pancreatitis 837 Chronic pancreatitis 839 Congenital abnormalities affecting the pancreas 842 Tumours of the pancreas 842

764 • GASTROENTEROLOGY Clinical examination of the gastrointestinal tract Observation Hands Clubbing Koilonychia Signs of liver disease (Ch. 22) Head and neck Pallor Jaundice Angular stomatitis Glossitis Parotid enlargement Mouth ulcers Dentition Lymphadenopathy Abdominal examination (see opposite) Multiple surgical scars, a prolapsing ileostomy and enterocutaneous fistulae in a patient with Crohn’s disease • Distressed/in pain? • Fever? • Dehydrated? • Habitus • Skin Skin and nutritional status Muscle bulk Signs of weight loss Groin Herniae Lymph nodes Perineum/rectal (see opposite) Fistulae Skin tags Haemorrhoids Masses Clubbing in patient with malabsorption Virchow’s gland in gastric cancer Pyoderma gangrenosum in ulcerative colitis Atrophic glossitis and angular stomatitis in vitamin B12 deficiency Observe Distension Respiratory movements Scars Colour Palpate Tender/guarding Masses Viscera Liver (Ch. 22) Kidneys (Ch. 15) Spleen Percuss Ascites Viscera Auscultate Bowel sounds Bruits

Clinical examination of the gastrointestinal tract • 765

Tumour Polyp Cancer Extrinsic Tumour Abscess Prostate Uterus/cervix Prolapse Stool Consistency Colour Steatorrhoea Bloody/black Faecal occult blood Anal disease Tags Haemorrhoids Polyps Crohn’s disease 6 Rectal examination: common findings Epigastric mass Gastric cancer Pancreatic cancer Aortic aneurysm Left upper quadrant mass ?Spleen Edge Can’t get above it Moves towards right iliac fossa Dull percussion note Notch ?Kidney Rounded Can get above it Moves down Resonant to percussion Ballotable Tender to palpation ?Peritonitis Guarding and rebound Absent bowel sounds Rigidity ?Obstruction Distended Tinkling bowel sounds Visible peristalsis Left iliac fossa mass Sigmoid colon cancer Constipation Diverticular mass Right iliac fossa mass Caecal carcinoma Crohn’s disease Appendix abscess Hepatomegaly Palpable gallbladder (Ch. 22) Generalised distension Fat (obesity) Fluid (ascites) Flatus (obstruction/ileus) Faeces (constipation) Fetus (pregnancy) Suprapubic mass Bladder Pregnancy Fibroids/carcinoma 4 Abdominal examination: possible findings

766 • GASTROENTEROLOGY Functional anatomy and physiology Oesophagus, stomach and duodenum The oesophagus is a muscular tube that extends 25 cm from the cricoid cartilage to the cardiac orifice of the stomach. It has an upper and a lower sphincter. A peristaltic swallowing wave propels the food bolus into the stomach (Fig. 21.1). The stomach acts as a ‘hopper’, retaining and grinding food, and then actively propelling it into the upper small bowel (Fig. 21.2). Diseases of the gastrointestinal tract are a major cause of morbidity and mortality. Approximately 10% of all GP consultations in the UK are for indigestion and 1 in 14 is for diarrhoea. Infective diarrhoea and malabsorption are responsible for much ill health and many deaths in the developing world. The gastrointestinal tract is the most common site for cancer development. Colorectal cancer is the third most common cancer in men and women and population-based screening programmes exist in many countries. Functional bowel disorders affect up to 10–15% of the population and consume considerable health-care resources. The inflammatory bowel diseases, Crohn’s disease and ulcerative colitis, together affect 1 in 250 people in the Western world, with substantial associated morbidity. Fig. 21.1 The oesophagus: anatomy and function. The swallowing wave. Swallowing begins as a voluntary process. The food bolus is forcibly propelled by the tongue into the pharynx The upper oesophageal sphincter relaxes Peristaltic activity, controlled by a brainstem centre, is mediated by autonomic nerves The lower oesophageal sphincter relaxes. The food enters the stomach

Upper sphincter (cricopharyngeus muscle) Lower oesophageal sphincter Endoscopic view Normal high-resolution manometry Fig. 21.2 Normal gastric and duodenal anatomy. Vagus nerves Cardia Fundus Antrum Body Pancreas First part of duodenum Second part of duodenum Common bile duct Endoscopic view Endoscopic view Third part of duodenum Diaphragm

Functional anatomy and physiology • 767

duodenal mucosa from the ulcerative properties of acid and pepsin. Small intestine The small bowel extends from the ligament of Treitz to the ileocaecal valve (Fig. 21.4). During fasting, a wave of peristaltic activity passes down the small bowel every 1–2 hours. Entry of food into the gastrointestinal tract stimulates small bowel peristaltic activity. Functions of the small intestine are: • digestion (mechanical, enzymatic and peristaltic) • absorption – the products of digestion, water, electrolytes and vitamins • protection against ingested toxins • immune regulation. Gastric secretion Gastrin, histamine and acetylcholine are the key stimulants of acid secretion. Hydrogen and chloride ions are secreted from the apical membrane of gastric parietal cells into the lumen of the stomach by a hydrogen–potassium adenosine triphosphatase (ATPase) (‘proton pump’) (Fig. 21.3). The hydrochloric acid sterilises the upper gastrointestinal tract and converts pepsino gen, which is secreted by chief cells, to pepsin. The glycoprotein intrinsic factor, secreted in parallel with acid, is necessary for vitamin B12 absorption. Gastrin, somatostatin and ghrelin The hormone gastrin is produced by G cells in the antrum, whereas somatostatin is secreted from D cells throughout the stomach. Gastrin stimulates acid secretion and mucosal growth while somatostatin suppresses it. Ghrelin, secreted from oxyntic glands, stimulates acid secretion but also appetite and gastric emptying. Protective factors Bicarbonate ions, stimulated by prostaglandins, mucins and trefoil factor family (TFF) peptides, together protect the gastroFig. 21.3 Control of acid secretion. Gastrin released from antral G cells in response to food (protein) binds to cholecystokinin receptors (CCK-2R) on the surface of enterochromaffin-like (ECL) cells, which in turn release histamine. The histamine binds to H2 receptors on parietal cells and this leads to secretion of hydrogen ions in exchange for potassium ions at the apical membrane. Parietal cells also express CCK-2R and it is thought that activation of these receptors by gastrin is involved in regulatory proliferation of parietal cells. Cholinergic (vagal) activity and gastric distension also stimulate acid secretion; somatostatin, vasoactive intestinal polypeptide (VIP) and gastric inhibitory polypeptide (GIP) may inhibit it. (ACh-R = acetylcholine receptor; ATPase = adenosine triphosphatase) Enterochromaffin-like cell Parietal cell Histamine Gastrin CCK-2R Gastrin CCK-2R H2 ACh-R (M3) Vagal stimulation Anticipation or smell of food Gastric distension H+/K+ ATPase K+ H+ Cl– Fig. 21.4 Small intestine: anatomy. Epithelial cells are formed in crypts and differentiate as they migrate to the tip of the villi to form enterocytes (absorptive cells) and goblet cells. Superior mesenteric artery Jejunum Arteries Veins Lymphatics Paneth cells Ligament of Treitz Brush border microvilli Crypts Villi Ileum

768 • GASTROENTEROLOGY energy-requiring process involving a carrier protein, and fructose enters by simple diffusion. Protein The steps involved in protein digestion are shown in Figure 21.6. Intragastric digestion by pepsin is quantitatively modest but important because the resulting polypeptides and amino acids stimulate cholecystokinin (CCK) release from the mucosa of the proximal jejunum, which in turn stimulates release of pancreatic proteases, including trypsinogen, chymotrypsinogen, pro-elastases and procarboxypeptidases, from the pancreas. On exposure to brush border enterokinase, inert trypsinogen is converted to the active proteolytic enzyme trypsin, which activates the other pancreatic pro-enzymes. Trypsin digests proteins to produce oligopeptides, peptides and amino acids. Oligopeptides are further hydrolysed by brush border enzymes to yield dipeptides, tripeptides and amino acids. These small peptides and the amino acids are actively transported into the enterocytes, where intracellular peptidases further digest peptides to amino acids. Amino acids are then actively transported across the basal cell membrane of the enterocyte into the portal circulation and the liver. Digestion and absorption Fat Dietary lipids comprise long-chain triglycerides, cholesterol esters and lecithin. Lipids are insoluble in water and undergo lipolysis and incorporation into mixed micelles before they can be absorbed into enterocytes along with the fat-soluble vitamins A, D, E and K. The lipids are processed within enterocytes and pass via lymphatics into the systemic circulation. Fat absorption and digestion can be considered as a stepwise process, as outlined in Figure 21.5. Carbohydrates Starch is hydrolysed by salivary and pancreatic amylases to: • α-limit dextrins containing 4–8 glucose molecules • the disaccharide maltose • the trisaccharide maltotriose. Disaccharides are digested by enzymes fixed to the microvillous membrane to form the monosaccharides glucose, galactose and fructose. Glucose and galactose enter the cell by an Fig. 21.5 Fat digestion. Step 1: Luminal phase. Fatty acids stimulate cholecystokinin (CCK) release from the duodenum and upper jejunum. The CCK stimulates release of amylase, lipase, colipase and proteases from the pancreas, causes gallbladder contraction and relaxes the sphincter of Oddi, allowing bile to flow into the intestine. Step 2: Fat solubilisation. Bile acids and salts combine with dietary fat to form mixed micelles, which also contain cholesterol and fat-soluble vitamins. Step 3: Digestion. Pancreatic lipase, in the presence of its co-factor, colipase, cleaves long-chain triglycerides, yielding fatty acids and monoglycerides. Step 4: Absorption. Mixed micelles diffuse to the brush border of the enterocytes. Within the brush border, long-chain fatty acids bind to proteins, which transport the fatty acids into the cell, whereas cholesterol, short-chain fatty acids, phospholipids and fat-soluble vitamins enter the cell directly. The bile salts remain in the small intestinal lumen and are actively transported from the terminal ileum into the portal circulation and returned to the liver (the enterohepatic circulation). Step 5: Re-esterification. Within the enterocyte, fatty acids are re-esterified to form triglycerides. Triglycerides combine with cholesterol ester, fat-soluble vitamins, phospholipids and apoproteins to form chylomicrons. Step 6: Transport. Chylomicrons leave the enterocytes by exocytosis, enter mesenteric lymphatics, pass into the thoracic duct and eventually reach the systemic circulation. Simple micelles Enterohepatic circulation Pancreatic enzyme secretion Gallbladder contraction C V P Digestion of triglycerides C V P C V P Apoproteins Absorption Chylomicrons Bile acids resorbed in terminal ileum

Fat emulsification by motor activity CCK release from duodenum Dietary fat Fat solubilisation (‘mixed’ micelles) Bile acids and salts Fat Lipase Colipase Monoglycerides Free fatty acids Triglycerides Lymphatics Enterocyte Triglyceride Glycerol Fatty acids Cholesterol (C) Phospholipids (P) Vitamins A, D, E and K (V)

Functional anatomy and physiology • 769

Fig. 21.6 Protein digestion. (CCK = cholecystokinin) CCK release Minor digestion by pepsins Trypsinogen Enterokinase Trypsin Proteins Activation of other pro-enzymes Peptides Amino acids Oligopeptides Brush border enzymes Small peptides Amino acids Enterocyte Peptides Peptidase Amino acids Portal circulation Liver Peptides Peptidase Amino acids Stomach Small intestine Pancreas Pancreatic pro-enzyme secretion Fig. 21.7 Fluid homeostasis in the gastrointestinal tract. Saliva 1500 mL Gastric 2000 mL Pancreas 1500 mL Small intestine 1500 mL 100 mL Food + H2O intake 1200 mL Bile 500 mL Colonic reabsorption 1400 mL Portal vein 6700 mL Total in Reabsorbed Stool excretion 8200 mL 8100 mL 100 mL Water and electrolytes Absorption and secretion of electrolytes and water occur throughout the intestine. Electrolytes and water are transported by two pathways: • the paracellular route, in which passive flow through tight junctions between cells is a consequence of osmotic, electrical or hydrostatic gradients • the transcellular route across apical and basolateral membranes by energy-requiring specific active transport carriers (pumps). In healthy individuals, fluid balance is tightly controlled, such that only 100 mL of the 8 litres of fluid entering the gastrointestinal tract daily is excreted in stools (Fig. 21.7). Vitamins and trace elements Water-soluble vitamins are absorbed throughout the intestine. The absorption of folic acid, vitamin B12, calcium and iron is described on page 943. Protective function of the small intestine Physical defence mechanisms There are several levels of defence in the small bowel (Fig. 21.8). Firstly, the gut lumen contains host bacteria (see below), mucins and secreted antibacterial products, including defensins and immunoglobulins that help combat pathogenic infections. Secondly, epithelial cells have relatively impermeable brush border membranes and passage between cells is prevented by tight and adherens junctions. These cells can react to foreign peptides (‘innate immunity’) using pattern recognition receptors found on cell surfaces (Toll receptors) or intracellularly. Lastly, in the subepithelial layer, immune responses occur under control of the adaptive immune system in response to pathogenic compounds. Immunological defence mechanisms Gastrointestinal mucosa-associated lymphoid tissue (MALT) constitutes 25% of the total lymphatic tissue of the body and is at the heart of adaptive immunity. Within Peyer’s patches,

770 • GASTROENTEROLOGY hormones (Fig. 21.9) and are activated by trypsin. Bicarbonate-rich fluid is secreted from ductular cells to produce an optimum alkaline pH for enzyme activity. The endocrine pancreas is discussed in Chapters 18 and 20. Colon The colon (Fig. 21.10) absorbs water and electrolytes. It also acts as a storage organ and has contractile activity. Two types of contraction occur. The first of these is segmentation (ring contraction), which leads to mixing but not propulsion; this promotes absorption of water and electrolytes. Propulsive (peristaltic contraction) waves occur several times a day and propel faeces to the rectum. All activity is stimulated after meals through the gastrocolic reflex in response to release of hormones such as 5-hydroxytryptamine (5-HT, serotonin), motilin and CCK. Faecal continence depends on maintenance of the anorectal angle and tonic contraction of the external anal sphincters. On defecation, there is relaxation of the anorectal muscles, increased intra-abdominal pressure from the Valsalva manœuvre and contraction of abdominal muscles, and relaxation of the anal sphincters. B lymphocytes differentiate to plasma cells following exposure to antigens and these migrate to mesenteric lymph nodes to enter the blood stream via the thoracic duct. The plasma cells return to the lamina propria of the gut through the circulation and release immunoglobulin A (IgA), which is transported into the lumen of the intestine. Intestinal T lymphocytes help localise plasma cells to the site of antigen exposure, as well as producing inflammatory mediators. Macrophages in the gut phagocytose foreign materials and secrete a range of cytokines, which mediate inflammation. Similarly, activation of mast-cell surface IgE receptors leads to degranulation and release of other molecules involved in inflammation. Pancreas The exocrine pancreas (Box 21.1) is necessary for the digestion of fat, protein and carbohydrate. Pro-enzymes are secreted from pancreatic acinar cells in response to circulating gastrointestinal Fig. 21.9 Pancreatic structure and function. Ductular cells secrete alkaline fluid in response to secretin. Acinar cells secrete digestive enzymes from zymogen granules in response to a range of secretagogues. The photograph shows a normal pancreatic duct (PD) and side branches, as defined at magnetic resonance cholangiopancreatography (MRCP). Note the incidental calculi in the gallbladder and common bile duct (arrow). (CCK = cholecystokinin; VIP = vasoactive intestinal polypeptide) Duodenum MRCP–normal pancreas CCK Acetylcholine Secretin VIP Bombesin Substance P Acinus Ductule Secretin Pro-enzyme HCO3- + water 5 cm Ampulla of Vater Accessory ampulla PD 21.1 Pancreatic enzymes Enzyme Substrate Product Amylase Starch and glycogen Limit dextrans Maltose Maltriose Lipase Colipase Triglycerides Monoglycerides and free fatty acids Proteolytic enzymes Trypsinogen Chymotrypsinogen Pro-elastase Pro-carboxypeptidases Proteins and polypeptides Short polypeptides Fig. 21.8 Intestinal defence mechanisms. See text for details.

Lumen

Epithelium

Subepithelial layer

Functional anatomy and physiology • 771

there are technical considerations to ensure consistency in methodologies and data analysis. Control of gastrointestinal function Secretion, absorption, motor activity, growth and differentiation of the gut are all modulated by a combination of neuronal and hormonal factors. The nervous system and gastrointestinal function The central nervous system (CNS), the autonomic system (ANS) and the enteric nervous system (ENS) interact to regulate gut function. The ANS comprises: • parasympathetic pathways (vagal and sacral efferent), which are cholinergic, and increase smooth muscle tone and promote sphincter relaxation • sympathetic pathways, which release noradrenaline (norepinephrine), reduce smooth muscle tone and stimulate sphincter contraction. The enteric nervous system In conjunction with the ANS, the ENS senses gut contents and conditions, and regulates motility, fluid exchange, secretion, blood flow and other key gut functions. It comprises two major networks intrinsic to the gut wall. The myenteric (Auerbach’s) plexus in the smooth muscle layer regulates motor control; and the submucosal (Meissner’s) plexus exerts secretory control over the epithelium, entero-endocrine cells and submucosal vessels. Together, these plexuses form a two-layered neuronal mesh along the length of Intestinal microbiota The human microbiota comprises 1014 microbial residents in the human body, vastly outnumbering host cells. Indeed, the number of bacterial genes in the microbiota genome exceeds that of the host by 100-fold or more. This represents a vast ecosystem that is central to health and homeostasis, and is disordered in disease. In terms of nomenclature, ‘microbiota’ refers to the microorganisms that live in a particular niche, while ‘microbiome’ refers to the collective genomes of these microbiota. The metabolic capacity of the gut microbiota is equivalent to that of the liver. The Human Microbiome Project revealed that there are unique communities at different body sites and in the gut particular phyla predominate: namely, Firmicutes, Bacteriodetes, Proteobacteria and Actinobacteria. There is a degree of heritability of this microbiota, as shown in twin studies, but it is clear that there are many environmental factors that can impact, including diet, drugs, physical activity, smoking, stress and natural ageing. Generally, we acquire our adult intestinal microbiota by the age of 2 years. A dysbiosis or imbalance between the different components of the intestinal microbiota has been associated with diseases of the gastrointestinal tract, such as inflammatory bowel disease and colorectal cancer; liver disease, including hepatocellular carcinoma; and pathologies outside the gastrointestinal tract, such as diabetes, obesity, cardiovascular disorders, cerebrovascular disorders, asthma and psychiatric disorders, such as depression. Many challenges remain in understanding the intestinal microbiota and how it impacts on health and disease. It is not clear what constitutes a ‘healthy’ phenotype; there are questions over best sampling practice from either the faecal stream or the mucosa; and Fig. 21.10 The normal colon, rectum and anal canal. Superior mesenteric artery Caecum Appendix Inferior mesenteric artery Rectum Anal canal External anal sphincter Internal anal sphincter Sigmoid colon Descending colon Ascending colon Ileocaecal valve Transverse colon

772 • GASTROENTEROLOGY Gut hormones The origin, action and control of the major gut hormones, peptides and non-peptide signalling transmitters are summarised in Box 21.2. Investigation of gastrointestinal disease A wide range of tests is available for the investigation of patients with gastrointestinal symptoms. These can be classified broadly into tests of structure, tests for infection and tests of function. Imaging Plain X-rays Plain X-rays of the abdomen are useful in the diagnosis of intestinal obstruction or paralytic ileus, where dilated loops of bowel and (in the erect position) fluid levels may be seen (Fig. 21.11). Calcified lymph nodes, gallstones and renal stones can also be detected. Chest X-ray (performed with the patient in erect position) is useful in the diagnosis of suspected perforation, as it shows subdiaphragmatic free air (Fig. 21.11). the gut. Although connected centrally via the ANS, the ENS can function autonomously using a variety of transmitters, including acetylcholine, noradrenaline (norepinephrine), 5-HT, nitric oxide, substance P and calcitonin gene-related peptide (CGRP). There are local reflex loops within the ENS but also loops involving the coeliac and mesenteric ganglia and the paravertebral ganglia. The parasympathetic system generally stimulates motility and secretion, while the sympathetic system generally acts in an inhibitory manner. Peristalsis Peristalsis is a reflex triggered by gut wall distension, which consists of a wave of circular muscle contraction to propel contents from the oesophagus to the rectum. It can be influenced by innervation but functions independently. It results from a basic electrical rhythm originating from the interstitial cells of Cajal in the circular layer of intestinal smooth muscle. These are stellate cells of mesenchymal origin with smooth muscle features, which act as the ‘pacemaker’ of the gut. Migrating motor complexes Migrating motor complexes (MMCs) are waves of contraction spreading from the stomach to the ileum, occurring at a frequency of about 5 per minute every 90 minutes or so, between meals and during fasting. They may serve to sweep intestinal contents distally in preparation for the next meal and are inhibited by eating. 21.2 Gut hormones and peptides Hormone Origin Stimulus Action Gastrin Stomach (G cell) Products of protein digestion Suppressed by acid and somatostatin Stimulates gastric acid secretion Stimulates growth of gastrointestinal mucosa Somatostatin Throughout gastrointestinal tract (D cell) Fat ingestion Inhibits gastrin and insulin secretion Decreases acid secretion Decreases absorption Inhibits pancreatic secretion Cholecystokinin (CCK) Duodenum and jejunum (I cells); also ileal and colonic nerve endings Products of protein digestion Fat and fatty acids Suppressed by trypsin Stimulates pancreatic enzyme secretion Stimulates gallbladder contraction Relaxes sphincter of Oddi Modulates satiety Decreases gastric acid secretion Reduces gastric emptying Regulates pancreatic growth Secretin Duodenum and jejunum (S cells) Duodenal acid Fatty acids Stimulates pancreatic fluid and bicarbonate secretion Decreases acid secretion Reduces gastric emptying Motilin Duodenum, small intestine and colon (Mo cells) Fasting Dietary fat Regulates peristaltic activity, including migrating motor complexes (MMCs) Gastric inhibitory polypeptide (GIP) Duodenum (K cells) and jejunum Glucose and fat Stimulates insulin release (also known as glucose-dependent insulinotrophic polypeptide) Inhibits acid secretion Enhances satiety Glucagon-like peptide-1 (GLP-1) Ileum and colon (L cells) Carbohydrates, protein and fat Stimulates insulin release Inhibits acid secretion and gastric emptying Enhances satiety Vasoactive intestinal peptide (VIP) Nerve fibres throughout gastrointestinal tract Unknown Has vasodilator action Relaxes smooth muscle Stimulates water and electrolyte secretion Ghrelin Stomach Fasting Inhibited by eating Stimulates appetite, acid secretion and gastric emptying Peptide YY Ileum and colon Feeding Modulates satiety

Investigation of gastrointestinal disease • 773

The double contrast technique improves mucosal visualisation by using gas to distend the barium-coated intestinal surface. Contrast studies are useful for detecting filling defects, such as tumours, strictures, ulcers and motility disorders, but are inferior to endoscopic procedures and more sophisticated cross-sectional imaging techniques, such as computed tomography and magnetic resonance imaging. The major uses and limitations of various contrast studies are shown in Box 21.3 and Figure 21.12. Contrast studies X-rays with contrast medium are usually performed to assess not only anatomical abnormalities but also motility. Barium sulphate provides good mucosal coating and excellent opacification but can precipitate impaction proximal to an obstructive lesion. Water-soluble contrast is used to opacify bowel prior to abdominal computed tomography and in cases of suspected perforation. Fig. 21.11 Examples of plain X-rays. A Abdominal X-ray showing dilatation of loops of small bowel (arrows), which are indicative of obstruction (in this case due to adhesions from previous surgery). B Chest X-ray showing free air under both hemi-diaphragms (arrows), which is indicative of acute perforation of an abdominal viscus. A B 21.3 Contrast radiology in the investigation of gastrointestinal disease Barium swallow/meal Barium follow-through Barium enema Indications and major uses Motility disorders (achalasia and gastroparesis) Perforation or fistula (non-ionic contrast) Diarrhoea and abdominal pain of small bowel origin Possible obstruction by strictures Suspected malabsorption Assessment of Crohn’s disease Altered bowel habit Evaluation of strictures or diverticular disease Megacolon Chronic constipation Limitations Risk of aspiration Poor mucosal detail Low sensitivity for early cancer Inability to biopsy Time-consuming nature Radiation exposure Relative insensitivity Difficulty in frail or incontinent patients Sigmoidoscopy needed to see rectum Low sensitivity for lesions < 1 cm Fig. 21.12 Examples of contrast radiology. A Barium swallow showing a large pharyngeal pouch (P) with retained contrast creating an air–fluid level. B Barium follow-through. There are multiple diverticula (arrows) in this patient with jejunal diverticulosis. C Barium enema showing severe diverticular disease. There is tortuosity and narrowing of the sigmoid colon with multiple diverticula (arrows). A P B C

774 • GASTROENTEROLOGY 21.4 Imaging in gastroenterology Ultrasound Computed tomography (CT) Magnetic resonance imaging (MRI) CT–positron emission tomography (CT-PET) Indications and major uses Abdominal masses Organomegaly Ascites Biliary tract dilatation Gallstones Guided biopsy of lesions Small bowel imaging Assessment of pancreatic disease Hepatic tumour deposits CT colonography (‘virtual colonoscopy’) Tumour staging Assessment of lesion vascularity Abscesses and collections Hepatic tumour staging MRCP Pelvic/perianal disease Crohn’s fistulae Small bowel visualisation Detection of metastases not seen on ultrasound or CT Images can be fused with CT to form composite image Limitations Low sensitivity for small lesions Little functional information Operator-dependent Gas and obesity may obscure view Cost Radiation dose Claustrophobic patients Contraindicated in presence of metallic prostheses, cardiac pacemaker, cochlear implants Signal detection depends on metabolic activity within tumour – not all are metabolically active Fig. 21.13 Examples of ultrasound, CT and MRI. A Ultrasound showing large gallstone (arrow) with acoustic shadowing. B Multidetector coronal CT showing large solid and cystic malignant tumour in the pancreatic tail (arrow). (PV = portal vein; L = liver) C Pelvic MRI showing large pelvic abscess (arrow) posterior to the rectum in a patient with Crohn’s disease. D Fused CT-PET image showing two liver metastases (arrows). A B C D L PV Ultrasound, computed tomography and magnetic resonance imaging Ultrasound, computed tomography (CT) and magnetic resonance imaging (MRI) are key tests in the evaluation of intra-abdominal disease. They are non-invasive and offer detailed images of the abdominal contents. Fluorodeoxyglucose–positron emission tomography (FDG-PET) is increasingly used in the staging of malignancies and images may be fused with CT to enhance localisation. Their main applications are summarised in Box 21.4 and Figure 21.13. Endoscopy Videoendoscopes provide high-definition imaging and accessories can be passed down the endoscope to allow both diagnostic and therapeutic procedures, some of which are illustrated in Figure 21.14. Endoscopes with magnifying lenses allow almost microscopic detail to be observed, and imaging modalities, such as confocal endomicroscopy, autofluorescence and ‘narrow-band imaging’, are increasingly used to detect subtle abnormalities not visible by standard ‘white light’ endoscopy. Upper gastrointestinal endoscopy This is performed under light intravenous benzodiazepine sedation, or using only local anaesthetic throat spray after the patient has fasted for at least 4 hours. With the patient in the left lateral position, the entire oesophagus (excluding pharynx), stomach and first two parts of duodenum can be seen. Indications, contraindications and complications are given in Box 21.5. Endoscopic ultrasound Endoscopic ultrasound (EUS) combines endoscopy with intraluminal ultrasonography using a high-frequency transducer to produce high-resolution ultrasound images. This allows visualisation through the wall of the gastrointestinal tract and into surrounding tissues, e.g. the pancreas or lymph nodes. It can therefore be used to perform fine needle aspiration or biopsy of mass lesions. EUS is helpful in the diagnosis of pancreatic tumours, chronic pancreatitis, pancreatic cysts, cholangiocarcinoma, common bile duct stones, ampullary lesions and submucosal tumours. It also plays an important role in the staging of certain cancers, e.g. those of oesophagus and pancreas. EUS can also be therapeutic, as in drainage of pancreatic fluid collections and coeliac plexus block for pain management. Possible complications of EUS include bleeding, infection, cardiopulmonary events and perforation. Capsule endoscopy Capsule endoscopy (Fig. 21.15) uses a capsule containing an imaging device, battery, transmitter and antenna; as it traverses the small intestine, it transmits images to a batterypowered recorder worn on a belt round the patient’s waist. After approximately 8 hours, the capsule is excreted. Images from the capsule are analysed as a video sequence and it is usually possible to localise the segment of small bowel in which lesions are seen. Abnormalities detected usually require enteroscopy

Investigation of gastrointestinal disease • 775

Fig. 21.14 Examples of therapeutic techniques in endoscopy. Control of bleeding Injection sclerotherapy Diathermy Variceal ligation Laser therapy Treatment of tumours Laser therapy Polypectomy Photodynamic therapy/radiofrequency ablation Treatment of strictures Stent insertion Balloon dilatation Bouginage Management of biliary and pancreatic disease Basket retrieval Endoscopic clipping Endoscopic mucosal resection Endoscopic submucosal dissection (ESD) Stent insertion Pseudocyst drainage Sphincterotomy Fig. 21.15 Wireless capsule endoscopy. A Examples of capsules. B Capsule endoscopy image of bleeding jejunal vascular malformation. A, Courtesy of Given Imaging. A B Indications • Dyspepsia in patients > 55 years of age or with alarm symptoms • Atypical chest pain • Dysphagia • Vomiting • Weight loss • Acute or chronic gastrointestinal bleeding • Screening for oesophageal varices in chronic liver disease • Abnormal CT scan or barium meal • Duodenal biopsies in the investigation of malabsorption and confirmation of a diagnosis of coeliac disease prior to commencement of gluten-free diet • Therapy, including treatment of bleeding lesions, banding/injection of varices, dilatation of strictures, insertion of stents, placement of percutaneous gastrostomies, ablation of Barrett’s oesophagus and resection of high-grade dysplastic lesions and early neoplasia in the upper gastrointestinal tract Contraindications • Severe shock • Recent myocardial infarction, unstable angina, cardiac arrhythmia* • Severe respiratory disease* • Atlantoaxial subluxation* • Possible visceral perforation Complications • Cardiorespiratory depression due to sedation • Aspiration pneumonia • Perforation *These are ‘relative’ contraindications; in experienced hands, endoscopy can be safely performed. 21.5 Upper gastrointestinal endoscopy

776 • GASTROENTEROLOGY 21.6 Wireless capsule endoscopy Indications • Obscure gastrointestinal bleeding • Small bowel Crohn’s disease • Assessment of coeliac disease and its complications • Screening and surveillance in familial polyposis syndromes Contraindications • Known or suspected small bowel stricture (risk of capsule retention) • Caution in people with pacemakers or implantable defibrillators Complications • Capsule retention (< 1%) for confirmation and therapy. Indications, contraindications and complications are listed in Box 21.6. Double balloon enteroscopy While endoscopy can reach the proximal small intestine in most patients, a technique called double balloon enteroscopy is also available, which uses a long endoscope with a flexible overtube. Sequential and repeated inflation and deflation of balloons on the tip of the overtube and enteroscope allow the operator to push and pull along the entire length of the small intestine to the terminal ileum, in order to diagnose or treat small bowel lesions detected by capsule endoscopy or other imaging modalities. Indications, contraindications and complications are listed in Box 21.7. Sigmoidoscopy and colonoscopy Sigmoidoscopy can be carried out either in the outpatient clinic using a 20 cm rigid plastic sigmoidoscope or in the endoscopy suite using a 60 cm flexible colonoscope following bowel preparation. When sigmoidoscopy is combined with proctoscopy, accurate detection of haemorrhoids, ulcerative colitis and distal colorectal neoplasia is possible. After full bowel cleansing, it is possible to examine the entire colon and the terminal ileum using a longer colonoscope. Indications, contraindications and complications of colonoscopy are listed in Box 21.8. 21.7 Double balloon enteroscopy Indications Diagnostic • Obscure gastrointestinal bleeding • Malabsorption or unexplained diarrhoea • Suspicious radiological findings • Suspected small bowel tumour • Surveillance of polyposis syndromes Therapeutic • Coagulation/diathermy of bleeding lesions • Jejunostomy placement Contraindications • As for upper gastrointestinal endoscopy Complications • As for upper gastrointestinal endoscopy • Post-procedure abdominal pain (≤ 20%) • Pancreatitis (1–3%) • Perforation (especially after resection of large polyps) 21.9 Endoscopy in old age • Tolerance: endoscopic procedures are generally well tolerated, even in very old people. • Side-effects from sedation: older people are more sensitive, and respiratory depression, hypotension and prolonged recovery times are more common. • Bowel preparation for colonoscopy: can be difficult in frail, immobile people. Sodium phosphate-based preparations can cause dehydration or hypotension and should be avoided in those with underlying cardiac or renal failure. Minimal-preparation CT colonograms provide an excellent alternative in these individuals. • Antiperistaltic agents: hyoscine should be avoided in those with glaucoma and can also cause tachyarrhythmias. Glucagon is preferred if an antiperistaltic agent is needed. Magnetic resonance cholangiopancreatography Magnetic resonance cholangiopancreatography (MRCP) has largely replaced endoscopic retrograde cholangiopancreatography (ERCP) in the evaluation of obstructive jaundice since it produces comparable images of the biliary tree and pancreas, providing information that complements that obtained from CT and endoscopic ultrasound examination (EUS). Endoscopic retrograde cholangiopancreatography Using a side-viewing duodenoscope, it is possible to cannulate the main pancreatic duct and common bile duct. Nowadays, ERCP is used mainly in the treatment of a range of biliary and pancreatic diseases that have been identified by other imaging techniques such as MRCP, EUS and CT. Indications for and risks of ERCP are listed in Box 21.10. Histology Biopsy material obtained endoscopically or percutaneously can provide useful information (Box 21.11). 21.8 Colonoscopy Indications* • Suspected inflammatory bowel disease • Chronic diarrhoea • Altered bowel habit • Rectal bleeding or iron deficiency anaemia • Assessment of abnormal CT colonogram or barium enema • Colorectal cancer screening • Colorectal adenoma and carcinoma follow-up • Therapeutic procedures, including endoscopic resection, dilatation of strictures, laser, stent insertion and argon plasma coagulation Contraindications • Acute severe ulcerative colitis (unprepared flexible sigmoidoscopy is preferred) • As for upper gastrointestinal endoscopy Complications • Cardiorespiratory depression due to sedation • Perforation • Bleeding following polypectomy *Colonoscopy is not useful in the investigation of constipation.

Investigation of gastrointestinal disease • 777

Tests of infection Bacterial cultures Stool cultures are essential in the investigation of diarrhoea, especially when it is acute or bloody, in order to identify pathogenic organisms (Ch. 11). Serology Detection of antibodies plays a limited role in the diagnosis of gastrointestinal infection caused by organisms such as Helicobacter pylori, Salmonella species and Entamoeba histolytica. Breath tests Non-invasive breath tests for H. pylori infection are discussed on page 800 and breath tests for suspected small intestinal bacterial overgrowth on page 808. Tests of function A number of dynamic tests can be used to investigate aspects of gut function, including digestion, absorption, inflammation and epithelial permeability. Some of the more common ones are listed in Box 21.12. In the assessment of suspected malabsorption, blood tests (full blood count, erythrocyte sedimentation rate (ESR), and measurement of C-reactive protein (CRP), folate, vitamin B12, Laparoscopic surgery is preferred in fit individuals who also require cholecystectomy. 21.10 Endoscopic retrograde cholangiopancreatography Indications Diagnostic • Biliary or pancreatic disease where other imaging is equivocal or contraindicated • Ampullary biopsy or biliary cytology Therapeutic • Biliary disease: Removal of common bile duct calculi Palliation of malignant biliary obstruction Management of biliary leaks/damage complicating surgery Dilatation of benign strictures Primary sclerosing cholangitis • Pancreatic disease: Drainage of pancreatic pseudocysts and fistulae Removal of pancreatic calculi (selected cases) Contraindications • Severe cardiopulmonary comorbidity • Coagulopathy Complications • Occur in 5–10% with a 30-day mortality of 0.5–1% General • As for upper endoscopy Specific • Biliary disease: Bleeding following sphincterotomy Cholangitis (if biliary obstruction is not relieved by ERCP) Gallstone impaction • Pancreatic disease: Acute pancreatitis Infection of pseudocyst 21.11 Reasons for biopsy or cytological examination • Suspected malignant lesions • Assessment of mucosal abnormalities • Diagnosis of infection (Candida, Helicobacter pylori, Giardia lamblia) • Analysis of genetic mutations 21.12 Tests of gastrointestinal function Process Test Principle Comments Absorption Lactose Lactose H2 breath test Measurement of breath H2 content after 50 g oral lactose. Undigested sugar is metabolised by colonic bacteria in hypolactasia and expired hydrogen is measured Non-invasive and accurate. May provoke pain and diarrhoea in sufferers Bile acids 75SeHCAT test Isotopic quantification of 7-day whole-body retention of oral dose 75Se-labelled homocholyltaurine (> 15% = normal, 5–15% borderline, < 5% = abnormal) Accurate and specific but requires two visits and involves radiation. Results can be equivocal. Serum 7α-hydroxycholestenone is almost as sensitive and specific Serum 7α-hydroxycholestenone Intermediate metabolite of the bile acid synthetic pathway. Serum levels indicate activity of the pathway and are elevated in bile acid diarrhoea Simple test to perform and only marginally less sensitive and specific than 75SeHCAT test Pancreatic exocrine function Pancreolauryl test Pancreatic esterases cleave fluorescein dilaurate after oral ingestion. Fluorescein is absorbed and quantified in urine Accurate and avoids duodenal intubation Takes 2 days. Accurate urine collection essential. Rarely performed Faecal elastase Immunoassay of pancreatic enzymes on stool sample Simple, quick and avoids urine collection. Does not detect mild disease Mucosal inflammation/ permeability Faecal calprotectin A protein secreted non-specifically by neutrophils into the colon in response to inflammation or neoplasia Useful screening test for gastrointestinal inflammation and for monitoring patients with Crohn’s disease and ulcerative colitis. Poor sensitivity for cancer (75SeHCAT = 75Se-homocholic acid taurine)

778 • GASTROENTEROLOGY iron status, albumin, calcium and phosphate) are essential, and endoscopy is undertaken to obtain mucosal biopsies. Faecal calprotectin is very sensitive at detecting mucosal inflammation. Oesophageal motility A barium swallow can give useful information about oesophageal motility. Videofluoroscopy, with joint assessment by a speech and language therapist and a radiologist, may be necessary in difficult cases. Oesophageal manometry (see Fig. 21.1), often in conjunction with 24-hour pH measurements, is of value in diagnosing cases of refractory gastro-oesophageal reflux, achalasia and non-cardiac chest pain. Oesophageal impedance testing is useful for detecting non-acid or gas reflux events, especially in patients with atypical symptoms or those who respond poorly to acid suppression. Gastric emptying This involves administering a test meal containing solids and liquids labelled with different radioisotopes and measuring the amount retained in the stomach afterwards (Box 21.13). It is useful in the investigation of suspected delayed gastric emptying (gastroparesis) when other studies are normal. Colonic and anorectal motility A plain abdominal X-ray taken on day 5 after ingestion of differentshaped inert plastic pellets on days 1–3 gives an estimate of whole-gut transit time. The test is useful in the evaluation of chronic constipation, when the position of any retained pellets can be observed, and helps to differentiate cases of slow transit from those due to obstructed defecation. The mechanism of defecation and anorectal function can be assessed by anorectal manometry, electrophysiological tests and defecating proctography. Radioisotope tests Many different radioisotope tests are used (Box 21.13). In some, structural information is obtained, such as the localisation of a Meckel’s diverticulum. Others provide functional information, such as the rate of gastric emptying or ability to reabsorb bile acids. Yet others are tests of infection and rely on the presence of bacteria to hydrolyse a radio-labelled test substance followed by detection of the radioisotope in expired air, such as the urea breath test for H. pylori. 21.13 Commonly used radioisotope tests in gastroenterology Test Isotope Major uses and principle of test Gastric emptying study 99mTc-sulphur 111In-DTPA Assessment of gastric emptying, particularly for possible gastroparesis Urea breath test 13C-urea Non-invasive diagnosis of Helicobacter pylori. Bacterial urease enzyme splits urea to ammonia and CO2, which is detected in expired air Meckel’s scan 99mTc-pertechnate Diagnosis of Meckel’s diverticulum in cases of obscure gastrointestinal bleeding. Isotope is injected intravenously and localises in ectopic parietal mucosa within diverticulum Somatostatin receptor scintigraphy (SRS) 111In-DTPA-octreotide Labelled somatostatin analogue binds to cell surface somatostatin receptors on pancreatic neuro-endocrine tumours Positron emission tomography (PET) 18F-fluorodeoxyglucose (FDG) 68Gallium-labelled somatostatin analogue Staging high-grade cancers More sensitive and specific than SRS for staging neuro-endocrine tumours Gut hormone testing Excess gut hormone secretion by some gastrointestinal and pancreatic neuro-endocrine tumours can be assessed by measuring levels in blood. Commonly measured hormones include gastrin, somatostatin, vasoactive intestinal polypeptide (VIP) and pancreatic polypeptide. Presenting problems in gastrointestinal disease Dysphagia Dysphagia is defined as difficulty in swallowing. It may coexist with heartburn or vomiting but should be distinguished from both globus sensation (in which anxious people feel a lump in the throat without organic cause) and odynophagia (pain during swallowing, usually from gastro-oesophageal reflux or candidiasis). Dysphagia can occur due to problems in the oropharynx or oesophagus (Fig. 21.16). Oropharyngeal disorders affect the initiation of swallowing at the pharynx and upper oesophageal sphincter. The patient has difficulty initiating swallowing and complains of choking, nasal regurgitation or tracheal aspiration. Drooling, dysarthria, hoarseness and cranial nerve or other neurological signs may be present. Oesophageal disorders cause dysphagia by obstructing the lumen or by affecting motility. Patients with oesophageal disease complain of food ‘sticking’ after swallowing, although the level at which this is felt correlates poorly with the true site of obstruction. Swallowing of liquids is normal until strictures become extreme. Investigations Dysphagia should always be investigated urgently. Endoscopy is the investigation of choice because it allows biopsy and dilatation of strictures. Even if the appearances are normal, biopsies should be taken to look for eosinophilic oesophagitis. If no abnormality is found, then barium swallow with videofluoroscopic swallowing assessment is indicated to detect major motility disorders. In some cases, oesophageal manometry is required. High-resolution manometry allows accurate classification of abnormalities. Figure 21.16 summarises a diagnostic approach to dysphagia and lists the major causes.

Presenting problems in gastrointestinal disease • 779

‘alarm’ features requiring urgent investigation (Box 21.15) and to detect atypical symptoms that might be due to problems outside the gastrointestinal tract. Dyspepsia affects up to 80% of the population at some time in life and most patients have no serious underlying disease. People who present with new dyspepsia at an age of more than 55 years and younger patients unresponsive to empirical treatment require investigation to exclude serious disease. An algorithm for the investigation of dyspepsia is outlined in Figure 21.17. Heartburn and regurgitation Heartburn describes retrosternal, burning discomfort, often rising up into the chest and sometimes accompanied by regurgitation of acidic or bitter fluid into the throat. These symptoms often occur after meals, on lying down or with bending, straining or heavy lifting. They are classical symptoms of gastro-oesophageal reflux but up to 50% of patients present with other symptoms, such as chest pain, belching, halitosis, chronic cough or sore throats. In young patients with typical symptoms and a good response to dietary changes, antacids or acid suppression investigation is not required, but in patients over 55 years of age and those with alarm symptoms or atypical features urgent endoscopy is necessary. Dyspepsia Dyspepsia describes symptoms such as discomfort, bloating and nausea, which are thought to originate from the upper gastrointestinal tract. There are many causes (Box 21.14), including some arising outside the digestive system. Heartburn and other ‘reflux’ symptoms are separate entities and are considered elsewhere. Although symptoms often correlate poorly with the underlying diagnosis, a careful history is important to detect Fig. 21.16 Investigation of dysphagia. Benign Malignant Oesophagitis Dysmotility Stricture Manometry/ barium swallow Endoscopy and biopsy Oesophageal dysphagia Videofluoroscopic swallowing assessment and neurological investigation Oropharyngeal dysphagia Food 'sticking' after swallowing ± regurgitation Dysphagia Neurological disease • Bulbar palsy • Pseudobulbar palsy • Myasthenia gravis • Achalasia • Non-specific motility disorder • Peptic • Candidiasis • Eosinophilic • Peptic • Fibrous rings • Eosinophilic oesophagitis • Drugs, e.g. bisphosphonates • Carcinoma of the oesophagus • Carcinoma of the stomach • Extrinsic compression Difficulty initiating swallow ± choking or aspiration 21.14 Causes of dyspepsia Upper gastrointestinal disorders • Peptic ulcer disease • Acute gastritis • Gallstones • Oesophageal spasm • Non-ulcer dyspepsia • Irritable bowel syndrome Other gastrointestinal disorders • Pancreatic disease (cancer, chronic pancreatitis) • Colonic carcinoma • Hepatic disease (hepatitis, metastases) Systemic disease • Renal failure • Hypercalcaemia Drugs • Non-steroidal antiinflammatory drugs (NSAIDs) • Glucocorticoids • Iron and potassium supplements • Digoxin Others • Psychological (anxiety, depression) • Alcohol 21.15 Alarm features in dyspepsia • Weight loss • Anaemia • Vomiting • Haematemesis and/or melaena • Dysphagia • Palpable abdominal mass

780 • GASTROENTEROLOGY Fig. 21.17 Investigation of dyspepsia. < 55 years Urgent endoscopy

55 years Test for Helicobacter pylori, e.g. serology, stool antigen or 13C urea breath test Endoscopy Positive Negative Helicobacter pylori eradication Treat symptomatically or consider other diagnoses Symptoms resolve Symptoms persist No follow-up Endoscopy Dyspepsia Are there 'alarm' features? Yes No Fig. 21.18 Causes of vomiting. (NSAIDs = non-steroidal anti-inflammatory drugs) Alcoholism Central nervous system disorders • Vestibular neuronitis • Migraine • Raised intracranial pressure • Meningitis Gastroduodenal • Peptic ulcer disease • Gastric cancer • Gastroparesis The acute abdomen • Appendicitis • Cholecystitis • Pancreatitis • Intestinal obstruction Metabolic • Diabetic ketoacidosis • Addison’s disease Uraemia Infections • Hepatitis • Gastroenteritis • Urinary tract infection Drugs • NSAIDs • Opiates • Digoxin • Antibiotics • Cytotoxins Psychogenic pressure and, combined with relaxation of the lower oesophageal sphincter, results in forcible ejection of gastric contents. It is important to distinguish true vomiting from regurgitation and to elicit whether the vomiting is acute or chronic (recurrent), as the underlying causes may differ. The major causes are shown in Figure 21.18. Gastrointestinal bleeding Acute upper gastrointestinal haemorrhage This is the most common gastrointestinal emergency, accounting for 50–170 admissions to hospital per 100 000 of the population each year in the UK. The mortality of patients admitted to hospital is about 10% but there is some evidence that outcome is better when individuals are treated in specialised units. Risk scoring systems have been developed to stratify the risk of needing endoscopic therapy or of having a poor outcome (Box 21.16). The advantage of the Blatchford score is that it may be used before endoscopy to predict the need for intervention to treat bleeding. Low scores (2 or less) are associated with a very low risk of adverse outcome. The common causes are shown in Figure 21.19. Clinical assessment Haematemesis is red with clots when bleeding is rapid and profuse, or black (‘coffee grounds’) when less severe. Syncope may occur and is caused by hypotension from intravascular volume depletion. Symptoms of anaemia suggest chronic bleeding. Melaena is the passage of black, tarry stools containing altered blood; it is usually caused by bleeding from the upper gastrointestinal tract, although haemorrhage from the right side of the colon is occasionally responsible. The characteristic colour and smell are the result of the action of digestive enzymes and of bacteria on haemoglobin. Severe acute upper gastrointestinal bleeding can sometimes cause maroon or bright red stool. Vomiting Vomiting is a complex reflex involving both autonomic and somatic neural pathways. Synchronous contraction of the diaphragm, intercostal muscles and abdominal muscles raises intra-abdominal

Presenting problems in gastrointestinal disease • 781

  1. Intravenous access The first step is to gain intravenous access using at least one large-bore cannula.
  2. Initial clinical assessment • Define circulatory status. Severe bleeding causes tachycardia, hypotension and oliguria. The patient is cold and sweating, and may be agitated. • Seek evidence of liver disease (p. 846). Jaundice, cutaneous stigmata, hepatosplenomegaly and ascites may be present in decompensated cirrhosis. • Identify comorbidity. The presence of cardiorespiratory, cerebrovascular or renal disease is important, both because these may be worsened by acute bleeding and because they increase the hazards of endoscopy and surgical operations. These factors can be combined using the Blatchford score (Box 21.16), which can be calculated at the bedside. A score of 2 or less is associated with a good prognosis, while progressively higher scores are associated with poorer outcomes.
  3. Basic investigations • Full blood count. Chronic or subacute bleeding leads to anaemia but the haemoglobin concentration may be normal after sudden, major bleeding until haemodilution occurs. Thrombocytopenia may be a clue to the presence of hypersplenism in chronic liver disease. • Urea and electrolytes. This test may show evidence of renal failure. The blood urea rises as the absorbed products of luminal blood are metabolised by the liver; an elevated blood urea with normal creatinine concentration implies severe bleeding. • Liver function tests. These may show evidence of chronic liver disease. • Prothrombin time. Check when there is a clinical suggestion of liver disease or patients are anticoagulated. • Cross-matching. At least 2 units of blood should be cross-matched if a significant bleed is suspected. 21.16 Modified Blatchford score: risk stratification in acute upper gastrointestinal bleeding Admission risk marker Score component value Blood urea ≥ 25 mmol/L (70 mg/dL)

10–25 mmol/L (28–70 mg/dL)

8–10 mmol/L (21.4–28 mg/dL)

6.5–8 mmol/L (18.2–22.4 mg/dL)

< 6.5 mmol/L (18.2 mg/dL)

Haemoglobin for men < 100 g/L (10 g/dL)

100–119 g/L (10–11.9 g/dL)

120–129 g/L (12–12.9 g/dL)

≥ 130 g/L (13 g/dL)

Haemoglobin for women < 100 g/L (10 g/dL)

100–119 g/L (10–11.9 g/dL)

≥ 120 g/L (12 g/dL)

Systolic blood pressure < 90 mmHg

90–99 mmHg

100–109 mmHg

109 mmHg

Other markers Presentation with syncope

Hepatic disease

Cardiac failure

Pulse ≥ 100 beats/min

Presentation with melaena

None of the above

Fig. 21.19 Causes of acute upper gastrointestinal haemorrhage. Frequency is given in parentheses. (NSAIDs = non-steroidal anti-inflammatory drugs) Liver disease Portal vein thrombosis Varices (2 – 9%) Oesophagitis (10%) Usually with hiatus hernia Retching Mallory–Weiss tear (5%) Cancer of stomach or oesophagus (2%) NSAIDs Helicobacter pylori Peptic ulcer (35 – 50%) Vascular malformations (5%) Aortic graft Aorto-duodenal fistula (0.2%) NSAIDs Alcohol Gastric erosions (10 – 20%) Management The principles of emergency management of non-variceal bleeding are discussed in detail below. Management of variceal bleeding is discussed on page 869.

782 • GASTROENTEROLOGY can also be carried out (a biopsy must be taken to exclude carcinoma). Local excision may be performed, but when neither is possible, partial gastrectomy is required. 9. Eradication Following treatment for ulcer bleeding, all patients should avoid non-steroidal anti-inflammatory drugs (NSAIDs) and those who test positive for H. pylori infection should receive eradication therapy (p. 800). Successful eradication should be confirmed by urea breath or faecal antigen testing. Lower gastrointestinal bleeding This may be caused by haemorrhage from the colon, anal canal or small bowel. It is useful to distinguish those patients who present with profuse, acute bleeding from those who present with chronic or subacute bleeding of lesser severity (Box 21.17). Severe acute lower gastrointestinal bleeding This presents with profuse red or maroon diarrhoea and with shock. Diverticular disease is the most common cause and is often due to erosion of an artery within the mouth of a diverticulum. Bleeding almost always stops spontaneously, but if it does not, the diseased segment of colon should be resected after confirmation of the site by angiography or colonoscopy. Angiodysplasia is a disease of the elderly, in which vascular malformations develop in the proximal colon. Bleeding can be acute and profuse; it usually 4. Resuscitation Intravenous crystalloid fluids should be given to raise the blood pressure, and blood should be transfused when the patient is actively bleeding with low blood pressure and tachycardia. Comorbidities should be managed as appropriate. Patients with suspected chronic liver disease should receive broad-spectrum antibiotics. 5. Oxygen This should be given to all patients in shock. 6. Endoscopy This should be carried out after adequate resuscitation, ideally within 24 hours, and will yield a diagnosis in 80% of cases. Patients who are found to have major endoscopic stigmata of recent haemorrhage (Fig. 21.20) can be treated endoscopically using a thermal or mechanical modality, such as a ‘heater probe’ or endoscopic clips, combined with injection of dilute adrenaline (epinephrine) into the bleeding point (‘dual therapy’). A biologically inert haemostatic mineral powder (TC325, ‘haemospray’) can be used as rescue therapy when standard therapy fails. This may stop active bleeding and, combined with intravenous proton pump inhibitor (PPI) therapy, may prevent rebleeding, thus avoiding the need for surgery. Patients found to have bled from varices should be treated by band ligation (p. 870); if this fails, balloon tamponade is another option, while arrangements are made for a transjugular intrahepatic portosystemic shunt (TIPSS). 7. Monitoring Patients should be closely observed, with hourly measurements of pulse, blood pressure and urine output. 8. Surgery Surgery is indicated when endoscopic haemostasis fails to stop active bleeding and if rebleeding occurs on one occasion in an elderly or frail patient, or twice in a younger, fitter patient. If available, angiographic embolisation is an effective alternative to surgery in frail patients. The choice of operation depends on the site and diagnosis of the bleeding lesion. Duodenal ulcers are treated by under-running, with or without pyloroplasty. Under-running for gastric ulcers Fig. 21.20 Major stigmata of recent haemorrhage and endoscopic treatment. A Active bleeding from a duodenal ulcer. B Haemostasis is achieved after endoscopic injection of adrenaline (epinephrine) and application of a heater probe. A B 21.17 Causes of lower gastrointestinal bleeding Severe acute • Diverticular disease • Angiodysplasia • Ischaemia • Meckel’s diverticulum • Inflammatory bowel disease (rarely) Moderate, chronic/subacute • Fissure • Haemorrhoids • Inflammatory bowel disease • Carcinoma • Large polyps • Angiodysplasia • Radiation enteritis • Solitary rectal ulcer

Presenting problems in gastrointestinal disease • 783

used to define a source of bleeding prior to enteroscopy. When all else fails, laparotomy with on-table endoscopy is indicated. Chronic occult gastrointestinal bleeding In this context, occult means that blood or its breakdown products are present in the stool but cannot be seen by the naked eye. Occult bleeding may reach 200 mL per day and cause iron deficiency anaemia. Any cause of gastrointestinal bleeding may be responsible but the most important is colorectal cancer, particularly carcinoma of the caecum, which may produce no gastrointestinal symptoms. In clinical practice, investigation of the upper and lower gastrointestinal tract should be considered whenever a patient presents with unexplained iron deficiency anaemia. Testing the stool for the presence of blood is unnecessary and should not influence whether or not the gastrointestinal tract is imaged because bleeding from tumours is often intermittent and a negative faecal occult blood (FOB) test does not exclude the diagnosis. The only value of FOB testing is as a means of population screening for colonic neoplasia in asymptomatic individuals (p. 832). Diarrhoea Diarrhoea is defined as the passage of more than 200 g of stool daily and measurement of stool volume is helpful in confirming this. The most severe symptom in many patients is urgency of defecation, and faecal incontinence is a common event in acute and chronic diarrhoeal illnesses. Acute diarrhoea This is extremely common and is usually caused by faecal–oral transmission of bacteria or their toxins, viruses or parasites (Ch. 11). Infective diarrhoea is usually short-lived and patients who present with a history of diarrhoea lasting more than 10 days rarely have an infective cause. A variety of drugs, including antibiotics, cytotoxic drugs, PPIs and NSAIDs, may be responsible. Chronic or relapsing diarrhoea The most common cause is irritable bowel syndrome (p. 824), which can present with increased frequency of defecation and loose, watery or pellety stools. Diarrhoea rarely occurs at night and is most severe before and after breakfast. At other times, the patient is constipated and there are other characteristic symptoms of irritable bowel syndrome. The stool often contains mucus but never blood, and 24-hour stool volume is less than 200 g. Chronic diarrhoea can be categorised as being caused by disease of the colon or small bowel, or to malabsorption (Box 21.18). Clinical presentation, examination of the stool, routine blood tests and imaging reveal a diagnosis in many cases. A series of negative investigations usually implies irritable bowel syndrome but some patients clearly have organic disease and need more extensive investigations. Malabsorption Diarrhoea and weight loss in patients with a normal diet are likely to be caused by malabsorption. The symptoms are diverse in nature and variable in severity. A few patients have apparently normal bowel habit but diarrhoea is usual and may be watery and voluminous. Bulky, pale and offensive stools that float in the toilet (steatorrhoea) signify fat malabsorption. Abdominal stops spontaneously but commonly recurs. Diagnosis is often difficult. Colonoscopy may reveal characteristic vascular spots and, in the acute phase, visceral angiography can show bleeding into the intestinal lumen and an abnormal large, draining vein. In some patients, diagnosis is achieved only by laparotomy with on-table colonoscopy. The treatment of choice is endoscopic thermal ablation but resection of the affected bowel may be required if bleeding continues. Bowel ischaemia due to occlusion of the inferior mesenteric artery can present with abdominal colic and rectal bleeding. It should be considered in patients (particularly the elderly) who have evidence of generalised atherosclerosis. The diagnosis is made at colonoscopy. Resection is required only in the presence of peritonitis. Meckel’s diverticulum with ectopic gastric epithelium may ulcerate and erode into a major artery. The diagnosis should be considered in children or adolescents who present with profuse or recurrent lower gastrointestinal bleeding. A Meckel’s 99mTc-pertechnetate scan is sometimes positive but the diagnosis is commonly made only by laparotomy, at which time the diverticulum is excised. Subacute or chronic lower gastrointestinal bleeding This can occur at all ages and is usually due to haemorrhoids or anal fissure. Haemorrhoidal bleeding is bright red and occurs during or after defecation. Proctoscopy can be used to make the diagnosis, but subjects who have altered bowel habit and those who present over the age of 40 years should undergo colonoscopy to exclude coexisting colorectal cancer. Anal fissure should be suspected when fresh rectal bleeding and anal pain occur during defecation. Major gastrointestinal bleeding of unknown cause In some patients who present with major gastrointestinal bleeding, upper endoscopy and colonoscopy fail to reveal a diagnosis. When severe life-threatening bleeding continues, urgent CT mesenteric angiography is indicated. This will usually identify the site if the bleeding rate exceeds 1 mL/min and then formal angiographic embolisation can often stop the bleeding. If angiography is negative or bleeding is less severe, push or double balloon enteroscopy can visualise the small intestine (Fig. 21.21) and treat the bleeding source. Wireless capsule endoscopy is often Fig. 21.21 Jejunal angiodysplastic lesion seen at enteroscopy in a patient with recurrent obscure bleeding.

784 • GASTROENTEROLOGY Pathophysiology Malabsorption results from abnormalities of the three processes that are essential to normal digestion: • Intraluminal maldigestion occurs when deficiency of bile or pancreatic enzymes results in inadequate solubilisation 21.18 Chronic or relapsing diarrhoea Colonic Malabsorption Small bowel Clinical features Blood and mucus in stool Cramping lower abdominal pain Steatorrhoea Undigested food in the stool Weight loss and nutritional disturbances Large-volume, watery stool Abdominal bloating Cramping mid-abdominal pain Some causes Inflammatory bowel disease Microscopic colitis Neoplasia Ischaemia Irritable bowel syndrome Pancreatic: Chronic pancreatitis Cancer of pancreas Cystic fibrosis Enteropathy: Coeliac disease Tropical sprue Lymphoma Lymphangiectasia Crohn’s disease VIPoma Drug-induced: NSAIDs Aminosalicylates SSRIs Investigations Faecal calprotectin Ileocolonoscopy with biopsies Faecal elastase Faecal calprotectin Ultrasound, CT and MRCP Stool volume Small-bowel biopsy Gut hormone profile Barium follow-through or small-bowel MRI Barium follow-through or small-bowel MRI (CT = computed tomography; MRCP = magnetic resonance cholangiopancreatography; MRI = magnetic resonance imaging; NSAIDs = non-steroidal anti-inflammatory drugs; SSRIs = selective serotonin re-uptake inhibitors; VIP = vasoactive intestinal polypeptide) distension, borborygmi, cramps, weight loss and undigested food in the stool may be present. Some patients complain only of malaise and lethargy. In others, symptoms related to deficiencies of specific vitamins, trace elements and minerals may occur (Fig. 21.22). Fig. 21.22 Possible physical consequences of malabsorption. Purpura and bruising (vitamins C, K) Poor wound healing (vitamin C, protein, zinc) Distension, steatorrhoea, watery diarrhoea Lethargy Depression Night blindness (vitamin A) Anaemia (iron, folate, B12) Angular stomatitis, glossitis (iron, folate, B12) Bleeding gums (vitamin C) Follicular hyperkeratosis (vitamin A) Acrodermatitis enteropathica (zinc) Koilonychia (iron) Paraesthesia, tetany (calcium, magnesium) Clubbing Osteomalacia, rickets (calcium, vitamin D) Muscle wasting (protein) Proximal myopathy (vitamin D) Peripheral neuropathy (B12) Peripheral oedema (hypoalbuminaemia)

Presenting problems in gastrointestinal disease • 785

cause. Routine blood tests may show one or more of the abnormalities listed in Box 21.19. Tests to confirm fat and protein malabsorption should be performed, as described on page 777. An approach to the investigation of malabsorption is shown in Figure 21.23. Weight loss Weight loss may be physiological, due to dieting, exercise, starvation, or the decreased nutritional intake that accompanies old age. Weight loss of more than 3 kg over 6 months is significant and often indicates the presence of an underlying disease. Hospital and general practice weight records may be valuable in confirming that weight loss has occurred, as may reweighing patients at intervals; sometimes weight is regained or stabilises in those with no obvious cause. Pathological weight loss can be due to psychiatric illness, systemic disease, gastrointestinal causes or advanced disease of many organ systems (Fig. 21.24). Physiological causes Weight loss can occur in the absence of serious disease in healthy individuals who have changes in physical activity or social circumstances. It may be difficult to be sure of this diagnosis in older patients, when the dietary history may be unreliable, and professional help from a dietitian is often valuable under these circumstances. Psychiatric illness Features of anorexia nervosa (p. 1203), bulimia (p. 1204) and affective disorders (p. 1198) may be apparent only after formal psychiatric input. Alcoholic patients lose weight as a consequence of self-neglect and poor dietary intake. Depression may cause weight loss. Systemic disease Chronic infections, including tuberculosis (p. 588), recurrent urinary or chest infections, and a range of parasitic and protozoan infections (Ch. 11), should be considered. A history of foreign travel, high-risk activities and specific features, such as fever, night sweats, rigors, productive cough and dysuria, must be sought. Promiscuous sexual activity and drug misuse suggest HIV-related illness (Ch. 12). Weight loss is a late feature of disseminated malignancy, but by the time the patient presents, other features of cancer are often present. Chronic inflammatory diseases, such as rheumatoid arthritis (p. 1021) and polymyalgia rheumatica (p. 1042), are often associated with weight loss. Gastrointestinal disease Almost any disease of the gastrointestinal tract can cause weight loss. Dysphagia and gastric outflow obstruction (pp. 778 and 801) cause weight loss by reducing food intake. Malignancy at any site may cause weight loss by mechanical obstruction, anorexia or cytokine-mediated systemic effects. Malabsorption from pancreatic diseases (p. 837) or small bowel causes may lead to profound weight loss with specific nutritional deficiencies (p. 704). Inflammatory diseases, such as Crohn’s disease or ulcerative colitis (p. 813), cause anorexia, fear of eating and loss of protein, blood and nutrients from the gut. Metabolic disorders and miscellaneous causes Weight loss may occur in association with metabolic disorders, as well as end-stage respiratory and cardiac disease. 21.19 Routine blood test abnormalities in malabsorption Haematology • Microcytic anaemia (iron deficiency) • Macrocytic anaemia (folate or B12 deficiency) • Increased prothrombin time (vitamin K deficiency) Biochemistry • Hypoalbuminaemia • Hypocalcaemia • Hypomagnesaemia • Hypophosphataemia • Low serum zinc Fig. 21.23 Investigation for suspected malabsorption. (CT = computed tomography; MRCP = magnetic resonance cholangiopancreatography; MRI = magnetic resonance imaging; 75SeHCAT = 75Se-homocholic acid taurine) Consider bile salt malabsorption • SeHCAT scan • Serum 7α-hydroxycholestenone Normal Normal Suspected malabsorption Clinical features of steatorrhoea • Blood tests (urea and electrolytes, immunoglobulins, Ca2+, Mg2+, full blood count, clotting, albumin, folate, B12, coeliac antibodies) Investigate small intestine • Duodenal biopsy • Barium studies or small bowel MRI • Faecal calprotectin • Lactulose/glucose hydrogen breath test Investigate pancreas • Pancreatic function tests, e.g. faecal elastase • Ultrasound scan/CT • MRCP and hydrolysis of nutrients. Fat and protein malabsorption results. This may also occur with small bowel bacterial overgrowth. • Mucosal malabsorption results from small bowel resection or conditions that damage the small intestinal epithelium, thereby diminishing the surface area for absorption and depleting brush border enzyme activity. • ‘Post-mucosal’ lymphatic obstruction prevents the uptake and transport of absorbed lipids into lymphatic vessels. Increased pressure in these vessels results in leakage into the intestinal lumen, leading to protein-losing enteropathy. Investigations Investigations should be performed both to confirm the presence of malabsorption and to determine the underlying

786 • GASTROENTEROLOGY Investigations In cases where the cause of weight loss is not obvious after thorough history taking and physical examination, or where an existing condition is considered unlikely, the following investigations are indicated: urinalysis for glucose, protein and blood; blood tests, including liver function tests, random blood glucose and thyroid function tests; CRP and ESR (may be raised in unsuspected infections, such as tuberculosis, connective tissue disorders and malignancy); and faecal calprotectin. Sometimes invasive tests, such as bone marrow aspiration or liver biopsy, may be necessary to identify conditions like cryptic miliary tuberculosis (p. 588). Rarely, abdominal and pelvic imaging by CT may be required, but before embarking on invasive or very costly investigations it is always worth revisiting the patient’s history and reweighing at intervals. Constipation Constipation is defined as infrequent passage of hard stools. Patients may also complain of straining, a sensation of incomplete evacuation and either perianal or abdominal discomfort. Constipation may occur in many gastrointestinal and other medical disorders (Box 21.20). Clinical assessment and management The onset, duration and characteristics are important; for example, a neonatal onset suggests Hirschsprung’s disease, while a recent change in bowel activity in middle age should raise the suspicion of an organic disorder, such as colonic carcinoma. The presence of rectal bleeding, pain and weight loss is important, as are excessive Fig. 21.24 Some important causes of weight loss. Chronic infection HIV/AIDS Tuberculosis Brucellosis Gut infestations Gastrointestinal Poor dentition Any cause of oral pain, dysphagia Malabsorption Malignancy at any site Inflammatory bowel disease Chronic infection Cirrhosis Respiratory Chronic obstructive pulmonary disease Pulmonary tuberculosis Occult malignancy (especially small-cell carcinoma) Empyema Psychosocial Deprivation, starvation Eating disorders Depression, bipolar illness Bereavement Chronic pain/sleep deprivation Alcoholism Rheumatological Rheumatoid arthritis Mixed connective tissue disease Systemic sclerosis Systemic lupus erythematosus Renal Occult malignancy Chronic renal failure Salt-losing nephropathy Cardiac Congestive cardiac failure Infective endocarditis Endocrine Type 1 diabetes Thyrotoxicosis Addison’s disease Neurodegenerative Parkinsonism Dementia Motor neuron disease 21.20 Causes of constipation Gastrointestinal causes Dietary • Lack of fibre and/or fluid intake Motility • Slow-transit constipation • Irritable bowel syndrome • Drugs (see below) • Chronic intestinal pseudo-obstruction Structural • Colonic carcinoma • Diverticular disease • Hirschsprung’s disease Defecation • Anorectal disease (Crohn’s, fissures, haemorrhoids) • Obstructed defecation Non-gastrointestinal causes Drugs • Opiates • Anticholinergics • Calcium antagonists • Iron supplements • Aluminium-containing antacids Neurological • Multiple sclerosis • Spinal cord lesions • Cerebrovascular accidents • Parkinsonism Metabolic/endocrine • Diabetes mellitus • Hypercalcaemia • Hypothyroidism • Pregnancy Others • Any serious illness with immobility, especially in the elderly • Depression

Presenting problems in gastrointestinal disease • 787

peritoneum is involved, when it becomes localised. Movement exacerbates the pain; abdominal rigidity and guarding occur. • Perforation. When a viscus perforates, pain starts abruptly; it is severe and leads to generalised peritonitis. • Obstruction. Pain is colicky, with spasms that cause the patient to writhe around and double up. Colicky pain that does not disappear between spasms suggests complicating inflammation. Initial clinical assessment If there are signs of peritonitis (guarding and rebound tenderness with rigidity), the patient should be resuscitated with oxygen, intravenous fluids and antibiotics. In other circumstances, further investigations are required (Fig. 21.25). Investigations Patients should have a full blood count, urea and electrolytes, glucose and amylase taken to look for evidence of dehydration, leucocytosis and pancreatitis. Urinalysis is useful in suspected renal colic and pyelonephritis. An erect chest X-ray may show air under the diaphragm, suggestive of perforation, and a plain abdominal film may show evidence of obstruction or ileus (see Fig. 21.11). An abdominal ultrasound may help if gallstones or renal stones are suspected. Ultrasonography is also useful in the detection of free fluid and any possible intra-abdominal abscess. Contrast studies, by either mouth or anus, are useful in the further evaluation of intestinal obstruction, and essential in the differentiation of pseudo-obstruction from mechanical large-bowel obstruction. Other investigations commonly used include CT (seeking evidence of pancreatitis, retroperitoneal collections or masses, including an aortic aneurysm or renal calculi) and angiography (mesenteric ischaemia). Diagnostic laparotomy should be considered when the diagnosis has not been revealed by other investigations. All patients must be carefully and regularly re-assessed (every 2–4 hours) so that any change in condition that might alter both the suspected diagnosis and clinical decision can be observed and acted on early. Management The general approach is to close perforations, treat inflammatory conditions with antibiotics or resection, and relieve obstructions. The speed of intervention and the necessity for surgery depend on the organ that is involved and on a number of other factors, straining, symptoms suggestive of irritable bowel syndrome, a history of childhood constipation and emotional distress. Careful examination contributes more to the diagnosis than extensive investigation. A search should be made for general medical disorders, as well as signs of intestinal obstruction. Neurological disorders, especially spinal cord lesions, should be sought. Perineal inspection and rectal examination are essential and may reveal abnormalities of the pelvic floor (abnormal descent, impaired sensation), anal canal or rectum (masses, faecal impaction, prolapse). It is neither possible nor appropriate to investigate every person with constipation. Most respond to increased fluid intake, dietary fibre supplementation, exercise and the judicious use of laxatives. Middle-aged or elderly patients with a short history or worrying symptoms (rectal bleeding, pain or weight loss) must be investigated promptly, by either barium enema or colonoscopy. For those with simple constipation, investigation will usually proceed along the lines described below. Initial visit Digital rectal examination, proctoscopy and sigmoidoscopy (to detect anorectal disease), routine biochemistry, including serum calcium and thyroid function tests, and a full blood count should be carried out. If these are normal, a 1-month trial of dietary fibre and/or laxatives is justified. Next visit If symptoms persist, then examination of the colon by barium enema or CT colonography is indicated to look for structural disease. Further investigation If no cause is found and disabling symptoms are present, then specialist referral for investigation of possible dysmotility may be necessary. The problem may be one of infrequent desire to defecate (‘slow transit’) or else may result from neuromuscular incoordination and excessive straining (‘functional obstructive defecation’, p. 803). Intestinal marker studies, anorectal manometry, electrophysiological studies and magnetic resonance proctography can all be used to define the problem. Abdominal pain There are four types of abdominal pain: • Visceral. Gut organs are insensitive to stimuli such as burning and cutting but are sensitive to distension, contraction, twisting and stretching. Pain from unpaired structures is usually, but not always, felt in the midline. • Parietal. The parietal peritoneum is innervated by somatic nerves and its involvement by inflammation, infection or neoplasia causes sharp, well-localised and lateralised pain. • Referred pain. Gallbladder pain, for example, may be referred to the back or shoulder tip. • Psychogenic. Cultural, emotional and psychosocial factors influence everyone’s experience of pain. In some patients, no organic cause can be found despite investigation, and psychogenic causes (depression or somatisation disorder) may be responsible (pp. 1198 and 1202). The acute abdomen This accounts for approximately 50% of all urgent admissions to general surgical units. The acute abdomen is a consequence of one or more pathological processes (Box 21.21): • Inflammation. Pain develops gradually, usually over several hours. It is initially rather diffuse until the parietal 21.21 Causes of acute abdominal pain Inflammation • Appendicitis • Diverticulitis • Cholecystitis • Pelvic inflammatory disease • Pancreatitis • Pyelonephritis • Intra-abdominal abscess Perforation/rupture • Peptic ulcer • Diverticular disease • Ovarian cyst • Aortic aneurysm Obstruction • Intestinal obstruction • Biliary colic • Ureteric colic Other (rare) • See Box 21.23

788 • GASTROENTEROLOGY treatment. The appendix can be removed through a conventional right iliac fossa skin crease incision or by laparoscopic techniques. Acute cholecystitis This can be successfully treated non-operatively but the high risk of recurrent attacks and the low morbidity of surgery have made early laparoscopic cholecystectomy the treatment of choice. Acute diverticulitis Conservative therapy is standard but if perforation has occurred, resection is advisable. Depending on peritoneal contamination and the state of the patient, primary anastomosis is preferable to a Hartmann’s procedure (oversew of rectal stump and end-colostomy). Small bowel obstruction If the cause is obvious and surgery inevitable (such as with a strangulated hernia), an early operation is appropriate. If the suspected cause is adhesions from previous surgery, only those patients who do not resolve within the first 48 hours or who develop signs of strangulation (colicky pain becoming constant, peritonitis, tachycardia, fever, leucocytosis) should have surgery. of which the presence or absence of peritonitis is the most important. A treatment summary of some of the more common surgical conditions follows. Acute appendicitis This should be treated by early surgery, since there is a risk of perforation and recurrent attacks with non-operative Fig. 21.25 Management of acute abdominal pain: an algorithm. Symptoms and signs of peritonitis Resuscitation Pain No clear evidence of peritonitis Blood tests ↑ Amylase/lipase Acute pancreatitis Free air Perforation Dilated loops of bowel Intestinal obstruction/ileus Gallstones and thickened gallbladder wall Cholecystitis Pseudo-obstruction CT scan Pancreatitis Abscess Aortic aneurysm Malignancy Erect chest X-ray Abdominal X-ray Ultrasound Contrast radiology Abnormality detected Abnormality detected Perforation Inconclusive investigations No diagnosis No free air No abnormality No abnormality No abnormality No abnormality Symptoms persist Symptoms settle Laparotomy Laparoscopy Observe 21.22 Acute abdominal pain in old age • Presentation: severity and localisation may blunt with age. Presentation may be atypical, e.g. with delirium, collapse and/or immobility. • Cancer: a more common cause of acute pain in those over 70 years of age than in those under 50 years. Older people with vague abdominal symptoms should therefore be carefully assessed. • Non-specific symptoms: intra-abdominal inflammatory conditions, such as diverticulitis, may present with non-specific symptoms, such as delirium or anorexia and relatively little abdominal tenderness. The reasons for this are not clear but may stem from altered sensory perception. • Outcome of abdominal surgery: determined by how frail the patient is and whether surgery is elective or emergency, rather than by chronological age.

Presenting problems in gastrointestinal disease • 789

Note should be made of the patient’s general demeanour, mood and emotional state, signs of weight loss, fever, jaundice or anaemia. If a thorough abdominal and rectal examination is normal, a careful search should be made for evidence of disease affecting other structures, particularly the vertebral column, spinal cord, lungs and cardiovascular system. Investigations will depend on the clinical features elicited during the history and examination: • Endoscopy and ultrasound are indicated for epigastric pain, and for dyspepsia and symptoms suggestive of gallbladder disease. • Colonoscopy is indicated for patients with altered bowel habit, rectal bleeding or features of obstruction suggesting colonic disease. • CT or MR angiography should be considered when pain is provoked by food in a patient with widespread atherosclerosis, since this may indicate mesenteric ischaemia. • Persistent symptoms require exclusion of colonic or small bowel disease. However, young patients with pain relieved by defecation, bloating and alternating bowel habit are likely to have irritable bowel syndrome (p. 824). Simple investigations (blood tests, faecal calprotectin and sigmoidoscopy) are sufficient in the absence of rectal bleeding, weight loss and abnormal physical findings. • Ultrasound, CT and faecal elastase are required for patients with upper abdominal pain radiating to the back. A history of alcohol misuse, weight loss and diarrhoea suggests chronic pancreatitis or pancreatic cancer. • Recurrent attacks of pain in the loins radiating to the flanks with urinary symptoms should prompt investigation for renal or ureteric stones by abdominal X-ray, ultrasound and computed tomography of the kidneys, ureters and bladder (CT KUB). • A past history of psychiatric disturbance, repeated negative investigations or vague symptoms that do not fit any disease or organ pattern suggest a psychological origin for the pain. Careful review of case notes and previous investigations, along with open and honest discussion with the patient, reduces the need for further cycles of unnecessary and invasive tests. Care must always be taken, however, not to miss rare pathology, such as acute intermittent porphyria (p. 378), or atypical presentations of common diseases. Constant abdominal pain Patients with chronic pain that is constant or nearly always present usually have features to suggest the underlying diagnosis. No cause will be found in a minority, despite thorough investigation, leading to the diagnosis of ‘chronic functional abdominal pain’. In these patients, there appears to be abnormal CNS processing of normal visceral afferent sensory input and psychosocial factors are often operative (p. 1186); the most important tasks are to provide symptom control, if not relief, and to minimise the effects of the pain on social, personal and occupational life. Patients are best managed in specialised pain clinics where, in addition to psychological support, appropriate use of drugs, including tricyclic antidepressants, gabapentin or pregabalin, ketamine and opioids, may be necessary. Large bowel obstruction Pseudo-obstruction should be treated non-operatively. Some patients benefit from colonoscopic decompression but mechanical obstruction merits resection, usually with a primary anastomosis. Differentiation between the two is made by water-soluble contrast enema. Perforated peptic ulcer Surgical closure of the perforation is standard practice but some patients without generalised peritonitis can be treated non-operatively once a water-soluble contrast meal has confirmed spontaneous sealing of the perforation. Adequate and aggressive resuscitation with intravenous fluids, antibiotics and analgesia is mandatory before surgery. For a more detailed discussion of acute abdominal pain, the reader is referred to the sister volume of this text, Principles and Practice of Surgery. Chronic or recurrent abdominal pain It is essential to take a detailed history, paying particular attention to features of the pain and any associated symptoms (Boxes 21.23 and 21.24). 21.23 Extra-intestinal causes of chronic or recurrent abdominal pain Retroperitoneal • Aortic aneurysm • Malignancy • Lymphadenopathy • Abscess Psychogenic • Depression • Anxiety • Hypochondriasis • Somatisation Locomotor • Vertebral compression/fracture • Abdominal muscle strain Metabolic/endocrine • Diabetes mellitus • Acute intermittent porphyria • Hypercalcaemia Drugs/toxins • Glucocorticoids • Azathioprine • Lead • Alcohol Haematological • Sickle-cell disease • Haemolytic disorders Neurological • Spinal cord lesions • Tabes dorsalis • Radiculopathy 21.24 How to assess abdominal pain • Duration • Site and radiation • Severity • Precipitating and relieving factors (food, drugs, alcohol, posture, movement, defecation) • Nature (colicky, constant, sharp or dull, wakes patient at night) • Pattern (intermittent or continuous) • Associated features (vomiting, dyspepsia, altered bowel habit)

790 • GASTROENTEROLOGY Oral cancer may present in many ways (Box 21.26) and a high index of suspicion is required. All possible sources of local trauma or infection should be treated in patients with suspicious lesions and they should be reviewed after 2 weeks, with biopsy if the lesion persists. Small cancers can be resected but extensive surgery, with neck dissection to remove involved lymph nodes, may be necessary. Some patients can be treated with radical radiotherapy alone, and sometimes radiotherapy is also given after surgery to treat microscopic residual disease. Some tumours may be amenable to photodynamic therapy (PDT), avoiding the need for surgery. Candidiasis The yeast Candida albicans is a normal mouth commensal but it may proliferate to cause thrush. This occurs in babies, debilitated patients, people receiving glucocorticoid or antibiotic therapy, individuals with diabetes and immunosuppressed patients, especially those receiving cytotoxic therapy and those with HIV infection. White patches are seen on the tongue and buccal mucosa. Odynophagia or dysphagia suggests pharyngeal and oesophageal candidiasis. A clinical diagnosis is sufficient to instigate therapy, although brushings or biopsies can be obtained for mycological examination. Oral thrush is treated using nystatin or amphotericin suspensions or lozenges. Resistant cases or immunosuppressed patients may require oral fluconazole. Parotitis Parotitis is caused by viral or bacterial infection. Mumps causes a self-limiting acute parotitis (p. 240). Bacterial parotitis usually occurs as a complication of major surgery. It is a consequence of dehydration and poor oral hygiene, and can be avoided by good post-operative care. Patients present with painful parotid swelling and this can be complicated by abscess formation. Broad-spectrum antibiotics are required, while surgical drainage is necessary for abscesses. Other causes of salivary gland enlargement are listed in Box 21.27. Diseases of the mouth and salivary glands Aphthous ulceration Aphthous ulcers are superficial and painful; they occur in any part of the mouth. Recurrent ulcers afflict up to 30% of the population and are particularly common in women prior to menstruation. The cause is unknown, but in severe cases other causes of oral ulceration must be considered (Box 21.25). Biopsy is occasionally necessary for diagnosis. Management is with topical glucocorticoids (such as 0.1% triamcinolone in Orabase) or choline salicylate (8.7%) gel. Symptomatic relief is achieved using local anaesthetic mouthwashes. Rarely, patients with very severe, recurrent aphthous ulcers may need oral glucocorticoids. 21.26 Symptoms and signs of oral cancer • Solitary ulcer without precipitant, e.g. local trauma • Solitary white patch (‘leukoplakia’) that fails to wipe off • Solitary red patch • Fixed lump • Lip numbness in absence of trauma or infection • Trismus (pain/difficulty in opening the mouth) • Cervical lymphadenopathy 21.25 Causes of oral ulceration Aphthous • Idiopathic • Premenstrual Infection • Fungal (candidiasis) • Viral (herpes simplex, HIV) • Bacterial, including syphilis, tuberculosis Gastrointestinal diseases • Crohn’s disease • Coeliac disease Dermatological conditions • Lichen planus • Immunobullous disorders (p. 1255) • Dermatitis herpetiformis • Erythema multiforme Drugs • Nicorandil, NSAIDs, methotrexate, penicillamine, losartan, ACE inhibitors • Stevens–Johnson syndrome (pp. 1254 and 1264) • Cytotoxic drugs Systemic diseases • Systemic lupus erythematosus (p. 1034) • Behçet’s disease (p. 1043) Neoplasia • Carcinoma • Leukaemia • Kaposi’s sarcoma (ACE = angiotensin-converting enzyme; NSAIDs = non-steroidal anti-inflammatory drugs) 21.27 Causes of salivary gland swelling • Infection: Mumps Bacterial (post-operative) • Calculi • Sjögren’s syndrome (p. 1038) • Sarcoidosis • Tumours: Benign: pleomorphic adenoma (95% of cases) Intermediate: mucoepidermoid tumour Malignant: carcinoma Oral cancer Squamous carcinoma of the oral cavity is common worldwide and the incidence has increased by 25% in the last decade in the UK. The mortality rate is around 50%, largely as a result of late diagnosis. Poor diet, alcohol excess and smoking or tobacco chewing are the traditional risk factors but high-risk, oncogenic strains of human papillomavirus (HPV-16 and HPV-18) have been identified as being responsible for much of the recent increase in incidence, especially in cases affecting the base of tongue, soft palate and tonsils. In parts of Asia, the disease is common among people who chew areca nuts wrapped in leaves of the betel plant (‘betel nuts’).

Diseases of the oesophagus • 791

Gastric contents Gastric acid is the most important oesophageal irritant and there is a close relationship between acid exposure time and symptoms. Pepsin and bile also contribute to mucosal injury. Defective gastric emptying Gastric emptying is delayed in patients with gastro-oesophageal reflux disease. The reason is unknown. Increased intra-abdominal pressure Pregnancy and obesity are established predisposing causes. Weight loss may improve symptoms. Dietary and environmental factors Dietary fat, chocolate, alcohol, tea and coffee relax the lower oesophageal sphincter and may provoke symptoms. The foods that trigger symptoms vary widely between affected individuals. Patient factors Visceral sensitivity and patient vigilance play a role in determining symptom severity and consulting behaviour in individual patients. Clinical features The major symptoms are heartburn and regurgitation, often provoked by bending, straining or lying down. ‘Waterbrash’, which is salivation due to reflex salivary gland stimulation as acid enters the gullet, is often present. The patient is often overweight. Some patients are woken at night by choking as refluxed fluid Diseases of the oesophagus Gastro-oesophageal reflux disease Gastro-oesophageal reflux resulting in heartburn affects approximately 30% of the general population. Pathophysiology Occasional episodes of gastro-oesophageal reflux are common in healthy individuals. Reflux is normally followed by oesophageal peristaltic waves that efficiently clear the gullet, alkaline saliva neutralises residual acid and symptoms do not occur. Gastrooesophageal reflux disease develops when the oesophageal mucosa is exposed to gastroduodenal contents for prolonged periods of time, resulting in symptoms and, in a proportion of cases, oesophagitis. Several factors are known to be involved in the development of gastro-oesophageal reflux disease and these are shown in Figure 21.26. Abnormalities of the lower oesophageal sphincter The lower oesophageal sphincter is tonically contracted under normal circumstances, relaxing only during swallowing (p. 766). Some patients with gastro-oesophageal reflux disease have reduced lower oesophageal sphincter tone, permitting reflux when intra-abdominal pressure rises. In others, basal sphincter tone is normal but reflux occurs in response to frequent episodes of inappropriate sphincter relaxation. Hiatus hernia Hiatus hernia (Box 21.29 and Fig. 21.27) causes reflux because the pressure gradient is lost between the abdominal and thoracic cavities, which normally pinches the hiatus. In addition, the oblique angle between the cardia and oesophagus disappears. Many patients who have large hiatus hernias develop reflux symptoms but the relationship between the presence of a hernia and symptoms is poor. Hiatus hernia is very common in individuals who have no symptoms, and some symptomatic patients have only a very small or no hernia. Nevertheless, almost all patients who develop oesophagitis, Barrett’s oesophagus or peptic strictures have a hiatus hernia. Delayed oesophageal clearance Defective oesophageal peristaltic activity is commonly found in patients who have oesophagitis. It is a primary abnormality, since it persists after oesophagitis has been healed by acid-suppressing drug therapy. Poor oesophageal clearance leads to increased acid exposure time. 21.28 Oral health in old age • Dry mouth: affects around 40% of healthy older people. • Gustatory and olfactory sensation: declines and chewing power is diminished. • Salivation: baseline salivary flow falls but stimulated salivation is unchanged. • Root caries and periodontal disease: common partly because oral hygiene deteriorates with increasing frailty. • Bacteraemia and sepsis: may complicate Gram-negative anaerobic infection in the periodontal pockets of the very frail. Fig. 21.26 Factors associated with the development of gastrooesophageal reflux disease. Acid-pepsin (bile) Delayed gastric emptying Hiatus hernia Defective oesophageal clearance Abnormal lower oesophageal sphincter • Reduced tone • Inappropriate relaxation Increased intra-abdominal pressure Obesity Dietary factors 21.29 Important features of hiatus hernia • Herniation of the stomach through the diaphragm into the chest • Occurs in 30% of the population over the age of 50 years • Often asymptomatic • Heartburn and regurgitation can occur • Gastric volvulus may complicate large hernias

792 • GASTROENTEROLOGY may be important in the pathogenesis. The molecular events underlying progression of Barrett’s oesophagus to dysplasia and cancer are incompletely understood but inactivation of the tumour suppression protein p16 by loss of heterozygosity or promoter hypermethylation is a key event, followed by somatic inactivation of TP53, which promotes aneuploidy and tumour progression. Studies are in progress to develop biomarkers that will allow detection of those at higher cancer risk. Diagnosis This requires multiple systematic biopsies to maximise the chance of detecting intestinal metaplasia and/or dysplasia. Management Neither potent acid suppression nor anti-reflux surgery stops progression or induces regression of Barrett’s Fig. 21.27 Types of hiatus hernia. A Rolling or para-oesophageal. Inset: Barium meal showing a large para-oesophageal hernia with intrathoracic stomach. B Sliding. Inset: Barium meal showing a gastric volvulus (small arrows) complicating a sliding hiatus hernia (large arrow). Lower oesophageal sphincter Lower oesophageal sphincter Diaphragm Diaphragm A B Fig. 21.28 Severe reflux oesophagitis. There is near-circumferential superficial ulceration and inflammation extending up the gullet. irritates the larynx. Others develop odynophagia or dysphagia. A variety of other features have been described, such as atypical chest pain that may be severe and can mimic angina; it may be due to reflux-induced oesophageal spasm. Others include hoarseness (‘acid laryngitis’), recurrent chest infections, chronic cough and asthma. The true relationship of these features to gastro-oesophageal reflux disease remains unclear. Complications Oesophagitis A range of endoscopic findings is recognised, from mild redness to severe bleeding ulceration with stricture formation, although appearances may be completely normal (Fig. 21.28). There is a poor correlation between symptoms and histological and endoscopic findings. Barrett’s oesophagus Barrett’s oesophagus is a pre-malignant condition, in which the normal squamous lining of the lower oesophagus is replaced by columnar mucosa (columnar lined oesophagus; CLO) that may contain areas of intestinal metaplasia (Fig. 21.29). It is an adaptive response to chronic gastro-oesophageal reflux and is found in 10% of patients undergoing gastroscopy for reflux symptoms. Community-based epidemiological studies suggest that the true prevalence may be up to 1.5–5% of the population, as the condition is often asymptomatic until discovered when the patient presents with oesophageal cancer. The relative risk of oesophageal cancer is increased 40–120-fold but the absolute risk is low (0.1–0.5% per year). The epidemiology and aetiology of Barrett’s oesophagus are poorly understood. The prevalence is increasing, and it is more common in men (especially white), the obese and those over 50 years of age. It is weakly associated with smoking but not alcohol intake. The risk of cancer seems to relate to the severity and duration of reflux rather than the presence of Barrett’s oesophagus per se, and it has been suggested that duodenogastro-oesophageal reflux of bile, pancreatic enzymes and pepsin, as well as gastric acid,

Diseases of the oesophagus • 793

Diagnosis is by endoscopy, when biopsies of the stricture can be taken to exclude malignancy. Endoscopic balloon dilatation or bouginage is helpful. Subsequently, long-term therapy with a PPI drug at full dose should be started to reduce the risk of recurrent oesophagitis and stricture formation. The patient should be advised to chew food thoroughly and it is important to ensure adequate dentition. Gastric volvulus Occasionally, a massive intrathoracic hiatus hernia may twist on itself, leading to a gastric volvulus. This gives rise to complete oesophageal or gastric obstruction and the patient presents with severe chest pain, vomiting and dysphagia. The diagnosis is made by chest X-ray (air bubble in the chest) and barium swallow (see Fig. 21.27B). Most cases spontaneously resolve but recurrence is common, and surgery is usually advised after the acute episode has been treated by nasogastric decompression. Investigations Young patients who present with typical symptoms of gastrooesophageal reflux, without worrying features such as dysphagia, weight loss or anaemia, can be treated empirically without investigation. Investigation is advisable if patients present over the age of 50–55 years, if symptoms are atypical or if a complication is suspected. Endoscopy is the investigation of choice. This is performed to exclude other upper gastrointestinal diseases that can mimic gastro-oesophageal reflux and to identify complications. A normal endoscopy in a patient with compatible symptoms should not preclude treatment for gastro-oesophageal reflux disease. Twenty-four-hour pH monitoring is indicated if the diagnosis is unclear or surgical intervention is under consideration. This involves tethering a slim catheter with a terminal radiotelemetry pH-sensitive probe above the gastro-oesophageal junction. The intraluminal pH is recorded while the patient undergoes normal activities, and episodes of symptoms are noted and related to pH. A pH of less than 4 for more than 6–7% of the study time is diagnostic of reflux disease. In a few patients with difficult reflux, impedance testing can detect weakly acidic or alkaline reflux that is not revealed by standard pH testing. Management A treatment algorithm for gastro-oesophageal reflux is outlined in Figure 21.30. Lifestyle advice should be given, including weight loss, avoidance of dietary items that the patient finds worsen symptoms, elevation of the bed head in those who experience nocturnal symptoms, avoidance of late meals and cessation of smoking. Patients who fail to respond to these measures should be offered PPIs, which are usually effective in resolving symptoms and healing oesophagitis. Recurrence of symptoms is common when therapy is stopped and some patients require life-long treatment at the lowest acceptable dose. When dysmotility features are prominent, domperidone can be helpful. There is no evidence that H. pylori eradication has any therapeutic value. Proprietary antacids and alginates can also provide symptomatic benefit. H2-receptor antagonist drugs relieve symptoms without healing oesophagitis. Long-term PPI therapy is associated with reduced absorption of iron, B12 and magnesium, and a small but increased risk of osteoporosis and fractures (odds ratio 1.2–1.5). The drugs also predispose to enteric infections with Salmonella, Campylobacter and possibly Clostridium difficile, and have recently been shown to have an undesirable impact on the composition of the gut oesophagus, and treatment is indicated only for symptoms of reflux or complications, such as stricture. Endoscopic therapies, such as radiofrequency ablation or photodynamic therapy, can induce regression but at present are used only for those with dysplasia or intramucosal cancer. Regular endoscopic surveillance can detect dysplasia at an early stage and may improve survival but, because most Barrett’s oesophagus is undetected until cancer develops, surveillance strategies are unlikely to influence the overall mortality rate of oesophageal cancer. Surveillance is expensive and cost-effectiveness studies have been conflicting. It is currently recommended that patients with Barrett’s oesophagus with intestinal metaplasia, but without dysplasia, should undergo endoscopy at 3–5-yearly intervals if the length of the Barrettic segment is less than 3 cm and at 2–3-yearly intervals if the length is greater than 3 cm. Those with low-grade dysplasia should be endoscoped at 6-monthly intervals. For those with high-grade dysplasia or intramucosal carcinoma, the treatment options are either oesophagectomy or endoscopic therapy, with a combination of endoscopic resection of any visibly abnormal areas and radiofrequency ablation of the remaining Barrett’s mucosa, as an ‘organ-preserving’ alternative to surgery. These cases should be discussed in a multidisciplinary team meeting and managed in specialist centres. Anaemia Iron deficiency anaemia can occur as a consequence of occult blood loss from long-standing oesophagitis. Most patients have a large hiatus hernia and bleeding can stem from subtle erosions in the neck of the sac (‘Cameron lesions’). Nevertheless, hiatus hernia is very common and other causes of blood loss, particularly colorectal cancer, must be considered in anaemic patients, even when endoscopy reveals oesophagitis. Benign oesophageal stricture Fibrous strictures can develop as a consequence of longstanding oesophagitis, especially in the elderly and those with poor oesophageal peristaltic activity. The typical presentation is with dysphagia that is worse for solids than for liquids. Bolus obstruction following ingestion of meat causes absolute dysphagia. A history of heartburn is common but not invariable; many elderly patients presenting with strictures have no preceding heartburn. Fig. 21.29 Barrett’s oesophagus. Tongues of pink columnar mucosa are seen extending upwards above the oesophago-gastric junction.

794 • GASTROENTEROLOGY is conservative, based on analgesia and nutritional support; vomiting and endoscopy should be avoided because of the high risk of oesophageal perforation. After the acute phase, a barium swallow should be performed to demonstrate the extent of stricture formation. Endoscopic dilatation is usually necessary but it is difficult and hazardous because strictures are often long, tortuous and easily perforated. Drugs Potassium supplements and NSAIDs may cause oesophageal ulcers when the tablets are trapped above an oesophageal stricture. Liquid preparations of these drugs should be used in such patients. Bisphosphonates cause oesophageal ulceration and should be used with caution in patients with known oesophageal disorders. Eosinophilic oesophagitis This is more common in children but increasingly recognised in young adults. It occurs more often in atopic individuals and is characterised by eosinophilic infiltration of the oesophageal mucosa. Patients present with dysphagia or food bolus obstruction more often than heartburn, and other symptoms, such as chest pain and vomiting, may be present. Endoscopy is usually normal but mucosal rings (that sometimes need endoscopic dilatation), strictures or a narrow-calibre oesophagus can occur. Children may respond to elimination diets but these are less successful in adults, who should first be treated with PPIs. The condition can be treated with 8–12 weeks of therapy with topical glucocorticoids, such as fluticasone or betamethasone. The usual approach is to prescribe a metered-dose inhaler but to tell the patient to spray this into the mouth and swallow it rather than inhale it. Refractory symptoms sometimes respond to montelukast, a leukotriene inhibitor. Motility disorders Pharyngeal pouch This occurs because of incoordination of swallowing within the pharynx, which leads to herniation through the cricopharyngeus muscle and formation of a pouch. It is rare, affecting 1 in 100 000 people; it usually develops in middle life but can arise at any age. Many patients have no symptoms but regurgitation, halitosis and dysphagia can be present. Some notice gurgling in the throat after swallowing. The investigation of choice is a barium swallow (see Fig. 21.12A), which demonstrates the pouch and reveals incoordination of swallowing, often with pulmonary aspiration. Endoscopy may be hazardous, since the instrument may enter and perforate the pouch. Surgical myotomy (‘diverticulotomy’), with or without resection of the pouch, is indicated in symptomatic patients. Achalasia of the oesophagus Pathophysiology Achalasia is characterised by: • a hypertonic lower oesophageal sphincter, which fails to relax in response to the swallowing wave • failure of propagated oesophageal contraction, leading to progressive dilatation of the gullet. The cause is unknown. Defective release of nitric oxide by inhibitory neurons in the lower oesophageal sphincter has been reported, and there is degeneration of ganglion cells within the microbiota. Long-term therapy increases the risk of Helicobacterassociated progression of gastric mucosal atrophy (see below) and H. pylori eradication is advised in patients requiring PPIs for more than 1 year. Patients who fail to respond to medical therapy, those who are unwilling to take long-term PPIs and those whose major symptom is severe regurgitation should be considered for laparoscopic anti-reflux surgery (see Principles and Practice of Surgery). Although heartburn and regurgitation are alleviated in most patients, a small minority develop complications, such as inability to vomit and abdominal bloating (‘gas-bloat’ syndrome’). Other causes of oesophagitis Infection Oesophageal candidiasis occurs in debilitated patients and those taking broad-spectrum antibiotics or cytotoxic drugs. It is a particular problem in patients with HIV/AIDS, who are also susceptible to a spectrum of other oesophageal infections (p. 316). Corrosives Suicide attempt by ingestion of strong household bleach or battery acid is followed by painful burns of the mouth and pharynx and by extensive erosive oesophagitis (p. 147). This may be complicated by oesophageal perforation with mediastinitis and by stricture formation. At the time of presentation, treatment Fig. 21.30 Treatment of gastro-oesophageal reflux disease: a ‘step-down’ approach. Symptoms Antacids/alginates Proton pump inhibitor at full dose Good response Poor response or side-effects Reconsider diagnosis Consider pH monitoring Normal Positive Proton pump inhibitor at maintenance dose H2-receptor antagonists Antacids Fundoplication 21.30 Gastro-oesophageal reflux disease in old age • Prevalence: higher. • Severity of symptoms: does not correlate with the degree of mucosal inflammation. • Complications: late complications, such as peptic strictures or bleeding from oesophagitis, are more common. • Recurrent pneumonia: consider aspiration from occult gastrooesophageal reflux disease.

Diseases of the oesophagus • 795

invasive than endoscopic dilatation. Both pneumatic dilatation and myotomy may be complicated by gastro-oesophageal reflux, and this can lead to severe oesophagitis because oesophageal clearance is so poor. For this reason, Heller’s myotomy is accompanied by a partial fundoplication anti-reflux procedure. PPI therapy is often necessary after surgery. Other oesophageal motility disorders Diffuse oesophageal spasm presents in late middle age with episodic chest pain that may mimic angina but is sometimes accompanied by transient dysphagia. Some cases occur in response to gastro-oesophageal reflux. Treatment is based on the use of PPI drugs when gastro-oesophageal reflux is present. Oral or sublingual nitrates or nifedipine may relieve attacks of pain. The results of drug therapy are often disappointing, as are the alternatives: pneumatic dilatation and surgical myotomy. ‘Nutcracker’ oesophagus is a condition in which extremely forceful peristaltic activity leads to episodic chest pain and dysphagia. Treatment is with nitrates or nifedipine. Some patients present with oesophageal motility disorders that do not fit into a specific disease entity. The patients are usually elderly and present with dysphagia and chest pain. Manometric abnormalities, ranging from poor peristalsis to spasm, occur. Treatment is with dilatation and/or vasodilators for chest pain. Secondary causes of oesophageal dysmotility In systemic sclerosis or CREST syndrome (p. 1037), the muscle of the oesophagus is replaced by fibrous tissue, which causes failure of peristalsis leading to heartburn and dysphagia. Oesophagitis is often severe and benign fibrous strictures occur. These patients require long-term therapy with PPIs. Dermatomyositis, rheumatoid arthritis and myasthenia gravis may also cause dysphagia. Benign oesophageal stricture Benign oesophageal stricture is usually a consequence of gastro-oesophageal reflux disease (Box 21.31) and occurs most often in elderly patients who have poor oesophageal clearance. Rings, caused by submucosal fibrosis, are found at the oesophago-gastric junction (‘Schatzki ring’) and cause intermittent sphincter and the body of the oesophagus. Loss of the dorsal vagal nuclei within the brainstem can be demonstrated in later stages. Infection with Trypanosoma cruzi in Chagas’ disease (p. 279) causes a syndrome that is clinically indistinguishable from achalasia. Clinical features The presentation is with dysphagia. This develops slowly, is initially intermittent, and is worse for solids and eased by drinking liquids and by standing and moving around after eating. Heartburn does not occur because the closed oesophageal sphincter prevents gastro-oesophageal reflux. Some patients experience episodes of chest pain due to oesophageal spasm. As the disease progresses, dysphagia worsens, the oesophagus empties poorly and nocturnal pulmonary aspiration develops. Achalasia predisposes to squamous carcinoma of the oesophagus. Investigations Endoscopy should always be carried out because carcinoma of the cardia can mimic the presentation and radiological and manometric features of achalasia (‘pseudo-achalasia’). A barium swallow shows tapered narrowing of the lower oesophagus and, in late disease, the oesophageal body is dilated, aperistaltic and food-filled (Fig. 21.31A). Manometry confirms the high-pressure, non-relaxing lower oesophageal sphincter with poor contractility of the oesophageal body (Fig. 21.31B). Management Endoscopic Forceful pneumatic dilatation using a 30–35-mm-diameter, fluoroscopically positioned balloon disrupts the oesophageal sphincter and improves symptoms in 80% of patients. Some patients require more than one dilatation but those needing frequent dilatation are best treated surgically. Endoscopically directed injection of botulinum toxin into the lower oesophageal sphincter induces clinical remission but relapse is common. Recently, a complex endoscopic technique has been developed in specialist centres (peroral endoscopic myotomy, POEM). Surgical Surgical myotomy (Heller’s operation), performed either laparoscopically or as an open operation, is effective but is more Fig. 21.31 Achalasia. A X-ray showing a dilated, barium-filled oesophagus (O) with fluid level and distal tapering, and a closed lower oesophageal sphincter (LOS). (D = diaphragm) B High-resolution manometry in achalasia showing absence of peristaltic swallowing wave in oesophageal body (black arrows) and raised LOS pressure with failure of relaxation on swallowing (white arrow). Compare with normal appearances in Figure 21.1 (p. 766). Time (secs) LOS D O A B

796 • GASTROENTEROLOGY spread and local invasion (Fig. 21.33). Invasion of the aorta, major airways or coeliac axis usually precludes surgery, but patients with resectable disease on imaging should undergo EUS to determine the depth of penetration of the tumour into the oesophageal wall and to detect locoregional lymph node dysphagia, often starting in middle age. A post-cricoid web is a rare complication of iron deficiency anaemia (Paterson–Kelly or Plummer–Vinson syndrome), and may be complicated by the development of squamous carcinoma. Benign strictures can be treated by endoscopic dilatation, in which wire-guided bougies or balloons are used to disrupt the fibrous tissue of the stricture. Tumours of the oesophagus Benign tumours The most common is a leiomyoma. This is usually asymptomatic but may cause bleeding or dysphagia. Carcinoma of the oesophagus Squamous oesophageal cancer (Box 21.32) is relatively rare in Caucasians (4 : 100 000) but is more common in Iran, parts of Africa and China (200 : 100 000). Squamous cancer can occur in any part of the oesophagus and almost all tumours in the upper oesophagus are squamous cancers. Adenocarcinomas typically arise in the lower third of the oesophagus from Barrett’s oesophagus or from the cardia of the stomach. The incidence is increasing and is now approximately 5: 100 000 in the UK; this is possibly because of the high prevalence of gastro-oesophageal reflux and Barrett’s oesophagus in Western populations. Despite modern treatment, the overall 5-year survival of patients presenting with oesophageal cancer is only 13%. Clinical features Most patients have a history of progressive, painless dysphagia for solid foods. Others present acutely because of food bolus obstruction. In the late stages, weight loss is often extreme; chest pain or hoarseness suggests mediastinal invasion. Fistulation between the oesophagus and the trachea or bronchial tree leads to coughing after swallowing, pneumonia and pleural effusion. Physical signs may be absent but, even at initial presentation, cachexia, cervical lymphadenopathy or other evidence of metastatic spread is common. Investigations The investigation of choice is upper gastrointestinal endoscopy (Fig. 21.32) with biopsy. A barium swallow demonstrates the site and length of the stricture but adds little useful information. Once a diagnosis has been made, investigations should be performed to stage the tumour and define operability. Thoracic and abdominal CT, often combined with positron emission tomography (PET-CT), should be carried out to identify metastatic 21.31 Causes of oesophageal stricture • Gastro-oesophageal reflux disease • Webs and rings • Carcinoma of the oesophagus or cardia • Eosinophilic oesophagitis • Extrinsic compression from bronchial carcinoma • Corrosive ingestion • Post-operative scarring following oesophageal resection • Post-radiotherapy • Following long-term nasogastric intubation • Bisphosphonates Fig. 21.32 Adenocarcinoma of the lower oesophagus. A polypoidal adenocarcinoma in association with Barrett’s oesophagus. Fig. 21.33 Positron emission tomography–computed tomography (PET-CT) staging of oesophageal carcinoma. Whole-body PET scan showing avid uptake in the primary tumour (thick arrow) but also in distant paratracheal (superior thin arrow) and gastro-oesophageal (inferior thin arrow) lymph nodes. 21.32 Squamous carcinoma: aetiological factors • Smoking • Alcohol excess • Chewing betel nuts or tobacco • Achalasia of the oesophagus • Coeliac disease • Post-cricoid web • Post-caustic stricture • Tylosis (familial hyperkeratosis of palms and soles)

Diseases of the stomach and duodenum • 797

Spontaneous oesophageal perforation (‘Boerhaave’s syndrome’) results from forceful vomiting and retching. Severe chest pain and shock occur as oesophago-gastric contents enter the mediastinum and thoracic cavity. Subcutaneous emphysema, pleural effusions and pneumothorax develop. The diagnosis can be made using a water-soluble contrast swallow but, in difficult cases, both CT and careful endoscopy (usually in an intubated patient) may be required. Treatment is surgical. Delay in diagnosis is a key factor in the high mortality associated with this condition. Diseases of the stomach and duodenum Gastritis Gastritis is a histological diagnosis, although it can also be recognised at endoscopy. Acute gastritis Acute gastritis is often erosive and haemorrhagic. Neutrophils are the predominant inflammatory cell in the superficial epithelium. Many cases result from alcohol, aspirin or NSAID ingestion (Box 21.33). Acute gastritis often produces no symptoms but may cause dyspepsia, anorexia, nausea or vomiting, and haematemesis or melaena. Many cases resolve quickly and do not merit investigation; in others, endoscopy and biopsy may be necessary to exclude peptic ulcer or cancer. Treatment should be directed at the underlying cause. Short-term symptomatic therapy with antacids, and acid suppression using PPIs, prokinetics (domperidone) or antiemetics (metoclopramide) may be necessary. Chronic gastritis due to Helicobacter pylori infection This is the most common cause of chronic gastritis (Box 21.33). The predominant inflammatory cells are lymphocytes and plasma cells. Correlation between symptoms and endoscopic or pathological findings is poor. Most patients are asymptomatic and do not require treatment but patients with dyspepsia may benefit from H. pylori eradication. Autoimmune chronic gastritis This involves the body of the stomach but spares the antrum; it results from autoimmune damage to parietal cells. The histological features are diffuse chronic inflammation, atrophy and loss of fundic glands, intestinal metaplasia and sometimes hyperplasia of enterochromaffin-like (ECL) cells. Circulating antibodies to parietal cell and intrinsic factor may be present. In some patients, the degree of gastric atrophy is severe and loss of intrinsic factor secretion leads to pernicious anaemia (p. 944). The gastritis itself is usually asymptomatic. Some patients have evidence of other organ-specific autoimmunity, particularly thyroid disease. In the long term, there is a two- to threefold increase in the risk of gastric cancer (see also p. 803). Ménétrier’s disease In this rare condition, the gastric pits are elongated and tortuous, with replacement of the parietal and chief cells by mucus-secreting cells. The cause is unknown but there is excessive production of transforming growth factor alpha (TGF-α). As a result, the involvement (Fig. 21.34). These investigations will define the TNM stage of the disease (p. 1322). Management The treatment of choice is surgery if the patient presents at a point at which resection is possible. For very early superficial tumours, endoscopic submucosal dissection may offer an alternative to surgery but is not widely used outside of Japan and Korea. Patients with tumours that have extended beyond the wall of the oesophagus (T3) or that have lymph node involvement (N1) carry a 5-year survival of around 10%. This figure improves significantly, however, if the tumour is confined to the oesophageal wall and there is no spread to lymph nodes. Overall survival following ‘potentially curative’ surgery (all macroscopic tumour removed) is about 30% at 5 years but recent studies have suggested that this can be improved by neoadjuvant chemotherapy. Although squamous carcinomas are radiosensitive, radiotherapy alone is associated with a 5-year survival of only 5% but combined chemoradiotherapy for these tumours can achieve 5-year survival rates of 25–30%. Approximately 70% of patients have extensive disease at presentation; in these, treatment is palliative and should focus on relief of dysphagia and pain. Endoscopic laser therapy or self-expanding metallic stents can be used to improve swallowing. Palliative radiotherapy may induce shrinkage of both squamous cancers and adenocarcinomas but symptomatic response may be slow. Quality of life can be improved by nutritional support and appropriate analgesia. Perforation of the oesophagus The most common cause is endoscopic perforation complicating dilatation or intubation. Malignant, corrosive or post-radiotherapy strictures are more likely to be perforated than peptic strictures. A perforated peptic stricture is managed conservatively using broad-spectrum antibiotics and parenteral nutrition; most cases heal within days. Malignant, caustic and radiotherapy stricture perforations require resection or stenting. Fig. 21.34 Endoscopic ultrasound staging of oesophageal carcinoma. There is a superficial adenocarcinoma of the oesophagus (T). The submucosa (white band, white arrows) is not involved but there is a small involved local lymph node (white arrow, inset). The tumour is therefore staged T1a, N1. T

798 • GASTROENTEROLOGY in the UK approximately 50% of people over the age of 50 years are infected. In the developing world infection is more common, affecting up to 90% of adults. These infections are probably acquired in childhood by person-to-person contact. The vast majority of colonised people remain healthy and asymptomatic, and only a minority develop clinical disease. Around 90% of duodenal ulcer patients and 70% of gastric ulcer patients are infected with H. pylori. The remaining 30% of gastric ulcers are caused by NSAIDs and this proportion is increasing in Western countries as a result of H. pylori eradication strategies. H. pylori is Gram-negative and spiral, and has multiple flagella at one end, which make it motile, allowing it to burrow and live beneath the mucus layer adherent to the epithelial surface. It uses an adhesin molecule (BabA) to bind to the Lewis b antigen on epithelial cells. Here the surface pH is close to neutral and any acidity is buffered by the organism’s production of the enzyme urease. This produces ammonia from urea and raises the pH around the bacterium and between its two cell membrane layers. H. pylori exclusively colonises gastric-type epithelium and is found in the duodenum only in association with patches of gastric metaplasia. It causes chronic gastritis by provoking a local inflammatory response in the underlying epithelium (Fig. 21.35). This depends on numerous factors, notably expression of bacterial cagA and vacA genes. The CagA gene product is injected into epithelial cells, interacting with numerous cell-signalling pathways involved in cell replication and apoptosis. H. pylori strains expressing CagA (CagA+) are more often associated with disease than CagA− strains. Most strains also secrete a large pore-forming protein called VacA, which causes increased cell permeability, efflux of micronutrients from the epithelium, induction of apoptosis and suppression of local immune cell activity. Several forms of VacA exist and pathology is most strongly associated with the s1/ml form of the toxin. The distribution and severity of H. pylori–induced gastritis determine the clinical outcome. In most people, H. pylori causes a mild pangastritis with little effect on acid secretion and the majority develop no significant clinical outcomes. In a minority (up mucosal folds of the body and fundus are greatly enlarged. Most patients are hypochlorhydric. While some patients have upper gastrointestinal symptoms, the majority present in middle or old age with protein-losing enteropathy (p. 811) due to exudation from the gastric mucosa. Endoscopy shows enlarged, nodular and coarse folds, although biopsies may not be deep enough to show all the histological features. Treatment with antisecretory drugs, such as PPIs with or without octreotide, may reduce protein loss and H. pylori eradication may be effective, but unresponsive patients require partial gastrectomy. Peptic ulcer disease The term ‘peptic ulcer’ refers to an ulcer in the lower oesophagus, stomach or duodenum, in the jejunum after surgical anastomosis to the stomach or, rarely, in the ileum adjacent to a Meckel’s diverticulum. Ulcers in the stomach or duodenum may be acute or chronic; both penetrate the muscularis mucosae but the acute ulcer shows no evidence of fibrosis. Erosions do not penetrate the muscularis mucosae. Gastric and duodenal ulcer The prevalence of peptic ulcer (0.1–0.2%) is decreasing in many Western communities as a result of widespread use of Helicobacter pylori eradication therapy but it remains high in developing countries. The male-to-female ratio for duodenal ulcer varies from 5 : 1 to 2 : 1, while that for gastric ulcer is 2 : 1 or less. Chronic gastric ulcer is usually single; 90% are situated on the lesser curve within the antrum or at the junction between body and antral mucosa. Chronic duodenal ulcer usually occurs in the first part of the duodenum and 50% are on the anterior wall. Gastric and duodenal ulcers coexist in 10% of patients and more than one peptic ulcer is found in 10–15% of patients. Pathophysiology H. pylori Peptic ulceration is strongly associated with H. pylori infection. The prevalence of the infection in developed nations rises with age and Fig. 21.35 Factors that influence the virulence of Helicobacter pylori. Flagella Urease Urea H2O 2CO2 NH3 Ammonia 'cloud' Other factors • Vacuolating cytotoxin (vacA) • Cytotoxin-associated gene (cagA) • Adhesins (babA) • Outer inflammatory protein A (oipA) Type IV secretion system 21.33 Common causes of gastritis Acute gastritis (often erosive and haemorrhagic) • Aspirin, NSAIDs • Helicobacter pylori (initial infection) • Alcohol • Other drugs, e.g. iron preparations • Severe physiological stress, e.g. burns, multi-organ failure, central nervous system trauma • Bile reflux, e.g. following gastric surgery • Viral infections, e.g. CMV, herpes simplex virus in HIV/AIDS (p. 316) Chronic non-specific gastritis • H. pylori infection • Autoimmune (pernicious anaemia) • Post-gastrectomy Chronic ‘specific’ forms (rare) • Infections, e.g. CMV, tuberculosis • Gastrointestinal diseases, e.g. Crohn’s disease • Systemic diseases, e.g. sarcoidosis, graft-versus-host disease • Idiopathic, e.g. granulomatous gastritis (CMV = cytomegalovirus; NSAIDs = non-steroidal anti-inflammatory drugs)

Diseases of the stomach and duodenum • 799

NSAIDs Treatment with NSAIDs is associated with peptic ulcers due to impairment of mucosal defences, as discussed on page 1002. Smoking Smoking confers an increased risk of gastric ulcer and, to a lesser extent, duodenal ulcer. Once the ulcer has formed, it is more likely to cause complications and less likely to heal if the patient continues to smoke. Clinical features Peptic ulcer disease is a chronic condition with spontaneous relapses and remissions lasting for decades, if not for life. The most common presentation is with recurrent abdominal pain that has three notable characteristics: localisation to the epigastrium, relationship to food and episodic occurrence. Occasional vomiting occurs in about 40% of ulcer subjects; persistent daily vomiting suggests gastric outlet obstruction. In one-third, the history is less characteristic, especially in elderly people or those taking NSAIDs. In this situation, pain may be absent or so slight that it is experienced only as a vague sense of epigastric unease. Occasionally, the only symptoms are anorexia and nausea, or early satiety after meals. In some patients, the ulcer is completely ‘silent’, presenting for the first time with anaemia from chronic undetected blood loss, as abrupt haematemesis or as acute perforation; in others, there is recurrent acute bleeding without ulcer pain. The diagnostic value of individual symptoms for peptic ulcer disease is poor; the history is therefore a poor predictor of the presence of an ulcer. Investigations Endoscopy is the preferred investigation (Fig. 21.38). Gastric ulcers may occasionally be malignant and therefore must always be biopsied and followed up to ensure healing. Patients should be tested for H. pylori infection. The current options available are listed in Box 21.34. Some are invasive and require endoscopy; others are non-invasive. They vary in sensitivity and specificity. Breath tests or faecal antigen tests are best because of accuracy, simplicity and non-invasiveness. to 10% in the West), the infection causes an antral-predominant pattern of gastritis characterised by hypergastrinaemia and a very exaggerated acid production by parietal cells, which could lead to duodenal ulceration (Fig. 21.36). In a much smaller number of infected people, H. pylori causes a corpus-predominant pattern of gastritis leading to gastric atrophy and hypochlorhydria. This phenotype is much more common in Asian countries, particularly Japan, China and Korea. The hypochlorhydria allows other bacteria to proliferate within the stomach; these other bacteria continue to drive the chronic inflammation and produce mutagenic nitrites from dietary nitrates, predisposing to the development of gastric cancer (Fig. 21.37). The effects of H. pylori are more complex in gastric ulcer patients compared to those with duodenal ulcers. The ulcer probably arises because of impaired mucosal defence resulting from a combination of H. pylori infection, NSAIDs and smoking, rather than excess acid. Fig. 21.36 Sequence of events in the pathophysiology of duodenal ulceration. G D

HCl Further inflammation and eventual ulceration Depletion of antral D-cell somatostatin Increased gastrin release from G cells Increased acid load in duodenum leads to gastric metaplasia Increased acid secretion Fig. 21.37 Consequences of Helicobacter pylori infection. (CagA = cytotoxin-associated gene; IL-1β = interleukin-1 beta; NSAIDs = non-steroidal anti-inflammatory drugs; TNF-α = tumour necrosis factor alpha; VacA = vacuolating cytotoxin) Host factors (IL-1β and TNF-α polymorphisms) Other environmental factors (NSAIDs, smoking) Helicobacter pylori factors (VacA, CagA) Gastric ulcer Duodenal ulcer Gastric cancer Antral gastritis Pangastritis Fig. 21.38 Endoscopic identification of a duodenal ulcer. The ulcer has a clean base and there are no stigmata of recent haemorrhage.

800 • GASTROENTEROLOGY first undergo eradication therapy to reduce ulcer risk. Subsequent co-prescription of a PPI along with the NSAID is advised but is not always necessary for patients being given low-dose aspirin, in whom the risk of ulcer complications is lower. Other indications for H. pylori eradication are shown in Box 21.36. Eradication of the infection has proven benefits in several extragastric disorders, including unexplained B12 deficiency and iron deficiency anaemia, once sources of gastrointestinal bleeding have been looked for and excluded. Platelet counts improve and may normalise after eradication therapy in patients with idiopathic thrombocytopenic purpura (p. 979); the mechanism for this is unclear. General measures Cigarette smoking, aspirin and NSAIDs should be avoided. Alcohol in moderation is not harmful and no special dietary advice is required. Maintenance treatment Continuous maintenance treatment should not be necessary after successful H. pylori eradication. For the minority who do require it, the lowest effective dose of PPI should be used. Surgical treatment Surgery is now rarely required for peptic ulcer disease but it is needed in some cases (Box 21.37). The operation of choice for a chronic non-healing gastric ulcer is partial gastrectomy, preferably with a Billroth I anastomosis, in which the ulcer itself and the ulcer-bearing area of the stomach are resected. The reason for this is to exclude an underlying Management The aims of management are to relieve symptoms, induce healing and prevent recurrence. H. pylori eradication is the cornerstone of therapy for peptic ulcers, as this will successfully prevent relapse and eliminate the need for long-term therapy in the majority of patients. H. pylori eradication All patients with proven ulcers who are H. pylori-positive should be offered eradication as primary therapy. Treatment is based on a PPI taken simultaneously with two antibiotics (from amoxicillin, clarithromycin and metronidazole) for at least 7 days. High-dose, twice-daily PPI therapy increases efficacy of treatment, as does extending treatment to 10–14 days. Success is achieved in 80–90% of patients, although adherence, side-effects (Box 21.35) and antibiotic resistance influence this. Resistance to amoxicillin is rare but rates of metronidazole resistance reach more than 50% in some countries and rates of clarithromycin resistance of 20–40% have recently become common. Where the latter exceed 15%, a quadruple therapy regimen, consisting of omeprazole (or another PPI), bismuth subcitrate, metronidazole and tetracycline (OBMT) for 10–14 days, is recommended. In areas of low clarithromycin resistance, this regimen should also be offered as second-line therapy to those who remain infected after initial therapy, once adherence has been checked. For those who are still colonised after two treatments, the choice lies between a third attempt guided by antimicrobial sensitivity testing, rescue therapy (levofloxacin, PPI and clarithromycin) or long-term acid suppression. H. pylori and NSAIDs are independent risk factors for ulcer disease and patients requiring long-term NSAID therapy should 21.35 Common side-effects of Helicobacter pylori eradication therapy • Diarrhoea: 30–50% of patients; usually mild but Clostridium difficile-associated diarrhoea can occur • Flushing and vomiting when taken with alcohol (metronidazole) • Nausea, vomiting • Abdominal cramps • Headache • Rash 21.34 Methods for the diagnosis of Helicobacter pylori infection Test Advantages Disadvantages Non-invasive Serology Rapid office kits available Good for population studies Lacks specificity Cannot differentiate current from past infection 13C-urea breath test High sensitivity and specificity Requires expensive mass spectrometer Faecal antigen test Cheap, specific (> 95%) Acceptability Invasive (antral biopsy) Histology Specificity False negatives Takes several days to process Rapid urease test Cheap, quick, specific (> 95%) Sensitivity 85% Microbiological culture ‘Gold standard’ Defines antibiotic sensitivity Slow and laborious Lacks sensitivity 21.36 Indications for Helicobacter pylori eradication Definite • Peptic ulcer • Extranodal marginal-zone lymphomas of MALT type • Family history of gastric cancer • Previous resection for gastric cancer • H. pylori-positive dyspepsia • Long-term NSAID or low-dose aspirin users • Chronic (> 1 year) PPI users • Extragastric disorders: Unexplained vitamin B12 deficiency* Idiopathic thrombocytopenic purpura* Iron deficiency anaemia* (see text) Not indicated • Gastro-oesophageal reflux disease • Asymptomatic people without gastric cancer risk factors (MALT = mucosa-associated lymphoid tissue; NSAID = non-steroidal anti-inflammatory drug; PPI = proton pump inhibitor) *If H. pylori-positive on testing. 21.37 Indications for surgery in peptic ulcer Emergency • Perforation • Haemorrhage Elective • Gastric outflow obstruction • Persistent ulceration despite adequate medical therapy • Recurrent ulcer following gastric surgery

Diseases of the stomach and duodenum • 801

independent risk factor for late development of malignancy in the gastric remnant but the risk is higher in those with hypochlorhydria, duodenogastric reflux of bile, smoking and H. pylori infection. Although the relative risk is increased, the absolute risk of cancer remains low and endoscopic surveillance is not indicated following gastric surgery. Complications of peptic ulcer disease Perforation When perforation occurs, the contents of the stomach escape into the peritoneal cavity, leading to peritonitis. This is more common in duodenal than in gastric ulcers and is usually found with ulcers on the anterior wall. About one-quarter of all perforations occur in acute ulcers and NSAIDs are often incriminated. Perforation can be the first sign of ulcer and a history of recurrent epigastric pain is uncommon. The most striking symptom is sudden, severe pain; its distribution follows the spread of the gastric contents over the peritoneum. The pain initially develops in the upper abdomen and rapidly becomes generalised; shoulder tip pain is caused by irritation of the diaphragm. The pain is accompanied by shallow respiration, due to limitation of diaphragmatic movements, and by shock. The abdomen is held immobile and there is generalised ‘board-like’ rigidity. Bowel sounds are absent and liver dullness to percussion decreases due to the presence of gas under the diaphragm. After some hours, symptoms may improve, although abdominal rigidity remains. Later, the patient’s condition deteriorates as general peritonitis develops. In at least 50% of cases, an erect chest X-ray shows free air beneath the diaphragm (see Fig. 21.11B, p. 773). If not, a water-soluble contrast swallow will confirm leakage of gastroduodenal contents. After resuscitation, the acute perforation should be treated surgically, either by simple closure or by conversion of the perforation into a pyloroplasty if it is large. On rare occasions, a ‘Polya’ partial gastrectomy is required. Following surgery, H. pylori should be treated (if present) and NSAIDs avoided. Perforation carries a mortality of 25%, reflecting the advanced age and significant comorbidity of the population that are affected. Gastric outlet obstruction The causes are shown in Box 21.39. The most common is an ulcer in the region of the pylorus. The presentation is with nausea, vomiting and abdominal distension. Large quantities of gastric content are often vomited and food eaten 24 hours or more previously may be recognised. Physical examination may show evidence of wasting and dehydration. A succussion splash may be elicited 4 hours or more after the last meal or drink. Visible gastric peristalsis is diagnostic of gastric outlet obstruction. Loss of acidic gastric contents leads to alkalosis and dehydration with low serum chloride and potassium and raised serum bicarbonate and urea concentrations (hypochloraemic metabolic alkalosis). cancer. In an emergency, ‘under-running’ the ulcer for bleeding or ‘oversewing’ (patch repair) for perforation is all that is required, in addition to taking a biopsy. For giant duodenal ulcers, partial gastrectomy using a ‘Polya’ or Billroth II reconstruction may be required. Complications of gastric resection or vagotomy Up to 50% of patients who undergo gastric surgery for peptic ulcer surgery experience long-term adverse effects. In most cases these are minor but in 10% they significantly impair quality of life. Dumping Rapid gastric emptying leads to distension of the proximal small intestine as the hypertonic contents draw fluid into the lumen. This leads to abdominal discomfort and diarrhoea after eating. Autonomic reflexes release a range of gastrointestinal hormones that provoke vasomotor features, such as flushing, palpitations, sweating, tachycardia and hypotension. Patients should therefore avoid large meals with high carbohydrate content. Chemical (bile reflux) gastropathy Duodenogastric bile reflux leads to chronic gastropathy. Treatment with aluminium-containing antacids or sucralfate may be effective. A few patients require revisional surgery with creation of a Roux en Y loop to prevent bile reflux. Diarrhoea and maldigestion Diarrhoea may develop after any peptic ulcer operation and usually occurs 1–2 hours after eating. Poor mixing of food in the stomach, with rapid emptying, inadequate mixing with pancreaticobiliary secretions, rapid transit and bacterial overgrowth, may lead to malabsorption. Diarrhoea often responds to small, dry meals with a reduced intake of refined carbohydrates. Antidiarrhoeal drugs, such as codeine phosphate (15–30 mg 4–6 times daily) or loperamide (2 mg after each loose stool), are helpful. Weight loss Most patients lose weight shortly after surgery and 30–40% are unable to regain all the weight that is lost. The usual cause is reduced intake because of a small gastric remnant but diarrhoea and mild steatorrhoea also contribute. Anaemia Anaemia is common many years after subtotal gastrectomy. Iron deficiency is the most common cause; folic acid and B12 deficiency are much less frequent. Inadequate dietary intake of iron and folate, lack of acid and intrinsic factor secretion, mild chronic low-grade blood loss from the gastric remnant and recurrent ulceration are responsible. Metabolic bone disease Both osteoporosis and osteomalacia can occur as a consequence of calcium and vitamin D malabsorption. Gastric cancer An increased risk of gastric cancer has been reported from several epidemiological studies. Surgery itself is an 21.38 Peptic ulcer disease in old age • Gastroduodenal ulcers: have a greater incidence, admission rate and mortality. • Causes: high prevalence of H. pylori, use of non-steroidal anti-inflammatory drugs and impaired defence mechanisms. • Atypical presentations: pain and dyspepsia are frequently absent or atypical. Older people often develop complications, such as bleeding or perforation, without a dyspeptic history. • Bleeding: older patients require more intensive management because they have more limited reserve to withstand hypovolaemia. 21.39 Differential diagnosis and management of gastric outlet obstruction Cause Management Fibrotic stricture from duodenal ulcer (pyloric stenosis) Balloon dilatation or surgery Oedema from pyloric channel or duodenal ulcer Proton pump inhibitor therapy Carcinoma of antrum Surgery Adult hypertrophic pyloric stenosis Surgery

802 • GASTROENTEROLOGY of MEN 1). Some patients present with metastatic disease and, in these circumstances, surgery is inappropriate. In the majority of these individuals, continuous therapy with omeprazole or other PPIs can be successful in healing ulcers and alleviating diarrhoea, although double the normal dose is required. The synthetic somatostatin analogue, octreotide, given by subcutaneous injection, reduces gastrin secretion and may be of value. Other treatment options for pancreatic neuro-endocrine tumours are discussed on page 678. Overall 5-year survival is 60–75% and all patients should undergo genetic screening for MEN 1. Functional disorders Functional dyspepsia This is defined as chronic dyspepsia in the absence of organic disease. Other commonly reported symptoms include early satiety, fullness, bloating and nausea. ‘Ulcer-like’ and ‘dysmotility-type’ subgroups are often reported but there is overlap between these and with irritable bowel syndrome. Pathophysiology The cause is poorly understood but probably covers a spectrum of mucosal, motility and psychiatric disorders. Clinical features Patients are usually young (< 40 years) and women are affected twice as commonly as men. Abdominal discomfort is associated with a combination of other ‘dyspeptic’ symptoms, the most common being nausea, satiety and bloating after meals. Morning symptoms are characteristic and pain or nausea may occur on waking. Direct enquiry may elicit symptoms suggestive of irritable bowel syndrome. Peptic ulcer disease must be considered, while in older people intra-abdominal malignancy is a prime concern. There are no diagnostic signs, apart from inappropriate tenderness on abdominal palpation, perhaps. Symptoms may appear disproportionate to clinical well-being and there is no weight loss. Patients often appear anxious. A drug history should be taken and the possibility of a depressive illness should be considered. Pregnancy should be ruled out in young women before radiological studies are undertaken. Alcohol misuse should be suspected when early-morning nausea and retching are prominent. Investigations The history will often suggest the diagnosis. All patients should be checked for H. pylori infection and patients over the age of 55 years should undergo endoscopy to exclude mucosal disease. While an ultrasound scan may detect gallstones, these are rarely responsible for dyspeptic symptoms. Management The most important elements are explanation and reassurance. Possible psychological factors should be explored and the concept of psychological influences on gut function should be explained. Idiosyncratic and restrictive diets are of little benefit but smaller portions and fat restriction may help. Up to 10% of patients benefit from H. pylori eradication therapy and this should be offered to infected individuals. Eradication also removes a major risk factor for peptic ulcers and gastric cancer but at the cost of a small risk of side-effects and worsening symptoms of underlying gastro-oesophageal reflux disease. Drug treatment is not especially successful but merits trial. Antacids, Paradoxical aciduria occurs because of enhanced renal absorption of Na+ in exchange for H+. Endoscopy should be performed after the stomach has been emptied using a wide-bore nasogastric tube. Intravenous correction of dehydration is undertaken and, in severe cases, at least 4 L of isotonic saline and 80 mmol of potassium may be necessary during the first 24 hours. In some patients, PPI drugs heal ulcers, relieve pyloric oedema and overcome the need for surgery. Endoscopic balloon dilatation of benign stenoses may be possible in some patients but in others partial gastrectomy is necessary; this is best done after a 7-day period of nasogastric aspiration, which enables the stomach to return to normal size. A gastroenterostomy is an alternative operation but, unless this is accompanied by vagotomy, patients will require long-term PPI therapy to prevent stomal ulceration. Bleeding See page 780. Zollinger–Ellison syndrome This is a rare disorder characterised by the triad of severe peptic ulceration, gastric acid hypersecretion and a neuro-endocrine tumour (p. 678) of the pancreas or duodenum (‘gastrinoma’). It probably accounts for about 0.1% of all cases of duodenal ulceration. The syndrome occurs in either sex at any age, although it is most common between 30 and 50 years of age. Pathophysiology The tumour secretes gastrin, which stimulates acid secretion to its maximal capacity and increases the parietal cell mass three- to sixfold. The acid output may be so great that it reaches the upper small intestine, reducing the luminal pH to 2 or less. Pancreatic lipase is inactivated and bile acids are precipitated. Diarrhoea and steatorrhoea result. Around 90% of tumours occur in the pancreatic head or proximal duodenal wall. At least half are multiple and tumour size can vary from 1 mm to 20 cm. Approximately one-half to two-thirds are malignant but are often slow-growing. Between 20% and 60% of patients have multiple endocrine neoplasia (MEN) type 1 (p. 688). Clinical features The presentation is with severe and often multiple peptic ulcers in unusual sites, such as the post-bulbar duodenum, jejunum or oesophagus. There is a poor response to standard ulcer therapy. The history is usually short, and bleeding and perforations are common. Diarrhoea is seen in one-third or more of patients and can be the presenting feature. Investigations Hypersecretion of acid under basal conditions, with little increase following pentagastrin, may be confirmed by gastric aspiration. Serum gastrin levels are grossly elevated (10- to 1000-fold). Injection of the hormone secretin normally causes no change or a slight decrease in circulating gastrin concentrations, but in Zollinger–Ellison syndrome it produces a paradoxical and dramatic increase in gastrin. Tumour localisation (and staging) is best achieved by a combination of CT and EUS; radio-labelled somatostatin receptor scintigraphy and 68gallium DOTATATE PET scanning may also be used for tumour detection and staging. Management Some 30% of small and single tumours can be localised and resected but many tumours are multifocal (especially in the context

Diseases of the stomach and duodenum • 803

after 50 years of age. Studies of Japanese migrants to the USA have revealed a much lower incidence in the second generation, confirming the importance of environmental factors. The overall prognosis is poor, with less than 30% surviving 5 years, and the best hope for improved survival lies in more efficient detection of tumours at an earlier stage. Pathophysiology Infection with H. pylori plays a key pathogenic role and the infection has been classified by the International Agency for Research on Cancer (IARC) as a definite human carcinogen. It is associated with chronic atrophic gastritis, gastric mucosal atrophy and gastric cancer (Fig. 21.39). It has been estimated that H. pylori infection may contribute to the occurrence of gastric cancer in 70% of cases. Although the majority of H. pylori-infected individuals have normal or increased acid secretion, a few become hypo- or achlorhydric and these people are thought to be at greatest risk. H. pylori-induced chronic inflammation with generation of reactive oxygen species and depletion of the normally abundant antioxidant ascorbic acid are also important. There is strong evidence that H. pylori eradication, especially if achieved before irreversible pre-neoplastic changes (atrophy and intestinal metaplasia) have developed, reduces the risk of cancer development in high-risk populations and is cost-effective. Diets rich in salted, smoked or pickled foods and the consumption of nitrites and nitrates may increase cancer risk. Carcinogenic N-nitroso-compounds are formed from nitrates by the action of nitrite-reducing bacteria that colonise the achlorhydric stomach. Diets lacking in fresh fruit and vegetables, as well as vitamins C and A, may also contribute. Other risk factors are listed in Box 21.40. No predominant genetic abnormality has been identified, although cancer risk is increased two- to threefold in first-degree relatives of patients, and links with blood group A have been reported. Some host genetic factors related to inflammatory genes and prostate stem cell antigen have recently been associated with increased risk of gastric caner. Rarely, gastric cancer may be inherited in an autosomal dominant manner in association with mutations of the E-cadherin (CDH1) gene. such as hydrotalcite, are sometimes helpful. Prokinetic drugs, such as metoclopramide (10 mg 3 times daily) or domperidone (10–20 mg 3 times daily), may be given before meals if nausea, vomiting or bloating is prominent. Metoclopramide may induce extrapyramidal side-effects, including tardive dyskinesia in young patients. H2-receptor antagonist drugs may be tried if night pain or heartburn is troublesome. Low-dose tricyclic agents, such as amitriptyline, are of value in up to two-thirds. Symptoms that can be associated with an identifiable cause of stress resolve with appropriate counselling. Some patients have major psychological disorders that result in persistent or recurrent symptoms and need behavioural or other formal psychotherapy (p. 1190). Functional causes of vomiting Psychogenic retching or vomiting may arise in anxiety. It typically occurs on wakening or immediately after breakfast, and only rarely later in the day. The disorder is probably a reaction to facing up to the worries of everyday life; in the young, it can be due to school phobia. Early morning vomiting also occurs in pregnancy, alcohol misuse and depression. Although functional vomiting may occur regularly over long periods, there is little or no weight loss. Children, and less often adults, sometimes suffer from acute and recurrent disabling bouts of vomiting for days at a time. The cause of this cyclical vomiting syndrome is unknown but in some adults it is associated with cannabis use. In all patients it is essential to exclude other common causes (p. 780). Tranquillisers and antiemetic drugs (metoclopramide 10 mg 3 times daily, domperidone 10 mg 3 times daily, prochlorperazine 5–10 mg 3 times daily) have only a secondary place in management. Antidepressants in full dose may be effective (p. 1199). Gastroparesis Defective gastric emptying without mechanical obstruction of the stomach or duodenum can occur as a primary event, due to inherited or acquired disorders of the gastric pacemaker, or can be secondary to disorders of autonomic nerves (particularly diabetic neuropathy) or the gastroduodenal musculature (systemic sclerosis, myotonic dystrophies and amyloidosis). Drugs such as opiates, calcium channel antagonists and those with anticholinergic activity (tricyclics, phenothiazines) can also cause gastroparesis. Early satiety and recurrent vomiting are the major symptoms; abdominal fullness and a succussion splash may be present on examination. Treatment is based on small, frequent, low-fat meals and the use of metoclopramide and domperidone. In severe cases, nutritional failure can occur and long-term jejunostomy feeding or total parenteral nutrition is required. Surgical insertion of a gastric neurostimulator has been successful in some cases, especially those complicating diabetic autonomic neuropathy. Tumours of the stomach Gastric carcinoma Gastric carcinoma is the third leading cause of cancer death worldwide but there is marked geographical variation in incidence. It is most common in China, Japan, Korea (incidence 40/100 000 males), Eastern Europe and parts of South America (20/100 000). Rates in the UK are 12/100 000 for men. In most countries, the incidence is 50% lower in women. In both sexes, it rises sharply Fig. 21.39 Gastric carcinogenesis: a possible mechanism. (CagA = cytotoxin-associated gene) Helicobacter pylori Diet Smoking Nitrosamines Dietary nitrates Helicobacter pylori CagA Carcinoma Normal gastric epithelium Chronic atrophic gastritis Intestinal metaplasia Dysplasia Bacterial colonisation of stomach Achlorhydria

804 • GASTROENTEROLOGY made, further imaging is necessary for staging and assessment of resectability. CT will provide evidence of intra-abdominal spread or liver metastases. Even with these techniques, laparoscopy with peritoneal washings is required to determine whether the tumour is resectable, as it is the only modality that will reliably detect peritoneal spread. Management Surgery Resection offers the only hope of cure and this can be achieved in about 90% of patients with early gastric cancer. For the majority of patients with locally advanced disease, total gastrectomy with lymphadenectomy is the operation of choice, preserving the spleen if possible. Proximal tumours involving the oesophagogastric junction also require a distal oesophagectomy. Small, distally sited tumours can be managed by a partial gastrectomy with lymphadenectomy and either a Billroth I or a Roux en Y reconstruction. More extensive lymph node resection may increase survival rates but carries greater morbidity. Even for those who cannot be cured, palliative resection may be necessary when patients present with bleeding or gastric outflow obstruction. Following surgery, recurrence is much more likely if serosal penetration has occurred, although complete removal of all macroscopic tumour combined with lymphadenectomy will achieve a 50–60% 5-year survival. Perioperative chemotherapy with epirubicin, cisplatin and fluorouracil (ECF) improves survival rates. Palliative treatment In patients with inoperable tumours, survival can be improved and palliation of symptoms achieved with chemotherapy using 5-fluorouracil and cisplatin, ECF or other platinum- and taxanebased regimens. The biological agent trastuzumab may benefit some patients whose tumours over-express HER2 (p. 1322). Endoscopic laser ablation for control of dysphagia or recurrent bleeding benefits some patients. Carcinomas at the cardia or pylorus may require endoscopic dilatation or insertion of expandable metallic stents for relief of dysphagia or vomiting. A nasogastric tube may offer temporary relief of vomiting due to gastric outlet obstruction (Box 21.41). Virtually all tumours are adenocarcinomas arising from mucussecreting cells in the base of the gastric crypts. Most develop on a background of chronic atrophic gastritis with intestinal metaplasia and dysplasia. Cancers are either ‘intestinal’, arising from areas of intestinal metaplasia with histological features reminiscent of intestinal epithelium, or ‘diffuse’, arising from normal gastric mucosa. Intestinal carcinomas are more common and arise against a background of chronic mucosal injury. Diffuse cancers tend to be poorly differentiated and occur in younger patients. In the developing world, 50% of gastric cancers develop in the antrum; 20–30% occur in the gastric body, often on the greater curve; and 20% are found in the cardia. In Western populations, however, proximal gastric tumours are becoming more common than those arising in the body and distal stomach. This change in disease pattern may be a reflection of changes in lifestyle or the decreasing prevalence of H. pylori in the West. Diffuse submucosal infiltration by a scirrhous cancer (linitis plastica) is uncommon. Early gastric cancer is defined as cancer confined to the mucosa or submucosa. It is more often recognised in Japan, where widespread screening is practised. Some cases can be cured by endoscopic mucosal or submucosal resection. The majority of patients (> 80%) in the West, however, present with advanced gastric cancer. Clinical features Early gastric cancer is usually asymptomatic but may be discovered during endoscopy for investigation of dyspepsia. Two-thirds of patients with advanced cancers have weight loss and 50% have ulcer-like pain. Anorexia and nausea occur in one-third, while early satiety, haematemesis, melaena and dyspepsia alone are less common. Dysphagia occurs in tumours of the gastric cardia that obstruct the gastro-oesophageal junction. Anaemia from occult bleeding is also common. Examination may reveal no abnormalities but signs of weight loss, anaemia and a palpable epigastric mass are not infrequent. Jaundice or ascites signifies metastatic spread. Occasionally, tumour spread occurs to the supraclavicular lymph nodes (Troisier’s sign), umbilicus (Sister Joseph’s nodule) or ovaries (Krukenberg tumour). Paraneoplastic phenomena, such as acanthosis nigricans, thrombophlebitis (Trousseau’s sign) and dermatomyositis, occur rarely. Metastases arise most commonly in the liver, lungs, peritoneum and bone marrow. Investigations Upper gastrointestinal endoscopy is the investigation of choice (Fig. 21.40) and should be performed promptly in any dyspeptic patient with ‘alarm features’ (see Box 21.15, p. 779). Multiple biopsies from the edge and base of a gastric ulcer are required. Barium meal is a poor alternative, since any abnormalities must be followed by endoscopy and biopsy. Once the diagnosis is 21.40 Risk factors for gastric cancer • Helicobacter pylori • Smoking • Alcohol • Dietary associations (see text) • Autoimmune gastritis (pernicious anaemia) • Adenomatous gastric polyps • Previous partial gastrectomy (> 20 years) • Ménétrier’s disease • Hereditary diffuse gastric cancer families (CDH1 mutations) • Familial adenomatous polyposis (p. 828) Fig. 21.40 Gastric carcinoma. Endoscopic finding of a large polypoidal mass arising from the wall of the stomach.

Diseases of the small intestine • 805

prognosis are stage I or II disease, small resectable tumours, tumours with low-grade histology, and age below 60 years. Other tumours of the stomach Gastrointestinal stromal cell tumours (GISTs), arising from the interstitial cells of Cajal, are occasionally found at upper gastrointestinal endoscopy. They are differentiated from other mesenchymal tumours by expression of the c-kit proto-oncogene, which encodes a tyrosine kinase receptor. These tumours, particularly the smaller lesions of less than 2 cm, are usually benign and asymptomatic, but the larger ones may have malignant potential and may occasionally be responsible for dyspepsia, ulceration and gastrointestinal bleeding. Small lesions (< 2 cm) are usually followed by endoscopy, while larger ones require surgical resection. Very large lesions should be treated pre-operatively with imatinib (a tyrosine kinase inhibitor) to reduce their size and make surgery easier. Imatinib can also provide prolonged control of metastatic GISTs. A variety of polyps occur. Hyperplastic polyps and fundic cystic gland polyps are common and of no consequence. Adenomatous polyps are rare but have malignant potential and should be removed endoscopically. Occasionally, gastric carcinoid tumours are seen in the fundus and body in patients with long-standing pernicious anaemia. These benign tumours arise from ECL or other endocrine cells, and are often multiple but rarely invasive. Unlike carcinoid tumours arising elsewhere in the gastrointestinal tract, they usually run a benign and favourable course. Large (> 2 cm) carcinoids may, however, metastasise and should be removed. Rarely, small nodules of ectopic pancreatic exocrine tissue are found. These ‘pancreatic rests’ may be mistaken for gastric neoplasms and usually cause no symptoms. EUS is the most useful investigation. Diseases of the small intestine Disorders causing malabsorption Coeliac disease Coeliac disease is an inflammatory disorder of the small bowel occurring in genetically susceptible individuals, which results from intolerance to wheat gluten and similar proteins found in rye, barley and, to a lesser extent, oats. It can result in malabsorption and responds to a gluten-free diet. The condition occurs worldwide but is more common in northern Europe. The prevalence in the UK is approximately 1%, although 50% of these people are asymptomatic. These include both undiagnosed ‘silent’ cases of the disease and cases of ‘latent’ coeliac disease – genetically susceptible people who may later develop clinical coeliac disease. Pathophysiology The precise mechanism of mucosal damage is unclear but immunological responses to gluten play a key role (Fig. 21.41). There is a strong genetic component, with around 10% of first-degree relatives of an index case affected, and there is strong (approximately 75%) concordance in monozygotic twins. There is a strong association with human leukocyte antigen (HLA)-DQ2/DQ8. Dysbiosis of the intestinal microbiota has been identified but it is unclear if this is pathological or a response to the underlying mucosal changes. Gastric lymphoma This is a rare tumour, accounting for less than 5% of all gastric malignancies. The stomach is, however, the most common site for extranodal non-Hodgkin lymphoma and 60% of all primary gastrointestinal lymphomas occur at this site. Lymphoid tissue is not found in the normal stomach but lymphoid aggregates develop in the presence of H. pylori infection. Indeed, H. pylori infection is closely associated with the development of a low-grade lymphoma (classified as extranodal marginal-zone lymphomas of MALT type). EUS plays an important role in staging these lesions by accurately defining the depth of invasion into the gastric wall. The clinical presentation is similar to that of gastric cancer and endoscopically the tumour appears as a polypoid or ulcerating mass. While initial treatment of low-grade lesions confined to the superficial layers of the gastric wall consists of H. pylori eradication and close observation, 25% contain t(11 : 18) chromosomal translocations. In these cases, additional radiotherapy or chemotherapy is usually necessary. High-grade B-cell lymphomas should be treated by a combination of rituximab, chemotherapy (p. 962), surgery and radiotherapy. The choice depends on the site and extent of tumour, the presence of comorbid illnesses, and other factors, such as symptoms of bleeding and gastric outflow obstruction. The prognosis depends on the stage at diagnosis. Features predicting a favourable 21.41 How to insert a nasogastric tube Equipment • 8–9F ‘fine-bore’ tube for feeding or 16–18F ‘wide-bore’ tube for drainage • Lubricant jelly • Cup of water and straw for sipping • Adhesive tape • pH (not litmus) paper • Sickness bowl and tissues • Catheter drainage bag and clamp (for drainage) Technique • A clear explanation and a calm patient are essential • Establish a ‘stop signal’ for the patient to use, if needed • Ask the patient to sit semi-upright • Examine the nose for deformity or blockage to determine which side to use • Measure the distance from ear to xiphoid process via the nose and mark the position on the tube • Advance the lubricated tube tip slowly along the floor of the nasal passage to the oropharynx • Ask the patient to sip water and advance the tube 2–3 cm with each swallow • Stop, withdraw and retry if the patient is distressed or coughing, as the tube may have entered the larynx • Advance until the mark on the tube reaches the tip of the nose and secure with tape • Aspirate the contents and check pH (gastric acid confirmed if pH < 5). If in doubt, perform a chest X-ray to confirm tube position (usually necessary with feeding tubes) • Attach the catheter drainage bag, if necessary, and clamp Aftercare • Flush the tube daily after feeding or drug dosing • Check position regularly and look for signs of displacement • Check with the pharmacist what drugs, if any, can be safely given via the tube

806 • GASTROENTEROLOGY usually characteristic but other causes of villous atrophy should be considered (Box 21.43 and Fig. 21.42). Sometimes the villi appear normal but there are excess numbers of intra-epithelial lymphocytes (lymphocytic duodenosis). Antibodies Antibody tests constitute a valuable screening tool in patients with diarrhoea or other suggestive symptoms but are not a diagnostic substitute for small bowel biopsy at present. Tissue transglutaminase (tTG) is now recognised as the autoantigen for Fig. 21.41 Pathophysiology of coeliac disease. After being taken up by epithelial cells, gluten peptides are deamidated by the enzyme tissue transglutaminase in the subepithelial layer. They are then able to fit the antigen-binding motif on human leucocyte antigen (HLA)-DQ2-positive antigenpresenting cells. Recognition by CD4+ T cells triggers a Th1 immune response with generation of pro-inflammatory cytokines: interleukin-1 (IL-1), interferon gamma (IFN-γ) and tumour necrosis factor alpha (TNF-α). Lymphocytes infiltrate the lamina propria and an increase in intra-epithelial lymphocytes (IELs), crypt hyperplasia and villous atrophy ensue. Antigenpresenting cell CD4+ T cell HLA-DQ2 Deamidation Th1 response • IL-1 • IFN-γ • TNF-α Lumen Brush border Epithelium Tissue transglutaminase Gluten peptides IEL IEL Clinical features Coeliac disease can present at any age. In infancy, it occurs after weaning on to cereals and typically presents with diarrhoea, malabsorption and failure to thrive. In older children, it may present with non-specific features, such as delayed growth. Features of malnutrition are found on examination and mild abdominal distension may be present. Affected children have growth and pubertal delay, leading to short stature in adulthood. In adults, the disease usually presents during the third or fourth decade and females are affected twice as often as males. The presentation is highly variable, depending on the severity and extent of small bowel involvement. Some have florid malabsorption, while others develop non-specific symptoms, such as tiredness, weight loss, folate deficiency or iron deficiency anaemia. Other presentations include oral ulceration, dyspepsia and bloating. Unrecognised coeliac disease is associated with mild under-nutrition and osteoporosis. Coeliac disease is associated with other HLA-linked autoimmune disorders and with certain other diseases (Box 21.42). In some centres, people at higher risk of developing coeliac disease, such as those with type 1 diabetes, may undergo periodic antibody screening. Such screening may identify people with asymptomatic or minimally symptomatic disease; there is controversy about the optimum management strategy for such individuals. Investigations These are performed to confirm the diagnosis and to look for consequences of malabsorption. Duodenal biopsy Endoscopic small bowel biopsy is the gold standard. Endoscopic appearances should not preclude biopsy, as the mucosa usually looks normal. As the histological changes can be patchy, an adequate number of biopsies – currently, more than four biopsies from the second part of the duodenum plus one from the duodenal bulb – should be retrieved. The histological features are 21.43 Important causes of subtotal villous atrophy • Coeliac disease • Tropical sprue • Dermatitis herpetiformis • Lymphoma • HIV-related enteropathy • Giardiasis • Hypogammaglobulinaemia • Radiation • Whipple’s disease • Zollinger–Ellison syndrome 21.42 Disease associations of coeliac disease • Type 1 diabetes mellitus (2–8%) • Thyroid disease (5%) • Primary biliary cirrhosis (3%) • Sjögren’s syndrome (3%) • Immunoglobulin A deficiency (2%) • Pernicious anaemia • Sarcoidosis • Neurological complications: Encephalopathy Cerebellar atrophy Peripheral neuropathy Epilepsy • Myasthenia gravis • Dermatitis herpetiformis • Down’s syndrome • Enteropathy-associated T-cell lymphoma • Small bowel carcinoma • Squamous carcinoma of oesophagus • Ulcerative jejunitis • Pancreatic insufficiency • Microscopic colitis • Splenic atrophy

Diseases of the small intestine • 807

circumstances, if the diet is satisfactory, then other conditions, such as pancreatic insufficiency or microscopic colitis, should be sought, as should complications of coeliac disease, such as ulcerative jejunitis or enteropathy-associated T-cell lymphoma. There remain a small number of patients who fail to respond adequately to a gluten-free diet and they require therapy with glucocorticoids or immunosuppressive drugs. Complications A twofold-increased risk of malignancy, particularly of enteropathyassociated T-cell lymphoma, small bowel carcinoma and squamous carcinoma of the oesophagus, has been reported. A few patients develop ulcerative jejuno-ileitis. This may present with fever, pain, obstruction or perforation. This diagnosis can be made by barium studies or enteroscopy but laparotomy and full-thickness biopsy may be required. Treatment is difficult. Glucocorticoids are used with mixed success and some patients require surgical resection and parenteral nutrition. The course is often progressive. Osteoporosis and osteomalacia may occur in patients with longstanding, poorly controlled coeliac disease. These complications are less common in those who adhere strictly to a gluten-free diet. Dermatitis herpetiformis This is characterised by crops of intensely itchy blisters over the elbows, knees, back and buttocks (p. 1256). Immunofluorescence shows granular or linear IgA deposition at the dermo-epidermal junction. Almost all patients have partial villous atrophy on duodenal biopsy, identical to that seen in coeliac disease, even though they usually have no gastrointestinal symptoms. In contrast, fewer than 10% of coeliac patients have evidence of dermatitis herpetiformis, although both disorders are associated with the same histocompatibility antigen groups. The rash usually responds to a gluten-free diet but some patients require additional treatment with dapsone (100–150 mg daily). Tropical sprue Tropical sprue is defined as chronic, progressive malabsorption in a patient in or from the tropics, associated with abnormalities of small intestinal structure and function. The disease occurs mainly in the West Indies and in southern India, Malaysia and Indonesia. Pathophysiology The epidemiological pattern and occasional epidemics suggest that an infective agent may be involved. Although no single bacterium has been isolated, the condition often begins after an acute diarrhoeal illness. Small bowel bacterial overgrowth with Escherichia coli, Enterobacter and Klebsiella is frequently seen. The changes closely resemble those of coeliac disease. anti-endomysial antibodies. If the antibody screen is positive, adult patients should remain on a gluten-containing diet until duodenal biopsies are taken. High-titre serology in children can be diagnostic without the need for endoscopy and biopsy. Antibody titres usually become negative with successful treatment. Anti-endomysial antibodies of the IgA class are detectable by immunofluorescence in most untreated cases. They are sensitive (85–95%) and specific (approximately 99%) for the diagnosis, except in very young infants. IgG antibodies, however, must be analysed in patients with coexisting IgA deficiency. The tTG assay has become the serological test of choice in many countries, as it is easier to perform, is semi-quantitative, has more than 95% sensitivity and specificity, and is more accurate in patients with IgA deficiency. Haematology and biochemistry A full blood count may show microcytic or macrocytic anaemia from iron or folate deficiency and features of hyposplenism (target cells, spherocytes and Howell–Jolly bodies). Biochemical tests may reveal reduced concentrations of calcium, magnesium, total protein, albumin or vitamin D. Serum IgA measurement is required to ensure an appropriate IgA response and to allow analysis of serological testing. Other investigations Measurement of bone density should be considered to look for evidence of osteoporosis, especially in older patients and post-menopausal women. Management The aims are to correct existing deficiencies of micronutrients, such as iron, folate, calcium and/or vitamin D, and to achieve mucosal healing through a life-long gluten-free diet. This requires the exclusion of wheat, rye, barley and initially oats, although oats may be re-introduced safely in most patients after 6–12 months. Initially, frequent dietary counselling is required to make sure the diet is being observed, as the most common reason for failure to improve with dietary treatment is accidental or unrecognised gluten ingestion. Mineral and vitamin supplements are also given when indicated but are seldom necessary when a strict gluten-free diet is adhered to. Booklets produced by coeliac societies in many countries, containing diet sheets and recipes for the use of gluten-free flour, are of great value. Dietetic follow-up is key to management. Patients should be followed up after initiation of a gluten-free diet, with assessment of symptoms, weight and nutritional status, and blood should be taken for measurement of tTG or anti-endomysial antibodies. There are currently no additional non-invasive tests to assess small bowel mucosal healing. Repeat small bowel biopsies are not required routinely but should be considered in patients whose symptoms fail to improve and those in whom antibody levels remain high. In these Fig. 21.42 Jejunal mucosa. A Normal. B Subtotal villous atrophy in coeliac disease. There is blunting of villi (B), crypt hyperplasia (H) and inflammatory infiltration of the lamina propria (I). A B H B I

808 • GASTROENTEROLOGY hypogammaglobulinaemia (p. 78), bacterial overgrowth occurs because the IgA and IgM levels in serum and jejunal secretions are reduced. Chronic diarrhoea and malabsorption occur because of bacterial overgrowth and recurrent gastrointestinal infections (particularly giardiasis, p. 287). Clinical features The patient presents with watery diarrhoea and/or steatorrhoea, and with anaemia due to B12 deficiency. These arise because of deconjugation of bile acids, which impairs micelle formation, and because of bacterial utilisation of vitamin B12. There may also be symptoms from the underlying intestinal cause. Investigations The diagnosis of blind loops or fistulae can often be made by barium small bowel meal and follow-through or small bowel MRI enterography. Endoscopic duodenal biopsies are useful in excluding coeliac disease. Jejunal contents for bacteriological examination can also be aspirated at endoscopy but laboratory analysis requires anaerobic and aerobic culture techniques. Bacterial overgrowth can also be diagnosed non-invasively using hydrogen breath tests, although they lack sensitivity. These simple, non-radioactive tests involve serial measurement of breath samples for hydrogen after oral ingestion of 50 g of glucose or lactulose. If bacteria are present within the small bowel, they rapidly metabolise the glucose, causing an early rise in exhaled hydrogen, in advance of that normally resulting from metabolism by colonic flora. Biochemical analysis may reveal low serum levels of vitamin B12, with normal or elevated folate levels because the bacteria produce folic acid. Hypogammaglobulinaemia can be diagnosed by measurement of serum immunoglobulins and by intestinal biopsy, which shows reduced or absent plasma cells and nodular lymphoid hyperplasia. Management The underlying cause of small bowel bacterial overgrowth should be addressed, where possible. A course of broad-spectrum antibiotic for 2 weeks is the first-line treatment, although there is no consensus on agent or dose. Examples include tetracycline (250 mg 4 times daily), metronidazole (400 mg 3 times daily), amoxicillin (250 mg 3 times daily) or ciprofloxacin (250 mg twice daily). If breath testing reveals high methane production, addition of neomycin (500 mg twice daily) may be beneficial. Up to 50% of patients do not respond adequately and relapse rates are high. Some patients require up to 4 weeks of treatment and, in a few, continuous rotating courses of antibiotics are necessary. Consideration should be given to the risk of emerging antimicrobial resistance. Intramuscular vitamin B12 supplementation may be needed in chronic cases, as the bacteria utilise vitamin B12. Patients with motility disorders, such as diabetes and systemic sclerosis, can sometimes benefit from antidiarrhoeal drugs (diphenoxylate (5 mg 3 times daily orally) or loperamide (2 mg 4–6 times daily) orally). Giardiasis should Clinical features There is diarrhoea, abdominal distension, anorexia, fatigue and weight loss. In visitors to the tropics, the onset of severe diarrhoea may be sudden and accompanied by fever. When the disorder becomes chronic, the features of megaloblastic anaemia (vitamin B12 and folic acid malabsorption) and other deficiencies, including ankle oedema, glossitis and stomatitis, are common. Remissions and relapses may occur. The differential diagnosis in the indigenous tropical population is an infective cause of diarrhoea. The important differential diagnosis in visitors to the tropics is giardiasis (p. 287). Management Tetracycline (250 mg 4 times daily for 28 days) is the treatment of choice and brings about long-term remission or cure. In most patients, pharmacological doses of folic acid (5 mg daily) improve symptoms and jejunal morphology. In some cases, treatment must be prolonged before improvement occurs and occasionally patients must leave the tropics. Small bowel bacterial overgrowth (‘blind loop syndrome’) The normal duodenum and jejunum contain fewer than 104/mL organisms, which are usually derived from saliva. The count of coliform organisms never exceeds 103/mL. In bacterial overgrowth, there may be 108–1010/mL organisms, most of which are normally found only in the colon. Disorders that impair the normal physiological mechanisms controlling bacterial proliferation in the intestine predispose to bacterial overgrowth (Box 21.44). The most important are loss of gastric acidity, impaired intestinal motility and structural abnormalities that allow colonic bacteria to gain access to the small intestine or provide a secluded haven from the peristaltic stream. Pathophysiology Bacterial overgrowth can occur in patients with small bowel diverticuli. Another cause is diabetic autonomic neuropathy (p. 760), which reduces small bowel motility and affects enterocyte secretion. In systemic sclerosis, bacterial overgrowth arises because the circular and longitudinal layers of the intestinal muscle are fibrosed and motility is abnormal. In idiopathic 21.44 Causes of small bowel bacterial overgrowth Mechanism Examples Hypo- or achlorhydria Pernicious anaemia Partial gastrectomy Long-term proton pump inhibitor therapy Impaired intestinal motility Systemic sclerosis Diabetic autonomic neuropathy Chronic intestinal pseudo-obstruction Structural abnormalities Gastric surgery (blind loop after Billroth II operation) Jejunal diverticulosis Enterocolic fistulae* Extensive small bowel resection Strictures* Impaired immune function Hypogammaglobulinaemia *Most commonly caused by Crohn’s disease. 21.45 Malabsorption in old age • Coeliac disease: symptoms such as dyspepsia tend to be vague; only 25% present classically with diarrhoea and weight loss. Metabolic bone disease, folate or iron deficiency, coagulopathy and small bowel lymphoma are more common. • Small bowel bacterial overgrowth: more common due to atrophic gastritis, resulting in hypo- or achlorhydria, increased prevalence of jejunal diverticulosis and long-term adverse effects of gastric surgery for ulcer disease.

Diseases of the small intestine • 809

usually resolve quickly and biopsy changes revert to normal in a few weeks. Long-term follow-up is essential, as clinical relapse occurs in up to one-third of patients, often within the CNS; in this case, the same therapy is repeated or else treatment with doxycycline and hydroxychloroquine is necessary. Bile acid diarrhoea Bile acid diarrhoea can occur idiopathically (type 1), as a complication of small bowel resection, post cholecystectomy (type 2) or in association with other conditions such as microscopic colitis, chronic pancreatitis, coeliac disease, small intestinal bacterial overgrowth or diabetes mellitus. The population prevalence is estimated at around 1% and the disease is often under-diagnosed. It is now appreciated that many patients diagnosed with diarrhoeapredominant irritable bowel syndrome have evidence of bile acid diarrhoea. The most common scenario is in patients with Crohn’s disease who have undergone ileal resection, which can also lead to other malabsorptive manifestations (Fig. 21.43). Unabsorbed bile salts pass into the colon, stimulating water and electrolyte secretion and causing diarrhoea. If hepatic synthesis of new bile acids cannot keep pace with faecal losses, fat malabsorption occurs. Another consequence is the formation of lithogenic bile, leading to gallstones. Renal calculi, rich in oxalate, develop. Normally, oxalate in the colon is bound to and precipitated by calcium. Unabsorbed bile salts preferentially bind calcium, leaving oxalate to be absorbed, with development of urinary oxalate calculi. Patients have urgent watery diarrhoea or mild steatorrhoea. Contrast studies and tests of B12 and bile acid absorption, such as the 75Se-homocholic acid taurine (SeHCAT) test (p. 777), are useful investigations but are not available throughout the world due to use of synthetic radio-labelled compound. An elevated serum 7α-hydroxycholestenone is a useful non-invasive marker of bile acid diarrhoea. Diarrhoea usually responds well to bile acid sequestrants, such as colestyramine or colesevelam, which bind bile salts in the intestinal lumen. Aluminium hydroxide can be used as an alternative. Short bowel syndrome This is discussed in detail on page 708. Radiation enteritis and proctocolitis Intestinal damage occurs in 10–15% of patients undergoing radiotherapy for abdominal or pelvic malignancy. The risk varies with total dose, dosing schedule and the use of concomitant chemotherapy. Pathophysiology The rectum, sigmoid colon and terminal ileum are most frequently involved. Radiation causes acute inflammation, shortening of villi, oedema and crypt abscess formation. These usually resolve completely but some patients develop an obliterative endarteritis affecting the endothelium of submucosal arterioles over 2–12 months. In the longer term, this can provoke a fibrotic reaction, leading to adhesions, ulceration, strictures, obstruction or fistula to adjacent organs. Clinical features In the acute phase, there is nausea, vomiting, cramping abdominal pain and diarrhoea. When the rectum and colon are involved, rectal mucus, bleeding and tenesmus occur. The chronic phase develops after 5–10 years in some patients and produces one or more of the problems listed in Box 21.47. be controlled in patients with hypogammaglobulinaemia using metronidazole or tinidazole, but if symptoms fail to respond adequately, immunoglobulin infusions may be required. Whipple’s disease This rare condition is characterised by infiltration of small intestinal mucosa by ‘foamy’ macrophages, which stain positive with periodic acid–Schiff (PAS) reagent. The disease is a multisystem one and almost any organ can be affected, sometimes long before gastrointestinal involvement becomes apparent (Box 21.46). Pathophysiology Whipple’s disease is caused by infection with the Gram-positive bacillus Tropheryma whipplei, which becomes resident within macrophages in the bowel mucosa. Villi are widened and flattened, containing densely packed macrophages in the lamina propria, which obstruct lymphatic drainage and cause fat malabsorption. Clinical features Middle-aged Caucasian men are most frequently affected and presentation depends on the pattern of organ involvement. Low-grade fever is common and most patients have joint symptoms to some degree, often as the first manifestation. Occasionally, neurological manifestations may predominate and CNS involvement is the most serious consequence. Investigations Diagnosis is made by the characteristic features on small bowel biopsy, with characterisation of the bacillus by polymerase chain reaction (PCR). Management Whipple’s disease is often fatal if untreated but responds well, at least initially, to intravenous ceftriaxone (2 g daily for 2 weeks), followed by oral co-trimoxazole for at least 1 year. Symptoms 21.46 Clinical features of Whipple’s disease Gastrointestinal (> 70%) • Diarrhoea (75%) • Steatorrhoea • Weight loss (90%) • Protein-losing enteropathy • Ascites • Hepatosplenomegaly (< 5%) Musculoskeletal (65%) • Seronegative large joint arthropathy • Sacroiliitis Cardiac (10%) • Pericarditis • Myocarditis • Endocarditis • Coronary arteritis Neurological (10–40%) • Apathy • Fits • Dementia • Myoclonus • Meningitis • Cranial nerve lesions Pulmonary (10–20%) • Chronic cough • Pleurisy • Pulmonary infiltrates Haematological (60%) • Anaemia • Lymphadenopathy Other (40%) • Fever • Pigmentation

810 • GASTROENTEROLOGY It leads to fat malabsorption and deficiency of fat-soluble vitamins. Jejunal biopsy reveals enterocytes distended with resynthesised triglyceride and normal villous morphology. Serum cholesterol and triglyceride levels are low. A number of other abnormalities occur in this syndrome, including acanthocytosis, retinitis pigmentosa and a progressive neurological disorder with cerebellar and dorsal column signs. Symptoms may be improved by a low-fat diet supplemented with medium-chain triglycerides and vitamins A, D, E and K. Motility disorders Chronic intestinal pseudo-obstruction Small intestinal motility is disordered in conditions that affect the smooth muscle or nerves of the intestine. Many cases are ‘primary’ (idiopathic), while others are ‘secondary’ to a variety of disorders or drugs (Box 21.48). Clinical features There are recurrent episodes of nausea, vomiting, abdominal discomfort and distension, often worse after food. Alternating constipation and diarrhoea occur and weight loss results from malabsorption (due to bacterial overgrowth) and fear of eating. There may also be symptoms of dysmotility affecting other parts of the gastrointestinal tract, such as dysphagia, and features of bladder dysfunction in primary cases. Some patients develop severe abdominal pain for reasons that are poorly understood and this can be difficult to manage. Investigations The diagnosis is often delayed and a high index of suspicion is needed. Plain X-rays show distended loops of bowel and air–fluid levels but barium studies demonstrate no mechanical obstruction. Laparotomy is sometimes required to exclude obstruction and to obtain full-thickness biopsies of the intestine. Examination of biopsy material using specialised techniques, such as electron microscopy, and immunohistochemistry can diagnose the many Investigations In the acute phase, the rectal changes at sigmoidoscopy resemble ulcerative proctitis (see Fig. 21.53, p. 819). An endoscopic biopsy from the rectal wall is associated with a 2% risk of fistula formation. The extent of the lesion can be assessed by colonoscopy. Barium follow-through or MRI enterography can be of diagnostic value in showing small bowel strictures, ulcers and fistulae. Management Diarrhoea in the acute phase should be treated with codeine phosphate, diphenoxylate or loperamide. Antibiotics may be required for bacterial overgrowth. Nutritional supplements are necessary when malabsorption is present. Colestyramine or colesevelam is useful for bile acid diarrhoea. Surgery should be avoided, if possible, because the injured intestine is difficult to resect and anastomose, but may be necessary for obstruction, perforation or fistula. In radiation proctitis, the underlying pathophysiology is tissue ischaemia rather than inflammation; glucocorticoid enemas are therefore not effective. Traditionally, endoscopic argon plasma coagulation therapy was used but this is of limited benefit and can induce fistula, stricture or perforation. Effective treatments include sucralfate enema and hyperbaric oxygen. Abetalipoproteinaemia This rare autosomal recessive disorder is caused by deficiency of apolipoprotein B, which results in failure of chylomicron formation. Fig. 21.43 Consequences of ileal resection. Decreased bile salt pool, lithogenic bile leading to gallstones Impaired bile salt absorption leading to watery diarrhoea B12 malabsorption Increased absorption of oxalate Oxalate calculi Impaired micelle formation and fat malabsorption 21.47 Chronic complications of intestinal irradiation • Proctocolitis • Bleeding from telangiectasia • Small bowel strictures • Fistulae: rectovaginal, colovesical, enterocolic • Adhesions • Malabsorption: bacterial overgrowth, bile acid diarrhoea (ileal damage)

Diseases of the small intestine • 811

Intestinal lymphangiectasia This may be primary, resulting from congenital malunion of lymphatics, or secondary to lymphatic obstruction due to lymphoma, filariasis or constrictive pericarditis. Impaired drainage of intestinal lymphatic vessels leads to discharge of protein and fat-rich lymph into the gastrointestinal lumen. The condition presents with peripheral lymphoedema, pleural effusions or chylous ascites, and steatorrhoea. Investigations reveal hypoalbuminaemia, lymphopenia and reduced serum immunoglobulin concentrations. The diagnosis can be made by CT scanning and by enteroscopy with jejunal biopsy, which shows greatly dilated lacteals. Treatment consists of a low-fat diet with medium-chain triglyceride supplements. Ulceration of the small intestine Small bowel ulcers are uncommon and are either idiopathic or secondary to underlying intestinal disorders (Box 21.50). Ulcers are more common in the ileum and cause bleeding, perforation, stricture formation or obstruction. Barium studies and enteroscopy confirm the diagnosis. rare diseases of enteric smooth muscle and nerves that can cause this syndrome. Management This is often difficult. Underlying causes should be addressed and further surgery avoided. Metoclopramide or domperidone may enhance motility and antibiotics are given for bacterial overgrowth. Nutritional and psychological support is also necessary. Miscellaneous disorders of the small intestine Protein-losing enteropathy This term is used when there is excessive loss of protein into the gut lumen, sufficient to cause hypoproteinaemia. Protein-losing enteropathy occurs in many gut disorders but is most common in those in which ulceration occurs (Box 21.49). In other disorders, protein loss can result from increased mucosal permeability or obstruction of intestinal lymphatic vessels. Patients present with peripheral oedema and hypoproteinaemia in the presence of normal liver function, low albumin and globulin, and without proteinuria. The diagnosis can be confirmed by measurement of faecal clearance of α1-antitrypsin or 51Cr-labelled albumin after intravenous injection. Other investigations should be performed to determine the underlying cause. Treatment is that of the underlying disorder, with nutritional support and measures to control peripheral oedema. 21.49 Causes of protein-losing enteropathy With mucosal erosions or ulceration • Crohn’s disease • Ulcerative colitis • Radiation damage • Oesophageal, gastric or colonic cancer • Lymphoma Without mucosal erosions or ulceration • Ménétrier’s disease • Bacterial overgrowth • Coeliac disease • Tropical sprue • Eosinophilic gastroenteritis • Systemic lupus erythematosus With lymphatic obstruction • Intestinal lymphangiectasia • Constrictive pericarditis • Lymphoma • Whipple’s disease 21.48 Causes of chronic intestinal pseudo-obstruction Primary or idiopathic • Rare familial visceral myopathies or neuropathies • Congenital aganglionosis Secondary • Drugs (opiates, tricyclic antidepressants, phenothiazines) • Smooth muscle disorders (systemic sclerosis, amyloidosis, mitochondrial myopathies) • Myenteric plexus disorders, e.g. paraneoplastic syndrome in small-cell lung cancer • Central nervous system disorders (Parkinson’s disease, autonomic neuropathy) • Endocrine and metabolic disorders (hypothyroidism, phaeochromocytoma, acute intermittent porphyria) 21.50 Causes of small intestinal ulcers • Idiopathic • Inflammatory bowel disease • Non-steroidal antiinflammatory drugs • Ulcerative jejuno-ileitis • Lymphoma and carcinoma • Infections (tuberculosis, typhoid, Yersinia enterocolitica) • Others (radiation, vasculitis) NSAID-associated small intestinal toxicity These drugs cause a spectrum of small intestinal lesions ranging from erosions and ulcers to mucosal webs, strictures and, rarely, a condition known as ‘diaphragm disease’, in which intense submucosal fibrosis results in circumferential stricturing. The condition can present with pain, obstruction, bleeding or anaemia, and may mimic Crohn’s disease, carcinoma or lymphoma. Enteroscopy or capsule endoscopy can reveal the diagnosis but sometimes this is discovered only at laparotomy. Eosinophilic gastroenteritis This disorder of unknown aetiology can affect any part of the gastrointestinal tract; it is characterised by eosinophil infiltration involving the gut wall, in the absence of parasitic infection or eosinophilia of other tissues. It may be mucosal, muscular or subserosal. Peripheral blood eosinophilia is present in 80% of cases. Clinical features There are features of obstruction and inflammation, such as colicky pain, nausea and vomiting, diarrhoea and weight loss. Protein-losing enteropathy occurs and up to 50% of patients have a history of other allergic disorders. Serosal involvement may produce eosinophilic ascites. Investigations and management The diagnosis is made by histological assessment of multiple endoscopic biopsies, although full-thickness biopsies are occasionally required. Other investigations should be performed

812 • GASTROENTEROLOGY symptoms. Addition of commercial lactase preparations to milk has been effective in some studies but is costly. Intolerance of other sugars ‘Osmotic’ diarrhoea can be caused by sorbitol, an unabsorbable carbohydrate that is used as an artificial sweetener. Fructose contained within fruit juices may also cause diarrhoea if it is consumed in greater quantities than can be absorbed. Food allergy Food allergies are immune-mediated disorders, most commonly due to type I hypersensitivity reactions with production of IgE antibodies, although type IV delayed hypersensitivity reactions are also seen (p. 83). Up to 20% of the population perceive themselves as suffering from food allergy but only 1–2% of adults and 5–7% of children have genuine food allergies. The most common culprits are peanuts, milk, eggs, soya and shellfish. Clinical manifestations occur immediately on exposure and range from trivial to life-threatening or even fatal anaphylaxis. The common oral allergy syndrome results from contact with benzoic acid in certain fresh fruit juices, leading to urticaria and angioedema of the lips and oropharynx. This is not, however, an immune-mediated reaction. ‘Allergic gastroenteropathy’ has features similar to eosinophilic gastroenteritis, while ‘gastrointestinal anaphylaxis’ consists of nausea, vomiting, diarrhoea and sometimes cardiovascular and respiratory collapse. Fatal reactions to trace amounts of peanuts are well documented. The diagnosis of food allergy is difficult to prove or refute. Skin-prick tests and measurements of antigen-specific IgE antibodies in serum have limited predictive value. Double-blind placebo-controlled food challenges are the gold standard but are laborious and are not readily available. In many cases, clinical suspicion and trials of elimination diets are used. Treatment of proven food allergy consists of detailed patient education and awareness, strict elimination of the offending antigen, and, in some cases, antihistamines or sodium cromoglicate. Anaphylaxis should be treated as a medical emergency with resuscitation, airway support and intravenous adrenaline (epinephrine). Teachers and other carers of affected children should be trained to deal with this. Patients should wear an information bracelet and be taught to carry and use a preloaded adrenaline syringe. Infections of the small intestine Travellers’ diarrhoea, giardiasis and amoebiasis See pages 232, 287 and 286. Abdominal tuberculosis Mycobacterium tuberculosis is a rare cause of abdominal disease in Caucasians but must be considered in people in and from the developing world and in AIDS patients. Gut infection usually results from human M. tuberculosis, which is swallowed after coughing. Many patients have no pulmonary symptoms and a normal chest X-ray. The area most commonly affected is the ileocaecal region. The presentation and radiological findings may be very similar to those of Crohn’s disease. Abdominal pain can be acute or of several months’ duration but diarrhoea is less common in tuberculosis to exclude parasitic infection and other causes of eosinophilia. The serum IgE concentration is often raised. Dietary manipulations are rarely effective, although elimination diets, especially of milk, may benefit a few patients. Severe symptoms are treated with prednisolone (20–40 mg daily) and/or sodium cromoglicate, which stabilises mast cell membranes. The prognosis is good in the majority of patients. Meckel’s diverticulum This is the most common congenital anomaly of the gastrointestinal tract and occurs in 0.3–3% of people, but the vast majority of affected individuals are asymptomatic throughout life. The diverticulum results from failure of closure of the vitelline duct, with persistence of a blind-ending sac arising from the antimesenteric border of the ileum; it usually occurs within 100 cm of the ileocaecal valve and is up to 5 cm long. Approximately 50% contain ectopic gastric mucosa; rarely, colonic, pancreatic or endometrial tissue is present. Complications most commonly occur in the first 2 years of life but are occasionally seen in young adults. Bleeding can result from ulceration of ileal mucosa adjacent to the ectopic parietal cells and presents as recurrent melaena or altered blood per rectum. The diagnosis can be made by scanning the abdomen using a gamma counter following an intravenous injection of 99mTc-pertechnetate, which is concentrated by ectopic parietal cells. Other complications include intestinal obstruction, diverticulitis, intussusception and perforation. Intervention is unnecessary unless complications occur. Adverse food reactions Adverse food reactions are common and are subdivided into food intolerance and food allergy, the former being much more common. In food intolerance, there is an adverse reaction to food that is not immune-mediated and results from pharmacological (histamine, tyramine or monosodium glutamate), metabolic (lactase deficiency) or other mechanisms (toxins or chemical contaminants in food). Lactose intolerance Human milk contains around 200 mmol/L (68 g/L) of lactose, which is normally digested to glucose and galactose by the brush border enzyme lactase prior to absorption. In most populations, enterocyte lactase activity declines throughout childhood. The enzyme is deficient in up to 90% of adult Africans, Asians and South Americans but only 5% of northern Europeans. In cases of genetically determined (primary) lactase deficiency, jejunal morphology is normal. ‘Secondary’ lactase deficiency occurs as a consequence of disorders that damage the jejunal mucosa, such as coeliac disease and viral gastroenteritis. Unhydrolysed lactose enters the colon, where bacterial fermentation produces volatile short-chain fatty acids, hydrogen and carbon dioxide. Clinical features In most people, lactase deficiency is completely asymptomatic. However, some complain of colicky pain, abdominal distension, increased flatus, borborygmi and diarrhoea after ingesting milk or milk products. Irritable bowel syndrome may be suspected but the correct diagnosis is suggested by clinical improvement on lactose withdrawal. The lactose hydrogen breath test is a useful non-invasive investigation. Dietary exclusion of lactose is recommended, although most sufferers are able to tolerate small amounts of milk without

Inflammatory bowel disease • 813

most lesions of this type. Enteroscopy, capsule endoscopy, mesenteric angiography and CT also play a role in investigation. Treatment is by surgical resection. Neuro-endocrine tumours These are discussed in detail on page 678. Lymphoma Non-Hodgkin lymphoma (p. 964) may involve the gastrointestinal tract as part of more generalised disease or may rarely arise in the gut, the small intestine being most commonly affected. Lymphomas occur with increased frequency in patients with coeliac disease, HIV/AIDS and other immunodeficiency states. Most are of B-cell origin, although lymphoma associated with coeliac disease is derived from T cells (enteropathy-associated T-cell lymphoma). Colicky abdominal pain, obstruction and weight loss are the presenting features and perforation is also seen occasionally. Malabsorption is a feature of diffuse bowel involvement and hepatosplenomegaly is rare. The diagnosis is made by small bowel biopsy, radiological contrast studies and CT. Staging investigations should be performed as for lymphomas occurring elsewhere (p. 962). Surgical resection, where possible, is the treatment of choice, with radiotherapy and combination chemotherapy reserved for those with advanced disease. The prognosis depends largely on the stage at diagnosis, cell type, patient age and the presence of ‘B’ symptoms (fever, weight loss, night sweats). Immunoproliferative small intestinal disease Immunoproliferative small intestinal disease (IPSID), also known as alpha heavy chain disease, is a rare condition occurring mainly in Mediterranean countries, the Middle East, India, Pakistan and North America. It is a variant of B-cell lymphoma of MALT type and often associated with Campylobacter jejuni infection. The condition varies in severity from relatively benign to frankly malignant. The small intestinal mucosa is diffusely affected, especially proximally, by a dense lymphoplasmacytic infiltrate. Enlarged mesenteric lymph nodes are also common. Most patients are young adults who present with malabsorption, anorexia and fever. Serum electrophoresis confirms the presence of alpha heavy chains (from the Fc portion of IgA). Prolonged remissions can be obtained with long-term antibiotic therapy but chemotherapy is required for those who fail to respond or who have aggressive disease. Inflammatory bowel disease Ulcerative colitis and Crohn’s disease are chronic inflammatory bowel diseases that pursue a protracted relapsing and remitting course, usually extending over years. The diseases have many similarities and it is sometimes impossible to differentiate between them. One crucial distinction is that ulcerative colitis involves only the colon, while Crohn’s disease can involve any part of the gastrointestinal tract from mouth to anus. A summary of the main features of ulcerative colitis and Crohn’s disease is provided in Box 21.51. The incidence of inflammatory bowel disease (IBD) varies widely between populations. There was a dramatic increase in the incidence of both ulcerative colitis and Crohn’s disease in the Western world, starting in the second half of the last century and than in Crohn’s disease. Low-grade fever is common but not invariable. Like Crohn’s disease, tuberculosis can affect any part of the gastrointestinal tract and perianal disease with fistula is recognised. Peritoneal tuberculosis may result in peritonitis with exudative ascites, associated with abdominal pain and fever. Granulomatous hepatitis occurs. Investigations Abdominal tuberculosis causes an elevated ESR; a raised serum alkaline phosphatase concentration suggests hepatic involvement. Histological confirmation should be sought by endoscopy, laparoscopy or liver biopsy. Caseation of granulomas is not always seen and acid- and alcohol-fast bacteria are often scanty. Culture may be helpful but identification of the organism may take 6 weeks and diagnosis is now possible on biopsy specimens using PCR-based techniques. Management When the presentation is very suggestive of abdominal tuberculosis, chemotherapy with multiple anti-tuberculous drugs should be commenced, even if bacteriological or histological proof is lacking. Isoniazid, pyrazinamide and ethambutol is a common standard regime (p. 590), though the precise choice will be dependent on local drug resistance patterns. Cryptosporidiosis Cryptosporidiosis and other protozoal infections, including cystoisosporiasis (Cystoisospora belli) and microsporidiosis, are dealt with on pages 287 and 317. Tumours of the small intestine The small intestine is rarely affected by neoplasia and fewer than 5% of all gastrointestinal tumours occur at this site. Benign tumours The most common are adenomas, GISTs, lipomas and hamartomas. Adenomas are most often found in the periampullary region and are usually asymptomatic, although occult bleeding or obstruction due to intussusception may occur. Transformation to adenocarcinoma is rare. Multiple adenomas are common in the duodenum of patients with familial adenomatous polyposis (FAP), who merit regular endoscopic surveillance. Hamartomatous polyps with almost no malignant potential occur in Peutz–Jeghers syndrome (p. 829). Malignant tumours These are rare and include, in decreasing order of frequency, adenocarcinoma, neuro-endocrine tumours, malignant GIST and lymphoma. The majority occur in middle age or later. Kaposi’s sarcoma of the small bowel may arise in patients with AIDS. Adenocarcinomas Adenocarcinomas occur with increased frequency in patients with FAP, coeliac disease, small bowel Crohn’s disease and Peutz–Jeghers syndrome. This is a rare cancer, accounting for less than 5% of all gastrointestinal malignancies. The non-specific presentation and rarity of these lesions often lead to a delay in diagnosis. Despite advances in imaging and endoscopic techniques, early diagnosis is difficult. Barium follow-through examination or small bowel enterography studies demonstrate

814 • GASTROENTEROLOGY butyrate and other short-chain fatty acids. There is emerging evidence that the virome and mycobiome (fungal species) may be important in the development of IBD. In both diseases, the intestinal wall is infiltrated with acute and chronic inflammatory cells, but there are important differences between the conditions in the distribution of lesions and in histological features (Fig. 21.45). coinciding with the introduction of a more ‘hygienic’ environment with the advent of domestic refrigeration and the widespread use of antibiotics. The developing world has seen similar patterns, as these countries adopt an increasingly Westernised lifestyle. In the West, the incidence of ulcerative colitis is stable at 10–20 per 100 000, with a prevalence of 100–200 per 100 000, while the incidence of Crohn’s disease is increasing and is now 5–10 per 100 000, with a prevalence of 50–100 per 100 000. Both diseases most commonly start in the second and third decades of life, with a second smaller incidence peak in the seventh decade. Approximately 240 000 people are affected by IBD in the UK (approximately 1.4 million in the USA), equating to a prevalence of about 1 in 250. Life expectancy in patients with IBD is similar to that of the general population. Although many patients require surgery and admission to hospital for other reasons, with substantial associated morbidity, the majority have an excellent work record and pursue a normal life. Pathophysiology IBD has both environmental and genetic components, and evidence from genome-wide association studies suggests that genetic variants that predispose to Crohn’s disease may have undergone positive selection by protecting against infectious diseases, including tuberculosis (Box 21.52). It is thought that IBD develops because these genetically susceptible individuals mount an abnormal inflammatory response to environmental triggers, such as intestinal bacteria. This leads to inflammation of the intestine with involvement of a wide array of innate and adaptive immune cell responses, with release of inflammatory mediators, including TNF-α, IL-12 and IL-23, which cause tissue damage (Fig. 21.44). There is an association between microbial dysbiosis and IBD. For example, there is a reduced diversity, primarily of Firmicutes and in particular, Faecalibacterium prausnitzii. Functional changes in the bacteria are important and include a reduction of anti-inflammatory metabolites, such as 21.51 Comparison of ulcerative colitis and Crohn’s disease Ulcerative colitis Crohn’s disease Age group Any Any Gender M = F Slight female preponderance Incidence Stable Increasing Ethnic group Any Any; more common in Ashkenazi Jews Genetic factors HLA-DR103; colonic epithelial barrier function (HNF4α, LAMB1, CDH1) Defective innate immunity and autophagy (NOD2, ATG16L1, IRGM) Risk factors More common in non-/ex-smokers Appendicectomy protects More common in smokers Anatomical distribution Colon only; begins at anorectal margin with variable proximal extension Any part of gastrointestinal tract; perianal disease common; patchy distribution, skip lesions Extra-intestinal manifestations Common Common Presentation Bloody diarrhoea Variable; pain, diarrhoea, weight loss all common Histology Inflammation limited to mucosa; crypt distortion, cryptitis, crypt abscesses, loss of goblet cells Submucosal or transmural inflammation common; deep fissuring ulcers, fistulae; patchy changes; granulomas Management 5-ASA; glucocorticoids; azathioprine; biological therapy (anti-TNF, anti-α4β7 integrin); colectomy is curative Glucocorticoids; azathioprine; methotrexate; biological therapy (anti-TNF, anti-α4β7 integrin); nutritional therapy; smoking cessation; surgery for complications is not curative; 5-ASA is not effective (5-ASA = 5-aminosalicylic acid; TNF = tumour necrosis factor) 21.52 Factors associated with the development of inflammatory bowel disease Genetic • Both CD and UC are common in Ashkenazi Jews • 10% have first-degree relative/1 or more close relative with IBD • High concordance in identical twins (40–50% CD; 20–25% UC) • 163 susceptibility loci identified at genome-wide levels of significance; most confer susceptibility to both CD and UC; many are also susceptibility loci for other inflammatory conditions (especially ankylosing spondylosis and psoriasis) • UC and CD are both associated with genetic variants at HLA locus, and with multiple genes involved with immune signalling (especially IL-23 and IL-10 pathways) • CD is associated with genetic defects in innate immunity and autophagy (NOD2, ATG16L1 and IRGM genes) • UC is associated with genetic defects in barrier function • NOD2 is associated with ileal and stricturing disease, and hence a need for resectional surgery • HLA-DR103 is associated with severe UC Environmental • UC is more common in non-smokers and ex-smokers • CD is more common in smokers (relative risk = 3) • CD is associated with a low-residue, high-refined-sugar diet • Commensal gut microbiota are altered (dysbiosis) in CD and UC • Appendicectomy protects against UC (CD = Crohn’s disease; HLA = human leucocyte antigen; IBD = inflammatory bowel disease; IL = interleukin; UC = ulcerative colitis)

Inflammatory bowel disease • 815

Ulcerative colitis Inflammation invariably involves the rectum (proctitis) and spreads proximally in a continuous manner to involve the entire colon in some cases (pancolitis). In long-standing pancolitis, the bowel can become shortened and post-inflammatory ‘pseudopolyps’ develop; these are normal or hypertrophied residual mucosa within areas of atrophy (Fig. 21.46). The inflammatory process is limited to the mucosa and spares the deeper layers of the bowel wall (Fig. 21.47). Both acute and chronic inflammatory cells infiltrate the lamina propria and the crypts (‘cryptitis’). Crypt abscesses are typical. Goblet cells lose their mucus and, in long-standing Fig. 21.44 Pathogenesis of inflammatory bowel disease. (1) Bacterial antigens are taken up by specialised M cells, pass between leaky epithelial cells or enter the lamina propria through ulcerated mucosa. (2) After processing, they are presented to type 1 T-helper cells by antigenpresenting cells (APCs) in the lamina propria. (3) T-cell activation and differentiation results in a Th1 T cell-mediated cytokine response (4) with secretion of cytokines, including interferon gamma (IFN-γ). Further amplification of T cells perpetuates the inflammatory process with activation of non-immune cells and release of other important cytokines, including interleukin 12 (IL-12), IL-23, IL-1, IL-6 and tumour necrosis factor alpha (TNF-α). These pathways occur in all normal individuals exposed to an inflammatory insult and this is self-limiting in healthy subjects. In genetically predisposed persons, dysregulation of innate immunity may trigger inflammatory bowel disease. M cell APC Macrophage Type 1 Th cell IL-12 IL-23 IFN-γ IL-1 IL-6 TNF-α release

Fig. 21.45 Common patterns of disease distribution in inflammatory bowel disease. Left-sided colitis 30–40% Perianal disease alone < 10% Crohn's disease Ileal or ileocolonic 40% Small intestinal 30–40% Crohn's colitis c. 20% Ulcerative colitis Proctitis 40–50% Extensive colitis (up to pancolitis) 20% Fig. 21.46 Pseudopolyposis in ulcerative colitis.

816 • GASTROENTEROLOGY subacute or even acute intestinal obstruction. The pain is often associated with diarrhoea, which is usually watery and does not contain blood or mucus. Almost all patients lose weight because they avoid food, since eating provokes pain. Weight loss may also be due to malabsorption and some patients present with features of fat, protein or vitamin deficiencies. Crohn’s colitis presents in an identical manner to ulcerative colitis but rectal cases, glands become distorted. Dysplasia, characterised by heaping of cells within crypts, nuclear atypia and increased mitotic rate, may herald the development of colon cancer. Crohn’s disease The sites most commonly involved are, in order of frequency, the terminal ileum and right side of colon, colon alone, terminal ileum alone, ileum and jejunum. The entire wall of the bowel is oedematous and thickened, and there are deep ulcers that often appear as linear fissures; thus the mucosa between them is described as ‘cobblestone’. These may penetrate through the bowel wall to initiate abscesses or fistulae involving the bowel, bladder, uterus, vagina and skin of the perineum. The mesenteric lymph nodes are enlarged and the mesentery is thickened. Crohn’s disease has a patchy distribution and the inflammatory process is interrupted by islands of normal mucosa. On histological examination, the bowel wall is thickened with a chronic inflammatory infiltrate throughout all layers (Fig. 21.48). Clinical features Ulcerative colitis The cardinal symptoms are rectal bleeding with passage of mucus and bloody diarrhoea. The presentation varies, depending on the site and severity of the disease (see Fig. 21.45), as well as the presence of extra-intestinal manifestations. The first attack is usually the most severe and is followed by relapses and remissions. Emotional stress, intercurrent infection, gastroenteritis, antibiotics or NSAID therapy may all provoke a relapse. Proctitis causes rectal bleeding and mucus discharge, accompanied by tenesmus. Some patients pass frequent, small-volume fluid stools, while others pass pellety stools due to constipation upstream of the inflamed rectum. Constitutional symptoms do not occur. Left-sided and extensive colitis causes bloody diarrhoea with mucus, often with abdominal cramps. In severe cases, anorexia, malaise, weight loss and abdominal pain occur and the patient is toxic, with fever, tachycardia and signs of peritoneal inflammation (Box 21.53). Crohn’s disease The major symptoms are abdominal pain, diarrhoea and weight loss. Ileal Crohn’s disease (Figs 21.49 and 21.50) may cause Fig. 21.47 Histology of ulcerative colitis. There is surface ulceration and inflammation is confined to the mucosa with excess inflammatory cells in the lamina propria, loss of goblet cells, and crypt abscesses (arrows). (SM = submucosa) SM Fig. 21.48 Histology of Crohn’s disease. A Inflammation is ‘transmural’; there is fissuring ulceration (arrow), with inflammation extending into the submucosa (SM). B At higher power, a characteristic non-caseating granuloma is seen. SM A B Fig. 21.49 Ileal Crohn’s disease. Small bowel magnetic resonance image showing a terminal ileum that is thickened, narrowed and enhancing (arrow), with dilatation immediately proximal to this.

Inflammatory bowel disease • 817

21.53 Assessment of disease severity in ulcerative colitis Mild Moderate Severe Daily bowel frequency < 4 4–6 ≥ 6* Blood in stools +/− +/++ +++ Stool volume < 200 g/24 hrs 200–400 g/24 hrs

400 g/24 hrs Pulse < 90 beats/min < 90 beats/min ≥ 90 beats/min* Temperature Normal Normal ≥ 37.8°C* Haemoglobin Normal Normal < 100 g/L (< 10 g/dL)* Erythrocyte sedimentation rate Normal Normal 30 mm/hr* (or equivalent C-reactive protein) Serum albumin 35 g/L (> 3.5 g/dL) < 30 g/L (< 3 g/dL) Abdominal X-ray Normal Normal Dilated bowel, mucosal islands, thumb-printing of mucosa, or absence of features Sigmoidoscopy Normal or erythema/granular mucosa Severe mucosal inflammatory changes; ulceration; blood in lumen The Truelove–Witts criteria for acute severe ulcerative colitis are ≥ 6 bloody stools/24 hrs plus one or more of: anaemia, fever, tachycardia and high inflammatory markers. Fig. 21.50 Barium follow-through showing terminal ileal Crohn’s disease. A long stricture is present (arrow A), and more proximally there is ulceration with characteristic ‘rose thorn’ ulcers (arrow B). A B Common; other causes are rare. 21.55 Differential diagnosis of small bowel Crohn’s disease • Other causes of right iliac fossa mass: Caecal carcinoma Appendix abscess • Infection (tuberculosis, Yersinia, actinomycosis) • Mesenteric adenitis • Pelvic inflammatory disease • Lymphoma 21.54 Conditions that can mimic ulcerative or Crohn’s colitis Infective Bacterial • Salmonella • Shigella • Campylobacter jejuni • Escherichia coli O157 • Gonococcal proctitis • Pseudomembranous colitis • Chlamydia proctitis Viral • Herpes simplex proctitis • Cytomegalovirus Protozoal • Amoebiasis Non-infective • Ischaemic colitis • Collagenous colitis • Non-steroidal antiinflammatory drugs • Diverticulitis • Radiation proctitis • Behçet’s disease • Colonic carcinoma sparing and the presence of perianal disease are features that favour a diagnosis of Crohn’s disease. Many patients present with symptoms of both small bowel and colonic disease. A few patients present with isolated perianal disease, vomiting from jejunal strictures or severe oral ulceration. Physical examination often reveals evidence of weight loss, anaemia with glossitis and angular stomatitis. There is abdominal tenderness, most marked over the inflamed area. An abdominal mass may be palpable and is due to matted loops of thickened bowel or an intra-abdominal abscess. Perianal skin tags, fissures or fistulae are found in at least 50% of patients. Differential diagnosis The differential diagnosis is summarised in Box 21.54. The most important issue is to distinguish the first attack of acute colitis from infection. In general, diarrhoea lasting longer than 10 days in Western countries is unlikely to be the result of infection, whereas a history of foreign travel, antibiotic exposure (Clostridium difficile/pseudomembranous colitis) or homosexual contact increases the possibility of infection, which should be excluded by the appropriate investigations (see below). The diagnosis of Crohn’s disease is usually more straightforward and is made on the basis of imaging and clinical presentation, but in atypical cases biopsy or surgical resection is necessary to exclude other diseases (Box 21.55).

818 • GASTROENTEROLOGY cumulative risk for dysplasia in ulcerative colitis may be as high as 20% after 30 years but is probably lower for Crohn’s colitis. The risk is particularly high in patients who have concomitant primary sclerosing cholangitis for unknown reasons. Tumours develop in areas of dysplasia and may be multiple. Patients with long-standing colitis are therefore entered into surveillance programmes beginning 10 years after diagnosis. Targeted biopsies of areas that show abnormalities on staining with indigo carmine or methylene blue increase the chance of detecting dysplasia and this technique (termed pancolonic chromo-endoscopy) has replaced colonoscopy with random biopsies taken every 10 cm in screening for malignancy. The procedure allows patients to be stratified into high-, medium- or low-risk groups to determine the interval between surveillance procedures. Family history of colon cancer is also an important factor to consider. If high-grade dysplasia is found, panproctocolectomy is usually recommended because of the high risk of colon cancer. Extra-intestinal complications Extra-intestinal complications are common in IBD and may dominate the clinical picture. Some of these occur during relapse of intestinal disease; others appear to be unrelated to intestinal disease activity (Fig. 21.52). Investigations Investigations are necessary to confirm the diagnosis, define disease distribution and activity, and identify complications. Full blood count may show anaemia resulting from bleeding or malabsorption of iron, folic acid or vitamin B12. Platelet count can also be high as a marker of chronic inflammation. Serum albumin concentration falls as a consequence of protein-losing enteropathy, inflammatory disease or poor nutrition. ESR and CRP are elevated in exacerbations and in response to abscess formation. Faecal calprotectin has a high sensitivity for detecting gastrointestinal inflammation and may be elevated, even when the CRP is normal. It is particularly useful for distinguishing inflammatory bowel disease from irritable bowel syndrome at diagnosis, and for subsequent monitoring of disease activity. Bacteriology At initial presentation, stool microscopy, culture and examination for Clostridium difficile toxin or for ova and cysts, blood cultures and serological tests should be performed. These investigations should be repeated in established disease to exclude superimposed enteric infection in patients who present with exacerbations of IBD. During acute flares necessitating hospital admission, three separate stool samples should be sent for bacteriology to maximise sensitivity. Endoscopy Patients who present with diarrhoea plus raised inflammatory markers or alarm features, such as weight loss, rectal bleeding and anaemia, should undergo ileocolonoscopy. Flexible sigmoidoscopy is occasionally performed to make a diagnosis, especially during acute severe presentations when ileocolonoscopy may confer an unacceptable risk; ileocolonoscopy should still be performed at a later date, however, in order to evaluate disease extent. In ulcerative colitis, there is loss of vascular pattern, granularity, friability and contact bleeding, with or without ulceration (Fig. 21.53). In Crohn’s disease, patchy inflammation, with discrete, deep ulcers, strictures and perianal disease (fissures, fistulae and skin tags), is typically observed, often with rectal sparing. In established disease, colonoscopy may show active inflammation Complications Life-threatening colonic inflammation This can occur in both ulcerative colitis and Crohn’s colitis. In the most extreme cases, the colon dilates (toxic megacolon) and bacterial toxins pass freely across the diseased mucosa into the portal and then systemic circulation. This complication arises most commonly during the first attack of colitis and is recognised by the features described in Box 21.53. An abdominal X-ray should be taken daily because, when the transverse colon is dilated to more than 6 cm (Fig. 21.51), there is a high risk of colonic perforation, although this complication can also occur in the absence of toxic megacolon. Severe colonic inflammation with toxic dilatation is a surgical emergency and most often requires colectomy. Haemorrhage Haemorrhage due to erosion of a major artery is rare but can occur in both conditions. Fistulae These are specific to Crohn’s disease. Enteroenteric fistulae can cause diarrhoea and malabsorption due to blind loop syndrome. Enterovesical fistulation causes recurrent urinary infections and pneumaturia. An enterovaginal fistula causes a faeculent vaginal discharge. Fistulation from the bowel may also cause perianal or ischiorectal abscesses, fissures and fistulae. Cancer The risk of dysplasia and cancer increases with the duration and extent of uncontrolled colonic inflammation. Thus patients who have long-standing, extensive colitis are at highest risk. Oral mesalazine therapy reduces the risk of dysplasia and neoplasia in ulcerative colitis. Azathioprine also seems to reduce the risk of colorectal cancer in ulcerative colitis and Crohn’s colitis. This protective effect probably extends to any medical treatment that results in sustained healing of the colonic mucosa. The Fig. 21.51 Plain abdominal X-ray showing a grossly dilated colon due to severe ulcerative colitis. There is also marked mucosal oedema and ‘thumb-printing’ (arrows).

Inflammatory bowel disease • 819

Fig. 21.52 Systemic complications of inflammatory bowel disease. See also Chapters 17 and 18. (HLA = human leukocyte antigen) Unrelated to inflammatory bowel disease activity Autoimmune hepatitis Primary sclerosing cholangitis and cholangiocarcinoma (ulcerative colitis) Gallstones Amyloidosis and oxalate calculi Sacroiliitis/ankylosing spondylitis (Crohn’s with HLA-B27) Metabolic bone disease Occur during the active phase of inflammatory bowel disease Mouth ulcers Conjunctivitis Iritis Episcleritis Mesenteric or portal vein thrombosis Fatty liver Liver abscess/portal pyaemia Venous thrombosis Large-joint arthritis Erythema nodosum Pyoderma gangrenosum Fig. 21.53 Sigmoidoscopic view of moderately active ulcerative colitis. Mucosa is erythematous and friable with contact bleeding. Submucosal blood vessels are no longer visible. with pseudopolyps or a complicating carcinoma. Biopsies should be taken from each anatomical segment (terminal ileum, right colon, transverse colon, left colon and rectum) to confirm the diagnosis and define disease extent, and also to seek dysplasia in patients with long-standing colitis guided by pancolonic chromoendoscopy. In Crohn’s disease, wireless capsule endoscopy is useful in the identification of small bowel inflammation but should be avoided in the presence of strictures. Enteroscopy may be required to make a histological diagnosis of small bowel Crohn’s disease, when the inflamed segment is out of reach of standard endoscopes. All children and most adults with Crohn’s disease should have upper gastrointestinal endoscopy and biopsy to complete their staging. Not only is upper gastrointestinal Crohn’s disease relatively common in this group, but also it may help to make a definitive diagnosis in patients who otherwise appear to have non-specific colonic inflammation. Radiology Barium enema is a less sensitive investigation than colonoscopy in patients with colitis and, where colonoscopy is incomplete, a CT colonogram is preferred. Small bowel imaging is essential to complete staging of Crohn’s disease. Traditional contrast imaging by barium follow-through demonstrates affected areas of the bowel as narrowed and ulcerated, often with multiple strictures (see Fig. 21.50). This has largely been replaced now by MRI enterography, which does not involve exposure to radiation and is a sensitive way of detecting extra-intestinal manifestations and of assessing pelvic and perineal involvement. These studies use an orally administered small bowel-distending agent and intravenous contrast to provide transmural imaging that can usefully distinguish between predominantly inflammatory strictures (that should respond to anti-inflammatory medical strategies)

820 • GASTROENTEROLOGY • by laboratory testing: haemoglobin, white cell count, albumin, electrolytes, ESR and CRP, stool culture • radiologically: for colonic dilatation on plain abdominal X-rays. All patients should be given supportive treatment with intravenous fluids to correct dehydration and enteral nutritional support should be provided for malnourished patients (Box 21.57). Intravenous glucocorticoids (methylprednisolone 60 mg or hydrocortisone 400 mg/day) should be given by intravenous infusion or bolus injection. Topical and oral aminosalicylates have no role to play in the acute severe attack. Response to therapy is judged over the first 3 days. Patients who do not respond promptly to glucocorticoids should be considered for medical rescue therapy with ciclosporin (intravenous infusion or oral) or infliximab (5 mg/kg), which can avoid the need for urgent colectomy in approximately 60% of cases. Patients who develop colonic dilatation (> 6 cm), those whose clinical and laboratory measurements deteriorate and those who do not respond after 7–10 days’ maximal medical treatment usually require urgent colectomy. Subtotal colectomy can also be performed laparoscopically, given sufficient local expertise. The surgical and medical teams should liaise early in the disease course and, if possible, the patient should have the opportunity to speak with the stoma nurse prior to colectomy. Maintenance of remission Life-long maintenance therapy is recommended for all patients with left-sided or extensive disease but is not necessary in those with proctitis (although 20% of these patients will develop proximal ‘extension’ over the lifetime of their disease). Once-daily oral 5-aminosalicylates are the preferred first-line agents. Sulfasalazine has a higher incidence of side-effects but is equally effective and can be considered in patients with coexistent arthropathy. Patients who frequently relapse despite aminosalicylate drugs should be treated with thiopurines (azathioprine or 6-mercaptopurine). Biologic therapy with anti-TNF antibodies (infliximab or adalimumab) or anti-α4β7 integrin antibodies (vedolizumab) can also be considered for maintenance treatment in patients with moderate to severe ulcerative colitis who are intolerant of or non-responsive to thiopurine immunosuppression. Crohn’s disease Principles of treatment Crohn’s disease is a progressive condition that may result in stricture or fistula formation if suboptimally treated. It is therefore important to agree long-term treatment goals with the patient; these are to induce remission and then maintain glucocorticoid-free remission with a normal quality of life. Treatment should focus on monitoring the patient carefully for evidence of disease activity and complications (Box 21.58), and ensuring that mucosal healing is achieved. Induction of remission Glucocorticoids remain the mainstay of treatment for active Crohn’s disease. The drug of first choice in patents with ileal disease is budesonide, since it undergoes 90% first-pass metabolism in the liver and has very little systemic toxicity. A typical regimen is 9 mg once daily for 6 weeks, with a gradual reduction in dose over the subsequent 2 weeks when therapy is stopped. If there is no response to budesonide within 2 weeks, the patient should be switched to prednisolone, which has greater potency. This is typically given in a dose of 40 mg daily, reducing by 5 mg/week over 8 weeks, at which point treatment is stopped. Oral prednisolone in the dose regimen described above is the treatment of choice for inducing remission and fibrotic strictures (that require a mechanical solution, such as surgical resection, stricturoplasty or endoscopic balloon dilatation). A plain abdominal X-ray is essential in the management of patients who present with severe active disease. Dilatation of the colon (see Fig. 21.51), mucosal oedema (thumb-printing) or evidence of perforation may be found. Patients with proctitis may have features of proximal faecal loading. In small bowel Crohn’s disease, there may be evidence of intestinal obstruction or displacement of bowel loops by a mass. Ultrasound is a very powerful tool to detect small bowel inflammation and stricture formation but it is operator-dependent. The role of CT is limited to screening for complications, such as perforation or abscess formation, in the acutely unwell. Management Drugs that are used in the treatment of IBD are listed in Box 21.56. Although medical therapy plays an important role, optimal management depends on establishing a multidisciplinary teambased approach involving physicians, surgeons, radiologists, nurse specialists and dietitians. Both ulcerative colitis and Crohn’s disease are life-long conditions and have important psychosocial implications; specialist nurses, counsellors and patient support groups have key roles in education, reassurance and coping. The key aims of medical therapy are to: • treat acute attacks (induce remission) • prevent relapses (maintain remission) • prevent bowel damage • detect dysplasia and prevent carcinoma • select appropriate patients for surgery. Ulcerative colitis Active proctitis Most patients with ulcerative proctitis respond to a 1 g mesalazine suppository but some will additionally require oral 5-aminosalicylate (5-ASA) therapy. Topical glucocorticoids are less effective and are reserved for patients who are intolerant of topical mesalazine. Patients with resistant disease may require treatment with systemic glucocorticoids and immunosuppressants. A stool softener may be required to treat proximal constipation. Active left-sided or extensive ulcerative colitis In mild to moderately active cases, the combination of a once-daily oral and a topical 5-ASA preparation (‘top and tail approach’) is usually effective. The topical preparation (1 g foam or liquid enema) is typically withdrawn after 1 month. The oral 5-ASA is continued long-term to prevent relapse and minimise the risk of dysplasia. In patients who do not respond to this approach within 2–4 weeks, oral prednisolone (40 mg daily, tapered by 5 mg/week over an 8-week total course) is indicated. Glucocorticoids should never be used for maintenance therapy. At the first signs of glucocorticoid resistance (lack of efficacy) or in patients who require recurrent glucocorticoid doses to maintain control, immunosuppressive therapy with a thiopurine should be introduced. Simultaneous calcium and vitamin D supplementation should be given along with glucocorticoids for bone protection. Severe ulcerative colitis Patients who fail to respond to maximal oral therapy and those who present with acute severe colitis (meeting the Truelove–Witts criteria; see Box 21.53) are best managed in hospital and should be monitored jointly by a physician and surgeon: • clinically: for the presence of abdominal pain, temperature, pulse rate, stool blood and frequency

Inflammatory bowel disease • 821

21.56 Drugs used in the treatment of inflammatory bowel disease Class Mechanism of action Notes Aminosalicylates (mesalazine (Asacol, Salofalk, Pentasa, Mezavant), olsalazine, sulfasalazine, balsalazide) Modulate cytokine release from mucosa Different means of delivery to colon: pH-dependent (Asacol, Salofalk) time-dependent (Pentasa) bacterial breakdown by colonic bacteria from a carrier molecule (sulfasalazine, balsalazide) No proven value in CD Available as oral or topical (enema/suppository) Sulfasalazine causes side-effects in 10–45%: headache, nausea, diarrhoea, blood dyscrasias Other aminosalicylates better tolerated; diarrhoea, headache in 2–5% Rarely, renal impairment (check urea and electrolytes 6-monthly) Glucocorticoids (prednisolone, hydrocortisone, budesonide) Anti-inflammatory Budesonide is a potent glucocorticoid efficiently cleared from circulation by liver, thereby minimising adrenocortical suppression and steroid side-effects Topical, oral or IV, according to disease severity Budesonide considered for active ileitis and ileocolitis High vigilance for complications Never used for maintenance therapy Calcium/vitamin D supplements Thiopurines (azathioprine, mercaptopurine) Immunomodulation by inducing T-cell apoptosis Azathioprine is metabolised in liver to mercaptopurine, then by TPMT to thioguanine nucleotides Effective 12 weeks after starting therapy Complications leading to drug withdrawal in approximately 20%: influenza-like syndrome with myalgia, nausea and vomiting; leucopenia in 3%, particularly in inherited TPMT deficiency; hepatotoxicity; pancreatitis 60% of those intolerant of azathioprine will tolerate mercaptopurine Increase in lymphoma (approximately 2–3-fold) and non-melanoma skin cancer (life-long sun protection advised) Check TPMT levels prior to starting treatment and avoid if deficient/ very low due to risk of toxicity Metabolite levels can be measured to tailor therapy Use with caution for patients presenting over the age of 60 years due to risk of malignancy Methotrexate Anti-inflammatory Intolerance in 10–18% Maximal efficacy when given by SC injection once weekly Nausea, stomatitis, diarrhoea, hepatotoxicity and pneumonitis Co-prescription of folic acid and antiemetics. Teratogenic; robust contraception required for males and females Ciclosporin Inhibits T-cell activation Rescue therapy to prevent surgery in UC responding poorly to glucocorticoids. No value in CD Major side-effects in 0–17%: nephrotoxicity, infections, neurotoxicity (including fits) Minor complications in up to 50%: tremor, paraesthesiae, abnormal liver function tests, hirsutism Anti-TNF antibodies (infliximab and adalimumab) Suppress inflammation and induce apoptosis of inflammatory cells Moderate to severe CD, including fistulating disease Moderate to severe UC and acute severe UC as rescue therapy Acute (anaphylactic) and delayed (serum sickness) infusion reactions after multiple infusions; anti-drug antibody titres and drug levels can be measured Contraindicated in infection; reactivation of latent tuberculosis and moderate to severe cardiac failure Increased risk of infections and possibly of malignancy Rarely, neurological adverse events Requires assessment for latent tuberculosis and hepatitis B and C prior to commencement Continue until treatment failure or 12 months and reassess Anti-α4β7 integrin (vedolizumab) Blocks integrin expressed on leukocytes and inhibits interaction with gut-specific receptor on endothelium, reducing leukocyte migration to gut mucosa Moderate to severe CD or moderate to severe UC where treatment with anti-TNF has failed or is not tolerated Side-effects include nasopharyngitis, arthralgia, headache Progressive multifocal leukoencephalopathy risk is reduced due to gut specificity Induction with 300 mg infusion at weeks 0, 2 and 6; maintenance 8-weekly infusions thereafter Discontinue if no improvement after 14 weeks Continue until treatment failure or 12 months and reassess Antibiotics Antibacterial Useful in perianal CD and pouchitis Major concern is peripheral neuropathy with long-term metronidazole Antidiarrhoeal agents (loperamide, co-phenoxylate) Reduce gut motility and small bowel secretion Loperamide improves anal function Avoided in acute flare-ups of disease May precipitate colonic dilatation (CD = Crohn’s disease; IV = intravenous; SC = subcutaneous; TNF = tumour necrosis factor; TPMT = thiopurine methyltransferase; UC = ulcerative colitis)

822 • GASTROENTEROLOGY of remission, a substantial proportion of patients (20–30%) remain well without the requirement for maintenance therapy. Patients with evidence of persistently active disease require further treatment (see below). Maintenance therapy Immunosuppressive treatment with thiopurines (azathioprine and mercaptopurine) forms the core of maintenance therapy but methotrexate is also effective and can be given once weekly, either orally or by subcutaneous injection. Women and men of child-bearing potential who are prescribed methotrexate must use a robust contraceptive method, and should be counselled to plan pregnancy with a 3-month methotrexate-free period prior to conception since it is teratogenic. Combination therapy with an immunosuppressant and an anti-TNF antibody is the most effective strategy but costs are high and there is an increased risk of serious adverse effects. In the UK, the use of anti-TNF therapy is limited to specific patient subgroups with severe disease (Box 21.59). Vedolizumab is a possible option in patients who have not responded to anti-TNF therapy. It is a humanised monoclonal antibody against anti-α4β7 integrin. The α4β7 is expressed on a specific subset of CD4+ leucocytes; vedolizumab binds to this integrin and blocks interaction with MAdCAM-1, expressed on gut endothelial cells, resulting in a reduced influx of immune cells to the inflamed gut mucosa. Serious systemic adverse effects, including progressive multifocal leukoencephalopathy, have been seen with other anti-integrin drugs (such as natalizumab) but this has not emerged with vedolizumab due to its gut specificity. Emerging novel medical therapies for Crohn’s disease are currently in phase III clinical trials and are likely to be available for clinical use in the near future. These include ustekinumab (anti-p40, inhibiting both IL-12 and IL-23) and tofacitinib (a Janus kinase inhibitor that blocks pro-inflammatory cytokine signalling). Cigarette smokers with Crohn’s disease should be strongly counselled to stop smoking at every possible opportunity. Those that do not manage to stop smoking fare much worse, with increased rates of relapse and surgical intervention. Careful monitoring of disease activity (see Box 21.58) is the key to maintaining sustained remission and preventing the accumulation of bowel damage in Crohn’s disease. in colonic Crohn’s disease. Calcium and vitamin D supplements should be co-prescribed in patients who are on glucocorticoids, to try to compensate for their inhibitory effect on intestinal calcium absorption. As an alternative to glucocorticoid therapy, enteral nutrition with either an elemental (constituent amino acids) or polymeric (liquid protein) diet may induce remission. Both types of diet are equally effective but the polymeric one is more palatable when taken by mouth. It is particularly effective in children, in whom equal efficacy to glucocorticoids has been demonstrated, and in extensive ileal disease in adults. As well as resting the gut and providing excellent nutritional support, it also has a direct anti-inflammatory effect. It is an effective bridge to urgent staging investigations at first presentation and can be given by mouth or by nasogastric tube. With sufficient explanation, encouragement and motivation, most patients will tolerate it well. Some individuals with severe colonic disease require admission to hospital for intravenous glucocorticoids. In severe ileal or panenteric disease, induction therapy with an anti-TNF agent is appropriate, provided that acute perforating complications, such as abscess, have not arisen. Both infliximab and adalimumab are licensed for use in the UK. Randomised trials have demonstrated that combination therapy with an anti-TNF antibody and a thiopurine is the most effective strategy for inducing and maintaining remission in luminal Crohn’s patients. This strategy is more effective than anti-TNF monotherapy, which, in turn, is more effective than thiopurine monotherapy. Following induction 21.58 Monitoring of inflammatory bowel disease (IBD) • Assess symptoms, including extra-intestinal manifestations • Examine for abdominal mass or perianal disease • Perform full blood count, urea and electrolytes, liver function tests, albumin, C-reactive protein (CRP) • Check haematinics (vitamin B12, folate, iron studies) at least annually • Check faecal calprotectin (to monitor each disease flare/change in therapy and assess response) • Perform stool cultures (at each flare to exclude infection) • Assess mucosal healing: surrogate markers (CRP/calprotectin), ileocolonoscopy and/or small bowel magnetic resonance imaging • Enrol patient in a dedicated IBD clinic (monitoring of stable, uncomplicated patients may be carried out by a nurse or phone clinic) • Arrange IBD multidisciplinary meeting for acutely ill or complex patients • Check vaccinations are up to date; ensure surveillance colonoscopy is scheduled where appropriate 21.57 Medical management of fulminant ulcerative colitis • Admit to hospital for intensive therapy and monitoring • Give IV fluids and correct electrolyte imbalance • Consider transfusion if haemoglobin is < 100 g/L (< 10 g/dL) • Give IV methylprednisolone (60 mg daily) or hydrocortisone (400 mg daily) • Give antibiotics until enteric infection is excluded • Arrange nutritional support • Give subcutaneous low-molecular-weight heparin for prophylaxis of venous thromboembolism • Avoid opiates and antidiarrhoeal agents • Consider infliximab (5 mg/kg) or ciclosporin (2 mg/kg) in stable patients not responding to 3–5 days of glucocorticoids 21.59 How to give anti-tumour necrosis factor (TNF) therapy in inflammatory bowel disease • Infliximab (5 mg/kg IV infusion) is given as three loading doses (at 0, 2 and 6 weeks), with 8-weekly maintenance thereafter • Adalimumab is given as SC injections, which patients can be trained to give themselves. Loading dose is 160 mg, followed by 80 mg 2 weeks later and 40 mg every second week thereafter; some patients require dose escalation to 40 mg once weekly • Concomitant immunosuppression with a thiopurine or methotrexate may be more efficacious than monotherapy but has more side-effects • Anti-TNF therapy is contraindicated in the presence of active infection and latent tuberculosis without appropriate prophylaxis; it carries an increased risk of opportunistic infections and a possible increased risk of malignancy; rarely, multiple sclerosis may be unmasked in susceptible individuals. Counselling about the balance of risk and benefit for each patient is important • Prior to therapy, latent tuberculosis must be excluded • Live vaccines should not be given • Certolizumab is effective for luminal Crohn’s disease but is not licensed in Europe • Etanercept is not effective in Crohn’s disease

Inflammatory bowel disease • 823

Surgery should be as conservative as possible in order to minimise the loss of viable intestine and to avoid the creation of a short bowel syndrome (p. 708). Obstructing or fistulating small bowel disease may require resection of affected tissue. Patients who have localised segments of Crohn’s colitis may be managed by segmental resection and/or multiple stricturoplasties, in which the stricture is not resected but instead incised in its longitudinal axis and sutured transversely. Others who have extensive colitis require total colectomy but ileal–anal pouch formation should be avoided because of the high risk of recurrence within the pouch and subsequent fistulae, abscess formation and pouch failure. Historical datasets show that around 80% of Crohn’s patients undergo surgery at some stage and 70% of these require more than one operation during their lifetime. Clinical recurrence following resectional surgery is present in 50% of all cases at 10 years. Emerging data demonstrate that aggressive medical therapy, coupled with intense monitoring, probably reduces the requirement for surgery substantially. IBD in special circumstances Childhood Chronic ill health in childhood or adolescent IBD may result in growth failure, metabolic bone disease and delayed puberty. Loss of schooling and social contact, as well as frequent hospitalisation, can have important psychosocial consequences. Treatment is similar to that described for adults and may require glucocorticoids, immunosuppressive drugs, biological agents and surgery. Monitoring of height, weight and sexual development is crucial. Children with IBD should be managed by specialised paediatric gastroenterologists and transitioned to adult care in dedicated clinics (Box 21.61). Pregnancy A women’s ability to become pregnant is adversely affected by active IBD. Pre-conceptual counselling should focus on optimising disease control. During pregnancy, the rule of thirds applies: roughly one-third of women improve, one-third get worse and one-third remain stable with active disease. In the post-partum period, these changes sometimes reverse spontaneously. Drug therapy, including aminosalicylates, glucocorticoids and Fistulae and perianal disease Fistulae may develop in relation to active Crohn’s disease and are often associated with sepsis. The first step is to define the site by imaging (usually MRI of the pelvis). Surgical exploration by an examination under anaesthetic is usually then required, to delineate the anatomy and drain abscesses. Seton sutures can be inserted through fistula tracts to ensure adequate drainage and to prevent future sepsis. Glucocorticoids are ineffective. Use of antibiotics, such as metronidazole and/ or ciprofloxacin, can aid healing as an adjunctive treatment. Thiopurines can be used in chronic disease but do not usually result in fistula healing. Infliximab and adalimumab can heal fistulae and perianal disease in many patients and are indicated when the measures described above have been ineffective. Other options for refractory perianal disease are proctectomy or diverting colostomy. Surgical treatment Ulcerative colitis Up to 60% of patients with extensive ulcerative colitis eventually require surgery. The indications are listed in Box 21.60. Impaired quality of life, with its impact on occupation and social and family life, is the most important of these. Surgery involves removal of the entire colon and rectum, and cures the patient. One-third of those with pancolitis undergo colectomy within 5 years of diagnosis. Before surgery, patients must be counselled by doctors, stoma nurses and patients who have undergone similar surgery. The choice of procedure is either panproctocolectomy with ileostomy, or proctocolectomy with ileal–anal pouch anastomosis. The sister text to this book, Principles and Practice of Surgery, should be consulted for further details. Crohn’s disease The indications for surgery are similar to those for ulcerative colitis. Operations are often necessary to deal with fistulae, abscesses and perianal disease, and may also be required to relieve small or large bowel obstruction. In contrast to ulcerative colitis, surgery is not curative and disease recurrence is the rule. The only method that has consistently been shown to reduce post-operative recurrence is smoking cessation. Antibiotics are effective in the short term only. Use of thiopurines post-surgery is suggested if there are indicators of a high chance of recurrence, i.e. more than one resection or evidence of penetrating disease, such as fistulae or abscess. Otherwise, it is common to undertake colonoscopy 6 months after surgery to inspect and biopsy the anastomosis and neo-terminal ileum. Patients with endoscopic recurrence are then prescribed thiopurines. 21.60 Indications for surgery in ulcerative colitis Impaired quality of life • Loss of occupation or education • Disruption of family life Failure of medical therapy • Dependence on oral glucocorticoids • Complications of drug therapy Fulminant colitis Disease complications unresponsive to medical therapy • Arthritis • Pyoderma gangrenosum Colon cancer or severe dysplasia 21.61 Inflammatory bowel disease in adolescence • Delayed growth and pubertal development: chronic active inflammation, malabsorption, malnutrition and long-term glucocorticoids contribute to short stature and delayed development, with physical and psychological consequences. • Metabolic bone disease: more common with chronic disease beginning in childhood, resulting from chronic inflammation, dietary deficiency and malabsorption of calcium and vitamin D. • Drug side-effects and adherence issues: young people are more likely to require azathioprine or biological therapy than adults. Poor adherence to therapy is more common than with adults, as younger patients may feel well, lack self-motivation to adhere and believe that drugs are ineffective or cause side-effects. • Loss of time from education: physical illness, surgery, fatigue in chronic inflammatory bowel disease, privacy and dignity issues, and social isolation may all contribute. • Emotional difficulties: may result from challenges in coping with illness, problems with forming interpersonal relationships, and issues relating to body image or sexual function.

824 • GASTROENTEROLOGY appearances are normal but histological examination of biopsies shows a range of abnormalities. It is therefore recommended that biopsies of the right and left colon plus the terminal ileum should be undertaken in all patients undergoing colonoscopy for diarrhoea. Collagenous colitis is characterised by the presence of a submucosal band of collagen, often with a chronic inflammatory infiltrate. The disease is more common in women and may be associated with rheumatoid arthritis, diabetes, coeliac disease and some drug therapies, such as NSAIDs or PPIs. Treatment with budesonide or 5-aminosalicylates is usually effective but the condition will recur in some patients on discontinuation of therapy. Irritable bowel syndrome Irritable bowel syndrome (IBS) is characterised by recurrent abdominal pain in association with abnormal defecation in the absence of a structural abnormality of the gut. About 10–15% of the population are affected at some time but only 10% of these consult their doctors because of symptoms. Nevertheless, IBS is the most common cause of gastrointestinal referral and accounts for frequent absenteeism from work and impaired quality of life. Young women are affected 2–3 times more often than men. Coexisting conditions, such as non-ulcer dyspepsia, chronic fatigue syndrome, dysmenorrhoea and fibromyalgia, are common. IBS is sometimes associated with a history of physical or sexual abuse and this is an important aspect of the history as these patients benefit from psychologically based therapy. Pathophysiology The cause of IBS is incompletely understood but biopsychosocial factors are thought to play an important role, along with luminal factors, such as diet and the gut microbiota, as discussed below. Behavioural and psychosocial factors Most patients seen in general practice do not have psychological problems but about 50% of patients referred to hospital have a psychiatric illness, such as anxiety, depression, somatisation and neurosis. Panic attacks are also common. Acute psychological stress and overt psychiatric disease are known to alter visceral perception and gastrointestinal motility. There is an increased prevalence of abnormal illness behaviour, with frequent consultations for minor symptoms and reduced coping ability (p. 1202). These factors contribute to but do not cause IBS. Physiological factors There is some evidence that IBS may be a serotoninergic (5-HT) disorder, as evidenced by relatively excessive release of 5-HT in diarrhoea-predominant IBS (D-IBS) and relative deficiency with constipation-predominant IBS (C-IBS). Accordingly, 5-HT3 receptor antagonists are effective in D-IBS, while 5-HT4 agonists improve bowel function in C-IBS. There is some evidence that IBS may represent a state of low-grade gut inflammation or immune activation, not detectable by tests, with raised numbers of mucosal mast cells that sensitise enteric neurons by releasing histamine and tryptase. Some patients respond positively to mast cell stabilisers, such as ketotifen, which supports a pathogenic role of mast cells in at least some patients. Immune activation may be associated with altered CNS processing of visceral pain signals. This is more common in women and in D-IBS, and may be triggered by a prior episode of gastroenteritis with Salmonella or Campylobacter species. azathioprine, can be safely continued throughout pregnancy but methotrexate must be avoided, both during pregnancy and if the patient is trying to conceive (Box 21.62). Anti-TNF agents are transmitted through the placenta (but not breast milk) and are omitted during the last trimester. Metabolic bone disease Patients with IBD are prone to developing osteoporosis due to the effects of chronic inflammation, glucocorticoids, weight loss, malnutrition and malabsorption. Osteomalacia can also occur in Crohn’s disease that is complicated by malabsorption, but is less common than osteoporosis. The risk of osteoporosis increases with age and with the dose and duration of glucocorticoid therapy. Refractory Crohn’s disease Crohn’s disease can be progressive despite maximal medical therapy and extensive surgery. There are several other immunomodulatory drugs in the clinical trial pipeline (see above). Microscopic colitis Microscopic colitis, which comprises two related conditions called lymphocytic colitis and collagenous colitis, has no known cause. The presentation is with watery diarrhoea. The colonoscopic 21.62 Pregnancy and inflammatory bowel disease (IBD) Pre-conception • Outcomes are best when pregnancy is carefully planned and disease is in remission • Methotrexate must be stopped 3 months prior to conception; other IBD drugs should be continued until discussed with a specialist • Aminosalicylates and azathioprine are safe in pregnancy • Glucocorticoids are probably safe • Anti-tumour necrosis factor biological therapy in pregnancy can continue if established pre-pregnancy but should be withheld in the third trimester due to placental transfer of antibody • No data are available for the use of vedolizumab in pregnancy • Daily high-dose (> 2 mg) folic acid supplements are recommended Pregnancy • Two-thirds of patients in remission will remain so in pregnancy • Active disease is likely to remain active • Severe active disease carries an increased risk of premature delivery and low birth weight • Gentle flexible sigmoidoscopy is safe after the first trimester • X-rays can be performed if clinically indicated but discuss with the radiologist first • Colonoscopy can be performed safely if the potential benefits outweigh the risks Labour • This needs careful discussion between patient, gastroenterologist and obstetrician • Normal labour and vaginal delivery are possible for most • Caesarean section may be preferred for patients with perianal Crohn’s or an ileo-anal pouch to reduce risks of pelvic floor damage, fistulation and late incontinence Breastfeeding • This is safe and does not exacerbate IBD • Data on the risk to babies from drugs excreted in breast milk are limited; most of these drugs are probably safe • Patients should discuss breastfeeding and drug therapy with their doctor

Irritable bowel syndrome • 825

or without sigmoidoscopy, are usually done and are normal in IBS. Colonoscopy should be undertaken in older patients (over 40 years of age) to exclude colorectal cancer. Endoscopic examination is also required in patients who report rectal bleeding to exclude colon cancer and IBD. Those who present atypically require investigations to exclude other gastrointestinal diseases. Diarrhoea-predominant patients justify investigations to exclude coeliac disease (p. 805), microscopic colitis (p. 824), lactose intolerance (p. 812), bile acid diarrhoea (p. 809), thyrotoxicosis (p. 635) and, in developing countries, parasitic infection. Management The most important steps are to make a positive diagnosis and reassure the patient. Many people are concerned that they have developed cancer. A cycle of anxiety leading to colonic symptoms, which further heighten anxiety, can be broken by explaining that symptoms are not due to a serious underlying disease but instead are the result of behavioural, psychosocial, physiological and luminal factors. In individuals who fail to respond to reassurance, treatment is traditionally tailored to the predominant symptoms (Fig. 21.54). Dietary management is effective for many patients (Box 21.65). Up to 20% may benefit from a wheat-free diet, some may respond to lactose exclusion, and excess intake of caffeine or artificial sweeteners, such as sorbitol, should be addressed. A more restrictive, ‘low-FODMAP’ diet, supervised by a dietitian, with gradual re-introduction of different food groups, may help some patients, as may a trial of a gluten-free diet. Probiotics, in capsule form, can be effective if taken for several months, although the optimum combination of bacterial strains and dose have yet to be clarified. Patients with intractable symptoms sometimes benefit from several months of therapy with a tricyclic antidepressant, such as amitriptyline or imipramine (10–25 mg orally at night). Side-effects include dry mouth and drowsiness but these are usually mild and the drug is generally well tolerated, although patients with features of somatisation tolerate the drug poorly and lower doses should be used. It may act by reducing visceral sensation and by altering gastrointestinal motility. Anxiety and affective disorders may also require specific treatment (pp. 1200 and 1198). The 5-HT4 agonist prucalopride, the guanylate cyclase-C receptor agonist linaclotide, and chloride channel activators, such as lubiprostone, can be effective in constipation- predominant IBS. Trials of anti-inflammatory agents, such as ketotifen or mesalazine, and the antibiotic rifaximin may be considered in 21.63 Rome III criteria for diagnosis of irritable bowel syndrome Recurrent abdominal pain or discomfort on at least 3 days per month in the last 3 months, associated with two or more of the following: • Improvement with defecation • Onset associated with a change in frequency of stool • Onset associated with a change in form (appearance) of stool Luminal factors Both quantitative and qualitative alterations in intestinal bacterial microbiota have been reported. Small intestinal bacterial overgrowth (SIBO) may be present in some patients and lead to symptoms. This ‘gut dysbiosis’ may explain the response to probiotics or the non-absorbable antibiotic rifaximin. Dietary factors are also important. Some patients have chemical food intolerances (not allergy) to poorly absorbed, short-chain carbohydrates (lactose, fructose and sorbitol, among others), collectively known as FODMAPs (fermentable oligo-, di- and monosaccharides, and polyols). Their fermentation in the colon leads to bloating, pain, wind and altered bowel habit. Non-coeliac gluten sensitivity (negative coeliac serology and normal duodenal biopsies) seems to be present in some IBS patients, while others may be intolerant of chemicals such as salicylates or benzoates, found in certain foods. Clinical features The most common presentation is that of recurrent abdominal discomfort (Box 21.63). This is usually colicky or cramping in nature, felt in the lower abdomen and relieved by defecation. Abdominal bloating worsens throughout the day; the cause is unknown but it is not due to excessive intestinal gas. The bowel habit is variable. Most patients alternate between episodes of diarrhoea and constipation but it is useful to classify them as having predominantly constipation or predominantly diarrhoea. Those with constipation tend to pass infrequent pellety stools, usually in association with abdominal pain or proctalgia. Those with diarrhoea have frequent defecation but produce low-volume stools and rarely have nocturnal symptoms. Passage of mucus is common but rectal bleeding does not occur. Patients do not lose weight and are constitutionally well. Physical examination is generally unremarkable, with the exception of variable tenderness to palpation. Investigations The diagnosis is clinical in nature and can be made confidently in most patients using the Rome criteria combined with the absence of alarm symptoms, without resorting to complicated tests (Box 21.64). Full blood count and faecal calprotectin, with 21.64 Supporting diagnostic features and alarm features in irritable bowel syndrome Features supporting a diagnosis of IBS • Presence of symptoms for more than 6 months • Frequent consultations for non-gastrointestinal problems • Previous medically unexplained symptoms • Worsening of symptoms by stress Alarm features • Age > 50 years; male gender • Weight loss • Nocturnal symptoms • Family history of colon cancer • Anaemia • Rectal bleeding 21.65 Dietary management of irritable bowel syndrome • Eat regularly and avoid missing meals • Take time to eat • Ensure adequate hydration and avoid carbonated and caffeinated drinks • Reduce alcohol intake • Reduce intake of ‘resistant’ starch and insoluble fibre • Avoid foods with artificial sweeteners • Consider a wheat-free diet • Consider a lactose exclusion diet • Consider a diet low in FODMAPs (FODMAPs = fermentable oligo-, di- and monosaccharides, and polyols)

826 • GASTROENTEROLOGY some patients with difficult symptoms but are best prescribed only after specialist referral. Psychological interventions, such as cognitive behavioural therapy, relaxation and gut-directed hypnotherapy, should be reserved for the most difficult cases. A range of complementary and alternative therapies exist; most lack a good evidence base but are popular and help some patients (Box 21.66). Most patients have a relapsing and remitting course. Exacerbations often follow stressful life events, occupational dissatisfaction and difficulties with interpersonal relationships. HIV/AIDS and the gastrointestinal tract Patients with HIV/AIDS may develop several symptoms referable to the gastrointestinal tract, as discussed in detail on page 316. HIV testing should be considered in all patients with atypical or unexplained gastrointestinal symptoms and in those resident in areas of high prevalence. Fig. 21.54 Management of irritable bowel syndrome. (FODMAP = fermentable oligo-, di- and monosaccharides, and polyols) • Duloxetine 30–60 mg at night • Relaxation therapy • Biofeedback • Hypnotherapy Symptoms persist Spasmolytic drugs • Mebeverine • Peppermint oil • Hyoscine • Probiotics • Rifaximin 600 mg daily for 2 weeks • Amitriptyline or imipramine 10–25 mg at night • Amitriptyline or imipramine 10–25 mg at night • Rifaximin 600 mg daily for 2 weeks Dietary changes • Low-FODMAP diet • Exclude wheat • Exclude dairy • Gluten-free diet Irritable bowel syndrome confirmed Reassurance Symptoms resolve Symptoms persist Constipation predominant Diarrhoea predominant Pain and bloating Avoid legumes and excessive dietary fibre. Consider trials of low-FODMAP or gluten-free diet Antidiarrhoeal drugs • Loperamide 2–8 mg daily • Codeine phosphate 30–90 mg daily • Colestyramine 1 sachet daily Symptoms persist Symptoms persist Symptoms persist Symptoms persist High-roughage diet Symptoms persist Ispaghula or psyllium Lactulose and/or macrogol Prucalopride or linaclotide 21.66 Complementary and alternative therapies for irritable bowel syndrome Manipulative and body-based • Massage, chiropractic Mind–body interventions • Meditation, hypnosis*, cognitive therapy Biologically based • Herbal products*, dietary additives, probiotics* Energy healing • Biofield therapies (reiki), bio-electromagnetic field therapies Alternative medical systems • Ayurveda, homeopathy, traditional Chinese medicine *Some evidence for benefit exists. From Hussain Z, Quigley EMM. Systematic review: complementary and alternative medicine in the irritable bowel syndrome. Aliment Pharmacol Ther 2006; 23:465–471.

Disorders of the colon and rectum • 827

is established by colonoscopy within 48 hours of presentation; otherwise, mucosal ulceration may have resolved. Resection is required for peritonitis. Chronic mesenteric ischaemia This results from atherosclerotic stenosis of the coeliac axis, superior mesenteric artery and inferior mesenteric artery. At least two of the three vessels must be affected for symptoms to develop. The typical presentation is with dull but severe mid- or upper abdominal pain developing about 30 minutes after eating. Weight loss is common because patients are reluctant to eat and some experience diarrhoea. Physical examination shows evidence of generalised arterial disease. An abdominal bruit is sometimes audible but is non-specific. The diagnosis is made by mesenteric angiography. Treatment is by vascular reconstruction or percutaneous angioplasty, if the patient’s clinical condition permits. The condition is frequently complicated by intestinal infarction, if left untreated. Disorders of the colon and rectum Tumours of the colon and rectum Polyps and polyposis syndromes Polyps may be neoplastic or non-neoplastic. The latter include hamartomas, metaplastic (‘hyperplastic’) polyps and inflammatory polyps. These have no malignant potential. Polyps may be single or multiple and vary from a few millimetres to several centimetres in size. Colorectal adenomas are extremely common in the Western world and the prevalence rises with age; 50% of people over 60 years of age have adenomas, and in half of these the polyps are multiple. They are more common in the rectum and distal colon and are either pedunculated or sessile. Histologically, they are classified as either tubular, villous or tubulovillous, according to the glandular architecture. Nearly all forms of colorectal carcinoma develop from adenomatous polyps, although not all polyps carry the same degree of risk. Features associated with a higher risk of subsequent malignancy are listed in Box 21.67. Adenomas are usually asymptomatic and discovered incidentally. Occasionally, they cause bleeding and anaemia. Villous adenomas can secrete large amounts of mucus, causing diarrhoea and hypokalaemia. Discovery of a polyp at sigmoidoscopy is an indication for colonoscopy because proximal polyps are present in 40–50% of such patients. Colonoscopic polypectomy should be carried out wherever possible, as this considerably reduces subsequent colorectal cancer risk (Fig. 21.55). Very large or sessile polyps can sometimes be removed safely by endoscopic mucosal resection (EMR) but many require surgery. Once all polyps have been removed, surveillance colonoscopy should be undertaken at 3–5-year intervals, as new polyps develop in 50% of patients. Patients over 75 years of age do not require repeated colonoscopies, as their subsequent lifetime cancer risk is low. Ischaemic gut injury Ischaemic gut injury is usually the result of arterial occlusion. Severe hypotension and venous insufficiency are less frequent causes. The presentation is variable, depending on the different vessels involved and the acuteness of the event. Diagnosis is often difficult. Acute small bowel ischaemia An embolus from the heart or aorta to the superior mesenteric artery is responsible for 40–50% of cases, thrombosis of underlying atheromatous disease for approximately 25%, and non-occlusive ischaemia due to hypotension complicating myocardial infarction, heart failure, arrhythmias or sudden blood loss for approximately 25%. Vasculitis and venous occlusion are rare causes. The clinical spectrum ranges from transient alteration of bowel function to transmural haemorrhagic necrosis and gangrene. Patients usually have evidence of cardiac disease and arrhythmia. Almost all develop abdominal pain that is more impressive than the physical findings. In the early stages, the only physical signs may be a silent, distended abdomen or diminished bowel sounds, with peritonitis developing only later. Leucocytosis, metabolic acidosis, hyperphosphataemia and hyperamylasaemia are typical. Plain abdominal X-rays show ‘thumb-printing’ due to mucosal oedema. Mesenteric or CT angiography reveals an occluded or narrowed major artery with spasm of arterial arcades, although most patients undergo laparotomy on the basis of a clinical diagnosis without angiography. Resuscitation, management of cardiac disease and intravenous antibiotic therapy, followed by laparotomy, are key steps. If treatment is instituted early, embolectomy and vascular reconstruction may salvage some small bowel. In these rare cases, a ‘second look’ laparotomy should be undertaken 24 hours later and further necrotic bowel resected. In patients at high surgical risk, thrombolysis may sometimes be effective. The results of therapy depend on early intervention; patients treated late have a 75% mortality rate. Survivors often have nutritional failure from short bowel syndrome (p. 708) and require intensive nutritional support, including home parenteral nutrition and anticoagulation. Small bowel transplantation can be considered in selected patients. Patients with mesenteric venous thrombosis also require surgery if there are signs of peritonitis but are otherwise treated with anticoagulation. Investigations for underlying prothrombotic disorders should be performed (p. 978). Acute colonic ischaemia The splenic flexure and descending colon have little collateral circulation and lie in ‘watershed’ areas of arterial supply. The spectrum of injury ranges from reversible colopathy to transient colitis, colonic stricture, gangrene and fulminant pancolitis. Arterial thromboembolism is usually responsible but colonic ischaemia can also follow severe hypotension, colonic volvulus, strangulated hernia, systemic vasculitis or hypercoagulable states. Ischaemia of the descending and sigmoid colon is also a complication of abdominal aortic aneurysm surgery (where the inferior mesenteric artery is ligated). The patient is usually elderly and presents with sudden onset of cramping, left-sided, lower abdominal pain and rectal bleeding. Symptoms usually resolve spontaneously over 24–48 hours and healing occurs in 2 weeks. Some may develop a fibrous stricture or segment of colitis. A minority develop gangrene and peritonitis. The diagnosis 21.67 Risk factors for malignant change in colonic polyps • Large size (> 2 cm) • Multiple polyps • Villous architecture • High-grade dysplasia

828 • GASTROENTEROLOGY accounting for 1% of all colorectal cancers. It results from germline mutation of the tumour suppressor APC gene, followed by acquired mutation of the remaining allele (Ch. 3). The APC gene is large and over 1400 different mutations have been reported, but most are loss-of-function mutations resulting in a truncated APC protein. This protein normally binds to and sequesters β-catenin but is unable to do so when mutated, allowing β-catenin to translocate to the nucleus, where it up-regulates the expression of many genes. Around 20% of cases arise as new mutations and have no family history. Hundreds to thousands of adenomatous colonic polyps develop in 80% of patients by age 15 (Fig. 21.56), with symptoms such as rectal bleeding beginning a few years later. In those affected, cancer will develop within 10–15 years of the appearance of adenomas and 90% of patients will develop colorectal cancer by the age of 50 years. Despite surveillance, approximately 1 in 4 patients with FAP have cancer by the time they undergo colectomy. Between 10% and 20% of polyps show histological evidence of malignancy. When cancer cells are found within 2 mm of the resection margin of the polyp, when the polyp cancer is poorly differentiated or when lymphatic invasion is present, segmental colonic resection is recommended because residual tumour or lymphatic spread (in up to 10%) may be present. Malignant polyps without these features can be followed up by surveillance colonoscopy. Polyposis syndromes are classified by histopathology (Box 21.68). It is important to note that, while the hamartomatous polyps in Peutz–Jeghers syndrome and juvenile polyposis are not themselves neoplastic, these disorders are associated with an increased risk of malignancy of the breast, colon, ovary and thyroid. Familial adenomatous polyposis Familial adenomatous polyposis (FAP) is an uncommon autosomal dominant disorder affecting 1 in 13 000 of the population and Fig. 21.55 Large rectal adenomatous polyp. A Before colonoscopic polypectomy. B After polypectomy. A B 21.68 Gastrointestinal polyposis syndromes Neoplastic Non-neoplastic1 Familial adenomatous polyposis Peutz–Jeghers syndrome Juvenile polyposis Cronkhite–Canada syndrome Cowden’s disease Inheritance Autosomal dominant2 Autosomal dominant Autosomal dominant in one-third None Autosomal dominant Oesophageal polyps − − − + + Gastric polyps + + + +++ +++ Small bowel polyps ++ +++ ++ ++ ++ Colonic polyps +++ ++ ++ +++ + Other features Colorectal cancer, bleeding, extraintestinal features (see Box 21.69) Pigmentation, bleeding, intussusception, bowel and other cancers Colorectal cancer Hair loss, pigmentation, nail dystrophy, malabsorption Many congenital anomalies, oral and cutaneous hamartomas, thyroid and breast tumours − absent; + may occur; ++ common; +++ very common. 1The polyps themselves are not neoplastic but cancer risk is increased in several syndromes. 2Rare autosomal recessive variant MUTYH (see text).

Disorders of the colon and rectum • 829

age and patients who are found to have the mutation should be offered colectomy after school or college education has been completed. The operation of choice is total proctocolectomy with ileal pouch–anal anastomosis. Periodic upper gastrointestinal endoscopy every 1–3 years is recommended to detect and monitor duodenal and periampullary adenomas. If large, these may be amenable to endoscopic resection. Peutz–Jeghers syndrome Multiple hamartomatous polyps occur in the small intestine and colon, as well as melanin pigmentation of the lips, mouth and digits (Fig. 21.57). Most cases are asymptomatic, although chronic bleeding, anaemia or intussusception can occur. There is a significant risk of small bowel or colonic adenocarcinoma and of cancer of the pancreas, lung, testis, ovary, breast and endometrium. Peutz–Jeghers syndrome is an autosomal dominant disorder, most commonly resulting from truncating mutations in a serine–threonine kinase gene on chromosome 19p (STK11). Diagnosis requires two of the three following features: • small bowel polyposis • mucocutaneous pigmentation • a family history suggesting autosomal dominant inheritance. The diagnosis can be made by genetic testing but this may be inconclusive, since mutations in genes other than STK11 can cause the disorder. Affected people should undergo regular upper endoscopy, colonoscopy and small bowel and pancreatic imaging. Polyps greater than 1 cm in size should be removed. Testicular examination is essential for men, while women should undergo pelvic examination, cervical smears and regular mammography. Asymptomatic relatives of affected patients should also undergo screening. Juvenile polyposis In juvenile polyposis, tens to hundreds of mucus-filled hamartomatous polyps are found in the colorectum. One-third of cases are inherited in an autosomal dominant manner and up to one-fifth develop colorectal cancer before the age of 40. The criteria for diagnosis are: • ten or more colonic juvenile polyps • juvenile polyps elsewhere in the gut, or • any polyps in those with a family history. Germline mutations in the SMAD4 gene are often found, as are PTEN mutations. Colonoscopy with polypectomy should be performed every 1–3 years and colectomy considered for extensive involvement. A second gene involved in base excision repair (MutY homolog, MUTYH) has been identified and may give rise to colonic polyposis. MUTYH displays autosomal recessive inheritance and leads to tens to hundreds of polyps and proximal colon cancer. This variant is referred to as MUTYH-associated polyposis (MAP). Non-neoplastic cystic fundic gland polyps occur in the stomach but adenomatous polyps also arise uncommonly. Duodenal adenomas are found in over 90% and are most common around the ampulla of Vater. Malignant transformation to adenocarcinoma takes place in 10% and is the leading cause of death in those who have had prophylactic colectomy. Many extra-intestinal features are also seen in FAP (Box 21.69). Desmoid tumours occur in up to one-third of patients and usually arise in the mesentery or abdominal wall. Although benign, they may become very large, causing compression of adjacent organs, intestinal obstruction or vascular compromise, and are difficult to remove. They sometimes respond to hormonal therapy with tamoxifen, and the NSAID sulindac may bring about regression in some, by unknown mechanisms. Congenital hypertrophy of the retinal pigment epithelium (CHRPE) occurs in some cases and is seen as dark, round, pigmented retinal lesions. When present in an at-risk individual, these are 100% predictive of the presence of FAP. A variant, Turcot’s syndrome, is characterised by FAP with primary CNS tumours (astrocytoma or medulloblastoma). Early identification of affected individuals before symptoms develop is essential. The diagnosis can be excluded if sigmoidoscopy is normal. In newly diagnosed cases, genetic testing should be carried out to confirm the diagnosis and identify the causal mutation. Subsequently, all first-degree relatives should also undergo testing (p. 46). In families with known FAP, adolescents should undergo mutation testing at 13–14 years of Fig. 21.56 Familial adenomatous polyposis. There are hundreds of adenomatous polyps throughout the colon. Fig. 21.57 Peutz–Jeghers syndrome. Typical lip pigmentation. 21.69 Extra-intestinal features of familial adenomatous polyposis • Congenital hypertrophy of the retinal pigment epithelium (CHRPE, 70–80%) • Epidermoid cysts (extremities, face, scalp)* (50%) • Benign osteomas, especially skull and angle of mandible* (50–90%) • Dental abnormalities (15–25%)* • Desmoid tumours (10–15%) • Other malignancies (brain, thyroid, liver, 1–3%) *Gardner’s syndrome.

830 • GASTROENTEROLOGY around 85% of colorectal cancers. Figure 21.59 outlines some of the common genes affected by CIN. • Microsatellite instability. This involves germline mutations in one of six genes encoding enzymes involved in repairing errors that occur normally during DNA replication (DNA mismatch repair); these genes are designated hMSH2, hMSH6, hMLH1, hMLH3, hPMS1 and hPMS2. Replication errors accumulate and can be detected in ‘microsatellites’ of repetitive DNA sequences. They also occur in important regulatory genes, resulting in a genetically unstable phenotype and accumulation of multiple somatic mutations throughout the genome that eventually lead to cancer. Around 15% of sporadic cancers develop this way, as do most cases of hereditary non-polyposis colon cancer (HNPCC). • CpG island methylator phenotype (CIMP). This phenotype is found in approximately 20–30% of colorectal cancers and results in widespread gene hypermethylation. The result is functional loss of tumour suppressor genes. Colorectal cancer Although relatively rare in the developing world, colorectal cancer is the second most common malignancy and the second leading cause of cancer deaths in Western countries. In the UK, the incidence is 50–60 per 100 000, equating to 30 000 cases per year. The condition becomes increasingly common over the age of 50 years. Pathophysiology Both environmental and genetic factors are important in colorectal carcinogenesis (Fig. 21.58). Environmental factors account for the wide geographical variation in incidence and the decrease in risk seen in migrants who move from high- to low-risk countries. Dietary factors are most important and these are summarised in Box 21.70; other recognised risk factors are listed in Box 21.71. Colorectal cancer development results from the accumulation of multiple genetic mutations. There are also associated epigenetic influences, such as microRNA expression signature, and potential influences from non-coding genetic variation. Currently, there are three main pathways of genetic instability and each is associated with histological, clinical and prognostic parameters: • Chromosomal instability. Mutations or deletions of portions of chromosomes arise, with loss of heterozygosity (LOH) and inactivation of specific tumour suppressor genes. In LOH, one allele of a gene is deleted but gene inactivation occurs only when a subsequent unrelated mutation affects the other allele. Chromosomal instability (CIN) occurs in Fig. 21.58 Pathogenesis of colorectal cancer (CRC). (FAP = familial adenomatous polyposis; HNPCC = hereditary non-polyposis colon cancer; JPS = juvenile polyposis syndrome; MAP = MUTYH-associated polyposis; PJS = Peutz–Jeghers syndrome) Pathogenesis of CRC Dietary risk factors Accumulation of multiple somatic mutations Single gene mutations (large effects) Multiple susceptibility genes (small effects) Sporadic CRC (~70%) Inherited CRC (~5%) Genetic predisposition to CRC (~25%) HNPCC (Lynch syndrome I) Lynch syndrome II FAP (APC) PJS (STK11) JPS (SMAD4) MAP (MUTYH) Without polyposis With polyposis 21.70 Dietary risk factors for colorectal cancer Risk factor Comments Increased risk Red meat* High saturated fat and protein content Carcinogenic amines formed during cooking Saturated animal fat* High faecal bile acid and fatty acid levels May affect colonic prostaglandin turnover Decreased risk Dietary fibre* Effects vary with fibre type; shortened transit time, binding of bile acids and effects on bacterial flora proposed Fruit and vegetables Green vegetables contain anticarcinogens, such as flavonoids Little evidence for protection from vitamins A, C and E Calcium Binds and precipitates faecal bile acids Folic acid Reverses DNA hypomethylation Omega-3 fatty acids May be of modest benefit *Evidence is inconsistent and a clear relationship is unproven. 21.71 Non-dietary risk factors for colorectal cancer Medical conditions • Colorectal adenomas (p. 827) • Long-standing extensive ulcerative colitis or Crohn’s colitis (p. 813), especially if associated with primary sclerosing cholangitis • Ureterosigmoidostomy • Acromegaly • Pelvic radiotherapy Others • Obesity and sedentary lifestyle – may be related to diet • Smoking (relative risk 1.5–3.0) • Alcohol (weak association) • Cholecystectomy (effect of bile acids in right colon) • Type 2 diabetes (hyperinsulinaemia) • Use of aspirin or NSAIDs (COX-2 inhibition) and perhaps statins associated with reduced risk (COX-2 = cyclo-oxygenase 2; NSAIDs = non-steroidal anti-inflammatory drugs)

Disorders of the colon and rectum • 831

A family history of colorectal cancer can be obtained in 20% of patients who do not fulfil the criteria for HNPCC. In these families, the lifetime risk of developing colon cancer is 1 in 12 and 1 in 6, respectively, when one or two first-degree relatives are affected. The risk is even higher if relatives were affected at an early age. The genes responsible for these cases are, however, unknown. Most colorectal cancers are ‘sporadic’ and arise from malignant transformation of a benign adenomatous polyp. Over 65% occur in the rectosigmoid and a further 15% occur in the caecum or ascending colon. Synchronous tumours are present in 2–5% of patients. Spread occurs through the bowel wall. Rectal cancers may invade the pelvic viscera and side walls. Lymphatic invasion is common at presentation, as is spread through both portal and systemic circulations to reach the liver and, less commonly, the lungs. Tumour stage at diagnosis is the most important determinant of prognosis (Fig. 21.60). Clinical features Symptoms vary, depending on the site of the carcinoma. In tumours of the left colon, fresh rectal bleeding is common and obstruction occurs early. Tumours of the right colon present with anaemia from occult bleeding or with altered bowel habit, but obstruction is a late feature. Colicky lower abdominal pain is present in two-thirds of patients and rectal bleeding occurs in 50%. A minority present with features of either obstruction or perforation, leading to peritonitis, localised abscess or fistula formation. Carcinoma of the rectum usually causes early bleeding, mucus discharge or a feeling of incomplete emptying. Between 10% and 20% of patients present with iron deficiency anaemia or weight loss. On examination, there may be a palpable mass, signs of anaemia or hepatomegaly from metastases. Low rectal tumours may be palpable on digital examination. With the advent of sophisticated sequencing methodologies, such as whole-exome or whole-genome sequencing, it is becoming clear that colorectal cancer displays molecular heterogeneity resulting from both common and rare genetic variants, all displaying differing levels of penetrance. About 5–10% of colon cancers are caused by HNPCC. Pedigrees with this disorder have an autosomal dominant mode of inheritance and a positive family history of colon cancer occurring at a young age. The lifetime risk in affected individuals is 80%, with a mean age at cancer development of 45 years. In contrast to sporadic colon cancer, two-thirds of tumours occur proximally. The diagnostic criteria are listed in Box 21.72. In a subset of patients, there is also an increased incidence of cancers of the endometrium, ovary, urinary tract, stomach, pancreas, small intestine and CNS, related to inheritance of different mismatch repair gene mutations. Those who fulfil the criteria for HNPCC should be referred for pedigree assessment, genetic testing (see above) and colonoscopy. These should begin around 25 years of age or 5–10 years earlier than the youngest case of cancer in the family. Colonoscopy needs to be repeated every 1–2 years but, even then, interval cancers can still occur. Fig. 21.59 The multistep origin of cancer: molecular events implicated in colorectal carcinogenesis. (GTP = guanine triphosphate) Late adenoma Carcinoma Key gene(s) Chromosome Alteration Normal function Effect APC (adenomatous polyposis coli) 5q Truncating mutations Inhibits translocation of β-catenin to nucleus and suppresses cell growth Progression to early adenoma development K-ras 12p Gain-of-function mutations Transmembrane GTP-binding protein mediating mitogenic signals (p21) Cell proliferation DCC (deleted in colon cancer) SMAD4 18q Allelic deletion or silencing (DCC) Gain-of-function mutations (SMAD4) DCC regulates apoptosis and has a tumour suppressor function SMAD4 regulates cell growth Enhanced tumour growth, invasion and metastasis TP53 17p Allelic deletion; gain-of-function mutations Up-regulated during cell damage to arrest cell cycle and allow DNA repair or apoptosis to occur Cell proliferation; impaired apoptosis Further mutations • Anchorage independence • Protease synthesis • Telomerase synthesis • Multidrug resistance • Evasion of immune system Intermediate adenoma Early adenoma Normal These criteria are strict and may miss some families with mutations. Hereditary non-polyposis colon cancer should also be considered in individuals with colorectal or endometrial cancer under 45 years of age. 21.72 Modified Amsterdam criteria for hereditary non-polyposis colon cancer • Three or more relatives with colon cancer (at least one first-degree) • Colorectal cancer in two or more generations • At least one member affected under 50 years of age • Familial adenomatous polyposis excluded

832 • GASTROENTEROLOGY Most recurrences are within 3 years of diagnosis and affect the liver, lung, distant lymph nodes and peritoneum. Adjuvant chemotherapy with 5-fluorouracil/folinic acid or capecitabine, preferably in combination with oxaliplatin, can reduce the risk of recurrence in patients with Dukes stage C cancers and some high-risk Dukes B cancers. Post-operative radiotherapy reduces the risk of local recurrence in rectal cancer if operative resection margins are involved. Palliation of advanced disease Surgical resection of the primary tumour is appropriate for some patients with metastases to treat obstruction, bleeding or pain. Palliative chemotherapy with 5-fluorouracil/folinic acid, capecitabine, oxaliplatin or irinotecan improves survival. Patients with advanced metastatic disease may be treated with monoclonal antibodies using bevacizumab or cetuximab, either alone or together with chemotherapy. Pelvic radiotherapy is sometimes useful for distressing rectal symptoms, such as pain, bleeding or severe tenesmus. Endoscopic laser therapy or insertion of an expandable metal stent can be used to relieve obstruction (Fig. 21.61). Prevention and screening Secondary prevention aims to detect and remove lesions at an early or pre-malignant stage by screening the asymptomatic general population. Several potential methods exist: • Population-based screening of people over the age of 50 years by regular faecal occult blood (FOB) testing reduces colorectal cancer mortality and increases the proportion of early cancers detected. The sensitivity and specificity of these tests need to be improved. Traditionally, serial stool testing with or without subsequent colonoscopy is the screening method of choice in the UK. • Colonoscopy remains the gold standard and allows preventative polypectomy but is expensive, requires bowel preparation and carries risks (perforation approximately 1 : 1000). Many countries lack the resources to offer this form of screening. • Flexible sigmoidoscopy is an alternative option and has been shown to reduce overall colorectal cancer mortality by approximately 35% (70% for cases arising in the Investigations Colonoscopy is the investigation of choice because it is more sensitive and specific than barium enema. Furthermore, lesions can be biopsied and polyps removed. Patients in whom colonoscopy is incomplete and those who are at high risk of complications can be investigated by CT colonography (virtual colonoscopy). This is a sensitive and non-invasive technique for diagnosing tumours and polyps of more than 6 mm diameter. When the diagnosis of colon cancer has been made, CT of the chest, abdomen and pelvis should be performed as a staging investigation, particularly to detect hepatic metastases. Pelvic MRI or endoanal ultrasound should be used for local staging of rectal cancer. Measurement of serum carcinoembryonic antigen (CEA) levels are of limited value in diagnosis, since values are normal in many patients, but CEA testing can be helpful during follow-up to monitor for recurrence. Management Surgery All patients should be discussed at a multidisciplinary team meeting. Those with locally advanced rectal cancer should be offered neoadjuvant radiotherapy or chemoradiotherapy to increase the subsequent chance of a complete (R0) surgical resection. A 1-week course of radiotherapy just prior to surgery reduces the risk of local recurrence in operable rectal cancer. The tumour should be removed, along with adequate resection margins and pericolic lymph nodes. Continuity should be restored by direct anastomosis, wherever possible. Carcinomas within 2 cm of the anal verge may require abdominoperineal resection and formation of a colostomy. All patients should be counselled pre-operatively about the possible need for a stoma. Total mesorectal excision reduces recurrence rates and increases survival in rectal cancer. Metastatic disease confined to liver or lung should be considered for resection, as this can be potentially curative if there is truly no disease at other sites. Post-operatively, patients should undergo colonoscopy after 6–12 months and then at 5 years to search for local recurrence or development of new lesions, which occur in 6% of cases. Adjuvant therapy About 30–40% of patients have lymph node involvement at presentation (Fig. 21.60) and are therefore at risk of recurrence. Fig. 21.60 Modified Dukes classification and survival in colorectal cancer. Prevalence at diagnosis (%) Dukes stage Definition 5-year survival rate (%) A B C D Distant metastases Tumour involving lymph nodes Extension through bowel wall Tumour confined within bowel wall

30–35

90

< 5

Disorders of the colon and rectum • 833

IBD and infection. Diverticular disease may be complicated by perforation, pericolic abscess, fistula formation (usually colovesical) or acute rectal bleeding. These complications are more common in patients who take NSAIDs or aspirin. After one attack of diverticulitis, the recurrence rate is around 3% per year. Over 10–30 years, perforation, obstruction or bleeding may occur, each affecting 5% of patients. Investigations Investigations are usually performed to exclude colorectal neoplasia. Diverticula can be seen during colonoscopy or on imaging modalities such as CT scan, CT colonography or barium enema (see Fig. 21.12C, p. 773). In severe diverticulosis, colonoscopy requires expertise and carries a risk of perforation. CT is used to assess complications, such as perforation or pericolic abscess. rectosigmoid). It is recommended in the USA every 5 years in all persons over the age of 50. • Screening for high-risk patients by molecular genetic analysis is an exciting prospect but is not yet available. • CT colonography is fast and low-risk, and offers equivalent sensitivity to colonoscopy. Disadvantages include reduced sensitivity to detect polyps of less than 6 mm, the requirement for bowel preparation, exposure to ionising radiation and its inability to offer therapeutic intent. Diverticulosis Diverticula are acquired and are most common in the sigmoid and descending colon of middle-aged people. Asymptomatic diverticula (diverticulosis) are present in over 50% of people above the age of 70 years. Symptomatic diverticular disease supervenes in 10–25% of cases, while complicated diverticulosis (acute diverticulitis, pericolic abscess, bleeding, perforation or stricture) is uncommon. Pathophysiology A life-long refined diet with a relative deficiency of fibre is widely thought to be responsible and the condition is rare in populations with a high dietary fibre intake, such as in Asia, where it more often affects the right side of the colon. It is postulated that small-volume stools require high intracolonic pressures for propulsion and this leads to herniation of mucosa between the taeniae coli (Fig. 21.62). Diverticula consist of protrusions of mucosa covered by peritoneum. There is commonly hypertrophy of the circular muscle coat. Inflammation is thought to result from impaction of diverticula with faecoliths. This may resolve spontaneously or progress to cause haemorrhage, perforation, local abscess formation, fistula and peritonitis. Repeated attacks of inflammation lead to thickening of the bowel wall, narrowing of the lumen and eventual obstruction. Clinical features Symptoms are usually the result of associated constipation or spasm. Colicky pain is suprapubic or felt in the left iliac fossa. The sigmoid colon may be palpable and, in attacks of diverticulitis, there is local tenderness, guarding, rigidity (‘left-sided appendicitis’) and sometimes a palpable mass. During these episodes, there may be diarrhoea, rectal bleeding or fever. The differential diagnosis includes colorectal cancer, ischaemic colitis, Fig. 21.61 Placement of a colonic stent for an inoperable cancer with impending obstruction. A The contrast study demonstrates an obstruction. B The stent is deployed across the tumour. C A satisfactory position is demonstrated on subsequent CT scanning. A B C Fig. 21.62 The human colon in diverticulosis. The colonic wall is weak between the taeniae. The blood vessels that supply the colon pierce the circular muscle and weaken it further by forming tunnels. Diverticula usually emerge through these points of least resistance. Mesocolon Circular muscle Diverticulum Taenia (longitudinal muscle)

834 • GASTROENTEROLOGY Faecal impaction In faecal impaction, a large, hard mass of stool fills the rectum. This tends to occur in disabled, immobile or institutionalised patients, especially the frail elderly or those with dementia. Constipating drugs, autonomic neuropathy and painful anal conditions also contribute. Megacolon, intestinal obstruction and urinary tract infections may supervene. Perforation and bleeding from pressure-induced ulceration are occasionally seen. Treatment involves adequate hydration and careful digital disimpaction after softening the impacted stool with arachis oil enemas. Stimulants should be avoided. Melanosis coli and laxative misuse syndromes Long-term consumption of stimulant laxatives leads to accumulation of lipofuscin pigment in macrophages in the lamina propria. This imparts a brown discoloration to the colonic mucosa, often described as resembling ‘tiger skin’. The condition is benign and resolves when the laxatives are stopped. Prolonged laxative use may rarely result in megacolon or ‘cathartic colon’, in which barium enema demonstrates a featureless mucosa, loss of haustra and shortening of the bowel. Surreptitious laxative misuse is a psychiatric condition seen in young women, some of whom have a history of bulimia or anorexia nervosa (pp. 1203 and 1204). They complain of refractory watery diarrhoea. Laxative use is usually denied and may continue, even when patients are undergoing investigation. Screening of urine for laxatives may reveal the diagnosis. Hirschsprung’s disease This disease is characterised by constipation and colonic dilatation (megacolon) due to congenital absence of ganglion cells in the large intestine. The incidence is approximately 1 : 5000. About one-third of patients have a positive family history and, in these families, the disease is inherited in an autosomal dominant manner with incomplete penetrance. About 50% of familial cases and 15% of sporadic cases have mutations affecting the RET protooncogene, which is also implicated in multiple endocrine neoplasia (MEN) types 2 and 3 (also known as MEN 2a and 2b, respectively; p. 688). Unlike MEN 2 and 3, which are caused by activating RET mutations, Hirschsprung’s disease is caused by loss-of-function mutations. In some kindreds, Hirschsprung’s disease and MEN can actually co-segregate and this presumably represents both ‘switch off’ and ‘switch on’ of RET in different tissues. Although RET is the most important susceptibility gene, some patients with Management Diverticular disease that is asymptomatic and discovered coincidentally requires no treatment. Constipation can be relieved by a high-fibre diet, with or without a bulking laxative (ispaghula husk, 1–2 sachets daily), taken with plenty of fluids. Stimulant laxatives (see Box 21.73 below) should be avoided. Antispasmodics may sometimes help. Acute attacks of diverticulitis can be treated with antibiotics active against Gram-negative and anaerobic organisms. Severe cases require intravenous fluids, intravenous antibiotics, analgesia and nasogastric suction, but randomised trials show no benefit from acute resection compared to conservative management. Emergency surgery is reserved for severe haemorrhage or perforation. Percutaneous drainage of acute paracolic abscesses can be effective and avoids the need for emergency surgery. Patients who have repeated attacks of obstruction should undergo elective surgery once the acute episode has settled, in order to resect the affected segment of bowel with restoration of continuity by primary anastomosis. Constipation and disorders of defecation The clinical approach to patients with constipation and its aetiology have been described on page 786. Simple constipation Simple constipation is extremely common and does not signify underlying organic disease. It usually responds to increased dietary fibre or the use of bulking agents; an adequate fluid intake is also essential. Many types of laxative are available, and these are listed in Box 21.73. Severe idiopathic constipation This occurs almost exclusively in young women and often begins in childhood or adolescence. The cause is unknown but some have ‘slow transit’ with reduced motor activity in the colon. Others have ‘obstructed defecation’, resulting from inappropriate contraction of the external anal sphincter and puborectalis muscle (anismus). The condition is often resistant to treatment. Bulking agents may exacerbate symptoms but prokinetic agents or balanced solutions of polyethylene glycol ‘3350’ benefit some patients with slow transit. Glycerol suppositories and biofeedback techniques are used for those with obstructed defecation. Others benefit from agents such as prucalopride or linaclotide. Rarely, subtotal colectomy may be necessary as a last resort. 21.74 Constipation in old age • Evaluation: particular attention should be paid to immobility, dietary fluid and fibre intake, drugs and depression. • Immobility: predisposes to constipation by increasing the colonic transit time; the longer this is, the greater the fluid absorption and the harder the stool. • Bulking agents: can make matters worse in patients with slow transit times and should be avoided. • Overflow diarrhoea: if faecal impaction develops, paradoxical overflow diarrhoea may occur. If antidiarrhoeal agents are given, the underlying impaction may worsen and result in serious complications, such as stercoral ulceration and bleeding. 21.73 Laxatives Class Examples Bulk-forming laxatives Ispaghula husk, methylcellulose Stimulants Bisacodyl, dantron (only for terminally ill patients), docusate, senna Faecal softeners Docusate, arachis oil enema Osmotic laxatives Lactulose, lactitol, magnesium salts Others Polyethylene glycol (PEG), phosphate enema *Also used for bowel preparation prior to investigation or surgery.

Disorders of the colon and rectum • 835

a high risk of perforation. Single-contrast or water-soluble barium enemas demonstrate the absence of mechanical obstruction. Management consists of treating the underlying disorder and correcting any biochemical abnormalities. The anticholinesterase neostigmine is effective in enhancing parasympathetic activity and gut motility. Decompression, with either a rectal tube or colonoscope, may be effective but needs to be repeated until the condition resolves. In severe cases, surgical or fluoroscopic defunctioning caecostomy is necessary. Anorectal disorders Faecal incontinence The normal control of anal continence is described on page 770. Common causes of incontinence are listed in Box 21.76. High-risk patients include frail older people, women after childbirth and those with severe neurological/spinal disorders, learning difficulties or cognitive impairment. Patients are often embarrassed to admit incontinence and may complain only of ‘diarrhoea’. A careful history and examination, especially of the anorectum and perineum, may help to establish the underlying cause. Endoanal ultrasound is valuable for defining the integrity of the anal sphincters, while anorectal physiology and MR proctography are also useful investigations. Management This is often very difficult. Underlying disorders should be treated and diarrhoea managed with loperamide, diphenoxylate or codeine phosphate. Attention must be paid to a proper diet and adequate fluid intake. Pelvic floor exercises, biofeedback and bowel retraining techniques help some patients, and those with confirmed anal sphincter defects may benefit from sphincter repair operations. Where sphincter repair is not appropriate, a trial of sacral nerve stimulation is undertaken with a view to insertion of a permanent stimulator but, if unsuccessful, creation of a neo-sphincter may be possible, by graciloplasty or by an artificial anal sphincter. Haemorrhoids Haemorrhoids (commonly known as piles) arise from congestion of the internal and/or external venous plexuses around the anal canal. They are extremely common in adults. The aetiology is unknown, although they are associated with constipation and straining, and may develop for the first time during pregnancy. First-degree piles bleed, while second-degree piles prolapse but retract spontaneously. Third-degree piles are those that require manual replacement after prolapsing. Bright red rectal bleeding occurs after defecation. Other symptoms include pain, pruritus ani and mucus discharge; thrombosis can occur in prolapsed piles, which can be very painful (Fig. 21.63). Treatment RET mutations do not develop clinical Hirschsprung’s disease, and mutations in other genes have been identified that interact to cause the disease. All of the genes implicated in Hirschsprung’s disease are involved in the regulation of enteric neurogenesis, and the mutations cause failure of migration of neuroblasts into the gut wall during embryogenesis. Ganglion cells are absent from nerve plexuses, most commonly in a short segment of the rectum and/or sigmoid colon. As a result, the internal anal sphincter fails to relax. Constipation, abdominal distension and vomiting usually develop immediately after birth but a few cases do not present until childhood or adolescence. The rectum is empty on digital examination. A plain abdominal X-ray or barium enema shows a small rectum and colonic dilatation above the narrowed segment. Full-thickness biopsies are required to demonstrate nerve plexuses and confirm the absence of ganglion cells. Histochemical stains for acetylcholinesterase are also used. Anorectal manometry demonstrates failure of the rectum to relax with balloon distension. Treatment involves resection of the affected segment. Acquired megacolon This may develop in childhood as a result of voluntary withholding of stool during toilet training. In such cases, it presents after the first year of life and is distinguished from Hirschsprung’s disease by the urge to defecate and the presence of stool in the rectum. It usually responds to osmotic laxatives. In adults, acquired megacolon has several causes. It is seen in patients with depression or dementia, either as part of the condition or as a side-effect of antidepressant drugs. Prolonged misuse of stimulant laxatives may cause degeneration of the myenteric plexus, while interruption of sensory or motor innervation may be responsible in a number of neurological disorders. Patients taking large doses of opioid analgesics can develop a megacolon: so-called ‘narcotic bowel syndrome’. Systemic sclerosis and hypothyroidism are other recognised causes. Most patients can be managed conservatively by treatment of the underlying cause, high-residue diets, laxatives and the judicious use of enemas. Prokinetics are helpful in a minority of patients. Opioid-associated constipation can be treated with the specific peripheral opioid receptor antagonist naloxegol. Subtotal colectomy is a last resort for the most severely affected patients. Acute colonic pseudo-obstruction Acute colonic pseudo-obstruction (Ogilvie’s syndrome) has many causes (Box 21.75) and is characterised by sudden onset of painless, massive enlargement of the proximal colon; there are no features of mechanical obstruction. Bowel sounds are normal or high-pitched, rather than absent. Left untreated, it may progress to perforation, peritonitis and death. Abdominal X-rays show colonic dilatation with air extending to the rectum. Caecal diameter greater than 10 cm is associated with 21.76 Causes of faecal incontinence • Obstetric trauma: childbirth, hysterectomy • Severe diarrhoea • Faecal impaction • Congenital anorectal anomalies • Anorectal disease: haemorrhoids, rectal prolapse, Crohn’s disease • Neurological disorders: spinal cord or cauda equina lesions, dementia 21.75 Causes of acute colonic pseudo-obstruction • Trauma, burns • Recent surgery • Drugs (opiates, phenothiazines) • Respiratory failure • Electrolyte and acid–base disorders • Diabetes mellitus • Uraemia

836 • GASTROENTEROLOGY and mucosal prolapse. The ulcer is seen at sigmoidoscopy and biopsies show a characteristic accumulation of collagen. Symptoms include minor bleeding and mucus per rectum, tenesmus and perineal pain. Treatment is often difficult but avoidance of straining at defecation is important and treatment of constipation may help. Marked mucosal prolapse is treated surgically. Anal fissure In this common problem, traumatic or ischaemic damage to the anal mucosa results in a superficial mucosal tear, most commonly in the midline posteriorly. Spasm of the internal anal sphincter exacerbates the condition. Severe pain occurs on defecation and there may be minor bleeding, mucus discharge and pruritus. The skin may be indurated and an oedematous skin tag, or ‘sentinel pile’, adjacent to the fissure is common. Avoidance of constipation with bulk-forming laxatives and increased fluid intake is important. Relaxation of the internal sphincter is normally mediated by nitric oxide, and 0.2% glyceryl trinitrate, which donates nitric oxide and improves mucosal blood flow, is effective in 60–80% of patients. Diltiazem cream (2%) can be used as an alternative. Resistant cases may respond to injection of botulinum toxin into the internal anal sphincter to induce relaxation. Manual dilatation under anaesthesia leads to long-term incontinence and should not be considered. The majority of cases can be treated without surgery, but where these measures fail, healing can be achieved surgically by lateral internal anal sphincterotomy or advancement anoplasty. Anorectal abscesses and fistulae Perianal abscesses develop between the internal and external anal sphincters and may point at the perianal skin. Ischiorectal abscesses occur lateral to the sphincters in the ischiorectal fossa. They usually result from infection of anal glands by normal intestinal bacteria. Crohn’s disease (p. 813) is sometimes responsible. Patients complain of extreme perianal pain, fever and/ or discharge of pus. Spontaneous rupture may lead to the development of fistulae. These may be superficial or track through the anal sphincters to reach the rectum. Abscesses are drained surgically and superficial fistulae are laid open with care to avoid sphincter damage. Diseases of the peritoneal cavity Peritonitis Surgical peritonitis occurs as the result of a ruptured viscus (for details see this book’s companion text, Principles and Practice of Surgery). Peritonitis may also complicate ascites in chronic liver disease (spontaneous bacterial peritonitis, p. 864) or may occur in children in the absence of ascites, due to infection with Streptococcus pneumoniae or β-haemolytic streptococci (p. 253). Chlamydial peritonitis is a complication of pelvic inflammatory disease (p. 336). The patient presents with right upper quadrant pain, pyrexia and a hepatic rub (the Fitz-Hugh–Curtis syndrome). Tuberculosis may cause peritonitis and ascites (p. 588). Tumours The most common is secondary adenocarcinoma from the ovary or gastrointestinal tract. Mesothelioma is a rare tumour complicating asbestos exposure. It presents as a diffuse involves measures to prevent constipation and straining. Band ligation is effective for many but a minority of patients require haemorrhoidectomy, which is usually curative. Haemorrhoidal artery ligation operation (HALO) procedures have been developed and may replace surgery. HALO involves using Doppler ultrasound to identify all the arteries feeding the haemorrhoids and ligating them. Pruritus ani This is common and can stem from many causes (Box 21.77), most of which result in contamination of the perianal skin with faecal contents. Itching may be severe and results in an itch–scratch–itch cycle that exacerbates the problem. When no underlying cause is found, all local barrier ointments and creams must be stopped. Good personal hygiene is essential, with careful washing after defecation. The perineal area must be kept dry and clean. Bulk-forming laxatives may reduce faecal soiling. Solitary rectal ulcer syndrome This is most common in young adults and occurs on the anterior rectal wall. It is thought to result from localised chronic trauma and/or ischaemia associated with disordered puborectalis function Fig. 21.63 Thrombosed prolapsed haemorrhoids. 21.77 Causes of pruritus ani Local anorectal conditions • Haemorrhoids • Fistula, fissures • Poor hygiene Infections • Threadworms • Candidiasis Skin disorders • Contact dermatitis • Psoriasis • Lichen planus Other • Diarrhoea or incontinence of any cause • Irritable bowel syndrome • Anxiety

Diseases of the pancreas • 837

B (NFκB), leading to mitochondrial dysfunction, autophagy and a vigorous inflammatory response. The normal pancreas has only a poorly developed capsule, and adjacent structures, including the common bile duct, duodenum, splenic vein and transverse colon, are commonly involved in the inflammatory process. The severity of acute pancreatitis is dependent on the balance between the activity of released proteolytic enzymes and antiproteolytic factors. The latter comprise an intracellular pancreatic trypsin inhibitor protein and circulating β2-macroglobulin, α1-antitrypsin and C1-esterase inhibitors. The causes of acute pancreatitis are listed in Box 21.80. Acute pancreatitis is often self-limiting, but in some patients with severe disease, local complications, such as necrosis, pseudocyst or abscess, occur, as well as systemic complications that lead to multi-organ failure. Clinical features The typical presentation is with severe, constant upper abdominal pain, of increasing intensity over 15–60 minutes, which radiates to the back. Nausea and vomiting are common. There is marked epigastric tenderness, but in the early stages (and in contrast to a perforated peptic ulcer), guarding and rebound tenderness are absent because the inflammation is principally retroperitoneal. Bowel sounds become quiet or absent as paralytic ileus develops. In severe cases, the patient becomes hypoxic and develops hypovolaemic shock with oliguria. Discoloration of the flanks abdominal mass, due to omental infiltration, and with ascites. The prognosis is extremely poor. Other disorders Endometriosis Ectopic endometrial tissue can become embedded on the serosal aspect of the intestine, most frequently in the sigmoid and rectum. The overlying mucosa is usually intact. Cyclical engorgement and inflammation result in pain, bleeding, diarrhoea, constipation and adhesions or obstruction. Low backache is frequent. The onset is usually between 20 and 45 years and the condition is more common in nulliparous women. Bimanual examination may reveal tender nodules in the pouch of Douglas. Endoscopic studies reveal the diagnosis only if carried out during menstruation, when a bluish mass with intact overlying mucosa is apparent. In some patients, laparoscopy is required. Treatment options include laparoscopic diathermy and hormonal therapy with progestogens (e.g. norethisterone), gonadotrophin-releasing hormone analogues or danazol. Pneumatosis cystoides intestinalis In this rare condition, multiple gas-filled submucosal cysts line the colonic and small bowel walls. The cause is unknown but the condition may be seen in patients with chronic cardiac or pulmonary disease, pyloric obstruction, systemic sclerosis or dermatomyositis. Most patients are asymptomatic, although there may be abdominal cramp, diarrhoea, tenesmus, rectal bleeding and mucus discharge. The cysts are recognised on sigmoidoscopy, plain abdominal X-rays or barium enema. Therapies reported to be effective include prolonged high-flow oxygen, elemental diets and antibiotics. Diseases of the pancreas Acute pancreatitis Acute pancreatitis accounts for 3% of all cases of abdominal pain admitted to hospital. It affects 2–28 per 100 000 of the population and is increasing in incidence. It is a potentially serious condition with an overall mortality of 10%. About 80% of all cases are mild and have a favourable outcome. Approximately 98% of deaths from pancreatitis occur in the 20% of patients with severe disease and about one-third of these arise within the first week, usually from multi-organ failure. After this time, the majority of deaths result from sepsis, especially that complicating infected necrosis. At admission, it is possible to predict patients at risk of these complications (Box 21.78). Individuals who are predicted to have severe pancreatitis (Box 21.79) and those with necrosis or other complications should be managed in a specialist centre with an intensive care unit and multidisciplinary hepatobiliary specialists. Pathophysiology Acute pancreatitis occurs as a consequence of premature intracellular trypsinogen activation, releasing proteases that digest the pancreas and surrounding tissue. Triggers for this are many, including alcohol, gallstones and pancreatic duct obstruction (Fig. 21.64). There is simultaneous activation of nuclear factor kappa 21.79 Features that predict severe pancreatitis Initial assessment • Clinical impression of severity • Body mass index > 30 kg/m2 • Pleural effusion on chest X-ray • APACHE II score > 8 (see Box 10.50, p. 214) 24 hours after admission • Clinical impression of severity • APACHE II score > 8 • Glasgow score > 3 (see Box 21.78) • Persisting organ failure, especially if multiple • CRP > 150 mg/L 48 hours after admission • Clinical impression of severity • Glasgow score > 3 • CRP > 150 mg/L • Persisting organ failure for 48 hours • Multiple or progressive organ failure (CRP = C-reactive protein) Severity and prognosis worsen as the number of these factors increases. More than three implies severe disease. 21.78 Glasgow criteria for prognosis in acute pancreatitis • Age > 55 years • PO2 < 8 kPa (60 mmHg) • White blood cell count > 15 × 109/L • Albumin < 32 g/L (3.2 g/dL) • Serum calcium < 2 mmol/L (8 mg/dL) (corrected) • Glucose > 10 mmol/L (180 mg/dL) • Urea > 16 mmol/L (45 mg/dL) (after rehydration) • Alanine aminotransferase > 200 U/L • Lactate dehydrogenase > 600 U/L

838 • GASTROENTEROLOGY ‘pseudocysts’ are common and usually asymptomatic, resolving as the pancreatitis recovers. Pseudocysts greater than 6 cm in diameter seldom disappear spontaneously and can cause constant abdominal pain and compress or erode surrounding structures, including blood vessels, to form pseudoaneurysms. Large pseudocysts can be detected clinically as a palpable abdominal mass. Pancreatic ascites occurs when fluid leaks from a disrupted pancreatic duct into the peritoneal cavity. Leakage into the thoracic cavity can result in a pleural effusion or a pleuro-pancreatic fistula. (Grey Turner’s sign) or the periumbilical region (Cullen’s sign) is a feature of severe pancreatitis with haemorrhage. The differential diagnosis includes a perforated viscus, acute cholecystitis and myocardial infarction. Various complications may occur and these are listed in Box 21.81. A collection of fluid and debris may develop in the lesser sac, following inflammatory rupture of the pancreatic duct; this is known as a pancreatic fluid collection. It is initially contained within a poorly defined, fragile wall of granulation tissue, which matures over a 6-week period to form a fibrous capsule (Fig. 21.65). Such Fig. 21.64 Pathophysiology of acute pancreatitis. Hyperstimulation of pancreas (alcohol, triglycerides) Pancreatic secretory trypsin inhibitors + + + + Defective intracellular transport and secretion of pancreatic zymogens Pancreatic duct obstruction (common bile duct stones, tumours) Reflux of infected bile or duodenal contents into pancreatic duct (sphincter of Oddi dysfunction) Activated proteolytic enzymes Acute pancreatitis Pro-enzymes 21.80 Causes of acute pancreatitis Common (90% of cases) • Gallstones • Alcohol • Idiopathic causes • Post-ERCP Rare • Post-surgical (abdominal, cardiopulmonary bypass) • Trauma • Drugs (azathioprine/mercaptopurine, thiazide diuretics, sodium valproate) • Metabolic (hypercalcaemia, hypertriglyceridaemia) • Pancreas divisum (p. 842) • Sphincter of Oddi dysfunction • Infection (mumps, Coxsackie virus) • Hereditary factors • Renal failure • Organ transplantation (kidney, liver) • Severe hypothermia • Petrochemical exposure (ERCP = endoscopic retrograde cholangiopancreatography) 21.81 Complications of acute pancreatitis Complication Cause Systemic Systemic inflammatory response syndrome (SIRS) Increased vascular permeability from cytokine, platelet-aggregating factor and kinin release Hypoxia Acute respiratory distress syndrome (ARDS) due to microthrombi in pulmonary vessels Hyperglycaemia Disruption of islets of Langerhans with altered insulin/glucagon release Hypocalcaemia Sequestration of calcium in fat necrosis, fall in ionised calcium Reduced serum albumin concentration Increased capillary permeability Pancreatic Necrosis Non-viable pancreatic tissue and peripancreatic tissue death; frequently infected Abscess Circumscribed collection of pus close to the pancreas and containing little or no pancreatic necrotic tissue Pseudocyst Disruption of pancreatic ducts Pancreatic ascites or pleural effusion Disruption of pancreatic ducts Gastrointestinal Upper gastrointestinal bleeding Gastric or duodenal erosions Variceal haemorrhage Splenic or portal vein thrombosis Erosion into colon Erosion by pancreatic pseudocyst Duodenal obstruction Compression by pancreatic mass Obstructive jaundice Compression of common bile duct Fig. 21.65 Computed tomogram showing large pancreatic pseudocyst (C) compressing the stomach (S). The pancreas is atrophic and calcified (arrows). S C

Diseases of the pancreas • 839

Management Management comprises several related steps: • establishing the diagnosis and disease severity • early resuscitation, according to whether the disease is mild or severe • detection and treatment of complications • treatment of the underlying cause. Opiate analgesics should be given to treat pain and hypovolaemia should be corrected using normal saline or other crystalloids. All severe cases should be managed in a high-dependency or intensive care unit. A central venous line and urinary catheter should be inserted to monitor patients with shock. Oxygen should be given to hypoxic patients, and those who develop systemic inflammatory response syndrome (SIRS) may require ventilatory support. Hyperglycaemia should be corrected using insulin and hypocalcaemia by intravenous calcium injection. Nasogastric aspiration is required only if paralytic ileus is present. Enteral feeding, if tolerated, should be started at an early stage in patients with severe pancreatitis because they are in a severely catabolic state and need nutritional support. Enteral feeding decreases endotoxaemia and so may reduce systemic complications. Nasogastric feeding is just as effective as feeding by the nasojejunal route. Prophylaxis of thromboembolism with subcutaneous low-molecular-weight heparin is also advisable. The use of prophylactic, broad-spectrum intravenous antibiotics to prevent infection of pancreatic necrosis is not indicated, but infected necrosis is treated with antibiotics that penetrate necrotic tissue, e.g. carbapenems or quinolones, and metronidazole. Patients who present with cholangitis or jaundice in association with severe acute pancreatitis should undergo urgent ERCP to diagnose and treat choledocholithiasis. In less severe cases of gallstone pancreatitis, biliary imaging (using MRCP or EUS) can be carried out after the acute phase has resolved. If the liver function tests return to normal and ultrasound has not demonstrated a dilated biliary tree, laparoscopic cholecystectomy with an on-table cholangiogram is appropriate because any common bile duct stones have probably passed. When the operative cholangiogram detects residual common bile duct stones, these should be removed by laparoscopic exploration of the duct or by post-operative ERCP. Cholecystectomy should be undertaken within 2 weeks of resolution of pancreatitis – and preferably during the same admission – to prevent further potentially fatal attacks of pancreatitis. Patients with infected pancreatic necrosis or pancreatic abscess require urgent endoscopic drainage or minimally invasive retroperitoneal pancreatic (MIRP) necrosectomy to debride all cavities of necrotic material. Pancreatic pseudocysts can be treated by drainage into the stomach or duodenum. This is usually performed after an interval of at least 6 weeks, once a pseudocapsule has matured, by surgical or endoscopic cystogastrostomy. Chronic pancreatitis Chronic pancreatitis is a chronic inflammatory disease characterised by fibrosis and destruction of exocrine pancreatic tissue. Diabetes mellitus occurs in advanced cases because the islets of Langerhans are involved (p. 733). Pathophysiology Around 80% of cases in Western countries result from alcohol misuse. In southern India, severe chronic calcific pancreatitis Investigations The diagnosis is based on raised serum amylase or lipase concentrations and ultrasound or CT evidence of pancreatic swelling. Plain X-rays should be taken to exclude other diagnoses, such as perforation or obstruction, and to identify pulmonary complications. Amylase is efficiently excreted by the kidneys and concentrations may have returned to normal if measured 24–48 hours after the onset of pancreatitis. A persistently elevated serum amylase concentration suggests pseudocyst formation. Peritoneal amylase concentrations are massively elevated in pancreatic ascites. Serum amylase concentrations are also elevated (but less so) in intestinal ischaemia, perforated peptic ulcer and ruptured ovarian cyst, while the salivary isoenzyme of amylase is elevated in parotitis. If available, serum lipase measurements are preferable to amylase, as they have greater diagnostic accuracy for acute pancreatitis. Ultrasound scanning can confirm the diagnosis, although in the earlier stages the gland may not be grossly swollen. The ultrasound scan is also useful because it may show gallstones, biliary obstruction or pseudocyst formation. Contrast-enhanced pancreatic CT performed 6–10 days after admission can be useful in assessing viability of the pancreas if persisting organ failure, sepsis or clinical deterioration is present, since these features may indicate that pancreatic necrosis has occurred. Necrotising pancreatitis is associated with decreased pancreatic enhancement on CT, following intravenous injection of contrast material. The presence of gas within necrotic material (Fig. 21.66) suggests infection and impending abscess formation, in which case percutaneous aspiration of material for bacterial culture should be carried out and appropriate antibiotics prescribed. Involvement of the colon, blood vessels and other adjacent structures by the inflammatory process is best seen by CT. Certain investigations stratify the severity of acute pancreatitis and have important prognostic value at the time of presentation (see Boxes 21.78 and 21.79). In addition, serial assessment of CRP is a useful indicator of progress. A peak CRP of > 210 mg/L in the first 4 days predicts severe acute pancreatitis with 80% accuracy. It is worth noting that the serum amylase concentration has no prognostic value. Fig. 21.66 Pancreatic necrosis. Lack of vascular enhancement of the pancreas during contrast-enhanced computed tomography indicates necrosis (arrow). The presence of gas suggests that infection has occurred.

840 • GASTROENTEROLOGY present with diarrhoea. Pain is due to a combination of increased pressure within the pancreatic ducts and direct involvement of peripancreatic nerves by the inflammatory process. Pain may be relieved by leaning forwards or by drinking alcohol. Approximately one-fifth of patients chronically consume opiate analgesics. Weight loss is common and results from a combination of anorexia, avoidance of food because of post-prandial pain, malabsorption and/or diabetes. Steatorrhoea occurs when more than 90% of the exocrine tissue has been destroyed; protein malabsorption develops only in the most advanced cases. Overall, 30% of patients have (secondary) diabetes but this figure rises to 70% in those with chronic calcific pancreatitis. Physical examination reveals a thin, malnourished patient with epigastric tenderness. Skin pigmentation over the abdomen and back is common and results from chronic use of a hot water bottle (erythema ab igne). Many patients have features of other alcohol- and smoking-related diseases. Complications are listed in Box 21.83. Investigations Investigations (Box 21.84 and Fig. 21.68) are carried out to: • make a diagnosis of chronic pancreatitis • define pancreatic function • demonstrate anatomical abnormalities prior to surgical intervention. occurs in non-alcoholics, possibly as a result of malnutrition, deficiency of trace elements and micronutrients, and cassava consumption. Other causes are listed in Box 21.82. The pathophysiology of chronic pancreatitis is shown in Figure 21.67. Clinical features Chronic pancreatitis predominantly affects middle-aged alcoholic men. Almost all present with abdominal pain. In 50%, this occurs as episodes of ‘acute pancreatitis’, although each attack results in a degree of permanent pancreatic damage. Relentless, slowly progressive chronic pain without acute exacerbations affects 35% of patients, while the remainder have no pain but Fig. 21.67 Pathophysiology of chronic pancreatitis. Alcohol and other risk factors may trigger acute pancreatitis through multiple mechanisms. The first (or ‘sentinel’) episode of acute pancreatitis initiates an inflammatory response involving T-helper (Th) cells. Ongoing exposure to alcohol drives further inflammation but this is modified by regulatory T cells (Treg) with subsequent fibrosis, via activation of pancreatic stellate cells. A cycle of inflammation and fibrosis ensues, with development of chronic pancreatitis. Alcohol is the most relevant risk factor, as it is involved at multiple steps. Clinical course Mechanisms Aetiology Normal Treg Th Acute pancreatitis Recurrent acute pancreatitis Recurrent acute pancreatitis Oxidative stress Alcohol Smoking Idiopathic Genetic Autoimmune Obstructive Toxic– metabolic Necrosis– fibrosis Duct obstruction Chronic pancreatitis Acinus Ductule These can be memorised by the mnemonic ‘TIGARO’. Gallstones do not cause chronic pancreatitis but may be observed as an incidental finding. 21.82 Causes of chronic pancreatitis Toxic–metabolic • Alcohol • Tobacco • Hypercalcaemia • Chronic kidney disease Idiopathic • Tropical • Early-/late-onset types Genetic • Hereditary pancreatitis (cationic trypsinogen mutation) • SPINK-1 mutation • Cystic fibrosis Autoimmune • In isolation or as part of multi-organ problem Recurrent and severe acute pancreatitis • Recurrent acute pancreatitis • Post-necrotic Obstructive • Ductal adenocarcinoma • Intraductal papillary mucinous neoplasia • Pancreas divisum • Sphincter of Oddi stenosis 21.83 Complications of chronic pancreatitis • Pseudocysts and pancreatic ascites, which occur in both acute and chronic pancreatitis • Obstructive jaundice due to benign stricture of the common bile duct as it passes through the diseased pancreas • Duodenal stenosis • Portal or splenic vein thrombosis leading to segmental portal hypertension and gastric varices • Peptic ulcer

Diseases of the pancreas • 841

Pain relief A range of analgesic drugs, particularly NSAIDs, are valuable but the severe and unremitting nature of the pain often leads to opiate use with the risk of addiction. Analgesics, such as pregabalin and tricyclic antidepressants at a low dose, may be effective. Oral pancreatic enzyme supplements suppress pancreatic secretion and their regular use reduces analgesic consumption in some patients. Patients who are abstinent from alcohol and who have severe chronic pain that is resistant to conservative measures should be considered for surgical or endoscopic pancreatic therapy (Box 21.85). Coeliac plexus neurolysis sometimes produces long-lasting pain relief, although relapse occurs in the majority of cases. In some patients, MRCP does not show a surgically or endoscopically correctable abnormality and, in these individuals, the only surgical approach is total pancreatectomy. Unfortunately, even after this operation, some continue to experience pain. Moreover, the procedure causes diabetes, which may be difficult to control, with a high risk of hypoglycaemia (since both insulin and glucagon are absent) and significant morbidity and mortality. Malabsorption This is treated by dietary fat restriction (with supplementary medium-chain triglyceride therapy in malnourished patients) and oral pancreatic enzyme supplements. A PPI is added to optimise duodenal pH for pancreatic enzyme activity. Management of complications Surgical or endoscopic therapy may be necessary for the management of pseudocysts, pancreatic ascites, common bile duct or duodenal stricture and the consequences of portal hypertension. Many patients with chronic pancreatitis also require treatment for other alcohol- and smoking- related diseases and for the consequences of self-neglect and malnutrition. Autoimmune pancreatitis Autoimmune pancreatitis (AIP) is a form of chronic pancreatitis that can mimic cancer but which responds to glucocorticoids. It is characterised by abdominal pain, weight loss or obstructive jaundice, without acute attacks of pancreatitis. Blood tests reveal increased serum IgG or IgG4 and the presence of other autoantibodies. Imaging shows a diffusely enlarged pancreas, narrowing of the pancreatic duct and stricturing of the lower bile duct. AIP may occur alone or with other autoimmune disorders, such as Sjögren’s syndrome, primary sclerosing cholangitis or IBD. The response to glucocorticoids is usually excellent but some patients require azathioprine. Management Alcohol misuse Alcohol avoidance is crucial in halting progression of the disease and reducing pain. Fig. 21.68 Imaging in chronic pancreatitis. A Computed tomogram showing a grossly dilated and irregular duct with a calcified stone (arrow A). Note the calcification in the head of the gland (arrow B). B Magnetic resonance cholangiopancreatogram of the same patient showing marked ductal dilatation with abnormal dilated side branches (arrows A). A small cyst is also present (arrow B). A B A B A B 21.84 Investigations in chronic pancreatitis Tests to establish the diagnosis • Ultrasound • Computed tomography (may show atrophy, calcification or ductal dilatation) • Abdominal X-ray (may show calcification) • Magnetic resonance cholangiopancreatography • Endoscopic ultrasound Tests to define pancreatic function • Collection of pure pancreatic juice after secretin injection (gold standard but invasive and seldom used) • Pancreolauryl test (see Box 21.12, p. 777) • Faecal pancreatic elastase Tests to demonstrate anatomy prior to surgery • Magnetic resonance cholangiopancreatography 21.85 Intervention in chronic pancreatitis Endoscopic therapy • Dilatation or stenting of pancreatic duct strictures • Removal of calculi (mechanical or shock-wave lithotripsy) • Drainage of pseudocysts Surgical methods • Partial pancreatic resection, preserving the duodenum • Pancreatico-jejunostomy

842 • GASTROENTEROLOGY as often as women. The disease is associated with increasing age, smoking and chronic pancreatitis. Between 5% and 10% of patients have a genetic predisposition: hereditary pancreatitis, HNPCC and familial atypical mole multiple melanoma syndrome (FAMMM). Overall survival is only 3–5%, with a median survival of 6–10 months for those with locally advanced disease and 3–5 months if metastases are present. Clinical features Many patients are asymptomatic until an advanced stage, when they present with central abdominal pain, weight loss and obstructive jaundice (Fig. 21.69). The pain results from invasion of the coeliac plexus and is characteristically incessant and gnawing. It often radiates from the upper abdomen through to the back and may be eased a little by bending forwards. Almost all patients lose weight and many are cachectic. Around 60% of tumours arise from the head of the pancreas, and involvement of the common bile duct results in the development of obstructive jaundice, often with severe pruritus. A few patients present with diarrhoea, vomiting from duodenal obstruction, diabetes mellitus, recurrent venous thrombosis, acute pancreatitis or depression. Physical examination reveals clear evidence of weight loss. An abdominal mass due to the tumour itself, a palpable gallbladder or hepatic metastasis is commonly found. A palpable gallbladder in a jaundiced patient is usually the consequence of distal biliary obstruction by a pancreatic cancer (Courvoisier’s sign). Investigations The diagnosis is usually made by ultrasound and contrastenhanced CT (Fig. 21.70). Diagnosis in non-jaundiced patients is often delayed because presenting symptoms are relatively non-specific. Fit patients with small, localised tumours should undergo staging to define operability. EUS or laparoscopy with laparoscopic ultrasound will define tumour size, involvement of blood vessels and metastatic spread. In patients unsuitable for surgery because of advanced disease, frailty or comorbidity, EUS- or CT-guided cytology or biopsy can be used to confirm the diagnosis (Fig. 21.70). MRCP and ERCP are sensitive methods of diagnosing pancreatic cancer and are valuable when the diagnosis is in doubt, although differentiation between cancer and localised chronic pancreatitis can be difficult. The main role of ERCP is to insert a stent into the common bile duct to relieve obstructive jaundice in inoperable patients. Management Surgical resection is the only method of effecting cure, and 5-year survival in patients undergoing a complete resection is around 12%. Clinical trials have demonstrated improved survival (21–29%) with adjuvant chemotherapy using gemcitabine. Unfortunately, only 10–15% of tumours are resectable for cure, since most are locally advanced at the time of diagnosis. For the great majority of patients, treatment is palliative. Chemotherapy with FOLFIRINOX (5-fluorouracil, leucovorin, irinotecan and oxaliplatin) improves median survival to 11 months. Pain relief can be achieved using analgesics but, in some patients, coeliac plexus neurolysis may be required. Jaundice can be relieved by choledochojejunostomy in fit patients, whereas percutaneous or endoscopic stenting is preferable in the elderly and those with very advanced disease. Ampullary or periampullary adenocarcinomas are rare neoplasms that arise from the ampulla of Vater or adjacent duodenum. They are often polypoid and may ulcerate; they frequently infiltrate the duodenum but behave less aggressively than pancreatic adenocarcinoma. Around 25% of patients undergoing resection Congenital abnormalities affecting the pancreas Pancreas divisum This is due to failure of the primitive dorsal and ventral ducts to fuse during embryonic development of the pancreas. As a consequence, most of the pancreatic drainage occurs through the smaller accessory ampulla rather than through the major ampulla. The condition occurs in 7–10% of the normal population and is usually asymptomatic, but some patients develop acute pancreatitis, chronic pancreatitis or atypical abdominal pain. Annular pancreas In this congenital anomaly, the pancreas encircles the second/ third part of the duodenum, leading to gastric outlet obstruction. Annular pancreas is associated with malrotation of the intestine, atresias and cardiac anomalies. Cystic fibrosis This disease is considered in detail on page 580. The major gastrointestinal manifestations are pancreatic insufficiency and meconium ileus. Peptic ulcer and hepatobiliary disease may also occur. In cystic fibrosis, pancreatic secretions are protein- and mucus-rich. The resultant viscous juice forms plugs that obstruct the pancreatic ductules, leading to progressive destruction of acinar cells. Steatorrhoea is universal and the large-volume bulky stools predispose to rectal prolapse. Malnutrition is compounded by the metabolic demands of respiratory failure and by diabetes, which develops in 40% of patients by adolescence. Nutritional counselling and supervision are important to ensure intake of high-energy foods, providing 120–150% of the recommended intake for normal subjects. Fats are an important calorie source and, despite the presence of steatorrhoea, fat intake should not be restricted. Supplementary fat-soluble vitamins are also necessary. High-dose oral pancreatic enzymes are required, in doses sufficient to control steatorrhoea and stool frequency. A PPI aids fat digestion by producing an optimal duodenal pH. Meconium ileus Mucus-rich plugs within intestinal contents can obstruct the small or large intestine of a newborn child. Meconium ileus is treated by the mucolytic agent N-acetylcysteine, given either orally, by Gastrografin enema or by gut lavage using polyethylene glycol. In resistant cases of meconium ileus, surgical resection may be necessary. Tumours of the pancreas Adenocarcinoma of the pancreas Some 90% of pancreatic neoplasms are adenocarcinomas that arise from the pancreatic ducts. These tumours involve local structures and metastasise to regional lymph nodes at an early stage. Most patients have advanced disease at the time of presentation. Neuro-endocrine tumours also arise in the pancreas but tend to grow more slowly and have a better prognosis; these are discussed in detail on page 678. Pancreatic adenocarcinoma affects 10–15 per 100 000 in Western populations, rising to 100 per 100 000 in those over the age of 70. Men are affected twice

Diseases of the pancreas • 843

Fig. 21.69 Features of pancreatic cancer. Lymphadenopathy Pancreatic tumour mass Sister Joseph’s nodule (tumour spread to umbilicus via umbilical vein) Erythema ab igne Venous thrombosis (‘thrombophlebitis migrans’) Metastases common Obstructed common bile duct and dilated gallbladder Cancer Dilated pancreatic duct Lymph node spread at early stage Jaundice Cachexia Depression Vomiting from duodenal obstruction Hepatomegaly (extrahepatic biliary obstruction/secondary deposits) Palpable gallbladder (Courvoisier’s sign) Scratch marks (obstructive jaundice) Fig. 21.70 Carcinoma of the pancreas. A A computed tomogram showing a large, necrotic mass encasing the coeliac axis (arrows). B Endoscopic ultrasound was subsequently performed to enhance staging and to obtain a fine needle aspiration biopsy, which confirmed pancreatic ductal adenocarcinoma. A B

844 • GASTROENTEROLOGY or to monitor depends on age and fitness of the patient and location, size and evolution of lesions. Further information Books and journal articles Canard JM, Letard J-C, Palazzo L, et al. Gastrointestinal endoscopy in practice. Edinburgh: Churchill Livingstone; 2011. Feldman M, Friedman LS, Brandt LJ. Sleisenger and Fordtran’s Gastrointestinal and liver disease, 10th edn. Philadelphia: Elsevier Saunders; 2015. Websites bsg.org.uk British Society of Gastroenterology. crohnsandcolitis.org.uk Crohn’s and Colitis UK. coeliac.org.uk Coeliac UK. ecco-ibd.eu European Crohn’s and Colitis Organisation. gastro.org American Gastroenterological Association and American Digestive Health Foundation. isg.org.in Indian Society of Gastroenterology. of ampullary or periampullary tumours survive for 5 years, in contrast to patients with pancreatic ductal cancer. Incidental pancreatic mass Cystic neoplasms of the pancreas are increasingly being seen with widespread use of CT. These are a heterogeneous group; serous cystadenomas rarely, if ever, become malignant and do not require surgery. Mucinous cysts occur more often in women, are usually in the pancreatic tail and display a spectrum of behaviour from benign to frankly malignant. Aspiration of the cyst contents for cytology and measurement of CEA and amylase concentrations in fluid obtained at EUS can help determine whether a lesion is mucinous or not. In fit patients, all mucinous lesions should be resected. A variant, called intraductal papillary mucinous neoplasia (IPMN), is often discovered coincidentally on CT, frequently in elderly men. This may affect the main pancreatic duct with marked dilatation and plugs of mucus, or may involve a side branch. The histology varies from villous adenomatous change to dysplasia or carcinoma. Since IPMN is a pre-malignant but indolent condition, the decision to resect

Ch04-3 Clinical Medicine

12-22 Hepatology

22 Hepatology

Hepatology QM Anstee DEJ Jones Clinical examination of the abdomen for liver and biliary disease 846 Functional anatomy and physiology 848 Applied anatomy 848 Hepatic function 850 Investigation of liver and hepatobiliary disease 852 Liver blood biochemistry 852 Haematological tests 853 Immunological tests 853 Imaging 853 Histological examination 855 Non-invasive markers of hepatic fibrosis 855 Presenting problems in liver disease 855 Acute liver failure 856 Abnormal liver function tests 859 Jaundice 860 Hepatomegaly 862 Ascites 862 Hepatic encephalopathy 864 Variceal bleeding 865 Cirrhosis 866 Portal hypertension 868 Infections and the liver 871 Viral hepatitis 871 HIV infection and the liver 879 Liver abscess 879 Alcoholic liver disease 880 Non-alcoholic fatty liver disease 882 Autoimmune liver and biliary disease 885 Autoimmune hepatitis 886 Primary biliary cholangitis 887 Primary sclerosing cholangitis 888 IgG4-associated cholangitis 890 Liver tumours and other focal liver lesions 890 Primary malignant tumours 890 Secondary malignant tumours 892 Benign tumours 893 Drugs and the liver 893 Drug-induced liver injury 894 Inherited liver diseases 895 Haemochromatosis 895 Wilson’s disease 896 Alpha1-antitrypsin deficiency 897 Gilbert’s syndrome 897 Vascular liver disease 898 Hepatic arterial disease 898 Portal venous disease 898 Hepatic venous disease 898 Pregnancy and the liver 899 Intercurrent and pre-existing liver disease 900 Pregnancy-associated liver disease 900 Liver transplantation 900 Indications and contraindications 900 Complications 901 Prognosis 901 Cholestatic and biliary disease 902 Chemical cholestasis 902 Benign recurrent intrahepatic cholestasis 902 Intrahepatic biliary disease 902 Extrahepatic biliary disease 902 Secondary biliary cirrhosis 903 Gallstones 903 Cholecystitis 905 Choledocholithiasis 906 Tumours of the gallbladder and bile duct 907 Miscellaneous biliary disorders 908

846 • HEPATOLOGY Clinical examination of the abdomen for liver and biliary disease Observation Face Jaundice Spider naevi Parotid swelling Chest Loss of body hair Abdomen: inspection Scars Distension Veins Testicular atrophy • Unkempt • Smell of alcohol or fetor hepaticus • Encephalopathy • Weight loss • Scratch marks from itching Hands Clubbing Dupuytren’s contracture Leuconychia Bruising Flapping tremor (hepatic encephalopathy) Legs Bruising Oedema Xanthelasma and jaundiced sclera in a patient with chronic cholestasis Palmar erythema Spider naevi Aspiration of ascitic fluid Gynaecomastia Abdomen: palpation/ percussion/auscultation Hepatomegaly Splenomegaly Ascites Palpable gallbladder Hepatic bruit (rare) Tumour Dilated abdominal wall veins (caput medusae) Kayser–Fleischer rings in Wilson’s disease

Insets (Spider naevi) From Hayes P, Simpson K. Gastroenterology and liver disease. Edinburgh: Churchill Livingstone, Elsevier Ltd; 1995; (Aspiration) Strachan M. Davidson’s Clinical cases. Edinburgh: Churchill Livingstone, Elsevier Ltd; 2008; (Palmar erythema) Goldman L, Schafter AI. Goldman’s Cecil medicine, 24th edn. Philadelphia: WB Saunders, Elsevier Inc.; 2012.

Clinical examination of the abdomen for liver and biliary disease • 847

5 Assessment of liver size Clinical assessment of hepatomegaly is important in diagnosing liver disease. • Start in the right iliac fossa. • Progress up the abdomen 2 cm with each breath (through open mouth). • Confirm the lower border of the liver by percussion. • Detect if smooth or irregular, tender or non-tender; ascertain the shape. • Identify the upper border by percussion. 1 Assessment of encephalopathy Flapping tremor. Jerky forward movements every 5–10 secs, when arms are outstretched and hands are dorsiflexed, suggest hepatic encephalopathy. The movements are coarser than those seen in tremor. Number connection test. These 25 numbered circles can normally be joined together within 30 secs. Serial observations may provide useful information, as long as the position of the numbers is varied to avoid the patient learning their pattern. Begin End

Constructional apraxia. Drawing stars and clocks may reveal marked abnormality. Doctor Patient Ascites Causes Associated clinical findings Exudative (high protein) Carcinoma Weight loss ± hepatomegaly Tuberculosis Weight loss ± fever Transudative (low protein) Cirrhosis Hepatomegaly Splenomegaly Spider naevi Renal failure (including nephrotic syndrome) Generalised oedema Peripheral oedema Congestive heart failure Elevated jugular venous pressure It is important to note that patients with liver disease can present silently following detection of abnormality on screening investigation. This occurs frequently in practice in three settings: Biochemical abnormality • Liver enzyme abnormality detected during health screening or drug monitoring Radiological abnormality • Observation of an unexpected structural lesion (liver mass most usually) following ultrasound, computed tomography or other imaging assessment undertaken for reasons unrelated to the liver Serological abnormality • Detection of a liver-related autoantibody Silent presentation of liver disease History and significance of abdominal signs These represent the combined effects of: Impairment of liver function and its metabolic sequelae • Jaundice (failure of bilirubin clearance) • Encephalopathy (failure of clearance of by-products of metabolism) • Bleeding (impaired liver synthesis of clotting factors) • Hypoglycaemia Ongoing presence of aetiological factors (e.g. alcohol) • Effects of aetiological agent, e.g. intoxication, withdrawal, cognitive impairment versus • Effects of liver injury from agent, e.g. encephalopathy Effects of chronic liver injury (> 6 months) Catabolic status (± poor nutrition) • Skin thinning (‘paper-money skin’) • Loss of muscle bulk • Leuconychia Impaired albumin synthesis • Reduced oncotic pressure (contributes to ascites) Reduced aldosterone clearance • Na+ retention (contributes to ascites) Reduced oestrogen clearance • Mild feminisation of males (loss of body hair, gynaecomastia) Presenting clinical features of liver disease

848 • HEPATOLOGY biliary tree. The segmental anatomy of the liver has an important influence on imaging and treatment of liver tumours, given the increasing use of surgical resection. A liver segment is made up of multiple smaller units known as lobules, comprised of a central vein, radiating sinusoids separated from each other by single liver cell (hepatocyte) plates, and peripheral portal tracts. The functional unit of the liver is the hepatic acinus (Fig. 22.2). Blood flows into the acinus via a single branch of the portal vein and hepatic artery situated centrally in the portal tracts. Blood flows outwards along the hepatic sinusoids into one of several tributaries of the hepatic vein at the periphery of the acinus. Bile, formed by active and passive excretion by hepatocytes into channels called cholangioles, which lie between them, flows in the opposite direction from the periphery of the acinus. The cholangioles converge in interlobular bile ducts in the portal tracts. The hepatocytes in each acinus lie in three zones, depending on their position relative to the portal tract. Those in zone 1 are closest to the terminal branches of the portal vein and hepatic artery, and are richly supplied with oxygenated blood, and with blood containing the highest concentration of nutrients and toxins. Conversely, hepatocytes in zone 3 are furthest from the portal tracts and closest to the hepatic veins, and are therefore relatively hypoxic and exposed to lower concentrations of nutrients and toxins compared to zone 1. The different perfusion and toxin exposure patterns, and thus vulnerability, of hepatocytes in the different zones contribute to the often patchy nature of liver injury. Liver cells Hepatocytes comprise 80% of liver cells. The remaining 20% are the endothelial cells lining the sinusoids, epithelial cells lining the intrahepatic bile ducts, cells of the immune system (including macrophages (Kupffer cells) and unique populations of atypical lymphocytes), and a key population of non-parenchymal cells called stellate or Ito cells. Fig. 22.1 Liver blood supply. Inferior vena cava VIII VII II I VI V IV III Left hemiliver (LHL) Right hemiliver (RHL) Hepatic vein Portal vein Fig. 22.2 Liver structure and microstructure. A Liver anatomy showing relationship with pancreas, bile duct and duodenum. B Hepatic lobule. C Hepatic acinus. Hepatic acinus Right hepatic duct Common hepatic duct Left hepatic duct Common bile duct Portal vein Central vein Hepatic lobule Hepatic artery Bile duct Sphincter of Oddi Pancreatic duct Pancreas Cholangiole A B C Liver Gallbladder Cystic duct Portal vein Hepatic artery Bile duct Central vein Zone 3 (pericentral) Mono-oxygenation Glycolysis Lipolysis Glucuronidation Zone 2 Zone 1 (perivenous) Good O2 supply Gluconeogenesis Bile salt formation Bile flow Blood flow Duodenum Functional anatomy and physiology Applied anatomy Normal liver structure and blood supply The liver weighs 1.2–1.5 kg and has multiple functions, including key roles in metabolism, control of infection, and elimination of toxins and by-products of metabolism. It is classically divided into left and right lobes by the falciform ligament, but a more useful functional division is into the right and left hemilivers, based on blood supply (Fig. 22.1). These are further divided into eight segments, according to subdivisions of the hepatic and portal veins. Each segment has its own branch of the hepatic artery and

Functional anatomy and physiology • 849

to the hepatocytes. Individual hepatocytes are separated from the leaky sinusoids by the space of Disse, which contains stellate cells that store vitamin A and play an important part in regulating liver blood flow. They may also be immunologically active and play a role in the liver’s contribution to defence against pathogens. The key role of stellate cells in terms of pathology is in the development of hepatic fibrosis, the precursor of cirrhosis. They undergo activation in response to cytokines produced following liver injury, differentiating into myofibroblasts, which are the major producers of the collagen-rich matrix that forms fibrous tissue (Fig. 22.4). Blood supply The liver is unique as an organ, as it has dual perfusion: it receives a majority of its supply via the portal vein, which drains blood from the gut via the splanchnic circulation and is the principal route for nutrient trafficking to the liver, and a minority from the hepatic artery. The portal venous contribution is 50–90%. The dual perfusion system, and the variable contribution from portal vein and hepatic artery, can have important effects on the clinical expression of liver ischaemia (which typically exhibits a less dramatic pattern than ischaemia in other organs, a fact that can sometimes lead to it being missed clinically), and can raise practical challenges in liver transplant surgery. Biliary system and gallbladder Hepatocytes provide the driving force for bile flow by creating osmotic gradients of bile acids, which form micelles in bile (bile Fig. 22.3 Non-parenchymal liver cells. (B cell = B lymphocyte; NK cell = natural killer cell; PMN cell = polymorphonuclear leucocyte; T cell = T lymphocyte). Space of Disse Hepatocyte Kupffer cell B cell Stellate cell Sinusoid lumen PMN cell Endothelial cell NK cell T cell Fig. 22.4 Pathogenic mechanisms in hepatic fibrosis. Stellate cell activation occurs under the influence of cytokines released by other cell types in the liver, including hepatocytes, Kupffer cells (tissue macrophages), platelets and lymphocytes. Once stellate cells become activated, they can perpetuate their own activation by synthesis of transforming growth factor beta (TGF-β1), and platelet-derived growth factor (PDGF) through autocrine loops. Activated stellate cells produce TGF-β1, stimulating the production of collagen matrix, as well as inhibitors of collagen breakdown. The inhibitors of collagen breakdown, matrix metalloproteinase 2 and 9 (MMP2 and MMP9), are inactivated in turn by tissue inhibitors TIMP1 and TIMP2, which are increased in fibrosis. Inflammation also contributes to fibrosis, with the cytokine profile produced by Th2 lymphocytes, such as interleukin-6 and 13 (IL-6 and IL-13). Activated stellate cells also produce endothelin 1 (ET1), which may contribute to portal hypertension. (EGF = epidermal growth factor; IGF1 = insulin-like growth factor 1; ROS = reactive oxygen species) Stellate cell Activated stellate cell Peroxide products IGF1 TGF-α Injured hepatocyte EGF Platelets TGF-β1 PDGF Initiation Activated Kupffer cell Chemotaxis Vasoconstriction (ET1) Cytokine production (IL-10) Perpetuation TGF-β1 PDGF ROS PDGF ROS Matrix degeneration (MMP2, TIMP1+ 2) Fibrogenesis (TGF-β1) TGF-β1 Endothelial cells line the sinusoids (Fig. 22.3), a network of capillary vessels that differ from other capillary beds in the body, in that there is no basement membrane. The endothelial cells have gaps between them (fenestrae) of about 0.1 micron in diameter, allowing free flow of fluid and particulate matter

850 • HEPATOLOGY converted to glycerol and fatty acids, thus preventing hyperglycaemia. During fasting, glucose is synthesised (gluconeogenesis) or released from glycogen in the liver, thereby preventing hypoglycaemia (p. 724). • The liver plays a central role in lipid metabolism, producing very low-density lipoproteins and further metabolising low- and high-density lipoproteins (see Fig. 14.13, p. 372). Dysregulation of lipid metabolism is thought to have a critical role in the pathogenesis of NAFLD. Lipids are now recognised to play a key part in the pathogenesis of hepatitis C, facilitating viral entry into hepatocytes. Clotting factors The liver produces key proteins that are involved in the coagulation cascade. Many of these coagulation factors (II, VII, IX and X) are post-translationally modified by vitamin K-dependent enzymes, and their synthesis is impaired in vitamin K deficiency (p. 918). Reduced clotting factor synthesis is an important and easily accessible biomarker of liver function in the setting of liver injury. Prothrombin time (PT; or the International Normalised Ratio, INR) is therefore one of the most important clinical tools available for the assessment of hepatocyte function. Note that the deranged PT or INR seen in liver disease may not directly equate to increased bleeding risk, as these tests do not capture the concurrent reduced synthesis of anticoagulant factors, including protein C and protein S. In general, therefore, correction of PT using blood products before minor invasive procedures should be guided by clinical risk rather than the absolute value of the PT. Bilirubin metabolism and bile The liver plays a central role in the metabolism of bilirubin and is responsible for the production of bile (Fig. 22.6). Between 425 and 510 mmol (250–300 mg) of unconjugated bilirubin is produced from the catabolism of haem daily. Bilirubin in the acid-dependent bile flow), and of sodium (bile acid-independent bile flow). Bile is secreted by hepatocytes and flows from cholangioles to the biliary canaliculi. The canaliculi join to form larger intrahepatic bile ducts, which in turn merge to form the right and left hepatic ducts. These ducts join as they emerge from the liver to form the common hepatic duct, which becomes the common bile duct after joining the cystic duct (see Fig. 22.2). The common bile duct is approximately 5 cm long and 4–6 mm wide. The distal portion of the duct passes through the head of the pancreas and usually joins the pancreatic duct before entering the duodenum through the ampullary sphincter (sphincter of Oddi). It should be noted, though, that the anatomy of the lower common bile duct can vary widely. Common bile duct pressure is maintained by rhythmic contraction and relaxation of the sphincter of Oddi; this pressure exceeds gallbladder pressure in the fasting state, so that bile normally flows into the gallbladder, where it is concentrated 10-fold by resorption of water and electrolytes. The gallbladder is a pear-shaped sac typically lying under the right hemiliver, with its fundus located anteriorly behind the tip of the 9th costal cartilage. Anatomical variation is common and should be considered when assessing patients clinically and radiologically. The function of the gallbladder is to concentrate, and provide a reservoir for, bile. Gallbladder tone is maintained by vagal activity, and cholecystokinin released from the duodenal mucosa during feeding causes gallbladder contraction and reduces sphincter pressure, so that bile flows into the duodenum. The body and neck of the gallbladder pass posteromedially towards the porta hepatis, and the cystic duct then joins it to the common hepatic duct. The cystic duct mucosa has prominent crescentic folds (valves of Heister), giving it a beaded appearance on cholangiography. Hepatic function Carbohydrate, amino acid and lipid metabolism The liver plays a central role in carbohydrate, lipid and amino acid metabolism, and is also involved in metabolising drugs and environmental toxins (Fig. 22.5). An important and increasingly recognised role for the liver is in the integration of metabolic pathways, regulating the response of the body to feeding and starvation. Abnormality in metabolic pathways and their regulation can play an important role both in liver disease (e.g. non-alcoholic fatty liver disease, NAFLD) and in diseases that are not conventionally regarded as diseases of the liver (such as type 2 diabetes and inborn errors of metabolism). Hepatocytes have specific pathways to handle each of the nutrients absorbed from the gut and carried to the liver via the portal vein: • Amino acids from dietary proteins are used for synthesis of plasma proteins, including albumin. The liver produces 8–14 g of albumin per day, and this plays a critical role in maintaining oncotic pressure in the vascular space and in the transport of small molecules like bilirubin, hormones and drugs throughout the body. Amino acids that are not required for the production of new proteins are broken down, with the amino group being converted ultimately to urea. • Following a meal, more than half of the glucose absorbed is taken up by the liver and stored as glycogen or Fig. 22.5 Important liver functions. Excretion Bile salts Bilirubin Drugs Phospholipid Cholesterol Storage Iron Copper Vitamins A, D and B12 Nutrient metabolism Carbohydrate Protein Lipids Protein synthesis Albumin Coagulation factors Complement factors Haptoglobin Caeruloplasmin Transferrin Protease inhibitors, e.g. α1-antitrypsin Immune functions Local cells (Kupffer cells) Innate factors (defensins etc.)

Functional anatomy and physiology • 851

fat-soluble vitamins, as occurs in biliary obstruction, results in a coagulopathy. The liver also stores minerals such as iron, in ferritin and haemosiderin, and copper, which is excreted in bile. Immune regulation Approximately 9% of the normal liver is composed of immune cells (see Fig. 22.3). Cells of the innate immune system include Kupffer cells derived from blood monocytes, the liver macrophages and natural killer (NK) cells, as well as ‘classical’ B and T cells of the adaptive immune response (p. 67). An additional type of atypical lymphocyte, with phenotypic features of both T cells and NK cells, is thought to play an important role in host defence through linking of innate and adaptive immunity. The enrichment of such cells in the liver reflects the unique importance of the liver in preventing microorganisms from the gut from entering the systemic circulation. Kupffer cells constitute the largest single mass of tissue-resident macrophages in the body and account for 80% of the phagocytic capacity of this system. They remove aged and damaged red blood cells, bacteria, viruses, antigen–antibody complexes and endotoxin. They also produce a wide variety of inflammatory mediators that can act locally or may be released into the systemic circulation. The immunological environment of the liver is unique in that antigens presented within it tend to induce immunological tolerance. This is of importance in liver transplantation, where classical major histocompatibility (MHC) barriers may be crossed, and also in chronic viral infections, when immune responses may be attenuated. The mechanisms that underlie this phenomenon have not been fully defined. blood is normally almost all unconjugated and, because it is not water-soluble, is bound to albumin and does not pass into the urine. Unconjugated bilirubin is taken up by hepatocytes at the sinusoidal membrane, where it is conjugated in the endoplasmic reticulum by UDP-glucuronyl transferase, producing bilirubin mono- and diglucuronide. Impaired conjugation by this enzyme is a cause of inherited hyperbilirubinaemias (see Box 22.17). These bilirubin conjugates are water-soluble and are exported into the bile canaliculi by specific carriers on the hepatocyte membranes. The conjugated bilirubin is excreted in the bile and passes into the duodenal lumen. Once in the intestine, conjugated bilirubin is metabolised by colonic bacteria to form stercobilinogen, which may be further oxidised to stercobilin. Both stercobilinogen and stercobilin are then excreted in the stool, contributing to its brown colour. Biliary obstruction results in reduced stercobilinogen in the stool, and the stools become pale. A small amount of stercobilinogen (4 mg/day) is absorbed from the bowel, passes through the liver and is excreted in the urine, where it is known as urobilinogen or, following further oxidisation, urobilin. The liver secretes 1–2 L of bile daily. Bile contains bile acids (formed from cholesterol), phospholipids, bilirubin and cholesterol. Several biliary transporter proteins have been identified (Fig. 22.7). Mutations in genes encoding these proteins have been identified in inherited intrahepatic biliary diseases presenting in childhood, and in adult-onset disease such as intrahepatic cholestasis of pregnancy and gallstone formation. Storage of vitamins and minerals Vitamins A, D and B12 are stored by the liver in large amounts, while others, such as vitamin K and folate, are stored in smaller amounts and disappear rapidly if dietary intake is reduced. The liver is also able to metabolise vitamins to more active compounds, e.g. 7-dehydrocholesterol to 25(OH) vitamin D. Vitamin K is a fat-soluble vitamin and so the inability to absorb Fig. 22.6 Pathway of bilirubin excretion. Liver Kidney Urobilinogen (4 mg/day) Urobilin Bilirubin mono- or diglucuronide (conjugated) Bile Stercobilinogen (100 –200 mg/day) Stercobilin Stool Colonic bacteria Large intestine Bilirubin (unconjugated) Urobilinogen (enterohepatic circulation) Blood Fig. 22.7 Biliary transporter proteins. On the hepatocyte basolateral membrane, sodium taurocholate co-transporting polypeptide (NTCP) mediates uptake of conjugated bile acids from portal blood. At the canalicular membrane, these bile acids are secreted via the bile salt export pump (BSEP) into bile. Multidrug resistance protein 3 (MDR3), also situated on the canalicular membrane, transports phospholipid to the outer side of the membrane. This solubilises bile acids, forming micelles and protecting bile duct membranes from bile salt damage. Familial intrahepatic cholestasis 1 (FIC1) moves phosphatidylserine from the inside to the outside of the canalicular membrane; mutations result in familial cholestasis syndrome in childhood. MDR2 (multidrug resistance 2) regulates transport of glutathione. Multidrug resistance protein 2 (MRP2) transports bilirubin and is induced by rifampicin. Organic anion transporter protein (OATP) transports bilirubin and organic anions. Bile duct NTCP Bile acids Bilirubin and organic anions OATP MDR3 BSEP Hepatocytes MDR2 Sinusoid Bile canaliculus MRP2 FIC1

852 • HEPATOLOGY Bilirubin and albumin The degree of elevation of bilirubin can reflect the degree of liver damage. A raised bilirubin often occurs earlier in the natural history of biliary disease (e.g. PBC) than in disease of the liver parenchyma (e.g. cirrhosis), where the hepatocytes are primarily involved. Swelling of the liver within its capsule in inflammation can, however, sometimes impair bile flow and cause an elevation of bilirubin level that is disproportionate to the degree of liver injury. Caution is therefore needed in interpreting the level of liver injury purely on the basis of bilirubin elevation. Serum albumin levels are often low in patients with liver disease. This is due to a change in the volume of distribution of albumin, and to reduced synthesis. Since the plasma half-life of albumin is about 2 weeks, albumin levels may be normal in acute liver failure but are almost always reduced in chronic liver failure. Alanine aminotransferase and aspartate aminotransferase Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) are located in the cytoplasm of the hepatocyte; AST is also located in the hepatocyte mitochondria. Although both transaminase enzymes are widely distributed, expression of ALT outside the liver is relatively low and this enzyme is therefore considered more specific for hepatocellular damage. Large increases of aminotransferase activity favour hepatocellular damage, and this pattern of LFT abnormality is known as ‘hepatitic’. Alkaline phosphatase and γ-glutamyl transferase Alkaline phosphatase (ALP) is the collective name given to several different enzymes that hydrolyse phosphate esters at alkaline pH. These enzymes are widely distributed in the body but the main sites of production are the liver, gastrointestinal tract, bone, placenta and kidney. ALPs are post-translationally modified, resulting in the production of several different isoenzymes, which differ in abundance in different tissues. ALP enzymes in the liver are located in cell membranes of the hepatic sinusoids and the biliary canaliculi. Accordingly, levels rise with intrahepatic and extrahepatic biliary obstruction and with sinusoidal obstruction, as occurs in infiltrative liver disease. Gamma-glutamyl transferase (GGT) is a microsomal enzyme found in many cells and tissues of the body. The highest concentrations are located in the liver, where it is produced by hepatocytes and by the epithelium lining small bile ducts. The function of GGT is to transfer glutamyl groups from γ-glutamyl peptides to other peptides and amino acids. The pattern of a modest increase in aminotransferase activity and large increases in ALP and GGT activity favours biliary obstruction and is commonly described as ‘cholestatic’ or ‘obstructive’ (Box 22.2). Isolated elevation of the serum GGT is relatively common and may occur during ingestion of microsomal enzyme-inducing drugs, including alcohol (Box 22.3), but also in NAFLD. Other biochemical tests Other widely available biochemical tests may become altered in patients with liver disease: • Hyponatraemia occurs in severe liver disease due to increased production of vasopressin (antidiuretic hormone, Investigation of liver and hepatobiliary disease Investigations play an important role in the management of liver disease in three settings: • identifying the presence of liver disease • establishing the aetiology • understanding disease severity (in particular, identification of cirrhosis with its complications). When planning investigations, it is important to be clear as to which of these goals is being addressed. Suspicion of the presence of liver disease is normally based on blood biochemistry abnormality (‘liver function tests’, or ‘LFTs’). Aetiology is typically established through a combination of history, specific blood tests and, where appropriate, imaging and liver biopsy. Staging of disease (in essence, the identification of cirrhosis) is largely histological, although there is increasing interest in noninvasive approaches, including novel imaging modalities, serum markers of fibrosis and the use of predictive scoring systems. The aims of investigation in patients with suspected liver disease are shown in Box 22.1. Liver blood biochemistry Liver blood biochemistry (LFTs) includes the measurement of serum bilirubin, aminotransferases, alkaline phosphatase, γ-glutamyl transferase and albumin. Most analytes measured by LFTs are not truly ‘function’ tests but instead, given that they are released by injured hepatocytes, provide biochemical evidence of liver cell damage. Liver function per se is best assessed by the serum albumin, PT and bilirubin because of the role played by the liver in synthesis of albumin and clotting factors and in clearance of bilirubin. Although LFT abnormalities are often non-specific, the patterns are frequently helpful in directing further investigations. In addition, levels of bilirubin and albumin and the PT are related to clinical outcome in patients with severe liver disease, reflected by their use in several prognostic scores: the Child–Pugh and MELD scores in cirrhosis (see Boxes 22.29 and 22.30, pp. 867 and 868), the Glasgow score in alcoholic hepatitis (see Box 22.47, p. 882) and the King’s College Hospital criteria for liver transplantation in acute liver failure (see Box 22.11, p. 858). These established predictive models, together with emerging disease-specific scoring systems in conditions such as non-alcoholic steatohepatitis (the NASH fibrosis score) and primary biliary cholangitis (PBC, formerly known as primary biliary cirrhosis; the UK-PBC risk score), systematise the approach to assessing abnormal LFTs and can be important for the targeting of more expensive and/or invasive confirmatory diagnostic tests. 22.1 Aims of investigations in patients with suspected liver disease • Detect hepatic abnormality • Measure the severity of liver damage • Detect the pattern of liver function test abnormality: hepatitic or obstructive/cholestatic • Identify the specific cause • Investigate possible complications

Investigation of liver and hepatobiliary disease • 853

A low platelet count is often an indicator of chronic liver disease, particularly in the context of hepatomegaly. Thrombocytosis is unusual in patients with liver disease but may occur in those with active gastrointestinal haemorrhage and, rarely, in hepatocellular carcinoma. Coagulation tests These are often abnormal in patients with liver disease. The normal half-lives of the vitamin K-dependent coagulation factors in the blood are short (5–72 hours), and so changes in the PT occur relatively quickly following liver damage; these changes provide valuable prognostic information in patients with both acute and chronic liver failure. An increased PT is evidence of severe liver damage in chronic liver disease. Vitamin K does not reverse this deficiency if it is due to liver disease, but will correct the PT if the cause is vitamin K deficiency, as may occur with biliary obstruction due to non-absorption of fat-soluble vitamins. Immunological tests A variety of tests are available to evaluate the aetiology of hepatic disease (Boxes 22.4 and 22.5). The presence of liverrelated autoantibodies can be suggestive of the presence of autoimmune liver disease (although false-positive results can occur in non-autoimmune inflammatory disease such as NAFLD). Elevation in overall serum immunoglobulin levels can also indicate autoimmunity (immunoglobulin G (IgG) and IgM). Elevated serum IgA can be seen, often in more advanced alcoholic liver disease and NAFLD, although the association is not specific. ADH; see Fig. 14.8, p. 359). Hyponatraemia can be a significant clinical problem in liver disease with aspects that are distinct from hyponatraemia of other causes. • Serum urea may be reduced in hepatic failure, whereas levels of urea may be increased following gastrointestinal haemorrhage. • When high levels of urea are accompanied by raised bilirubin, high serum creatinine and low urinary sodium, this suggests hepatorenal failure, which carries a grave prognosis. • Significantly elevated ferritin suggests haemochromatosis. Modest elevations can be seen in inflammatory disease, NAFLD and alcohol excess. Haematological tests Blood count The peripheral blood count is often abnormal and can give a clue to the underlying diagnosis: • A normochromic normocytic anaemia may reflect recent gastrointestinal haemorrhage, whereas chronic blood loss is characterised by a hypochromic microcytic anaemia secondary to iron deficiency. A high erythrocyte mean cell volume (macrocytosis) is associated with alcohol misuse, but target cells in any jaundiced patient also result in a macrocytosis. Macrocytosis can persist for a long period of time after alcohol cessation, making it a poor marker of ongoing consumption. • Leucopenia may complicate portal hypertension and hypersplenism, whereas leucocytosis may occur with cholangitis, alcoholic hepatitis and hepatic abscesses. Atypical lymphocytes are seen in infectious mononucleosis, which may be complicated by an acute hepatitis. • Thrombocytopenia is common in cirrhosis and is due to reduced platelet production and increased breakdown because of hypersplenism. Thrombopoietin, required for platelet production, is produced in the liver and levels fall with worsening liver function. Thus platelet levels are usually more depressed than white cells and haemoglobin in the presence of hypersplenism in patients with cirrhosis. 22.2 ‘Hepatitic’ and ‘cholestatic’/‘obstructive’ liver function tests Pattern AST/ALT GGT ALP Biliary obstruction ↑ ↑↑ ↑↑↑ Hepatitis ↑↑↑ ↑ ↑ Alcohol/enzyme-inducing drugs N/↑ ↑↑ N N = normal; ↑ mild elevation (< twice normal); ↑↑ moderate elevation (2–5 times normal); ↑↑↑ marked elevation (> 5 times normal). (ALT = alanine aminotransferase; ALP = alkaline phosphatase; AST = aspartate aminotransferase; GGT = gamma-glutamyltransferase) 22.3 Drugs that increase levels of γ-glutamyltransferase • Barbiturates • Carbamazepine • Ethanol • Griseofulvin • Rifampicin • Phenytoin 22.4 Chronic liver disease screen • Hepatitis B surface antigen • Hepatitis C antibody • Liver autoantibodies (antinuclear antibody, smooth muscle antibody, antimitochondrial antibody) • Immunoglobulins • Ferritin • α1-antitrypsin • Caeruloplasmin Imaging Several imaging techniques can be used to determine the site and general nature of structural lesions in the liver and biliary tree. In general, however, imaging techniques are unable to identify hepatic inflammation and have poor sensitivity for liver fibrosis unless advanced cirrhosis with portal hypertension is present. Ultrasound Ultrasound is non-invasive and most commonly used as a ‘first-line’ test to identify gallstones, biliary obstruction (Fig. 22.8) or thrombosis in the hepatic vasculature. Ultrasound is good for the identification of splenomegaly and abnormalities in liver texture but is less effective at identifying diffuse parenchymal disease. Focal lesions, such as tumours, may not be detected if they are less than 2 cm in diameter and have similar echogenicity to normal liver tissue. Bubble-based contrast media are now used routinely and can enhance discriminant capability. Doppler ultrasound allows blood flow in the hepatic artery, portal vein

854 • HEPATOLOGY Hepatic angiography is seldom used nowadays as a diagnostic tool, since CT and MRI are both able to provide images of hepatic vasculature, but it still has a therapeutic role in the embolisation of vascular tumours, such as hepatocellular carcinoma. Hepatic venography is now rarely performed. Cholangiography Cholangiography can be undertaken by magnetic resonance cholangiopancreatography (MRCP; Fig. 22.10), endoscopy (endoscopic retrograde cholangiopancreatography, ERCP) or the percutaneous approach (percutaneous transhepatic and hepatic veins to be investigated. Endoscopic ultrasound provides high-resolution images of the pancreas, biliary tree and liver (see below and Fig. 22.46, p. 906). Computed tomography and magnetic resonance imaging Computed tomography (CT) detects smaller focal lesions in the liver, especially when combined with contrast injection (Fig. 22.9). Magnetic resonance imaging (MRI) can also be used to localise and confirm the aetiology of focal liver lesions, particularly primary and secondary tumours. Fig. 22.8 Ultrasound showing a stone in the gallbladder (A) with acoustic shadow (S). S T 22.5 How to identify the cause of liver function test (LFT) abnormality Diagnosis Clinical clue Initial test Additional tests Alcoholic liver disease History LFTs AST > ALT; high MCV Random blood alcohol Non-alcoholic fatty liver disease (NAFLD) Metabolic syndrome (central obesity, diabetes, hypertension) LFTs Liver biopsy Chronic hepatitis B Injection drug use; blood transfusion HBsAg HBeAg, HBeAb HBV-DNA Chronic hepatitis C Injection drug use; blood transfusion HCV antibody HCV-RNA Primary biliary cholangitis Itching; raised ALP AMA Liver biopsy Primary sclerosing cholangitis Inflammatory bowel disease MRCP ANCA Autoimmune hepatitis Other autoimmune diseases ASMA, ANA, LKM, immunoglobulin Liver biopsy Haemochromatosis Diabetes/joint pain Transferrin saturation, ferritin HFE gene test Wilson’s disease Neurological signs; haemolysis Caeruloplasmin 24-hour urinary copper α1-antitrypsin Lung disease α1-antitrypsin level α1-antitrypsin genotype Drug-induced liver disease Drug/herbal remedy history LFTs Liver biopsy Coeliac disease Malabsorption Tissue transglutaminase Duodenal biopsy (ALP = alkaline phosphatase; ALT = alanine aminotransferase; AMA = antimitochondrial antibody; ANA = antinuclear antibody; ANCA = antineutrophil cytoplasmic antibody; ASMA = anti-smooth muscle antibody; AST = aspartate aminotransferase; HBeAb = antibody to hepatitis B e antigen; HBeAg = hepatitis B e antigen; HBsAg = hepatitis B surface antigen; HBV = hepatitis B virus; HCV = hepatitis C virus; HFE = haemochromatosis (high iron/Fe); LKM = liver–kidney microsomal antibody; MCV = mean cell volume; MRCP = magnetic resonance cholangiopancreatography) Fig. 22.9 Computed tomography in a patient with cirrhosis. The liver is small and has an irregular outline (black arrow), the spleen is enlarged (long white arrow), fluid (ascites) is seen around the liver, and collateral vessels are present around the proximal stomach (short white arrow).

Presenting problems in liver disease • 855

• the procedure is conducted percutaneously under ultrasound control and the needle track is then plugged with procoagulant material. In patients with potentially resectable malignancy, biopsy should be avoided due to the potential risk of tumour dissemination. Operative or laparoscopic liver biopsy may sometimes be valuable. Although the pathological features of liver disease are complex, with several features occurring together, liver disorders can be broadly classified histologically into fatty liver (steatosis), hepatitis (inflammation, ‘grade’) and cirrhosis (fibrosis, ‘stage’). The use of special histological stains can help in determining aetiology. The clinical features and prognosis of these changes are dependent on the underlying aetiology and are discussed in the relevant sections below. Non-invasive markers of hepatic fibrosis Non-invasive markers of liver fibrosis can reduce the need for liver biopsy to assess the extent of fibrosis in some settings. In general, they have high negative predictive value, being able to exclude the presence of advanced fibrosis, but a relatively low positive predictive value. It is important to note that many of these tests have been validated only in certain aetiologies of liver disease and therefore results cannot be extrapolated to all other liver diseases. Alcohol-related liver disease is particularly poorly served in this respect. Serological markers of hepatic fibrosis, such as α2-macroglobulin, haptoglobin and routine clinical biochemistry tests, are used in the Fibrotest®. The Enhanced Liver Fibrosis (ELF®) serological assay uses a combination of hyaluronic acid, procollagen peptide III (PIIINP) and tissue inhibitor of metalloproteinase 1 (TIMP1). These tests are good at differentiating severe fibrosis from mild scarring but are limited in their ability to detect subtle changes. A number of non-commercial scores based on standard biochemical and anthropometric indices have also been described that provide similar levels of sensitivity and specificity (e.g. the FIB4 score, which is based on age, ALT/AST ratio and platelet count). An alternative to serological markers is vibration-controlled transient elastography (Fibroscan®), in which ultrasound-based shock waves are sent through the liver to measure liver stiffness as a surrogate for hepatic fibrosis. Once again, this test is good at differentiating severe fibrosis from mild scarring, but it is limited in its ability to detect subtle changes and validity may be affected by obesity. Similar techniques, including magnetic resonance elastography, are promising but not yet widely available. Presenting problems in liver disease Liver injury may be either acute or chronic. The main causes are listed in Figure 22.11 and discussed in detail later in the chapter. In Fig. 22.10 Magnetic resonance cholangiopancreatography showing a biliary stricture due to cholangiocarcinoma in the distal common bile duct (arrow). The proximal common bile duct (CBD) is dilated but the pancreatic duct (PD) is normal. cholangiography, PTC). The latter does not allow the ampulla of Vater or pancreatic duct to be visualised. Endoscopic ultrasound can also provide high-quality biliary imaging safely (see below). MRCP is as good as ERCP at providing images of the biliary tree but is safer, and there is now little, if any, role for diagnostic ERCP. Both endoscopic and percutaneous approaches allow therapeutic interventions, such as the insertion of biliary stents across bile duct strictures. The percutaneous approach is used only if it is not possible to access the bile duct endoscopically. Endoscopic ultrasound Endoscopic ultrasound (EUS; p. 774) is complementary to MRCP in the diagnostic evaluation of the extrahepatic biliary tree, ampulla of Vater and pancreas. With the ultrasonic probe in the duodenum, high-quality images are obtained, tissue sampling can be performed and, increasingly, therapeutic drainage of biliary obstruction can be performed. EUS has the advantage over ERCP of not exposing patients to the risk of pancreatitis, among other complications of bile duct cannulation. Histological examination An ultrasound-guided liver biopsy can confirm the severity of liver damage and provide aetiological information. It is performed percutaneously with a Trucut or Menghini needle, usually through an intercostal space under local anaesthesia, or radiologically using a transjugular approach. Percutaneous liver biopsy is a relatively safe procedure if the conditions detailed in Box 22.6 are met, but carries a mortality of about 0.01%. The main complications are abdominal and/or shoulder pain, bleeding and biliary peritonitis. Biliary peritonitis is rare and usually occurs when a biopsy is performed in a patient with obstruction of a large bile duct. Liver biopsies can be carried out in patients with defective haemostasis if: • the defect is corrected with fresh frozen plasma and platelet transfusion • the biopsy is obtained by the transjugular route, or 22.6 Conditions required for safe percutaneous liver biopsy • Cooperative patient • Prothrombin time < 4 secs prolonged • Platelet count > 80 × 109/L • Exclusion of bile duct obstruction, localised skin infection, advanced chronic obstructive pulmonary disease, marked ascites and severe anaemia

856 • HEPATOLOGY significantly increased risk, whereas decompensation can be a complication in all cases and the presence of portal hypertension with intra-abdominal varices can make abdominal surgery more hazardous. The possibility of undiagnosed liver disease should be borne in mind in all patients in at-risk groups undergoing significant surgery. Acute liver failure Acute liver failure is an uncommon but serious condition characterised by a relatively rapid progressive deterioration in liver function. The presence of encephalopathy is a cardinal feature, with mental changes progressing from delirium to coma. The syndrome was originally defined further as occurring within 8 weeks of onset of the precipitating illness, in the absence of evidence of pre-existing liver disease. This distinguishes it from instances in which hepatic encephalopathy represents a deterioration in chronic liver disease. Liver failure occurs when there is insufficient metabolic and synthetic function for the needs of the patient. Although the direct cause is usually acute loss of functional hepatocytes, this can occur in different settings, which have implications for outcome and treatment. In a patient whose liver was previously normal (fulminant liver failure), the level of injury needed to cause liver Fig. 22.11 Causes of acute and chronic liver injury. Although there is often evidence of chronic liver disease at presentation, may present acutely with jaundice. In alcoholic liver disease this is due to superimposed alcoholic hepatitis. (NAFLD = non-alcoholic fatty liver disease; PBC = primary biliary cholangitis; PSC = primary sclerosing cholangitis) Acute liver injury Viral hepatitis (A, B, E) Alcoholic liver disease Autoimmune hepatitis* Drugs Chronic liver injury Chronic viral hepatitis (B + C) PBC PSC NAFLD Haemochromatosis a1-antitrypsin deficiency Cryptogenic (unknown) Wilson’s disease Fig. 22.12 Standardised UK mortality rates showing the rise in liver-related mortality. From Williams R, Aspinall R, Bellis M, et al. Addressing liver disease in the UK: a blueprint for attaining excellence in health care and reducing premature mortality from lifestyle issues of excess consumption of alcohol, obesity, and viral hepatitis. Reprinted with permission from Elsevier (The Lancet 2014; 384:1953–1997). Circulatory Ischaemic heart Cerebrovascular Neoplasms Respiratory Liver Endocrine or metabolic Diabetes

Year

Disease Standardised mortality (% change) the UK, liver disease is the only one of the top causes of mortality that is steadily increasing (Fig. 22.12). Mortality rates have risen substantially over the last 30 years, with a near-fivefold increase in liver-related mortality in people younger than 65 years. The rate of increase is substantially higher in the UK than in other countries in Western Europe. • Acute liver injury may present with non-specific symptoms of fatigue and abnormal LFTs, or with jaundice and acute liver failure. • Chronic liver injury is defined as hepatic injury, inflammation and/or fibrosis occurring in the liver for more than 6 months. In the early stages, patients can be asymptomatic with fluctuating abnormal LFTs. With more severe liver damage, however, the presentation can be with jaundice, portal hypertension or other signs of cirrhosis and hepatic decompensation (Box 22.7). Patients with clinically silent chronic liver disease frequently present when abnormalities in liver function are observed on routine blood testing, or when clinical events, such as an intercurrent infection or surgical intervention, cause the liver to decompensate. Patients with compensated cirrhosis can undergo most forms of surgery without 22.7 Presentation of liver disease Severity Acute liver injury Chronic liver injury Mild/moderate Abnormal liver function tests Abnormal liver function tests Severe Jaundice Signs of cirrhosis ± portal hypertension Very severe Acute liver failure Chronic liver failure* Jaundice Ascites Hepatic encephalopathy Portal hypertension with variceal bleeding *May not occur until several years after cirrhosis has presented.

Presenting problems in liver disease • 857

Clinical assessment Cerebral disturbance (hepatic encephalopathy and/or cerebral oedema) is the cardinal manifestation of acute liver failure, but in the early stages this can be mild and episodic, and so its absence does not exclude a significant acute liver injury. The initial clinical features are often subtle and include reduced alertness and poor concentration, progressing through behavioural abnormalities, such as restlessness and aggressive outbursts, to drowsiness and coma (Box 22.9). Cerebral oedema may occur due to increased intracranial pressure, causing unequal or abnormally reacting pupils, fixed pupils, hypertensive episodes, bradycardia, hyperventilation, profuse sweating, local or general myoclonus, focal fits or decerebrate posturing. Papilloedema occurs rarely and is a late sign. More general symptoms include weakness, nausea and vomiting. Right hypochondrial discomfort is an occasional feature. The patient may be jaundiced but jaundice may not be present at the outset (e.g. in paracetamol overdose), and there are a number of exceptions, including Reye’s syndrome, in which jaundice is rare. Occasionally, death may occur in fulminant cases of acute liver failure before jaundice develops. Fetor hepaticus can be present. The liver is usually of normal size but later becomes smaller. Hepatomegaly is unusual and, in failure, and thus the patient risk, is very high. In a patient with pre-existing chronic liver disease, the additional acute insult needed to precipitate liver failure is much less. It is critical, therefore, to understand whether liver failure is a true acute event or an acute deterioration on a background of pre-existing injury (which may itself not have been diagnosed). Although liver biopsy may ultimately be necessary, it is the presence or absence of the clinical features suggesting chronicity that guides the clinician. More recently, newer classifications have been developed to reflect differences in presentation and outcome of acute liver failure. One such classification divides acute liver failure into hyperacute, acute and subacute, according to the interval between onset of jaundice and encephalopathy (Box 22.8). Pathophysiology Any cause of liver damage can produce acute liver failure, provided it is sufficiently severe (Fig. 22.13). Acute viral hepatitis is the most common cause worldwide, whereas paracetamol toxicity (p. 137) is the most frequent cause in the UK. Acute liver failure occurs occasionally with other drugs, or from Amanita phalloides (mushroom) poisoning, in pregnancy, in Wilson’s disease, following shock (p. 199) and, rarely, in extensive malignant disease of the liver. In 10% of cases, the cause of acute liver failure remains unknown and these patients are often labelled as having ‘non-A–E viral hepatitis’ or ‘cryptogenic’ acute liver failure. Fig. 22.13 Causes of acute liver failure in the UK. The relative frequency of the different causes varies according to geographical area. Miscellaneous (< 5%) Acute liver failure Viral infections (5%) Drugs (70–80%) Poisons (< 5%) Amanita phalloides Paracetamol Halothane Antituberculous drugs Methylenedioxymethamphetamine (MDMA, 'ecstasy') Herbal remedies Hepatitis A, B, E (rare) Wilson's disease Acute fatty liver of pregnancy Shock and cardiac failure Budd–Chiari syndrome Leptospirosis Liver metastases Lymphoma Cryptogenic (5–10%) Non-A–E viral hepatitis 22.8 Classification of acute liver failure Type Time: jaundice to encephalopathy Cerebral oedema Common causes Hyperacute < 7 days Common Viral, paracetamol Acute 8–28 days Common Cryptogenic, drugs Subacute 29 days to 12 weeks Uncommon Cryptogenic, drugs 22.9 How to assess clinical grade of hepatic encephalopathy Clinical grade Clinical signs Grade 1 Poor concentration, slurred speech, slow mentation, disordered sleep rhythm Grade 2 Drowsy but easily rousable, occasional aggressive behaviour, lethargic Grade 3 Marked delirium, drowsy, sleepy but responds to pain and voice, gross disorientation Grade 4 Unresponsive to voice, may or may not respond to painful stimuli, unconscious

858 • HEPATOLOGY bilirubin reflects the degree of jaundice. Plasma aminotransferase activity is particularly high after paracetamol overdose, reaching 100–500 times normal, but falls as liver damage progresses and is not helpful in determining prognosis. Plasma albumin remains normal unless the course is prolonged. Percutaneous liver biopsy is contraindicated because of the severe coagulopathy, but biopsy can be undertaken using the transjugular route if appropriate. Management Patients with acute liver failure should be treated in a highdependency or intensive care unit as soon as progressive prolongation of the PT occurs or hepatic encephalopathy is identified (Box 22.12), so that prompt treatment of complications can be initiated (Box 22.13). Conservative treatment aims to maintain life in the hope that hepatic regeneration will occur, but early transfer to a specialised transplant unit should always be considered. N-acetylcysteine therapy may improve outcome, particularly in patients with acute liver failure due to paracetamol poisoning. Liver transplantation is an increasingly important treatment option for acute liver failure, and criteria have been developed to identify patients unlikely to survive without a transplant (see Box 22.11). Patients should, wherever possible, be transferred to a transplant centre before these criteria are met to allow time for assessment and to maximise the time for a donor liver to become available. Survival following liver transplantation Predict a mortality rate of ≥ 90% and are an indication for referral for possible liver transplantation. 22.11 Adverse prognostic criteria in acute liver failure Paracetamol overdose • H+ > 50 nmol/L (pH < 7.3) at or beyond 24 hours following the overdose Or • Serum creatinine > 300 μmol/L (≅ 3.38 mg/dL) plus prothrombin time > 100 secs plus encephalopathy grade 3 or 4 Non-paracetamol cases • Prothrombin time > 100 secs Or • Any three of the following: Jaundice to encephalopathy time > 7 days Age < 10 or > 40 years Indeterminate or drug-induced causes Bilirubin > 300 μmol/L (≅ 17.6 mg/dL) Prothrombin time > 50 secs Or • Factor V level < 15% and encephalopathy grade 3 or 4 22.10 Investigations to determine the cause of acute liver failure • Toxicology screen of blood and urine • HBsAg, IgM anti-HBc • IgM anti-HAV • Anti-HEV, HCV, cytomegalovirus, herpes simplex, Epstein–Barr virus • Caeruloplasmin, serum copper, urinary copper, slit-lamp eye examination • Autoantibodies: ANA, ASMA, LKM, SLA • Immunoglobulins • Ultrasound of liver and Doppler of hepatic veins (ANA = antinuclear antibody; anti-HBc = antibody to hepatitis B core antigen; ASMA = anti-smooth muscle antibody; HAV = hepatitis A virus; HBsAg = hepatitis B surface antigen; HCV = hepatitis C virus; HEV = hepatitis E virus; IgM = immunoglobulin M; LKM = liver–kidney microsomal antibody; SLA = soluble liver antigen) 22.12 Monitoring in acute liver failure Cardiorespiratory • Pulse • Blood pressure • Central venous pressure • Respiratory rate Neurological • Intracranial pressure monitoring (specialist units, p. 208) • Conscious level Fluid balance • Hourly output (urine, vomiting, diarrhoea) • Input: oral, intravenous Blood analyses • Arterial blood gases • Peripheral blood count (including platelets) • Sodium, potassium, HCO3−, calcium, magnesium • Creatinine, urea • Glucose (2-hourly in acute phase) • Prothrombin time Infection surveillance • Cultures: blood, urine, throat, sputum, cannula sites • Chest X-ray • Temperature the presence of a sudden onset of ascites, suggests venous outflow obstruction as the cause (Budd–Chiari syndrome, p. 898). Splenomegaly is uncommon and never prominent. Ascites and oedema are late developments and may be a consequence of fluid therapy. Other features are related to the development of complications (see below). Investigations The patient should be investigated to determine the cause of the liver failure and the prognosis (Boxes 22.10 and 22.11). Hepatitis B core IgM antibody is the best screening test for acute hepatitis B infection, as liver damage is due to the immunological response to the virus, which has often been eliminated, and the test for hepatitis B surface antigen (HBsAg) may be negative. The PT rapidly becomes prolonged as coagulation factor synthesis fails; this is the laboratory test of greatest prognostic value and should be carried out at least twice daily. Its prognostic importance emphasises the necessity of avoiding the use of fresh frozen plasma to correct raised PT in acute liver failure, except in the setting of frank bleeding. Factor V levels can be used instead of the PT to assess the degree of liver impairment. The plasma 22.13 Complications of acute liver failure • Encephalopathy and cerebral oedema • Hypoglycaemia • Metabolic acidosis • Infection (bacterial, fungal) • Renal failure • Multi-organ failure (hypotension and respiratory failure)

Presenting problems in liver disease • 859

When abnormal LFTs are detected, a thorough history should be compiled to determine the patient’s alcohol consumption, drug use (prescribed drugs or otherwise), risk factors for viral hepatitis (e.g. blood transfusion, injection drug use, tattoos), the presence of autoimmune diseases, family history, neurological symptoms, and the presence of features of the metabolic syndrome (p. 730), including diabetes and/or obesity (see Box 22.5 and Fig. 19.5, p. 698). The presence or absence of stigmata of 22.14 Common causes of elevated serum transaminases Minor elevation (< 100 U/L*) • Chronic hepatitis C • Chronic hepatitis B • Haemochromatosis • Fatty liver disease Moderate elevation (100–300 U/L*) As above plus: • Alcoholic hepatitis • Non-alcoholic steatohepatitis • Autoimmune hepatitis • Wilson’s disease Major elevation (> 300 U/L*) • Drugs (e.g. paracetamol) • Acute viral hepatitis • Autoimmune liver disease • Ischaemic liver • Toxins (e.g. Amanita phalloides poisoning) • Flare of chronic hepatitis B *These ranges are indicative but do not rigidly discriminate between different aetiologies. for acute liver failure is improving and 1-year survival rates of about 60% can be expected. A number of artificial liver support systems have been developed and evaluated for use as a bridge to either transplantation or recovery. None, however, has entered routine clinical use. Abnormal liver function tests Frequently, LFTs are requested in patients who have no symptoms or signs of liver disease, as part of routine health checks, insurance medicals or drug monitoring. When abnormal results are found, it is important for the clinician to be able to interpret them and to investigate appropriately. Many patients with chronic liver disease are asymptomatic or have vague, non-specific symptoms. Apparently asymptomatic abnormal LFTs are therefore a common occurrence. When LFTs are measured routinely prior to elective surgery, 3.5% of patients are discovered to have mildly elevated transaminases. The prevalence of abnormal LFTs has been reported to be as high as 10% in some studies. The most common abnormalities are alcoholic (p. 880) or non-alcoholic fatty liver disease (p. 882). Since effective medical treatments are now available for many types of chronic liver disease, further evaluation is usually warranted to make sure the patient does not have a treatable condition. Although transient mild abnormalities in LFTs may not be clinically significant, the majority of individuals with persistently abnormal LFTs do have significant liver disease. Biochemical abnormalities in chronic liver disease often fluctuate over time; even mild abnormalities can therefore indicate significant underlying disease and so warrant follow-up and investigation. Fig. 22.14 Suggested management of abnormal liver function tests in asymptomatic patients. *No further investigation needed. (α1AT = alpha1 antitrypsin; BMI = body mass index; ERCP = endoscopic retrograde cholangiopancreatography; GGT = γ-glutamyl transferase; HBsAg = hepatitis B surface antigen; HCVAb = antibody to hepatitis C virus; MRCP = magnetic resonance cholangiopancreatography; NAFLD = non-alcoholic fatty liver disease) Action Clinical situation Management Liver screen, i.e. Full history Chronic liver disease screen (Box 22.4) Ultrasound abdomen HBsAg HCVAb α1-antitrypsin Autoimmune profile Ferritin Caeruloplasmin Immunoglobulins Dilated bile ducts Non-dilated bile ducts Cholangiography MRCP or ERCP Consider liver biopsy and treat underlying disorder Abnormal alkaline phosphatase or serum transaminases

2 × upper limit of normal Check GGT if raised alkaline phosphatase Recheck LFTs in 3–6 months Abnormal alkaline phosphatase or serum transaminases < 2 × upper limit of normal Persistently abnormal LFT Determine whether: NAFLD/increased BMI Enzyme induction from drugs Alcohol Increased GGT only Recheck with conjugated bilirubin, exclude haemolysis Increased bilirubin only Stage disease; lifestyle modification (diet and exercise) Alcohol abstinence Review current medication Reassure, as likely Gilbert’s syndrome Alcohol abstinence Stop hepatotoxic drugs Advise weight loss if BMI > 25

860 • HEPATOLOGY In haemolysis, destruction of red blood cells or their marrow precursors causes increased bilirubin production. Jaundice due to haemolysis is usually mild because a healthy liver can excrete a bilirubin load six times greater than normal before unconjugated bilirubin accumulates in the plasma. This does not apply to newborns, who have less capacity to metabolise bilirubin. The most common form of non-haemolytic hyperbilirubinaemia is Gilbert’s syndrome, an inherited disorder of bilirubin metabolism (Box 22.17). Other inherited disorders of bilirubin metabolism are very rare. Hepatocellular jaundice Hepatocellular jaundice results from an inability of the liver to transport bilirubin into the bile, occurring as a consequence of parenchymal disease. Bilirubin transport across the hepatocytes may be impaired at any point between uptake of unconjugated bilirubin into the cells and transport of conjugated bilirubin into the canaliculi. In addition, swelling of cells and oedema resulting from the disease itself may cause obstruction of the biliary canaliculi. In hepatocellular jaundice, the concentrations of both unconjugated and conjugated bilirubin in the blood increase. 22.16 Key history points in patients with jaundice Symptoms* • Itching preceding jaundice • Abdominal pain (suggests stones) • Weight loss (chronic liver disease and malignancy) • Dark urine and pale stools • Fever ± rigors • Dry eyes/dry mouth • Fatigue Recent drug history Other • Exposure to intravenous drug or blood transfusions • Travel history and country of birth • Metabolic syndrome (increased body mass index ± type 2 diabetes/ hypertension) • Autoimmune disease history • Alcohol history • Inflammatory bowel disease • Family history of liver disease, autoimmune disease or the metabolic syndrome *Symptoms may be absent and abnormal liver function tests detected incidentally. 22.17 Congenital non-haemolytic hyperbilirubinaemia Syndrome Inheritance Abnormality Clinical features Treatment Unconjugated hyperbilirubinaemia Gilbert’s Can be autosomal recessive or dominant ↓Glucuronyl transferase Mild jaundice, especially with fasting None necessary ↓Bilirubin uptake Crigler–Najjar: Type I Autosomal recessive Absent glucuronyl transferase Rapid death in neonate (kernicterus) Type II Autosomal recessive ↓↓Glucuronyl transferase Presents in neonate Phenobarbital, phototherapy or liver transplant Conjugated hyperbilirubinaemia Dubin–Johnson Autosomal recessive ↓Canalicular excretion of organic anions, including bilirubin Mild jaundice None necessary Pigmentation of liver biopsy tissue Rotor’s Autosomal recessive ↓Bilirubin uptake Mild jaundice None necessary ↓Intrahepatic binding 22.15 Causes of cholestatic jaundice Intrahepatic • Primary biliary cholangitis • Primary sclerosing cholangitis • Alcohol • Drugs • Hepatic infiltrations (lymphoma, granuloma, amyloid, metastases) • Cystic fibrosis • Severe bacterial infections • Pregnancy (p. 899) • Inherited cholestatic liver disease, e.g. benign recurrent intrahepatic cholestasis • Chronic right heart failure Extrahepatic • Carcinoma: Ampullary Pancreatic Bile duct (cholangiocarcinoma) Liver metastases • Choledocholithiasis • Parasitic infection • Traumatic biliary strictures • Chronic pancreatitis chronic liver disease does not reliably identify those individuals with significant disease and investigations are indicated, even in the absence of these signs. Both the pattern of LFT abnormality (hepatitic or obstructive) and the degree of elevation are helpful in determining the cause of underlying liver disease (Boxes 22.14 and 22.15). The investigations that make up a standard liver screen and additional or confirmatory tests are shown in Boxes 22.4 and 22.5. An algorithm for investigating abnormal LFTs is provided in Figure 22.14. Jaundice Jaundice is usually detectable clinically when the plasma bilirubin exceeds 40 μmol/L (~2.5 mg/dL). The causes of jaundice overlap with the causes of abnormal LFTs discussed above. In a patient with jaundice it is useful to consider whether the cause might be pre-hepatic, hepatic or post-hepatic, and there are often important clues in the history (Box 22.16). Pre-hepatic jaundice This is caused either by haemolysis or by congenital hyperbilirubinaemia, and is characterised by an isolated raised bilirubin level.

Presenting problems in liver disease • 861

Hepatocellular jaundice can be due to acute or chronic injury (see Fig. 22.11), and clinical features of acute or chronic liver disease may be detected clinically (see Box 22.7). Characteristically, jaundice due to parenchymal liver disease is associated with increases in transaminases (AST, ALT), but increases in other LFTs, including cholestatic enzymes (GGT, ALP), may occur and suggest specific aetiologies (see below). Acute jaundice in the presence of an ALT of > 1000 U/L is highly suggestive of an infectious cause (e.g. hepatitis A or B), drugs (e.g. paracetamol) or hepatic ischaemia. Imaging is essential, in particular to identify features suggestive of cirrhosis, define the patency of the hepatic vasculature and obtain evidence of portal hypertension. Liver biopsy has an important role in defining the aetiology of hepatocellular jaundice and the extent of liver injury. Obstructive (cholestatic) jaundice Cholestatic jaundice may be caused by: • failure of hepatocytes to initiate bile flow • obstruction of the bile ducts or portal tracts • obstruction of bile flow in the extrahepatic bile ducts between the porta hepatis and the papilla of Vater. In the absence of treatment, cholestatic jaundice tends to become progressively more severe because conjugated bilirubin is unable to enter the bile canaliculi and passes back into the blood, and also because there is a failure of clearance of unconjugated bilirubin arriving at the liver cells. The causes of cholestatic jaundice are listed in Box 22.15. Cholestasis may result from defects at more than one of these levels. Those confined to 22.18 Clinical features and complications of cholestatic jaundice Cholestasis Early features • Jaundice • Dark urine • Pale stools • Pruritus Late features • Malabsorption (vitamins A, D, E and K): weight loss, steatorrhoea, osteomalacia, bleeding tendency • Xanthelasma and xanthomas Cholangitis • Fever • Rigors • Pain (if gallstones present) Fig. 22.15 Investigation of jaundice. (ERCP = endoscopic retrograde cholangiopancreatography; LFTs = liver function tests; MRCP = magnetic resonance cholangiopancreatography) History and examination Serum for biochemical liver tests (LFTs) Liver ultrasound Urine for bilirubin Isolated bilirubin rise (other LFTs normal) Normal ultrasound Urobilinogen present Pre-hepatic jaundice Unconjugated bilirubin rise Conjugated bilirubin rise Blood film/ reticulocyte count Dubin–Johnson/ Rotor’s syndrome (very rare) Gilbert’s syndrome Coombs test + Haemolysis work-up Raised conjugated bilirubin and other LFTs abnormal Evidence of biliary disease Raised conjugated bilirubin and other LFTs abnormal No evidence of biliary disease Biliary obstruction (i.e. dilated bile ducts) Obstructive jaundice Cholangiography (MRCP or ERCP) Hepatocellular jaundice Clotting Hepatitis/serology Immunoglobulins Autoantibodies Copper studies Iron studies the extrahepatic bile ducts may be amenable to surgical or endoscopic correction. Clinical features (Box 22.18) comprise those due to cholestasis itself, those due to secondary infection (cholangitis) and those of the underlying condition (Box 22.19). Obstruction of the bile duct drainage due to blockage of the extrahepatic biliary tree is characteristically associated with pale stools and dark urine. Pruritus may be a dominant feature and can be accompanied by skin excoriations. Peripheral stigmata of chronic liver disease are absent. If the gallbladder is palpable, the jaundice is unlikely to be caused by biliary obstruction due to gallstones, probably because a chronically inflamed, stone-containing gallbladder cannot readily dilate. This is Courvoisier’s Law, and suggests

862 • HEPATOLOGY that jaundice is due to a malignant biliary obstruction (e.g. pancreatic cancer). Cholangitis is characterised by ‘Charcot’s triad’ of jaundice, right upper quadrant pain and fever. Cholestatic jaundice is characterised by a relatively greater elevation of ALP and GGT than the aminotransferases. Ultrasound is indicated to determine whether there is evidence of mechanical obstruction and dilatation of the biliary tree (Fig. 22.15). EUS provides an additional investigation modality for investigation of lower common bile duct obstruction. Management of cholestatic jaundice depends on the underlying cause and is discussed in the relevant sections below. Hepatomegaly Hepatomegaly may occur as the result of a general enlargement of the liver or because of primary or secondary liver tumour 22.20 Causes of change in liver size Large liver (hepatomegaly) • Liver metastases • Multiple or large hepatic cysts • Cirrhosis (early): non-alcoholic fatty liver disease, alcohol, haemochromatosis • Hepatic vein outflow obstruction • Infiltration: amyloid Small liver • Cirrhosis (late) 22.21 Causes of ascites Low SAAG (exudative) High SAAG (transudative) Common causes Malignant disease: Hepatic Peritoneal Cardiac failure Hepatic cirrhosis Other causes Acute pancreatitis Lymphatic obstruction Infection: Tuberculosis Nephrotic syndrome Hypoproteinaemia: Protein-losing enteropathy Malnutrition Hepatic venous occlusion: Budd–Chiari syndrome Sinusoidal obstruction syndrome (Veno-occlusive disease) Rare causes Hypothyroidism Meigs’ syndrome* Constrictive pericarditis *Meigs’ syndrome is the association of a right pleural effusion with or without ascites and a benign ovarian tumour. The ascites resolves on removal of the tumour. (SAAG = serum ascites albumin gradient; see text) (Box 22.20). The most common liver tumour in Western countries is liver metastasis, whereas primary liver cancer complicating chronic viral hepatitis is more common in the Far East. Unlike carcinoma metastases, those from neuro-endocrine tumours typically cause massive hepatomegaly but without significant weight loss. Cirrhosis can be associated with either hepatomegaly or reduced liver size in advanced disease. Although all causes of cirrhosis can involve hepatomegaly, it is much more common in alcoholic liver disease and haemochromatosis. Hepatomegaly may resolve in patients with alcoholic cirrhosis when they stop drinking. Ascites Ascites is present when there is accumulation of free fluid in the peritoneal cavity. Small amounts of ascites are asymptomatic, but with larger accumulations of fluid (> 1 L) there is abdominal distension, fullness in the flanks, shifting dullness on percussion and, when the ascites is marked, a fluid thrill/fluid wave. Other features include eversion of the umbilicus, herniae, abdominal striae, divarication of the recti and scrotal oedema. Dilated superficial abdominal veins may be seen if the ascites is due to portal hypertension. Pathophysiology Ascites has numerous causes, the most common of which are malignant disease, cirrhosis and heart failure. Many primary disorders of the peritoneum and visceral organs can also cause ascites, and these need to be considered even in a patient with chronic liver disease (Box 22.21). Splanchnic vasodilatation is thought to be the main factor leading to ascites in cirrhosis. This is mediated by vasodilators (mainly nitric oxide) that are released when portal hypertension causes shunting of blood into the systemic circulation. Systemic arterial pressure falls due to pronounced splanchnic vasodilatation as cirrhosis advances. This leads to activation of the renin–angiotensin system with secondary aldosteronism, increased sympathetic nervous activity, increased atrial natriuretic hormone secretion and altered activity Each of these diseases can give rise to almost any of the clinical features shown but the box indicates the most likely cause of the clinical features listed. 22.19 Clinical features suggesting an underlying cause of cholestatic jaundice Clinical feature Causes Jaundice Static or increasing Carcinoma Primary biliary cholangitis Primary sclerosing cholangitis Fluctuating Choledocholithiasis Stricture Pancreatitis Choledochal cyst Primary sclerosing cholangitis Abdominal pain Choledocholithiasis Pancreatitis Choledochal cyst Cholangitis Stone Stricture Choledochal cyst Abdominal scar Stone Stricture Irregular hepatomegaly Hepatic carcinoma Palpable gallbladder Carcinoma below cystic duct (usually pancreas) Abdominal mass Carcinoma Pancreatitis (cyst) Choledochal cyst Occult blood in stools Ampullary tumour

Presenting problems in liver disease • 863

indicated by an albumin gradient of > 11 g/L (1.1 g/dL) but, unlike in cirrhosis, the total protein content is usually > 25 g/L (2.5 g/dL). High protein ascites (‘exudate’; protein concentration > 25 g/L (2.5 g/dL) or a SAAG of < 11 g/L (1.1 g/dL) raises the possibility of infection (especially tuberculosis), malignancy, pancreatic ascites or, rarely, hypothyroidism. Ascites amylase activity of

1000 U/L identifies pancreatic ascites, whereas low ascites glucose concentrations suggest malignant disease or tuberculosis. Cytological examination may reveal malignant cells (one-third of cirrhotic patients with a bloody tap have a hepatocellular carcinoma). Polymorphonuclear leucocyte counts of > 250 × 106/L strongly suggest infection (spontaneous bacterial peritonitis; see below). Laparoscopy can be valuable in detecting peritoneal disease. The presence of triglyceride at a level > 1.1 g/L (110 mg/dL) is diagnostic of chylous ascites and suggests anatomical or functional abnormality of lymphatic drainage from the abdomen. The ascites in this context has a characteristic milky-white appearance. Management Successful treatment relieves discomfort but does not prolong life; if over-vigorous, it can produce serious disorders of fluid and electrolyte balance, and precipitate hepatic encephalopathy (p. 864). Treatment of transudative ascites is based on restricting sodium and water intake, promoting urine output with diuretics and, if necessary, removing ascites directly by paracentesis. Exudative ascites due to malignancy is treated with paracentesis but fluid replacement is generally not required. During management of ascites, the patient should be weighed regularly. Diuretics should be titrated to remove no more than 1 L of fluid daily, so body weight should not fall by more than 1 kg daily to avoid excessive fluid depletion. Sodium and water restriction Restriction of dietary sodium intake is essential to achieve negative sodium balance and a few patients can be managed satisfactorily by this alone. Restriction of sodium intake to 100 mmol/24 hrs (‘no added salt diet’) is usually adequate. Drugs containing relatively large amounts of sodium, and those promoting sodium retention, such as non-steroidal anti-inflammatory drugs (NSAIDs), must be avoided (Box 22.23). Restriction of water intake to 1.0–1.5 L/24 hrs is necessary only if the plasma sodium falls below 125 mmol/L. of the kallikrein–kinin system (Fig. 22.16). These systems tend to normalise arterial pressure but produce salt and water retention. In this setting, the combination of splanchnic arterial vasodilatation and portal hypertension alters intestinal capillary permeability, promoting accumulation of fluid within the peritoneum. Investigations Ultrasonography is the best means of detecting ascites, particularly in the obese and those with small volumes of fluid. Paracentesis (if necessary under ultrasonic guidance) can be used to obtain ascitic fluid for analysis. The appearance of ascitic fluid may point to the underlying cause (Box 22.22). Pleural effusions are found in about 10% of patients, usually on the right side (hepatic hydrothorax); most are small and identified only on chest X-ray, but occasionally a massive hydrothorax occurs. Pleural effusions, particularly those on the left side, should not be assumed to be due to the ascites. Measurement of the protein concentration and the serum– ascites albumin gradient (SAAG) can be a useful tool to distinguish ascites of different aetiologies. Cirrhotic patients typically develop ascites with a low protein concentration (‘transudate’; protein concentration < 25 g/L (2.5 g/dL)) and relatively few cells. In up to 30% of patients, however, the total protein concentration is > 30 g/L (3.0 g/dL). In these cases, it is useful to calculate the SAAG by subtracting the concentration of the ascites fluid albumin from the serum albumin. A gradient of > 11 g/L (1.1 g/dL) is 96% predictive that ascites is due to portal hypertension. Venous outflow obstruction due to cardiac failure or hepatic venous outflow obstruction can also cause a transudative ascites, as Fig. 22.16 Pathogenesis of ascites. Ascites Transudation of fluid ↓ Oncotic pressure Portal hypertension Reduced aldosterone metabolism Aldosterone Reduced renal blood flow Under-filling of circulation Activation of renin–angiotensin system Splanchnic vasodilatation Reduced albumin Salt and water retention Lymph formation exceeds lymph return Cirrhosis To calculate the serum–ascites albumin gradient (SAAG). 22.22 Ascitic fluid: appearance and analysis Cause/appearance • Cirrhosis: clear, straw-coloured or light green • Malignant disease: bloody • Infection: cloudy • Biliary communication: heavy bile staining • Lymphatic obstruction: milky-white (chylous) Useful investigations • Total albumin (plus serum albumin) and protein • Amylase • Neutrophil count • Cytology • Microscopy and culture

864 • HEPATOLOGY 1 month). There is usually no proteinuria, a urine sodium excretion of less than 10 mmol/24 hrs and a urine/plasma osmolarity ratio of more than 1.5. Other non-functional causes of renal failure must be excluded before the diagnosis is made. Treatment consists of albumin infusions in combination with terlipressin (or octreotide and midodrine where terlipressin is not approved for use) and is effective in about two-thirds of patients. Haemodialysis should not be used routinely because it does not improve the outcome. Patients who survive should be considered for liver transplantation, which, along with TIPSS, is an effective treatment in appropriate patients. Type 2 hepatorenal syndrome This usually occurs in patients with refractory ascites, is characterised by a moderate and stable increase in serum creatinine, and has a better prognosis. Spontaneous bacterial peritonitis Spontaneous bacterial peritonitis (SBP) may present with abdominal pain, rebound tenderness, absent bowel sounds and fever in a patient with obvious features of cirrhosis and ascites. Abdominal signs are mild or absent in about one-third of patients, and in these individuals hepatic encephalopathy and fever are the main features. Diagnostic paracentesis may show cloudy fluid, and an ascites neutrophil count of > 250 × 106/L almost invariably indicates infection. The source of infection cannot usually be determined, but most organisms isolated are of enteric origin and Escherichia coli is the most frequently found. Ascitic culture in blood culture bottles gives the highest yield of organisms. SBP needs to be differentiated from other intra-abdominal emergencies, and the finding of multiple organisms on culture should arouse suspicion of a perforated viscus. Treatment should be started immediately with broad-spectrum antibiotics, such as cefotaxime or piperacillin/tazobactam). Recurrence of SBP is common but may be reduced with prophylactic quinolones, such as norfloxacin or ciprofloxacin. Prophylactic antibiotics reduce the incidence of SBP and improve survival in cirrhotic patients with gastrointestinal bleeding. In patients with a previous episode of SBP and continued ascites, norfloxacin (400 mg/day) prevents recurrence. Prognosis Only 10–20% of patients survive for 5 years from the first appearance of ascites due to cirrhosis. The outlook is not universally poor, however, and is best in those with well-maintained liver function and a good response to therapy. The prognosis is also better when a treatable cause for the underlying cirrhosis is present or when a precipitating cause for ascites, such as excess salt intake, is found. The mortality at 1 year is 50% following the first episode of bacterial peritonitis. Hepatic encephalopathy Hepatic encephalopathy is a neuropsychiatric syndrome caused by liver disease. As it progresses, delirium is followed by coma. Simple delirium needs to be differentiated from delirium tremens and Wernicke’s encephalopathy, and coma from subdural haematoma, which can occur in alcoholics after a fall (Box 22.24). Features include changes of intellect, personality, emotions and consciousness, with or without neurological signs. The degree of encephalopathy can be graded from 1 to 4, depending on these features, and this is useful in assessing response to therapy (see Box 22.9). When an episode develops acutely, a precipitating factor may be found (Box 22.25). The earliest features are very Diuretics Most patients require diuretics in addition to sodium restriction. Spironolactone (100–400 mg/day) is the first-line drug because it is a powerful aldosterone antagonist; it can, however, cause painful gynaecomastia and hyperkalaemia, in which case amiloride (5–10 mg/day) can be substituted. Some patients also require loop diuretics, such as furosemide, but these can lead to fluid and electrolyte imbalance and renal dysfunction. Diuresis may be improved if patients are rested in bed, perhaps because renal blood flow increases in the horizontal position. Patients who do not respond to doses of 400 mg spironolactone and 160 mg furosemide, or who are unable to tolerate these doses due to hyponatraemia or renal impairment, are considered to have refractory or diuretic-resistant ascites and should be treated by other measures. Paracentesis First-line treatment of refractory ascites is large-volume paracentesis. Paracentesis to dryness is safe, provided the circulation is supported with an intravenous colloid such as human albumin (6–8 g per litre of ascites removed, usually as 100 mL of 20% or 25% human albumin solution (HAS) for every 1.5–2 L of ascites drained) or another plasma expander. Paracentesis can be used as an initial therapy or when other treatments fail. Transjugular intrahepatic portosystemic stent shunt A transjugular intrahepatic portosystemic stent shunt (TIPSS; p. 870) can relieve resistant ascites but does not prolong life; it may be an option where the only alternative is frequent, largevolume paracentesis. TIPSS can be used in patients awaiting liver transplantation or in those with reasonable liver function, but can aggravate encephalopathy in those with poor function. Complications Renal failure Renal failure can occur in patients with ascites. It can be pre-renal and due to vasodilatation from sepsis and/or diuretic therapy, or due to hepatorenal syndrome. Hepatorenal syndrome This occurs in 10% of patients with advanced cirrhosis complicated by ascites. There are two clinical types; both are mediated by renal vasoconstriction due to under-filling of the arterial circulation. Type 1 hepatorenal syndrome This is characterised by progressive oliguria, a rapid rise of the serum creatinine and a very poor prognosis (without treatment, median survival is less than 22.23 Some drugs containing relatively large amounts of sodium or causing sodium retention High sodium content • Alginates • Antacids • Antibiotics • Phenytoin • Effervescent preparations (e.g. aspirin, calcium, paracetamol) • Sodium valproate Sodium retention • Carbenoxolone • Glucocorticoids • Metoclopramide • Non-steroidal antiinflammatory drugs • Oestrogens

Presenting problems in liver disease • 865

Some degree of liver failure is a key factor, as portosystemic shunting of blood alone hardly ever causes encephalopathy. The ‘neurotoxins’ causing encephalopathy are unknown but are thought to be mainly nitrogenous substances produced in the gut, at least in part by bacterial action. These substances are normally metabolised by the healthy liver and excluded from the systemic circulation. Ammonia has traditionally been considered an important factor. Recent interest has focused on γ-aminobutyric acid (GABA) as a mediator, along with octopamine, amino acids, mercaptans and fatty acids that can act as neurotransmitters. The brain in cirrhosis may also be sensitised to other factors, such as drugs that can precipitate hepatic encephalopathy (Box 22.25). Disruption of the function of the blood–brain barrier is a feature of acute hepatic failure and may lead to cerebral oedema. Investigations The diagnosis can usually be made clinically; when doubt exists, an electroencephalogram shows diffuse slowing of the normal alpha waves with eventual development of delta waves. The arterial ammonia is usually increased in patients with hepatic encephalopathy. Increased concentrations can, however, occur in the absence of clinical encephalopathy, rendering this investigation of little diagnostic value. Management The principles are to treat or remove precipitating causes (Box 22.25) and to suppress the production of neurotoxins by bacteria in the bowel. Dietary protein restriction is rarely needed and is no longer recommended as first-line treatment because it is unpalatable and can lead to a worsening nutritional state in already malnourished patients. Lactulose (15–30 mL 3 times daily) is increased gradually until the bowels are moving twice daily. It produces an osmotic laxative effect, reduces the pH of the colonic content, thereby limiting colonic ammonia absorption, and promotes the incorporation of nitrogen into bacteria. Rifaximin (400 mg 3 times daily) is a well-tolerated, non-absorbed antibiotic that acts by reducing the bacterial content of the bowel and has been shown to be effective. It can be used in addition, or as an alternative, to lactulose if diarrhoea becomes troublesome. Chronic or refractory encephalopathy is one of the main indications for liver transplantation. Variceal bleeding Acute upper gastrointestinal haemorrhage from gastro-oesophageal varices (Fig. 22.17) is common in chronic liver disease. Investigation mild and easily overlooked, but as the condition becomes more severe, apathy, inability to concentrate, delirium, disorientation, drowsiness, slurring of speech and eventually coma develop. Convulsions sometimes occur. Examination usually shows a flapping tremor (asterixis), inability to perform simple mental arithmetic tasks or to draw objects such as a star (constructional apraxia; p. 847), and, as the condition progresses, hyper-reflexia and bilateral extensor plantar responses. Hepatic encephalopathy rarely causes focal neurological signs; if these are present, other causes must be sought. Fetor hepaticus, a sweet musty odour to the breath, is usually present but is more a sign of liver failure and portosystemic shunting than of hepatic encephalopathy. Rarely, chronic hepatic encephalopathy (hepatocerebral degeneration) gives rise to variable combinations of cerebellar dysfunction, Parkinsonian syndromes, spastic paraplegia and dementia. Pathophysiology Hepatic encephalopathy is thought to be due to a disturbance of brain function provoked by circulating neurotoxins that are normally metabolised by the liver. Accordingly, most affected patients have evidence of liver failure and portosystemic shunting of blood, but the balance between these varies from individual to individual. Fig. 22.17 Varices: endoscopic views. A Oesophageal varices (arrows) at the lower end of the oesophagus. B Gastric varices (arrows). C Appearance of oesophageal varices following application of strangulating bands (band ligation, arrow). B A C 22.25 Factors precipitating hepatic encephalopathy • Drugs (especially sedatives, antidepressants) • Dehydration (including diuretics, paracentesis) • Portosystemic shunting • Infection • Hypokalaemia • Constipation • ↑Protein load (including gastrointestinal bleeding) 22.24 Differential diagnosis of hepatic encephalopathy • Intracranial bleed (subdural/extradural haematoma, p. 1133) • Drug or alcohol intoxication (pp. 1194 and 1195) • Delirium tremens/alcohol withdrawal (p. 1194) • Wernicke’s encephalopathy (p. 1195) • Primary psychiatric disorders (p. 1191) • Hypoglycaemia (p. 738) • Neurological Wilson’s disease (p. 1115) • Post-ictal state

866 • HEPATOLOGY non-specific and include weakness, fatigue, muscle cramps, weight loss, anorexia, nausea, vomiting and upper abdominal discomfort (Box 22.27). Cirrhosis will occasionally present because of shortness of breath due to a large right pleural effusion, or with hepatopulmonary syndrome (p. 898). Hepatomegaly is common when the cirrhosis is due to alcoholic liver disease or haemochromatosis. Progressive hepatocyte destruction and fibrosis gradually reduce liver size as the disease progresses in other causes of cirrhosis. A reduction in liver size is especially common if the cause is viral hepatitis or autoimmune liver disease. The liver is often hard, irregular and non-tender. Jaundice is mild when it first appears and is due primarily to a failure to excrete bilirubin. Palmar erythema and management are discussed on page 780 and the specific management of variceal bleeding on page 869. Cirrhosis Cirrhosis is characterised by diffuse hepatic fibrosis and nodule formation. It can occur at any age, has significant morbidity and is an important cause of premature death. It is the most common cause of portal hypertension and its complications. Worldwide, the most common causes are chronic viral hepatitis, prolonged excessive alcohol consumption and NAFLD but any condition leading to persistent or recurrent hepatocyte death may lead to cirrhosis. The causes of cirrhosis are listed in Box 22.26. Cirrhosis may also occur in prolonged biliary damage or obstruction, as is found in primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC) and post-surgical biliary strictures. Persistent blockage of venous return from the liver, such as is found in sinusoidal obstruction syndrome (SOS; veno-occlusive disease) and Budd–Chiari syndrome, can also result in cirrhosis. Pathophysiology Following liver injury, stellate cells in the space of Disse (see Fig. 22.3, p. 849) are activated by cytokines produced by Kupffer cells and hepatocytes. This transforms the stellate cell into a myofibroblast-like cell, capable of producing collagen, pro-inflammatory cytokines and other mediators that promote hepatocyte damage and tissue fibrosis (see Fig. 22.4, p. 849). Cirrhosis is a histological diagnosis (Fig. 22.18). It evolves over years as progressive fibrosis and widespread hepatocyte loss lead to distortion of the normal liver architecture that disrupts the hepatic vasculature, causing portosystemic shunts. These changes usually affect the whole liver but in biliary cirrhosis (e.g. PBC) they can be patchy. Cirrhosis can be classified histologically into: • Micronodular cirrhosis, characterised by small nodules about 1 mm in diameter and typically seen in alcoholic cirrhosis. • Macronodular cirrhosis, characterised by larger nodules of various sizes. Areas of previous collapse of the liver architecture are evidenced by large fibrous scars. Clinical features The clinical presentation is highly variable. Some patients are asymptomatic and the diagnosis is made incidentally at ultrasound or at surgery. Others present with isolated hepatomegaly, splenomegaly, signs of portal hypertension (p. 868) or hepatic insufficiency. When symptoms are present, they are often Fig. 22.18 Histological features in normal liver, hepatic fibrosis and cirrhosis. A Normal liver. Columns of hepatocytes 1–2 cells thick radiate from the portal tracts (PT) to the central veins. The portal tract contains a normal intralobular bile duct branch of the hepatic artery and portal venous radical. B Bridging fibrosis (stained pink, arrows) spreading out around the hepatic vein and single liver cells (pericellular) and linking adjacent portal tracts and hepatic veins. C A cirrhotic liver. The liver architecture is disrupted. The normal arrangement of portal tracts and hepatic veins is now lost and nodules of proliferating hepatocytes are broken up by strands of pink-/orange-staining fibrous tissue (arrows) forming cirrhotic nodules (CN). PT PT PT CN A B C 22.26 Causes of cirrhosis • Alcohol • Chronic viral hepatitis (B or C) • Non-alcoholic fatty liver disease • Immune: Primary sclerosing cholangitis Autoimmune liver disease • Biliary: Primary biliary cholangitis Secondary biliary cirrhosis Cystic fibrosis • Genetic: Haemochromatosis Wilson’s disease α1-antitrypsin deficiency • Cryptogenic (unknown – 15%) • Chronic venous outflow obstruction • Any chronic liver disease

Cirrhosis • 867

to screen for oesophageal varices (p. 869) and repeated every 2 years. As cirrhosis is associated with an increased risk of hepatocellular carcinoma, patients should be placed under regular surveillance for it (p. 890). Chronic liver failure due to cirrhosis can also be treated by liver transplantation. This currently accounts for about three-quarters of all liver transplants (p. 900). Prognosis The overall prognosis is poor. Many patients present with advanced disease and/or serious complications that carry a high mortality. Overall, only 25% of patients survive 5 years from diagnosis, but where liver function is good, 50% survive for 5 years and 25% for up to 10 years. The prognosis is more favourable when the underlying cause can be corrected, as in alcohol misuse, haemochromatosis or Wilson’s disease. Laboratory tests give only a rough guide to prognosis in individual patients. Deteriorating liver function, as evidenced by jaundice, ascites or encephalopathy, indicates a poor prognosis unless a treatable cause such as infection is found. Increasing bilirubin, falling albumin (or an albumin concentration of < 30 g/L (3.0 g/dL)), marked hyponatraemia (< 120 mmol/L) not due to diuretic therapy, and a prolonged PT are all bad prognostic features (Box 22.29 and Fig. 22.19). The Child–Pugh and MELD (Model for End-stage Liver Disease) scores can be used to assess prognosis. The MELD is more difficult to calculate at the bedside but, unlike the Child–Pugh score, includes renal function; if this is impaired, it is known to be a poor prognostic feature in end-stage disease (Box 22.30). Although these scores give a guide to prognosis, the course of cirrhosis can be unpredictable, as complications such as variceal bleeding may occur. can be seen early in the disease but is of limited diagnostic value, as it occurs in many other conditions associated with a hyper-dynamic circulation, including normal pregnancy, as well as being found in some healthy people. Spider telangiectasias occur and comprise a central arteriole (that occasionally raises the skin surface), from which small vessels radiate. They vary in size from 1 to 2 mm in diameter and are usually found only above the nipples. One or two small spider telangiectasias may be present in about 2% of healthy people and may occur transiently in greater numbers in the third trimester of pregnancy, but otherwise they are a strong indicator of liver disease. Florid spider telangiectasia, gynaecomastia and parotid enlargement are most common in alcoholic cirrhosis. Pigmentation is most striking in haemochromatosis and in any cirrhosis associated with prolonged cholestasis. Pulmonary arteriovenous shunts also develop, leading to hypoxaemia and eventually to central cyanosis, but this is a late feature. Endocrine changes are noticed more readily in men, who show loss of male hair distribution and testicular atrophy. Gynaecomastia is common and can be due to drugs such as spironolactone. Easy bruising becomes more frequent as cirrhosis advances. Splenomegaly and collateral vessel formation are features of portal hypertension, which occurs in more advanced disease (see below). Ascites also signifies advanced disease. Evidence of hepatic encephalopathy also becomes common with disease progression. Non-specific features of chronic liver disease include clubbing of the fingers and toes. Dupuytren’s contracture is traditionally regarded as a complication of cirrhosis but the evidence for this is weak. Chronic liver failure develops when the metabolic capacity of the liver is exceeded. It is characterised by the presence of encephalopathy and/ or ascites. The term ‘hepatic decompensation’ or ‘decompensated liver disease’ is often used when chronic liver failure occurs. Other clinical and laboratory features may be present (Box 22.28); these include peripheral oedema, renal failure, jaundice, and hypoalbuminaemia and coagulation abnormalities due to defective protein synthesis. Management This includes treatment of the underlying cause, maintenance of nutrition and treatment of complications, including ascites, hepatic encephalopathy, portal hypertension and varices. Once the diagnosis of cirrhosis is made, endoscopy should be performed 22.27 Clinical features of hepatic cirrhosis • Hepatomegaly (although liver may also be small) • Jaundice • Ascites • Circulatory changes: spider telangiectasia, palmar erythema, cyanosis • Endocrine changes: loss of libido, hair loss Men: gynaecomastia, testicular atrophy, impotence Women: breast atrophy, irregular menses, amenorrhoea • Haemorrhagic tendency: bruises, purpura, epistaxis • Portal hypertension: splenomegaly, collateral vessels, variceal bleeding • Hepatic (portosystemic) encephalopathy • Other features: pigmentation, digital clubbing, Dupuytren’s contracture 22.29 Child–Pugh classification of prognosis in cirrhosis Score

Encephalopathy None Mild Marked Bilirubin (μmol/L (mg/dL))* Primary biliary cholangitis/sclerosing cholangitis < 68 (4 ) 68–170 (4–10 )

170 (10 ) Other causes of cirrhosis < 34 (2 ) 34–50 (2–3 ) 50 (3 ) Albumin (g/L (g/dL)) 35 (3.5 ) 28–35 (2.8–3.5 ) < 28 (2.8 ) Prothrombin time (secs prolonged) < 4 4–6 6 Ascites None Mild Marked Add the individual scores: < 7 = Child’s A, 7–9 = Child’s B, > 9 = Child’s C *To convert bilirubin in μmol/L to mg/dL, divide by 17. 22.28 Features of chronic liver failure • Worsening synthetic liver function: Prolonged prothrombin time Low albumin • Jaundice • Portal hypertension • Variceal bleeding • Hepatic encephalopathy • Ascites: Spontaneous bacterial peritonitis Hepatorenal failure

868 • HEPATOLOGY more than 5 cm below the left costal margin in adults but more marked splenomegaly can occur in childhood and adolescence. Collateral vessels may be visible on the anterior abdominal wall and occasionally several radiate from the umbilicus to form a ‘caput medusae’ (p. 846). Rarely, a large umbilical collateral vessel has a blood flow sufficient to give a venous hum on auscultation (Cruveilhier–Baumgarten syndrome). The most important collateral vessel formation occurs in the oesophagus and stomach, and this can be a source of severe bleeding. Rectal varices also cause bleeding and are often mistaken for haemorrhoids (which are no more common in portal hypertension than in the general population). Fetor hepaticus results from portosystemic shunting of blood, which allows mercaptans to pass directly to the lungs. Portal hypertension Portal hypertension frequently complicates cirrhosis but has other causes. The normal hepatic venous pressure gradient (difference between the wedged hepatic venous pressure (WHVP) and free hepatic venous pressure; see below) is 5–6 mmHg. Clinically significant portal hypertension is present when the gradient exceeds 10 mmHg and risk of variceal bleeding increases beyond a gradient of 12 mmHg. Increased vascular resistance is common. Causes are classified in accordance with the main sites of obstruction to blood flow in the portal venous system (Fig. 22.20). Extrahepatic portal vein obstruction is the usual source of portal hypertension in childhood and adolescence, while cirrhosis causes at least 90% of cases of portal hypertension in adults in developed countries. Schistosomiasis is the most common cause of portal hypertension worldwide but is infrequent outside endemic areas, such as Egypt (p. 294). Clinical features The clinical features result principally from portal venous congestion and collateral vessel formation (Box 22.31). Splenomegaly is a cardinal finding and a diagnosis of portal hypertension is unusual when splenomegaly cannot be detected clinically or by ultrasonography. The spleen is rarely enlarged Fig. 22.20 Classification of portal hypertension according to site of vascular obstruction. *Most common cause. Note that splenic vein occlusion can also follow pancreatitis, leading to gastric varices. Post-hepatic post-sinusoidal Budd–Chiari syndrome

Intrahepatic post-sinusoidal Veno-occlusive disease

Sinusoidal Cirrhosis* Polycystic liver disease Nodular regenerative hyperplasia Metastatic malignant disease

Intrahepatic pre-sinusoidal Schistosomiasis* Congenital hepatic fibrosis Drugs Vinyl chloride Sarcoidosis

Pre-hepatic pre-sinusoidal Portal vein thrombosis due to sepsis (umbilical, portal pyaemia) or procoagulopathy or secondary to cirrhosis Abdominal trauma including surgery

Splenic vein Spleen Superior mesenteric vein Blood from gut Heart Inferior vena cava Hepatic vein Portal vein Blood flow Liver Blood flow Fig. 22.19 Survival in cirrhosis by Child–Pugh score.

(%)

A B C

1 year 5 years 10 years 22.30 One-year survival rate depending on MELD score MELD score 1-year survival (%) No complications Complications* < 9

10–19

20–29

30–39

MELD from SI units 10 × (0.378 [In serum bilirubin (μmol/L) + 1.12 [In INR] + 0.957 [In serum creatinine (μmol/L)] + 0.643) MELD from non-SI units 3.8 [In serum bilirubin (mg/dL)] + 11.2 [In INR] + 9.3 [In serum creatinine (mg/dL)] + 6.4 In = natural log. To calculate online, go to https://optn.transplant.hrsa .gov/resources/allocation-calculators/meld-calculator/ *‘Complications’ means the presence of ascites, encephalopathy or variceal bleeding. (INR = International Normalised Ratio; MELD = Model for End-stage Liver Disease) 22.31 Complications of portal hypertension • Variceal bleeding: oesophageal, gastric, other (rare) • Congestive gastropathy • Hypersplenism • Ascites • Iron deficiency anaemia • Renal failure • Hepatic encephalopathy

Portal hypertension • 869

important to remember, though, that bleeding can also result from peptic ulceration, which is more common in patients with liver disease than in the general population. The investigation and management of gastrointestinal bleeding are dealt with in more detail on page 780. Primary prevention of variceal bleeding If non-bleeding varices are identified at endoscopy, β-adrenoceptor antagonist (β-blocker) therapy with propranolol (80–160 mg/ day) or nadolol (40–240 mg/day) is effective in reducing portal venous pressure. Administration of these drugs at doses that reduce the heart rate by 25% has been shown to be effective in the primary prevention of variceal bleeding. In patients with cirrhosis, treatment with propranolol reduces variceal bleeding by 47% (number needed to treat for benefit (NNTB) 10), death from bleeding by 45% (NNTB 25) and overall mortality by 22% (NNTB 16). The efficacy of β-blockers in primary prevention is similar to that of prophylactic banding, which may also be considered, particularly in patients who are unable to tolerate or adhere to β-blocker therapy. Carvedilol, a non-cardioselective vasodilating β-blocker, is also effective and may be better tolerated at doses of 6.25–12.5 mg/day). For these, dose should be titrated, as tolerated, to achieve a heart rate of 50–55 beats/min, if possible. Management of acute variceal bleeding The priority in acute bleeding is to restore the circulation with blood and plasma, not least because shock reduces liver blood flow and causes further deterioration of liver function. The source of bleeding should always be confirmed by endoscopy because about 20% of patients are bleeding from non-variceal lesions. Management of acute variceal bleeding is described in Box 22.32 and illustrated in Figure 22.21. All patients with cirrhosis and gastrointestinal bleeding should receive prophylactic broadspectrum antibiotics, such as oral ciprofloxacin or intravenous cephalosporin or piperacillin/tazobactam, because sepsis is common and treatment with antibiotics improves outcomes. The measures used to control acute variceal bleeding include vasoactive medications (e.g. terlipressin), endoscopic therapy (banding or sclerotherapy), balloon tamponade, TIPSS and, rarely, oesophageal transection. 22.32 Emergency management of bleeding Management Reason Intravenous fluids To replace extracellular volume Vasopressor (terlipressin)* To reduce portal pressure, acute bleeding and risk of early rebleeding Prophylactic antibiotics (cephalosporin IV) To reduce incidence of spontaneous bacterial peritonitis Emergency endoscopy To confirm variceal rather than ulcer bleed Variceal band ligation To stop bleeding Proton pump inhibitor To prevent peptic ulcers Phosphate enema and/or lactulose To prevent hepatic encephalopathy *Caution in patients with significant coronary artery, peripheral or other vascular disease. Ascites occurs as a result of renal sodium retention and portal hypertension that may be due, for example, to post-hepatic causes (hepatic outflow obstruction, p. 862) or cirrhosis. The most important consequence of portal hypertension is variceal bleeding, which commonly arises from oesophageal varices located within 3–5 cm of the gastro-oesophageal junction, or from gastric varices. The size of the varices, endoscopic variceal features such as red spots and stripes, high portal pressure and liver failure are all general factors that predispose to bleeding. Drugs capable of causing mucosal erosion, such as salicylates and NSAIDs, can also precipitate bleeding. Variceal bleeding is often severe, and recurrent if preventative treatment is not given. Pathophysiology Increased portal vascular resistance leads to a gradual reduction in the flow of portal blood to the liver and simultaneously to the development of collateral vessels, allowing portal blood to bypass the liver and enter the systemic circulation directly. Portosystemic shunting occurs, particularly in the gastrointestinal tract and especially the distal oesophagus, stomach and rectum, in the anterior abdominal wall, and in the renal, lumbar, ovarian and testicular vasculature. Stomal varices can also occur at the site of an ileostomy. As collateral vessel formation progresses, more than half of the portal blood flow may be shunted directly to the systemic circulation. Increased portal flow contributes to portal hypertension but is not the dominant factor. Investigations The diagnosis is often made clinically. Portal venous pressure measurements are rarely needed for clinical assessment or routine management but can be used to confirm portal hypertension and to differentiate sinusoidal and pre-sinusoidal forms. Pressure measurements are made by using a balloon catheter inserted using the transjugular route (via the inferior vena cava into a hepatic vein and then hepatic venule) to measure the WHVP. This is an indirect measurement of portal vein pressure. Thrombocytopenia is common due to hypersplenism, and platelet counts are usually in the region of 100 × 109/L; values below 50 × 109/L are uncommon. Leucopenia occurs occasionally but anaemia is seldom attributed directly to hypersplenism; if anaemia is found, a source of bleeding should be sought. Endoscopy is the most useful investigation to determine whether gastro-oesophageal varices are present (see Fig. 22.17). Once the diagnosis of cirrhosis is made, endoscopy should be performed to screen for oesophageal varices (and repeated every 2 years). Ultrasonography often shows features of portal hypertension, such as splenomegaly and collateral vessels, and can sometimes indicate the cause, such as liver disease or portal vein thrombosis. CT and magnetic resonance angiography can identify the extent of portal vein clot and are used to identify hepatic vein patency. Management Acute upper gastrointestinal haemorrhage from gastrooesophageal varices is a common manifestation of chronic liver disease. In the presence of portal hypertension, the risk of a variceal bleed occurring within 2 years varies from 7% for small varices up to 30% for large varices. The mortality following a variceal bleed has improved to around 15% overall but is still about 45% in those with poor liver function (i.e. Child–Pugh C). The management of portal hypertension is largely focused on the prevention and/or control of variceal haemorrhage. It is

870 • HEPATOLOGY Regular follow-up endoscopy is required to identify and treat any recurrence of varices. Band ligation has fewer side-effects than sclerotherapy, a technique in which varices are injected with a sclerosing agent, and has largely replaced it. Banding is best suited to the treatment of oesophageal varices. It is associated with a lower risk of oesophageal perforation or stricturing than sclerotherapy. Prophylactic acid suppression with proton pump inhibitors reduces the risk of secondary bleeding from bandinginduced ulceration. In the case of gastric fundal varices, banding is less effective and so endoscopic therapy relies on injection of agents such as thrombin or cyanoacrylate glue directly into the varix to induce thrombosis. Although highly effective, cyanoacrylate injection treatment may be complicated by ‘glue embolism’ to the lungs. Active bleeding may make endoscopic therapy difficult. Protection of the patient’s airway with endotracheal intubation aids the endoscopist, facilitating therapy and significantly reducing the risk of pulmonary aspiration. Balloon tamponade This technique employs a Sengstaken– Blakemore tube, which consists of two balloons that exert pressure in the fundus of the stomach and in the lower oesophagus, respectively (Fig. 22.22). Additional lumens allow contents to be aspirated from the stomach and from the oesophagus above the oesophageal balloon. This technique may be used in the event of life-threatening haemorrhage if early endoscopic therapy is not available or is unsuccessful. Endotracheal intubation prior to tube insertion reduces the risk of pulmonary aspiration. The tube should be passed through the mouth and its presence in the stomach should be checked by auscultating the upper abdomen while injecting air and by confirming with radiology. The safest technique is Pharmacological reduction of portal venous pressure Terlipressin is a synthetic vasopressin analogue that, in contrast to vasopressin, can be given by intermittent injection rather than continuous infusion. It reduces portal blood flow and/or intrahepatic resistance and hence brings down portal pressure. It lowers mortality in the setting of acute variceal bleeding. The dose of terlipressin is 2 mg IV 4 times daily until bleeding stops, and then 1 mg 4 times daily for up to 72 hours. Caution is needed in patients with severe ischaemic heart disease or peripheral vascular disease because of the drug’s vasoconstrictor properties. In countries where terlipressin is not available, octreotide is a frequently used alternative. Variceal ligation (‘banding’) and sclerotherapy This is the most widely used initial treatment and is undertaken, if possible, at the time of diagnostic endoscopy (see Fig. 22.17C). It stops variceal bleeding in 80% of patients and can be repeated if bleeding recurs. Band ligation involves the varices being sucked into a cap placed on the end of the endoscope, allowing them to be occluded with a tight rubber band. The occluded varix subsequently sloughs with variceal obliteration. Banding is repeated every 2–4 weeks until all varices are obliterated. Fig. 22.22 Sengstaken–Blakemore tube. Oesophageal balloon Oesophageal aspirate Traction Gastric balloon (clamped) Gastric aspirate Gastric balloon (inflated with 200–250 mL of air) Oesophageal balloon (deflated) Fig. 22.21 Management of acute bleeding from oesophageal varices. (TIPSS = transjugular intrahepatic portosystemic stent shunt) Start IV terlipressin and antibiotic prophylaxis Suspected variceal haemorrhage Varices present? Urgent upper gastrointestinal endoscopy Yes Endoscopic therapy (variceal banding, sclerotherapy) Haemostasis? No Stop terlipressin (treat as for nonvariceal haemorrhage) Yes Continue terlipressin to 72 hrs Introduce β-blocker as secondary prophylaxis Enter patient into endoscopic banding programme to obliterate varices No Further endoscopic therapy or Balloon tamponade or Emergency TIPSS

Infections and the liver • 871

Fig. 22.23 Transjugular intrahepatic portosystemic stent shunt (TIPSS). X-ray showing placement of a TIPSS within the portal vein (PV), allowing blood to flow from the portal vein into the hepatic vein (HV) and then the inferior vena cava (IVC). IVC HV PV Secondary prevention of variceal bleeding Beta-blockers are used as a secondary measure to prevent recurrent variceal bleeding. Following successful endoscopic therapy, patients should be entered into an oesophageal banding programme with repeated sessions of therapy at 12–24-week intervals until the varices are obliterated. In selected individuals, TIPSS may also be considered in this setting. Congestive ‘portal hypertensive’ gastropathy Long-standing portal hypertension causes chronic gastric congestion, which is recognisable at endoscopy as multiple areas of punctate erythema (‘portal hypertensive gastropathy’ or ‘snakeskin gastropathy’). Rarely, similar lesions occur more distally in the gastrointestinal tract. These areas may become eroded, causing bleeding from multiple sites. Acute bleeding can occur but repeated minor bleeding causing iron deficiency anaemia is more common. Anaemia may be prevented by oral iron supplements but repeated blood transfusions can become necessary. Reduction of the portal pressure using propranolol (80–160 mg/day) is the best initial treatment. If this is ineffective, a TIPSS procedure can be undertaken. Infections and the liver The liver may be subject to a number of different infections. These include hepatotropic viral infections and bacterial and protozoal infections. Each has specific clinical features and requires targeted therapies. Viral hepatitis This must be considered in anyone presenting with hepatitic liver blood tests (high transaminases). The causes are listed in Box 22.33. All these viruses cause illnesses that have similar clinical and pathological features and are frequently anicteric or even asymptomatic. They differ in their tendency to cause acute and chronic infections. The features of the major hepatitis viruses are shown in Box 22.34. Therapeutic developments for viral hepatitis, in particular hepatitis C, are evolving very rapidly, with several new classes of drugs entering clinical practice. Clinical features of acute infection A non-specific prodromal illness characterised by headache, myalgia, arthralgia, nausea and anorexia usually precedes the development of jaundice by a few days to 2 weeks. Vomiting and diarrhoea may follow and abdominal discomfort is common. to inflate the balloon in the stomach under direct endoscopic vision. Gentle traction is essential to maintain pressure on the varices. Initially, only the gastric balloon should be inflated, with 200–250 mL of air, as this will usually control bleeding. Inflation of the gastric balloon must be stopped if the patient experiences pain because inadvertent inflation in the oesophagus can cause oesophageal rupture. If the oesophageal balloon needs to be used because of continued bleeding, it should be deflated for about 10 minutes every 3 hours to avoid oesophageal mucosal damage. Pressure in the oesophageal balloon should be monitored with a sphygmomanometer and should not exceed 40 mmHg. Balloon tamponade will almost always stop oesophageal and gastric fundal variceal bleeding but is only a bridge to more definitive therapy. Self-expanding removable oesophageal stents are a new alternative in patients with bleeding oesophageal, but not gastric, varices. TIPSS This technique uses a stent placed between the portal vein and the hepatic vein within the liver to provide a portosystemic shunt and therefore reduce portal pressure (Fig. 22.23). It is carried out under radiological control via the internal jugular vein; prior patency of the portal vein must be determined angiographically, coagulation deficiencies may require correction with fresh frozen plasma, and antibiotic cover is provided. Successful shunt placement stops and prevents further variceal bleeding, and is an effective treatment for both oesophageal and gastric varices. Further bleeding necessitates investigation and treatment (e.g. angioplasty) because it is usually associated with shunt narrowing or occlusion. Hepatic encephalopathy may occur following TIPSS and is managed by reducing the shunt diameter. Although TIPSS is associated with less rebleeding than endoscopic therapy, survival is not improved. Portosystemic shunt surgery Surgery prevents recurrent bleeding but carries a high mortality and often leads to encephalopathy. In practice, portosystemic shunts are now reserved for when other treatments have not been successful and are offered only to patients with good liver function. Oesophageal transection Rarely, surgical transection of the varices may be performed as a last resort when bleeding cannot be controlled by other means but operative mortality is high. 22.33 Causes of viral hepatitis Common • Hepatitis A • Hepatitis B ± hepatitis D • Hepatitis C • Hepatitis E Less common • Cytomegalovirus • Epstein–Barr virus Rare • Herpes simplex • Yellow fever

872 • HEPATOLOGY Hepatitis A The hepatitis A virus (HAV) belongs to the picornavirus group of enteroviruses. HAV is highly infectious and is spread by the faecal–oral route. Infected individuals, who may be asymptomatic, excrete the virus in faeces for about 2–3 weeks before the onset of symptoms and then for a further 2 weeks or so. Infection is common in children but often asymptomatic, and so up to 30% of adults will have serological evidence of past infection but give no history of jaundice. Infection is also more common in areas of overcrowding and poor sanitation. In occasional outbreaks, water and shellfish have been the vehicles of transmission. In contrast to hepatitis B, a chronic carrier state does not occur. Investigations Only one HAV antigen has been found and infected people make an antibody to this antigen (anti-HAV). Anti-HAV is important in diagnosis, as HAV is present in the blood only transiently during the incubation period. Excretion in the stools occurs for only 7–14 days after the onset of the clinical illness and the virus cannot be grown readily. Anti-HAV of the IgM type, indicating a primary immune response, is already present in the blood at the onset of the clinical illness and is diagnostic of an acute HAV infection. Titres of this antibody fall to low levels within about 3 months of recovery. Anti-HAV of the IgG type is of no diagnostic value, as HAV infection is common and this antibody persists for years after infection, but it can be used as a marker of previous HAV infection. Its presence indicates immunity to HAV. Management Infection in the community is best prevented by improving social conditions, especially overcrowding and poor sanitation. Individuals can be given substantial protection from infection by active immunisation with an inactivated virus vaccine. Immunisation should be considered for individuals with chronic hepatitis B or C infections. Immediate protection can be provided by immune serum globulin if this is given soon after exposure to the virus. The protective effect of immune serum globulin is attributed to its anti-HAV content. Immunisation should be Dark urine and pale stools may precede jaundice. There are usually few physical signs. The liver is often tender but only minimally enlarged. Occasionally, mild splenomegaly and cervical lymphadenopathy are seen. These features are more frequent in children or those with Epstein–Barr virus (EBV) infection. Symptoms rarely last longer than 3–6 weeks. Complications may occur but are rare (Box 22.35). Investigations A hepatitic pattern of LFTs develops, with serum transaminases typically between 200 and 2000 U/L in an acute infection (usually lower and fluctuating in chronic infections). The plasma bilirubin reflects the degree of liver damage. The ALP rarely exceeds twice the upper limit of normal. Prolongation of the PT indicates the severity of the hepatitis but rarely exceeds 25 seconds, except in rare cases of acute liver failure. The white cell count is usually normal with a relative lymphocytosis. Serological tests confirm the aetiology of the infection. Management Most individuals do not need hospital care. Drugs such as sedatives and narcotics, which are metabolised in the liver, should be avoided. No specific dietary modifications are required. Alcohol should not be taken during the acute illness. Elective surgery should be avoided in cases of acute viral hepatitis, as there is a risk of post-operative liver failure. Liver transplantation is very rarely indicated for acute viral hepatitis complicated by liver failure, but is commonly performed for complications of cirrhosis resulting from chronic hepatitis B and C infection. 22.34 Features of the main hepatitis viruses Hepatitis A Hepatitis B Hepatitis C Hepatitis D Hepatitis E Virus Group Enterovirus Hepadnavirus Flavivirus Incomplete virus Calicivirus Nucleic acid RNA DNA RNA RNA RNA Size (diameter) 27 nm 42 nm 30–38 nm 35 nm 27 nm Incubation (weeks) 2–4 4–20 2–26 6–9 3–8 Spread* Faeces Yes No No No Yes Blood Uncommon Yes Yes Yes No Saliva Yes Yes Yes Unknown Unknown Sexual Uncommon Yes Uncommon Yes Unknown Vertical No Yes Uncommon Yes No Chronic infection No Yes Yes Yes No (except immune- compromised) Prevention Active Vaccine Vaccine No Prevented by hepatitis B vaccination No Passive Immune serum globulin Hyperimmune serum globulin No No *All body fluids are potentially infectious, although some (e.g. urine) are less infectious than others. 22.35 Complications of acute viral hepatitis • Acute liver failure • Cholestatic hepatitis (hepatitis A) • Aplastic anaemia • Chronic liver disease and cirrhosis (hepatitis B and C) • Relapsing hepatitis

Infections and the liver • 873

evident in the absence of a significant innate or inflammatory response. • Finally, very high loads of antigen may lead to so-called ‘exhaustion’ of cellular immune responses. The state of tolerance is not permanent, however, and may be reversed as a result of therapy, or through spontaneous changes in innate responses, such as interferon alpha (IFN-α) and NK cells, accompanied by host-mediated immunopathology. Chronic hepatitis can lead to cirrhosis or hepatocellular carcinoma, usually after decades of infection (Fig. 22.25). Chronic HBV infection is a dynamic process that can be divided into five phases (Box 22.37); these are not necessarily sequential, however, and not all patients will go through all phases. It is important to remember that the virus is not directly cytotoxic to cells; rather, it is an immune response to viral antigens displayed on infected hepatocytes that initiates liver injury. This explains why there may be very high levels of viral replication but little hepatocellular damage during the ‘immune-tolerant’ phase. Investigations Serology HBV contains several antigens to which infected persons can make immune responses (Fig. 22.26); these antigens and their antibodies are important in identifying HBV infection (Boxes 22.37 and 22.38), although the widespread availability of polymerase chain reaction (PCR) techniques to measure viral DNA levels in peripheral blood means that longitudinal monitoring is now also frequently guided by direct assessment of viral load. Hepatitis B surface antigen Hepatitis B surface antigen (HBsAg) is an indicator of active infection, and a negative test for HBsAg makes HBV infection very unlikely. In acute liver failure from hepatitis B, the liver damage is mediated by viral clearance and so HBsAg is negative, with evidence of recent infection provided by the presence of hepatitis B core IgM. HBsAg appears in the blood late in the incubation period but before the prodromal phase of acute type B hepatitis; it may be present for a few days only, disappearing even before jaundice has developed, but usually lasts for 3–4 weeks and can persist for up to 5 months. The persistence of HBsAg for longer than 6 months indicates chronic infection. Antibody to HBsAg (anti-HBs) usually appears after about 3–6 months and persists for many years or perhaps permanently. Anti-HBs implies either a previous infection, in which case anti-HBc (see below) is usually also present, or previous vaccination, in which case anti-HBc is not present. Hepatitis B core antigen Hepatitis B core antigen (HBcAg) is not found in the blood, but antibody to it (anti-HBc) appears early considered for those at particular risk, such as close contacts of HAV-infected patients, the elderly, those with other major disease and perhaps pregnant women. Immune serum globulin can be effective in an outbreak of hepatitis, in a school or nursery, as injection of those at risk prevents secondary spread to families. People travelling to endemic areas are best protected by vaccination. Acute liver failure is rare in hepatitis A (0.1%) and chronic infection does not occur. Infection in patients with chronic liver disease, however, may cause serious or life-threatening disease. In adults, a cholestatic phase with elevated ALP levels may complicate infection. There is no role for antiviral drugs in the therapy of HAV infection. Hepatitis B The hepatitis B virus consists of a core containing DNA and a DNA polymerase enzyme needed for virus replication. The core of the virus is surrounded by surface protein (Fig. 22.24). The virus, also called a Dane particle, and an excess of its surface protein (known as hepatitis B surface antigen, HBsAg) circulate in the blood. Humans are the only source of infection. Hepatitis B is one of the most common causes of chronic liver disease and hepatocellular carcinoma worldwide. Approximately one-third of the world’s population have serological evidence of past or current infection with hepatitis B and approximately 350–400 million people are chronic HBsAg carriers. Hepatitis B may cause an acute viral hepatitis; however, acute infection is often asymptomatic, particularly when acquired at birth. Many individuals with chronic hepatitis B are also asymptomatic. The risk of progression to chronic liver disease depends on the source and timing of infection (Box 22.36). Vertical transmission from mother to child in the perinatal period is the most common cause of infection worldwide and carries the highest risk of ongoing chronic infection. In this setting, adaptive immune responses to HBV may be absent initially, with apparent immunological tolerance. Several mechanisms contribute towards this: • Firstly, the introduction of antigen in the neonatal period is tolerogenic. • Secondly, the presentation of such antigen within the liver, as described above, promotes tolerance; this is particularly Fig. 22.24 Schematic diagram of the hepatitis B virus. Hepatitis B surface antigen (HBsAg) is a protein that makes up part of the viral envelope. Hepatitis B core antigen (HBcAg) is a protein that makes up the capsid or core part of the virus (found in the liver but not in blood). Hepatitis B e antigen (HBeAg) is part of the HBcAg that can be found in the blood and indicates infectivity. HBV-DNA HBV-DNA polymerase HBsAg HBcAg HBeAg (blood) 22.36 Source of hepatitis B infection and risk of chronic infection Horizontal transmission (10%) • Injection drug use • Infected unscreened blood products • Tattoos/acupuncture needles • Sexual transmission • Close living quarters/playground play as a toddler (may contribute to high rate of horizontal transmission in Africa) Vertical transmission (90%) • Hepatitis B surface antigen (HBsAg)-positive mother

874 • HEPATOLOGY Hepatitis B e antigen Hepatitis B e antigen (HBeAg) is an indicator of viral replication. In acute hepatitis B it may appear only transiently at the outset of the illness; its appearance is followed by the production of antibody (anti-HBe). The HBeAg reflects active replication of the virus in the liver. in the illness and rapidly reaches a high titre, which subsides gradually but then persists. Anti-HBc is initially of IgM type, with IgG antibody appearing later. Anti-HBc (IgM) can sometimes reveal an acute HBV infection when the HBsAg has disappeared and before anti-HBs has developed (see Fig. 22.26 and Box 22.38). Fig. 22.25 Natural history of chronic hepatitis B virus (HBV) infection. There is an initial immunotolerant phase with high levels of virus and normal liver biochemistry. An immunological response to the virus then occurs, with elevation in serum transaminases, which causes liver damage: chronic hepatitis. If this response is sustained over many years and viral clearance does not occur promptly, chronic hepatitis may result in cirrhosis. In individuals with a successful immunological response, viral load falls, HBe antibody (HBeAg) develops and there is no further liver damage. Some individuals may subsequently develop HBV-DNA mutants that escape from immune regulation, and viral load again rises with further chronic hepatitis. Mutations in the core protein result in the virus’s inability to secrete HBe antigen despite high levels of viral replication; such individuals have HBeAg-negative chronic hepatitis. (ALT = alanine aminotransferase; AST = aspartate aminotransferase) HBeAg-positive HBeAg-negative Viral load HBV-tolerant HBV clearance Latent phase HBV mutant Liver transaminases ALT/AST Time (years) Chronic infection Liver histology Normal Chronic hepatitis Minimal inflammation Chronic hepatitis Cirrhosis Hepatocellular carcinoma 22.37 The five phases of chronic hepatitis B virus (HBV) infection Phase HBsAg HBeAg Anti-HBe Ab Viral load ALT Histology Notes ‘Immune-tolerant’ phase + + – +++ Normal/ low Normal/minimal necroinflammation Prolonged in perinatally infected individuals; may be short or absent if infected as an adult. High viral load and so very infectious ‘Immune-reactive’ HBeAg-positive chronic hepatitis phase + + – ++ Raised Moderate/severe necroinflammation May last weeks or years. High risk of cirrhosis or HCC if prolonged. Increased chance of spontaneous loss of HBeAg with seroconversion to anti-HBe antibody-positive state ‘Inactive carrier’ phase + – + –/+ Normal Normal/minimal necroinflammation Low risk of cirrhosis or HCC in majority HBeAg-negative chronic hepatitis phase + – + Fluctuating +/++ Raised/ fluctuating Moderate/severe necroinflammation May represent late immune reactivation or presence of ‘pre-core mutant’ HBV. High risk of cirrhosis or HCC HBsAg-negative phase – – + –/± Normal Normal Ultrasensitive techniques may detect low-level HBV even after HBsAg loss (HBeAg = hepatitis B e antigen; HBsAg = hepatitis B surface antigen; HCC = hepatocellular carcinoma)

Infections and the liver • 875

affected are classified as having e antigen-negative chronic hepatitis. They respond differently to antiviral drugs from those with classical e antigen-positive chronic hepatitis. Measurement of viral load is important in monitoring antiviral therapy and identifying patients with pre-core mutants. Specific HBV genotypes (A–H) can also be identified using PCR. In some settings, these may be useful in guiding therapy, as genotype A tends to respond better to pegylated interferon-alfa compared to genotypes C and D. Management of acute hepatitis B Treatment is supportive with monitoring for acute liver failure, which occurs in less than 1% of cases. There is no definitive evidence that antiviral therapy reduces the severity or duration of acute hepatitis B. Full recovery occurs in 90–95% of adults following acute HBV infection. The remaining 5–10% develop a chronic hepatitis B infection that usually continues for life, although later recovery occasionally occurs. Infection passing from mother to child at birth leads to chronic infection in the child in 90% of cases and recovery is rare. Chronic infection is also common in immunodeficient individuals, such as those with Down’s syndrome or human immunodeficiency virus (HIV) infection. Fulminant liver failure due to acute hepatitis B occurs in less than 1% of cases. Recovery from acute HBV infection occurs within 6 months and is characterised by the appearance of antibody to viral antigens. Persistence of HBeAg beyond this time indicates chronic infection. Combined HBV and hepatitis delta virus (HDV) infection causes more aggressive disease. Management of chronic hepatitis B Treatments are still limited, as no drug is consistently able to eradicate hepatitis B infection completely (i.e. render the Chronic HBV infection (see below) is marked by the presence of HBsAg and anti-HBc (IgG) in the blood. Usually, HBeAg or anti-HBe is also present; HBeAg indicates continued active replication of the virus in the liver. The absence of HBeAg usually implies low viral replication; the exception is HBeAg-negative chronic hepatitis B (also called ‘pre-core mutant’ infection, discussed below), in which high levels of viral replication, serum HBV-DNA and hepatic necroinflammation are seen, despite negative HBeAg. Viral load and genotype HBV-DNA can be measured by PCR in the blood. Viral loads are usually in excess of 105 copies/mL in the presence of active viral replication, as indicated by the presence of e antigen. In contrast, in individuals with low viral replication, who are HBsAg- and anti-HBe-positive, viral loads are less than 105 copies/mL. The exception is in patients who have a mutation in the pre-core protein, which means they cannot secrete e antigen into serum (Fig. 22.27). Such individuals will be anti-HBe-positive but have a high viral load and often evidence of chronic hepatitis. These mutations are common in the Far East, and those patients Fig. 22.26 Serological responses to hepatitis B virus infection. (anti-HBc = antibody to hepatitis B core antigen; anti-HBe = antibody to HBeAg; anti-HBs = antibody to HBsAg; HBeAg = hepatitis B e antigen; HBsAg = hepatitis B surface antigen; IgM = immunoglobulin M)

Relative amount of product detectable Clinical illness HBeAg HBsAg Anti-HBe Anti-HBs Anti-HBc IgM anti-HBc Time after exposure (months) 22.38 How to interpret the serological tests of acute hepatitis B virus infection Interpretation HBsAg Anti-HBc IgM Anti-HBc IgG Anti-HBs Incubation period + + – – Acute hepatitis Early + + – – Established + + + – Established (occasional) – + + – Convalescence (3–6 months) – ± + ± (6–9 months) – – + + Post-infection – – + ± Immunisation without infection – – – +

876 • HEPATOLOGY may cause a rise in serum transaminases and precipitate liver failure. Longer-acting pegylated interferons that can be given once weekly have been evaluated in both HBeAg-positive and HBeAg-negative chronic hepatitis. Side-effects are common and include fatigue, depression, irritability, bone marrow suppression and the triggering of autoimmune thyroid disease. Liver transplantation Historically, liver transplantation was contraindicated in hepatitis B because infection often recurred in the graft. The use of post- liver transplant prophylaxis with direct-acting antiviral agents and hepatitis B immunoglobulins has, however, reduced the reinfection rate to 10% and increased 5-year survival to 80%, making transplantation an acceptable treatment option. Prevention Individuals are most infectious when markers of continuing viral replication, such as HBeAg, and high levels of HBV-DNA are present in the blood. HBV-DNA can be found in saliva, urine, semen and vaginal secretions (although urine is not usually considered to be capable of transmitting infection). The virus is about ten times more infectious than hepatitis C, which in turn is about ten times more infectious than HIV. A recombinant hepatitis B vaccine containing HBsAg is available (Engerix) and is capable of producing active immunisation in 95% of normal individuals. The vaccine should be offered to those at special risk of infection who are not already immune, as evidenced by anti-HBs in the blood (Box 22.39). The vaccine is ineffective in those already infected by HBV. Infection can also be prevented or minimised by the intramuscular injection of specific hepatitis B immunoglobulin (HBIg) prepared from blood containing anti-HBs. This should be given within 48 hours, or at most a week, of exposure to infected blood in circumstances likely to cause infection (e.g. needlestick injury, contamination of cuts or mucous membranes). Vaccine can be given together with HBIg (active–passive immunisation). Neonates born to hepatitis B-infected mothers should be immunised at birth and given immunoglobulin. Hepatitis B serology should then be checked at 12 months of age. Co-infection with HIV Around 10% of the HIV-infected population has concurrent HBV and this figure may be as high as 25% in areas where both viruses are prevalent. Up to half of injection drug users with HIV are co-infected with HBV. Co-infection increases the morbidity and mortality compared to either infection alone: there are greater levels of HBV viraemia, faster progression to chronic infection and greater risk of cirrhosis and hepatocellular carcinoma than with HBV infection alone. The immunosuppression that is seen in HIV infection can lead to loss of anti-HBs antibodies, reactivation of infection and a poorer antibody response to HBV vaccination. patient HBsAg-negative). The goals of treatment are HBeAg seroconversion, reduction in HBV-DNA and normalisation of the LFTs. The indication for treatment is a high viral load in the presence of active hepatitis, as demonstrated by elevated serum transaminases and/or histological evidence of inflammation and fibrosis. The oral antiviral agents are more effective in reducing viral loads in patients with e antigen-negative chronic hepatitis B than in those with e antigen-positive chronic hepatitis B, as the pre-treatment viral loads are lower. Most patients with chronic hepatitis B are asymptomatic and develop complications, such as cirrhosis and hepatocellular carcinoma, only after many years (see Fig. 22.25). Cirrhosis develops in 15–20% of patients with chronic HBV over 5–20 years. This proportion is higher in those who are e antigen-positive. Two different types of drug are used to treat hepatitis B: direct-acting nucleoside/nucleotide analogues and pegylated interferon-alfa. Direct-acting nucleoside/nucleotide antiviral agents Orally administered nucleoside/nucleotide antiviral agents are the mainstay of therapy. These act by inhibiting the reverse transcription of pre-genomic RNA to HBV-DNA by HBV-DNA polymerase but do not directly affect the covalently closed circular DNA (cccDNA) template for viral replication, and so relapse is common if treatment is withdrawn. One major concern is the selection of antiviral-resistant mutations with long-term treatment. This is particularly important with some of the older agents, such as lamivudine, as mutations induced by previous antiviral exposure may also induce resistance to newer agents. Entecavir and tenofovir (see below) are potent antivirals with a high barrier to genetic resistance and so are the most appropriate first-line agents. Lamivudine Although effective, long-term therapy is often complicated by the development of HBV-DNA polymerase mutants (e.g. the ‘YMDD variant’), which lead to viral resistance. These occur after approximately 9 months and are characterised by a rise in viral load during treatment. Outside resource-limited settings, this agent is now seldom used for the treatment of HBV but may be used to prevent reactivation of HBV in previously infected, HBsAg-negative patients if they are undergoing chemotherapy. Entecavir and tenofovir Monotherapy with entecavir or tenofovir is substantially more effective than lamivudine in reducing viral load in HBeAg-positive and HBeAg-negative chronic hepatitis. Antiviral resistance mutations occur in only 1–2% after 3 years of entecavir drug exposure. Both drugs have anti-HIV action and so their use as monotherapy is contraindicated in HIV-positive patients, as it may lead to HIV antiviral drug resistance. Current European guidelines advise that the other nucleoside/nucleotide antivirals should not be used as first-line monotherapy due to the induction of viral mutations, unless more potent drugs with a high barrier to resistance are not available or appropriate. Interferon-alfa This is most effective in patients with a low viral load and serum transaminases greater than twice the upper limit of normal, in whom it acts by augmenting a native immune response. In HBeAg-positive chronic hepatitis, 33% lose e antigen after 4–6 months of treatment, compared to 12% of controls. Response rates are lower in HBeAg-negative chronic hepatitis, even when patients are given longer courses of treatment. Interferon is contraindicated in the presence of cirrhosis, as it 22.39 At-risk groups meriting hepatitis B vaccination in low-endemic areas • Parenteral drug users • Men who have sex with men • Close contacts of infected individuals: Newborn of infected mothers Regular sexual partners • Patients on chronic haemodialysis • Patients with chronic liver disease • Medical, nursing and laboratory personnel

Infections and the liver • 877

Hepatitis C infection is usually identified in asymptomatic individuals screened because they have risk factors for infection, such as previous injecting drug use (Box 22.40), or have incidentally been found to have abnormal liver blood tests. Although most people remain asymptomatic until progression to cirrhosis occurs, fatigue can complicate chronic infection and is unrelated to the degree of liver damage. Hepatitis C is the most common cause of what used to be known as ‘non-A, non-B hepatitis’. If hepatitis C infection is left untreated, progression from chronic hepatitis to cirrhosis occurs over 20–40 years. Risk factors for progression include male gender, immunosuppression (such as co-infection with HIV), prothrombotic states and heavy alcohol misuse. Not everyone with hepatitis C infection will necessarily develop cirrhosis but approximately 20% do so within 20 years. Once cirrhosis has developed, the 5- and 10-year survival rates are 95% and 81%, respectively. One-quarter of people with cirrhosis will develop complications within 10 years and, once complications such as ascites develop, the 5-year survival is around 50%. Once cirrhosis is present, 2–5% per year will develop primary hepatocellular carcinoma. Investigations Serology and virology The HCV genome encodes a large polypeptide precursor that is modified post-translationally to at least ten proteins, including several antigens that give rise to antibodies in an infected person; these are used in diagnosis. It may take 6–12 weeks for antibodies to appear in the blood following acute infection, such as a needlestick injury. In these cases, hepatitis C RNA can be identified in the blood as early as 2–4 weeks after infection. Active infection is confirmed by the presence of serum hepatitis C RNA in anyone who is antibody-positive. Anti-HCV antibodies persist in serum even after viral clearance, whether spontaneous or post-treatment. Molecular analysis There are six common viral genotypes, the distribution of which varies worldwide. Genotype has no effect on progression of liver disease but does affect response to treatment. Genotype 1 is most common in northern Europe and was less easy to eradicate than genotypes 2 and 3 with traditional pegylated interferon alfa-/ribavirin-based treatments. Knowledge of viral genotype still remains relevant in guiding selection of drugs to treat HCV. Liver function tests LFTs may be normal or show fluctuating serum transaminases between 50 and 200 U/L. Jaundice is rare and only usually appears in end-stage cirrhosis. Pregnancy poses particular problems in co-infected patients, with increased risk of perinatal transmission of HBV to the child. Treatment can also be problematic. Several nucleoside analogues have dual antiviral activity and some regimens have been associated with emergence of drug resistance. Co-infection is also associated with diminished response to interferons and increased resistance to lamivudine in some patients. Co-infection should be managed by specialists with expertise in this area and combinations of antiviral agents need to be thought through carefully. Antiviral therapy should be considered for co-infected pregnant women, using drugs with dual activity, e.g. tenofovir with emtricitabine or lamivudine. Globally, there is a need to identify co-infected patients earlier, especially in endemic areas, as well as a need for early effective interventions, particularly in pregnant women, to reduce perinatal transmission. Hepatitis D (Delta virus) The hepatitis D virus (HDV) is an RNA-defective virus that has no independent existence; it requires HBV for replication and has the same sources and modes of spread. It can infect individuals simultaneously with HBV or can superinfect those who are already chronic carriers of HBV. Simultaneous infections give rise to acute hepatitis, which is often severe but is limited by recovery from the HBV infection. Infections in individuals who are chronic carriers of HBV can cause acute hepatitis with spontaneous recovery, and occasionally there is simultaneous cessation of the chronic HBV infection. Chronic infection with HBV and HDV can also occur, and this frequently causes rapidly progressive chronic hepatitis and eventually cirrhosis. HDV has a worldwide distribution. It is endemic in parts of the Mediterranean basin, Africa and South America, where transmission is mainly by close personal contact and occasionally by vertical transmission from mothers who also carry HBV. In non-endemic areas, transmission is mainly a consequence of parenteral drug misuse. Investigations HDV contains a single antigen to which infected individuals make an antibody (anti-HDV). Delta antigen appears in the blood only transiently, and in practice diagnosis depends on detecting anti-HDV. Simultaneous infection with HBV and HDV, followed by full recovery, is associated with the appearance of low titres of anti-HDV of IgM type within a few days of the onset of the illness. This antibody generally disappears within 2 months but persists in a few patients. Super-infection of patients with chronic HBV infection leads to the production of high titres of anti-HDV, initially IgM and later IgG. Such patients may then develop chronic infection with both viruses, in which case anti-HDV titres plateau at high levels. Management Effective management of hepatitis B prevents hepatitis D. Hepatitis C This is caused by an RNA flavivirus. Acute symptomatic infection with hepatitis C is rare. Most individuals are unaware of when they became infected and are identified only when they develop chronic liver disease. Eighty per cent of individuals exposed to the virus become chronically infected and late spontaneous viral clearance is rare. There is no active or passive protection against hepatitis C virus (HCV). 22.40 Risk factors for the acquisition of chronic hepatitis C infection • Intravenous drug misuse (95% of new cases in the UK) • Unscreened blood products • Vertical transmission (3% risk) • Needlestick injury (3% risk) • Iatrogenic parenteral transmission (e.g. contaminated vaccination needles) • Sharing toothbrushes/razors

878 • HEPATOLOGY Since 2011, new classes of direct-acting antiviral agents (DAAs) have been developed. There are four main classes of DAA, which are defined according to their mechanism of action and therapeutic target (Box 22.41). These compounds are targeted to specific steps in the hepatitis C viral life cycle to disrupt viral replication (Fig. 22.28). Initially, DAAs were added to interferon-/ ribavirin-based regimens; more recently, however, combinations of DAAs have increasingly been used in ‘interferon-free’ regimens. This maximises treatment efficacy by directly interfering with replication at multiple points in the viral life cycle without exposing patients to the side-effect profile of interferon-alfa therapy. For example, 12 weeks of treatment with oral sofosbuvir plus ledipasvir plus ribavirin can achieve a 99% SVR in treatment-naïve genotype 1 patients. Sofosbuvir plus velpatasvir achieves similar results and is pan-genotypic. Although not without side-effects, DAAs are often orally administered, efficacious and, in general, well tolerated. Liver transplantation should be considered when complications of cirrhosis occur, such as diuretic-resistant ascites. Unfortunately, if the virus is not cleared, hepatitis C will infect the transplanted liver and up to 15% of patients then develop cirrhosis in the liver graft within 5 years of transplantation. This should no longer happen, as modern antiviral therapy post-transplant achieves excellent results. Hepatitis E Hepatitis E is caused by an RNA virus that is endemic in India and the Middle East. Prevalence is now increasing across Asia and Europe, especially south-west France, so it is important to note that infection is no longer seen only in travellers from an endemic area. The clinical presentation and management of hepatitis E are similar to those of hepatitis A. Disease is spread via the faecal–oral route or through contaminated food; the virus is commonly present in uncooked game and pig-liver sausage in southern France, and this may be a route of infection. In most cases, it presents as a self-limiting acute hepatitis and does not usually cause chronic liver disease. There is increasing recognition that hepatitis E may develop into chronic infection, usually in immunocompromised patients and especially in organ-transplant recipients, although this remains uncommon. If treatment is required for chronic infection, agents such as ribavirin may be used. Blood donations are now routinely screened for hepatitis E. Hepatitis E differs from hepatitis A in that infection during pregnancy is associated with the development of acute liver failure, which has a high mortality. In acute infection, IgM antibodies to hepatitis E virus (HEV) are positive. Other forms of viral hepatitis Non-A, non-B, non-C (NANBNC) or non-A–E hepatitis is the term used to describe hepatitis thought to be due to a virus that is not HAV, HBV, HCV or HEV. Other viruses that affect the liver probably exist but the viruses described above now account for the majority of hepatitis infections. Cytomegalovirus and EBV infection causes abnormal LFTs in most patients and occasionally jaundice occurs. Herpes simplex is a rare cause of hepatitis in adults, most of whom are immunocompromised. Herpes simplex virus hepatitis can be very severe in pregnancy. Abnormal LFTs are also common in chickenpox, measles, rubella and acute HIV infection. Liver histology Serum transaminase levels in hepatitis C are a poor predictor of the degree of liver fibrosis and so a liver biopsy may be required to stage the extent of liver damage. The degree of inflammation and fibrosis can be scored histologically. The most common way of doing this in hepatitis C is the Metavir system, which scores fibrosis from 1 to 4, the latter equating to cirrhosis. Recently, non-invasive markers and fibrosis scoring systems have been used routinely, with biopsy being reserved for cases where these give conflicting results. Management The aim of treatment is to eradicate infection. In recent years, there have been substantial advances, so much so that rates of viral clearance achieved 6 months after finishing treatment (termed sustained virological response, SVR) have risen from less than 40% a decade ago to levels approaching 100% with some of the newer direct-acting antivirals. The infection is cured in more than 99% of patients who achieve an SVR. These newer drugs are extremely expensive, however, and so their use is placing substantial strain on the finite health-care resources of developed countries and has severely limited their availability in resource-poor settings. Until 2011, the treatment of choice was dual therapy with pegylated interferon-alfa, given as a weekly subcutaneous injection, together with oral ribavirin, a synthetic nucleotide analogue. Treatment was long – up to 12 months for genotype 1 infection, and both agents had significant side-effects that limited tolerability: ribavirin induces haemolytic anaemia and is teratogenic, while interferon induces influenza-like symptoms, irritability and depression, all of which can affect quality of life. As already mentioned, efficacy of these agents was poor (12 months’ treatment for genotype 1 resulted in only a 40% SVR, rising to an SVR of over 70% for genotypes 2 or 3 after 6 months’ treatment). 22.41 Direct-acting antiviral agents for hepatitis C Drug class Therapeutic target Selected drugs Protease inhibitors (PIs) Non-structural viral protein NS3/4A (protease that cleaves the HCV polyprotein) Telaprevir Boceprevir Simeprevir Paritaprevir Grazoprevir Nucleoside polymerase inhibitors (NPIs) Non-structural viral protein NS5B (RNA-dependent RNA polymerase needed for viral replication) Sofosbuvir Non-nucleoside polymerase inhibitors (NNPIs) Non-structural viral protein NS5B (RNA-dependent RNA polymerase needed for viral replication) Dasabuvir NS5A replication complex inhibitors Non-structural viral protein NS5A (assembly of viral replication complex) Daclatasvir Velpatasvir Ledipasvir Ombitasvir Elbasvir Host-targeting antiviral drugs (HTAs) Cyclophilin (pharmacological inhibitor targets host cell functions involved in the HCV life cycle) Alisporivir (HCV = hepatitis C virus)

Infections and the liver • 879

Liver abscess Liver abscesses are classified as pyogenic, hydatid or amoebic. Pyogenic liver abscess Pyogenic liver abscesses are uncommon but important because they are potentially curable, carry significant morbidity and mortality if untreated, and are easily overlooked. The mortality of liver abscesses is 20–40%; failure to make the diagnosis is the most common cause of death. Older patients and those with multiple abscesses have a higher mortality. Pathophysiology Infection can reach the liver in several ways (Box 22.43). Pyogenic abscesses are most common in older patients and usually result from ascending infection due to biliary obstruction (cholangitis) or contiguous spread from an empyema of the gallbladder. They can also complicate dental sepsis or colonic pathology, e.g. cancer, diverticulitis or inflammatory bowel disease causing portal pyaemia. HIV infection and the liver Several causes of abnormal LFTs occur in HIV infection, as shown in Box 22.42. This topic is discussed in more detail on page 317. Co-infection with HIV and HBV is discussed on page 876. Fig. 22.28 Direct-acting antiviral agents. These compounds are targeted to specific steps in the hepatitis C viral life cycle to disrupt replication. (5′NTR = 5′ non-translated region; HCV = hepatitis C virus; IFN = interferon) 1 Receptor binding and endocytosis 2 Hepatocyte entry 3 Fusion and RNA coating 5 Polyprotein cleaved into functional proteins by protease 6 RNA replication by encoded polymerase 7 Lipoviral particle assembly 8 Transport and release 4 Translation of RNA into protein Endoplasmic reticulum Nucleus Golgi apparatus Metalloprotease Serine protease RNA helicase Transmembrane protein Region encoding polyprotein precursor Non-structural proteins Structural proteins p22 C gp35 E1 gp70 E2 p7 NS1 p8 NS 4A p23 NS2 p27 NS4B p56/58 NS5A p68 NS5B p70 NS3 5′ NTR 5′ NTR HCV-RNA IFN-resistance protein RNA polymerase Co-factors Envelope glycoproteins Nucleocapsid NS5A inhibitors NS3/4A protease inhibitors NS5B polymerase inhibitors 22.42 Causes of abnormal liver blood tests in HIV infection Hepatitic blood tests • Chronic hepatitis C • Chronic hepatitis B • Antiretroviral drugs • Cytomegalovirus Cholestatic blood tests • Tuberculosis • Atypical mycobacterium • Sclerosing cholangitis due to cryptosporidia

880 • HEPATOLOGY Alcoholic liver disease Alcohol is one of the most common causes of chronic liver disease worldwide, with consumption continuing to increase in many countries. Patients with alcoholic liver disease (ALD) may also have risk factors for other liver diseases (e.g. coexisting NAFLD or chronic viral hepatitis infection), and these may interact to increase disease severity. In the UK, a unit of alcohol contains 8 g of ethanol (Box 22.44). An upper threshold of 14 units/week in women and 21 units/week in men is generally considered safe. Recently, however, Public Health England advice has adopted a more conservative threshold of 14 units/week for both men and women. The risk threshold for developing ALD is variable but begins at 30 g/day of ethanol. There is no clear linear relationship between dose and liver damage, however. For many, consumption of more than 80 g/day, for more than 5 years, is required to confer significant risk of advanced liver disease. The average alcohol consumption of a man with cirrhosis is 160 g/day for over 8 years. Some of the risk factors for ALD are: • Drinking pattern. ALD and alcohol dependence are not synonymous; many of those who develop ALD are not alcohol-dependent and most dependent drinkers have normal liver function. Liver damage is more likely to occur in continuous rather than intermittent or ‘binge’ drinkers, as this pattern gives the liver a chance to recover. It is therefore recommended that people should have at least two alcohol-free days each week. The type of beverage does not affect risk. • Gender. The incidence of ALD is increasing in women, who have higher blood ethanol levels than men after consuming the same amount of alcohol. This may be related to the reduced volume of distribution of alcohol. • Genetics. Alcoholism is more concordant in monozygotic than dizygotic twins. While polymorphisms in the genes involved in alcohol metabolism, such as aldehyde dehydrogenase, may alter drinking behaviour, they have not been linked to ALD. The patatin-like phospholipase domain-containing 3 (PNPLA3) gene, also known as adiponutrin, has been implicated in the pathogenesis of both ALD and NAFLD (p. 883). • Nutrition. Obesity increases the incidence of liver-related mortality by over fivefold in heavy drinkers. Ethanol itself produces 7 kcal/g (29.3 kJ/g) and many alcoholic drinks also contain sugar, which further increases the calorific Abscesses complicating suppurative appendicitis used to be common in young adults but are now rare. Immunocompromised patients are particularly likely to develop liver abscesses. Single lesions are more common in the right liver; multiple abscesses are usually due to infection secondary to biliary obstruction. Escherichia coli and various streptococci, particularly Strep. milleri, are the most common organisms; anaerobes, including streptococci and Bacteroides, can often be found when infection has been transmitted from large bowel pathology via the portal vein, and multiple organisms are present in one-third of patients. Clinical features Patients are generally ill with fever and sometimes rigors and weight loss. Abdominal pain is the most common symptom and is usually in the right upper quadrant, sometimes with radiation to the right shoulder. The pain may be pleuritic in nature. Tender hepatomegaly is found in more than 50% of patients. Mild jaundice may be present, becoming severe if large abscesses cause biliary obstruction. Atypical presentations are common and explain the frequency with which the diagnosis is made only at autopsy. This is a particular problem in patients with gradually developing illnesses or pyrexia of unknown origin without localising features. Necrotic colorectal metastases can be misdiagnosed as hepatic abscess. Investigations Liver imaging is the most revealing investigation and shows 90% or more of symptomatic abscesses. Needle aspiration under ultrasound guidance confirms the diagnosis and provides pus for culture. A leucocytosis is frequently found, plasma ALP activity is usually increased, and the serum albumin is often low. The chest X-ray may show a raised right diaphragm and lung collapse, or an effusion at the base of the right lung. Blood cultures are positive in 50–80%. Abscesses caused by gut-derived organisms require active exclusion of significant colonic pathology, such as a colonoscopy to exclude colorectal carcinoma. Management Pending the results of culture of blood and pus from the abscess, treatment should be commenced with a combination of antibiotics, such as ampicillin, gentamicin and metronidazole. Aspiration or drainage with a catheter placed in the abscess under ultrasound guidance is required if the abscess is large or if it does not respond to antibiotics. Any associated biliary obstruction and cholangitis require biliary drainage (preferably endoscopically). Surgical abscess drainage is rarely undertaken, although hepatic resection may be indicated for a chronic persistent abscess or ‘pseudotumour’. Hydatid cysts and amoebic liver abscesses These are described on pages 299 and 287. Leptospirosis This is described on page 257. 22.44 Amount of alcohol in an average drink Alcohol type % Alcohol by volume Amount Units* Beer 3.5 568 mL (1 pint)

568 mL (1 pint)

Wine

125 mL

750 mL

‘Alcopops’

330 mL

Sherry 17.5 750 mL

Vodka/rum/gin 37.5 25 mL

Whisky/brandy

700 mL

*1 unit = 8 g. 22.43 Causes of pyogenic liver abscesses • Biliary obstruction (cholangitis) • Haematogenous: Portal vein (intra-abdominal infections) Hepatic artery (bacteraemia) • Direct extension • Trauma: Penetrating or non-penetrating • Infection of liver tumour or cyst

Alcoholic liver disease • 881

The pathological features of ALD are shown in Box 22.45. In about 80% of patients with severe alcoholic hepatitis, cirrhosis will coexist at presentation. Iron deposition is common and does not necessarily indicate haemochromatosis. Figure 22.30A below shows the histological features of alcoholic liver disease, which are identical to those of non-alcoholic steatohepatitis. Clinical features ALD has a wide clinical spectrum, ranging from mild abnormalities of LFTs on biochemical testing to advanced cirrhosis. The liver is often enlarged in ALD, even in the presence of cirrhosis. Stigmata of chronic liver disease, such as palmar erythema, are more common in alcoholic cirrhosis than in cirrhosis of other aetiologies. Alcohol misuse may also cause damage of other organs and this should be specifically looked for (see Box 28.22, p. 1194). Three types of ALD are recognised (Box 22.46) but these overlap considerably, as do the pathological changes seen in the liver. Alcoholic fatty liver disease Alcoholic fatty liver disease (AFLD) usually presents with elevated transaminases in the absence of hepatomegaly. It has a good prognosis and steatosis usually disappears after 3 months of abstinence. Alcoholic hepatitis This presents with jaundice and hepatomegaly; complications of portal hypertension may also be present. It has a significantly worse prognosis than AFLD. About one-third of patients die in the acute episode, particularly those with hepatic encephalopathy or a prolonged PT. Cirrhosis often coexists; if not present, it is the likely outcome if drinking continues. Patients with acute alcoholic hepatitis often deteriorate during the first 1–3 weeks in hospital. Even if they abstain, it may take up to 6 months for jaundice to resolve. In patients presenting with jaundice who subsequently abstain, the 3- and 5-year survival is 70%. In contrast, those who continue to drink have 3- and 5-year survival rates of 60% and 34%, respectively. value and may contribute to weight gain. Excess alcohol consumption is frequently associated with nutritional deficiencies that contribute to morbidity. Pathophysiology Alcohol reaches peak blood concentrations after about 20 minutes, although this may be influenced by stomach contents. It is metabolised almost exclusively by the liver via one of two pathways (Fig. 22.29). Approximately 80% of alcohol is metabolised to acetaldehyde by the mitochondrial enzyme, alcohol dehydrogenase. Acetaldehyde is then metabolised to acetyl-CoA and acetate by aldehyde dehydrogenase. This generates NADH from NAD (nicotinamide adenine dinucleotide), which changes the redox potential of the cell. Acetaldehyde forms adducts with cellular proteins in hepatocytes that activate the immune system, contributing to cell injury. The remaining 20% of alcohol is metabolised by the microsomal ethanol-oxidising system (MEOS) pathway. Cytochrome CYP2E1 is an enzyme that oxidises ethanol to acetate. It is induced by alcohol, and during metabolism of ethanol it releases oxygen free radicals, leading to lipid peroxidation and mitochondrial damage. The CYP2E1 enzyme also metabolises acetaminophen, and hence chronic alcoholics are more susceptible to hepatotoxicity from low doses of paracetamol. It is thought that pro-inflammatory cytokines may also be involved in inducing hepatic damage in alcoholic hepatitis, since endotoxin is released into the blood because of increased gut permeability, leading to release of tumour necrosis factor alpha (TNF-α) and interleukin 1 (IL-1), IL-2 and IL-8 from immune cells. All of these cytokines have been implicated in the pathogenesis of liver fibrosis (see Fig. 22.4, p. 849). Fig. 22.29 Factors involved in the pathogenesis of alcoholic liver disease. Alcohol Genetic susceptibility Alcoholic liver disease Acetaldehyde Adducts Gut permeability CYP2E1 Immune system Endotoxin Kupffer cells Inflammation Coexistent disorders, e.g. viral hepatitis haemochromatosis Tumour necrosis factor alpha Interleukin-6 ↑Oxidative stress • Lipid peroxidation • Low glutathione 22.45 Pathological features of alcoholic liver disease • Alcoholic hepatitis: Lipogranuloma Neutrophil infiltration Mallory’s hyaline Pericellular fibrosis • Macrovesicular steatosis • Fibrosis and cirrhosis • Central hyaline sclerosis 22.46 Clinical syndromes of alcoholic liver disease Fatty liver • Asymptomatic abnormal liver biochemistry • Normal/large liver Alcoholic hepatitis • Jaundice • Malnutrition • Hepatomegaly • Features of portal hypertension (e.g. ascites, encephalopathy) Cirrhosis • Stigmata of chronic liver disease • Ascites/varices/ encephalopathy • Large, normal or small liver • Hepatocellular carcinoma

882 • HEPATOLOGY 22.47 How to assess prognosis using the Glasgow alcoholic hepatitis score Score

Age < 50

50 White cell count (× 109/L) < 15 15 Urea (mmol/L (BUN mg/dl)) < 5 (14 ) 5 (14 ) PT ratio < 1.5 1.5–2.0 2.0 Bilirubin (μmol/L (mg/dL)) < 125 (7.4 ) 125–250 (7.4–14.8 ) 250 (14.8 ) A score of ≥ 9 is associated with a 40% 28-day survival, compared to 80% for patients with a score of < 9. (BUN = blood urea nitrogen; PT = prothrombin time) Alcoholic cirrhosis Alcoholic cirrhosis often presents with a serious complication, such as variceal haemorrhage or ascites, and only half of such patients will survive for 5 years from presentation. However, most who survive the initial illness and who become abstinent will survive beyond 5 years. Investigations Investigations aim to establish alcohol misuse, exclude alternative or additional coexistent causes of liver disease, and assess the severity of liver damage. The clinical history from patient, relatives and friends is important to establish alcohol misuse duration and severity. Biological markers, particularly macrocytosis in the absence of anaemia, may suggest and support a history of alcohol misuse. A raised GGT is not specific for alcohol misuse and may also be elevated in the presence of other conditions, including NAFLD. The level may therefore not return to normal with abstinence if chronic liver disease is present, and GGT should not be relied on as an indicator of ongoing alcohol consumption. The presence of jaundice may suggest alcoholic hepatitis. Determining the extent of liver damage often requires a liver biopsy. In alcoholic hepatitis, PT and bilirubin are used to calculate a ‘discriminant function’ (DF), also known as the Maddrey score, which enables the clinician to assess prognosis (PT = prothrombin time; serum bilirubin in μmol/L is divided by 17 to convert to mg/dL): DF Increase in PT Bilirubin mg/dL = ×

[ . (sec)] ( ) 4 6 A value over 32 implies severe liver disease with a poor prognosis and is used to guide treatment decisions (see below). A second scoring system, the Glasgow score, uses the age, white cell count and renal function, in addition to PT and bilirubin, to assess prognosis and has a cut-off of 9 (Box 22.47). Management Cessation of alcohol consumption is the single most important treatment and prognostic factor. Life-long abstinence is the best advice. General health and life expectancy are improved when this occurs, irrespective of the stage of liver disease. Abstinence is even effective at preventing progression, hepatic decompensation and death once cirrhosis is present. Treatment of alcohol dependency is discussed on page 1195. In the acute presentation of ALD it is important to identify and anticipate alcohol withdrawal and Wernicke’s encephalopathy, which need treating in parallel with the liver disease and any complications of cirrhosis. Nutrition Good nutrition is very important, and enteral feeding via a fine-bore nasogastric tube may be needed in severely ill patients. Drug therapy The optimum treatment of severe alcoholic hepatitis (Maddrey’s discriminative score > 32) has been debated for some time. The STOPAH study was a large, multicentre, double-blind, randomised trial to evaluate the relative merits of glucocorticoids and/or a weak anti-TNF agent (pentoxifylline), alone or in combination. In a cohort of 1103 patients, no significant benefit from pentoxifylline treatment was identified but treatment with prednisolone (40 mg daily for 28 days) led to a modest reduction in short-term mortality, from 17% in placebo-treated patients to 14% in the prednisolone group. These findings were consistent with earlier studies where an improvement in 28-day survival from 52% to 78% is seen when glucocorticoids are given to those with a Glasgow score of more than 9. Neither glucocorticoids nor pentoxifylline improved survival at 90 days or 1 year, however. Sepsis is the main side-effect of glucocorticoids, and existing sepsis and variceal haemorrhage are the main contraindications to their use. If the bilirubin has not fallen 7 days after starting glucocorticoids, the drugs are unlikely to reduce mortality and should be stopped. Liver transplantation The role of liver transplantation in the management of ALD remains controversial. In many centres, ALD is a common indication for liver transplantation. The challenge is to identify patients with an unacceptable risk of returning to harmful alcohol consumption. Many programmes require a 6-month period of abstinence from alcohol before a patient is considered for transplantation. Although this relates poorly to the incidence of alcohol relapse after transplantation, liver function may improve to the extent that transplantation is no longer necessary. The outcome of transplantation for ALD is good and if the patient remains abstinent there is no risk of disease recurrence. Transplantation for alcoholic hepatitis has been thought to have a poorer outcome and is seldom performed due to concerns about recidivism; studies to quantify this are ongoing. Non-alcoholic fatty liver disease Increasingly sedentary lifestyles and changing dietary patterns mean that the prevalence of obesity and insulin resistance has increased worldwide, and so fat accumulation in the liver is a common finding during abdominal imaging studies and on liver biopsy. In the absence of high alcohol consumption (typically, a threshold of < 20 g/day for women and < 30 g/day for men is adopted), this is called non-alcoholic fatty liver disease (NAFLD). NAFLD includes a spectrum of progressive liver disease ranging from fatty infiltration alone (steatosis) to fatty infiltration with inflammation (non-alcoholic steatohepatitis, NASH) and may progress to cirrhosis and primary liver cancer (Fig. 22.30B). NAFLD is considered by many to be the hepatic manifestation of the ‘metabolic syndrome’ (p. 730), as it is strongly associated with obesity, dyslipidaemia, type 2 diabetes and hypertension. Estimates vary between populations, although one large European study found NAFLD to be present in 94% of obese patients

Non-alcoholic fatty liver disease • 883

Fig. 22.30 Non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH). A Features. Rate of progression is determined by environmental (dietary) and genetic factors. B The spectrum of NAFLD. (FA = fatty acid; TGF-β = transforming growth factor beta; TNF-α = tumour necrosis factor alpha; VLDL = very low-density lipoprotein) Fat infiltration > 5% with or without mild inflammation Steatosis + necroinflammation (ballooning, Mallory bodies, megamitochondria) Increasing fibrosis, eventually leading to cirrhosis Steatosis NASH Cirrhosis TNF-α Oxidant stress Endotoxin Immune factors TGF-β Stellate cell activation ↑FA influx ↓FA oxidation ↑FA synthesis ↓VLDL assembly Insulin resistance Metabolic syndrome NAFLD/steatosis NASH A B the liver leads to the development of steatosis. This may be an adaptive response through which hepatocytes store potentially toxic lipids as relatively inert triglyceride. A ‘two-hit’ hypothesis has been proposed to describe the pathogenesis of NAFLD, the ‘first hit’ causing steatosis that then progresses to NASH if a ‘second hit’ occurs. In reality, progression probably follows hepatocellular injury caused by a combination of several different ‘hits’, including: • oxidative stress due to free radicals produced during fatty acid oxidation • direct lipotoxicity from fatty acids and other metabolites in the liver • endoplasmic reticulum stress • gut-derived endotoxin • cytokine release (TNF-α etc.) and immune-mediated hepatocellular injury. Cellular damage triggers cell death and inflammation, which leads to stellate cell activation and development of hepatic fibrosis that culminates in cirrhosis (Fig. 22.30A). As with many other liver diseases, subtle inter-patient genetic variations and environmental factors interact to determine disease progression. Several genetic modifiers of disease severity have been identified, with PNPLA3 and its product, adiponutrin, being the best validated. This should not be confused with acute fatty liver, which can occur in hepatic mitochondrial cytopathies, e.g. acute fatty liver of pregnancy (p. 1283), or in other situations, e.g. Reye’s syndrome (p. 241) or drug toxicity (sodium valproate, tetracyclines), or with bacterial toxins (e.g. Bacillus cereus). In these, defective mitochondrial beta-oxidation of lipids leads to fat droplet accumulation in hepatocytes and microvesicular steatosis. (body mass index (BMI) > 30 kg/m2), 67% of overweight patients (BMI > 25 kg/m2) and 25% of normal-weight patients. The overall prevalence of NAFLD in patients with type 2 diabetes ranges from 40% to 70%. Histological NASH has been found in 3–16% of apparently healthy potential living liver donors in Europe and 6–15% in the USA. Overall, NAFLD is estimated to affect 20–30% of the general population in Western countries and 5–18% in Asia, with about 1 in 10 NAFLD cases exhibiting NASH. The frequency of steatosis varies with ethnicity (45% in Hispanics, 33% in whites and 24% in blacks) and gender (42% white males versus 24% white females) but only a minority of patients will progress to cirrhosis and end-stage liver disease. However, because obesity is common and the prevalence of NAFLD is rising, this still represents a large number of patients, placing a substantial burden on health-care resources. Over a median 12-year follow-up period in a cohort of 619 NAFLD patients, an overall 33.2% risk of death or liver transplantation was observed, with liver-related mortality being the third most common cause of death after cardiovascular disease and extra-hepatic malignancy. NAFLD is the leading cause of liver dysfunction in the non-alcoholic, viral hepatitis-negative population in Europe and North America, and is predicted to become the main aetiology in patients undergoing liver transplantation during the next 5 years. Pathophysiology The initiating events in NAFLD are based on the development of obesity and insulin resistance, leading to increased hepatic free fatty acid flux. This imbalance between the rate of import/ synthesis and the rate of export/catabolism of fatty acids in

884 • HEPATOLOGY fibrosis in many NAFLD patients. This allows care to focus on those most likely to have advanced disease. Imaging Ultrasound is most often used and provides a qualitative assessment of hepatic fat content, as the liver appears ‘bright’ due to increased echogenicity; sensitivity is limited when fewer than 33% of hepatocytes are steatotic, however. CT, MRI or MR spectroscopy offer greater sensitivity for detecting lesser degrees of steatosis, but these are resource-intensive and not widely used. No routine imaging modality can distinguish simple steatosis from steatohepatitis or accurately quantify hepatic fibrosis short of cirrhosis. Liver biopsy Liver biopsy remains the ‘gold standard’ investigation for diagnosis and assessment of degree of inflammation and extent of liver fibrosis. The histological definition of NASH is based on a combination of three lesions (steatosis, hepatocellular injury and inflammation; see Fig. 22.30A) with a mainly centrilobular, acinar zone 3 distribution. Specific features include hepatocyte ballooning degeneration with or without acidophil bodies or spotty necrosis and a mild, mixed inflammatory infiltrate. These may be accompanied by Mallory–Denk bodies (also known as Mallory’s hyaline). Perisinusoidal fibrosis is a characteristic feature of NASH. Histological scoring systems are widely used to assess disease severity semi-quantitatively. It is important to note that hepatic fat content tends to diminish as cirrhosis develops and so NASH is likely to be under-diagnosed in the setting of advanced liver disease, where it is thought to be the underlying cause of 30–75% of cases in which no specific aetiology is readily identified (so-called ‘cryptogenic cirrhosis’). Management As it is a marker of the metabolic syndrome, identification of NAFLD should prompt screening for and treatment of cardiovascular risk factors in all patients. It is also necessary to assess whether patients have progressive disease and advanced fibrosis so that liver-targeted treatment can be focused particularly on those patients. While liver biopsy is best able to do this, it is invasive and unsuitable for widespread use outside the specialist care setting. An example of an algorithm for the assessment and risk stratification of patients with NAFLD is provided in Figure 22.31. Non-pharmacological treatment Current treatment comprises lifestyle interventions to promote weight loss and improve insulin sensitivity through dietary changes Clinical features NAFLD is frequently asymptomatic, although it may be associated with fatigue and mild right upper quadrant discomfort. It is commonly identified as an incidental biochemical abnormality during routine blood tests or as a fatty liver during an ultrasound or CT scan of the abdomen. Alternatively, patients with progressive NASH may present late in the natural history of the disease with complications of cirrhosis and portal hypertension, such as variceal haemorrhage, or with hepatocellular carcinoma. The average age of NASH patients is 40–50 years (50–60 years for NASH–cirrhosis); however, the emerging epidemic of childhood obesity means that NASH is present in increasing numbers of younger patients. Recognised independent risk factors for disease progression are age over 45 years, presence of diabetes (or severity of insulin resistance), obesity (BMI > 30 kg/m2) and hypertension. These factors help with identification of ‘high-risk’ patient groups. NAFLD is also associated with polycystic ovary syndrome, obstructive sleep apnoea and small-bowel bacterial overgrowth. Investigations Investigation of patients with suspected NAFLD should be directed first towards exclusion of excess alcohol consumption and other liver diseases (including viral, autoimmune and other metabolic causes) and then at confirming the presence of NAFLD, discriminating simple steatosis from NASH and determining the extent of any hepatic fibrosis that is present. Biochemical tests There is no single diagnostic blood test for NAFLD. Elevations of serum ALT and AST are modest, and usually less than twice the upper limit of normal. ALT levels fall as hepatic fibrosis increases and the characteristic AST : ALT ratio of < 1 seen in NASH reverses (AST : ALT > 1) as disease progresses towards cirrhosis, meaning that steatohepatitis with advanced disease may be present even in those with normal-range ALT levels. Other laboratory abnormalities that may be present include non-specific elevations of GGT, low-titre antinuclear antibody (ANA) in 20–30% of patients and elevated ferritin levels. Although routine blood tests are unable to determine the degree of liver fibrosis/cirrhosis accurately, calculated scores, such as the NAFLD Fibrosis Score and FIB-4 Score, which are based on the results of routinely available blood tests and anthropometrics, have a high negative predictive value for advanced fibrosis/ cirrhosis (Box 22.48) and so can be used to rule out advanced 22.48 Simple non-invasive scores for non-alcoholic fatty liver disease (NAFLD)/fibrosis* Test Formula Thresholds Age < 65 years Age > 65 years NAFLD Fibrosis Score (NFS) −1.675 + 0.037 × Age (years) + 0.094 × BMI (kg/m2) + 1.13 × IFG or diabetes (yes = 1, no = 0) + 0.99 × AST/ALT ratio − 0.013 × platelet count (× 109/L) − 0.66 × albumin (g/dL) High risk (NFS > 0.676) Indeterminate risk (NFS −1.455–0.676) Low risk (NFS < −1.455) High risk (NFS > 0.676) Indeterminate risk (NFS 0.12–0.676) Low risk (NFS < 0.12) FIB-4 Score Age (years) × AST (IU/L)/platelet count (× 109/L) × ¥ALT (IU/L) High risk (FIB-4 > 2.67) Indeterminate risk (FIB-4 1.30–2.67) Low risk (FIB-4 < 1.30) High risk (FIB-4 > 2.67) Indeterminate risk (2.00–2.67) Low risk (FIB-4 < 2.00) (ALT = alanine aminotransferase; AST = aspartate aminotransferase; BMI = body mass index; IFG = impaired fasting glucose) *Predict advanced fibrosis and cirrhosis (F3–4). Simple scores like NFS and FIB-4 are based on the results of routinely available blood tests and anthropometrics. Online calculators for these are widely available.

Autoimmune liver and biliary disease • 885

evidence that high doses may be associated with an increased risk of prostate cancer and all-cause mortality, which has limited its use. Several new medicines are currently in late-phase clinical trials and so liver-targeted pharmacological treatments are likely to be available within the next few years. Autoimmune liver and biliary disease The liver is an important target for autoimmune injury. The clinical picture is dictated by the nature of the autoimmune process and, in particular, the target cell for immune injury. The disease patterns are quite distinctive for primary hepatocellular injury (in the context of autoimmune hepatitis) and biliary epithelial cell injury (primary biliary cholangitis and primary sclerosing cholangitis). and physical exercise. Sustained weight reduction of 7–10% is associated with significant improvement in histological and biochemical NASH severity. Pharmacological treatment No pharmacological agents are currently licensed specifically for NASH therapy. Treatment directed at coexisting metabolic disorders, such as dyslipidaemia and hypertension, should be given. Although use of HMG-CoA reductase inhibitors (statins) does not ameliorate NAFLD, there does not appear to be any increased risk of hepatotoxicity or other side-effects from these agents, and so they may be used to treat dyslipidaemia. Specific insulin-sensitising agents, in particular glitazones, may help selected patients, while recent results with bezafibrate, a lipid-lowering fibrate, have been encouraging. Positive results with high-dose vitamin E (800 U/day) have been tempered by Fig. 22.31 Assessment and risk stratification of patients with non-alcoholic fatty liver disease (NAFLD). (HCC = hepatocellular carcinoma; M probe = medium probe; XL = large probe) Suspected NAFLD Features of the metabolic syndrome, radiological evidence of steatosis and/or abnormal liver biochemistry, alternative diagnoses excluded Calculate NAFLD fibrosis score (NFS) Refer to liver specialist care Transient elastography (fibroscan) Age <65: -1.455 to 0.676 Age >65: 0.12 to 0.676 NFS >0.676 Age <65: NFS <-1.455 Age >65: NFS <0.12 Low risk Indeterminate High risk Consider liver biopsy M probe 7.9–9.6 kPa XL probe 7.2–9.3 kPa M probe <7.9 kPa XL probe <7.2 kPa M probe >9.6 kPa XL probe >9.3 kPa Advanced [F3–4] fibrosis excluded Advanced [F3–4] fibrosis likely Indeterminate Fibrosis F2–3 Fibrosis F0–1 Recalculate NFS in 3–5 years or if patient develops type 2 diabetes Cirrhosis F4 Lifestyle advice Address cardiovascular risks NAFLD-directed therapy Manage in primary care Lifestyle advice Address cardiovascular risks Recalculate NFS in 3– 5 years Lifestyle advice Address cardiovascular risks NAFLD-directed therapy HCC and variceal surveillance

886 • HEPATOLOGY typically adult patients, often with aggressive disease and usually lacking autoantibodies of other specificities. Clinical features The onset is usually insidious, with fatigue, anorexia and eventually jaundice. The non-specific nature of the early features can lead to the diagnosis being missed in the early disease stages. In about one-quarter of patients the onset is acute, resembling viral hepatitis, but resolution does not occur. This acute presentation can lead to extensive liver necrosis and liver failure. Other features include fever, arthralgia, vitiligo and epistaxis. Amenorrhoea can occur. Jaundice is mild to moderate or occasionally absent, but signs of chronic liver disease, especially spider naevi and hepatosplenomegaly, can be present. Associated autoimmune disease, such as Hashimoto’s thyroiditis or rheumatoid arthritis, is often present and can modulate the clinical presentation. Investigations Serological tests for autoantibodies are often positive (Box 22.50), but low titres of these antibodies occur in some healthy people and in patients with other inflammatory liver diseases. ANA also occur in connective tissue diseases and other autoimmune diseases (with an identical pattern of homogenous nuclear staining) while anti-smooth muscle antibody has been reported in infectious mononucleosis and a variety of malignant diseases. Anti-microsomal antibodies (anti-LKM) occur particularly in children and adolescents. Elevated serum IgG levels are an important diagnostic and treatment response feature if present, but the diagnosis is still possible in the presence of normal IgG levels. If the diagnosis of autoimmune hepatitis is suspected, liver biopsy should be performed. It typically shows interface hepatitis, with or without cirrhosis. Scoring systems, such as the International Autoimmune Hepatitis Group (IAIHG) criteria, are useful for epidemiological study and for assessing trial eligibility but are complex for normal clinical practice. Management Treatment with glucocorticoids is life-saving in autoimmune hepatitis, particularly during exacerbations of active and symptomatic disease. Initially, prednisolone (40 mg/day) is given orally; the dose is then gradually reduced as the patient and LFTs improve. Maintenance therapy should only be instituted once LFTs are normal (as well as IgG if elevated). Approaches to maintenance include reduced-dose prednisolone (ideally, below 5–10 mg/day), usually in the context of azathioprine (1.0–1.5 mg/kg/day). Azathioprine can also be used as the sole maintenance immunosuppressive agent in patients with low-activity disease. Newer agents, such as mycophenolate mofetil (MMF), are increasingly being used but formal evidence to inform practice in this area is lacking. Patients should be monitored for acute exacerbations (LFT and IgG screening with patients alerted Autoimmune hepatitis Autoimmune hepatitis is a disease of immune-mediated liver injury characterised by the presence of serum antibodies and peripheral blood T lymphocytes reactive with self-proteins, a strong association with other autoimmune diseases (Box 22.49), and high levels of serum immunoglobulins – in particular, elevation of IgG. Although most commonly seen in women, particularly in the second and third decades of life, it can develop in either sex at any age. The reasons for the breakdown in immune tolerance in autoimmune hepatitis remain unclear, although cross-reactivity with viruses such as HAV and EBV in immunogenetically susceptible individuals (typically those with human leucocyte antigen (HLA)-DR3 and DR4, particularly HLA-DRB30101 and HLA-DRB10401) has been suggested as a mechanism. Pathophysiology Several subtypes of this disorder have been proposed that have differing immunological markers. Although the different patterns can be associated with variation in disease aspects, such as response to immunosuppressive therapy, histological patterns are similar in the different settings and the basic approach to treatment (complete control of liver injury using immunosuppressive drugs and maintained with appropriate therapy) is the same. The formal classification into disease types has fallen out of favour in recent years. The most frequently seen autoantibody pattern is high titre of antinuclear and anti-smooth muscle antibodies, typically associated with IgG hyperglobulinaemia (type I autoimmune hepatitis in the old classification), frequently seen in young adult females. Disease characterised by the presence of anti-liver–kidney microsomal (LKM) antibodies, recognising cytochrome P450-IID6 expressed on the hepatocyte membrane, is typically seen in paediatric populations and can be more resistant to treatment than ANA-positive disease. Adult onset of anti-LKM can be seen in chronic HCV infection. This was classified as type II disease in the old system. More recently, a pattern of antibody reactivity with anti-soluble liver antigen (anti-SLA) has been described in 22.49 Conditions associated with autoimmune hepatitis • Migrating polyarthritis • Urticarial rashes • Lymphadenopathy • Hashimoto’s thyroiditis • Thyrotoxicosis • Myxoedema • Pleurisy • Coombs-positive haemolytic anaemia • Transient pulmonary infiltrates • Ulcerative colitis • Glomerulonephritis • Nephrotic syndrome 22.50 Frequency of autoantibodies in chronic non-viral liver diseases and in healthy people Disease Antinuclear antibody (%) Anti-smooth muscle antibody (%) Antimitochondrial antibody* Healthy controls

1.5 0.01 Autoimmune hepatitis

Primary biliary cholangitis

Cryptogenic cirrhosis

*Patients with antimitochondrial antibody frequently have cholestatic liver function tests and may have primary biliary cholangitis (see text).

Autoimmune liver and biliary disease • 887

patients with severe pruritus. Jaundice is prominent only late in the disease and can become intense. Xanthomatous deposits occur in a minority, especially around the eyes. Mild hepatomegaly is common and splenomegaly becomes increasingly common as portal hypertension develops. Liver failure may supervene. Associated diseases Autoimmune and connective tissue diseases occur with increased frequency in PBC, particularly the sicca syndrome (p. 1038), systemic sclerosis, coeliac disease (p. 805) and thyroid diseases. Hypothyroidism should always be considered in patients with fatigue. Diagnosis and investigations The LFTs show a pattern of cholestasis (see Box 22.2, p. 853). Hypercholesterolaemia is common and worsens as disease progresses but appears not to be associated with increased cardiac risk. AMA is present in over 95% of patients; when it is absent, the diagnosis should not be made without obtaining histological evidence and considering cholangiography (typically, MRCP) to exclude other biliary disease. ANA and anti-smooth muscle antibodies are present in around 15% of patients (see Box 22.50); autoantibodies found in associated diseases may also be present. Ultrasound examination shows no sign of biliary obstruction. Liver biopsy is necessary only if there is diagnostic uncertainty. The histological features of PBC correlate poorly with to the possible symptoms) and such exacerbations should be treated with glucocorticoids. Although treatment can significantly reduce the rate of progression to cirrhosis, end-stage disease can be seen in patients despite treatment. Primary biliary cholangitis Primary biliary cholangitis (PBC, known as primary biliary cirrhosis until 2015, when the name was changed to reflect more accurately the disease seen in the modern era) is a chronic, progressive cholestatic liver disease that predominantly affects women aged 30 and over. It is strongly associated with the presence of antimitochondrial antibodies (AMA), which are diagnostic, and is characterised by a granulomatous inflammation of the portal tracts, leading to progressive damage and eventually loss of the small and middle-sized bile ducts. This, in turn, leads to fibrosis and cirrhosis of the liver. The condition can present with an insidious onset of itching and/or tiredness; it may also frequently be found incidentally as the result of routine blood tests. Epidemiology The prevalence of PBC varies across the world. It is relatively common in northern Europe and North America but is rare in Africa and Asia. There is a strong female-to-male predominance of 9 : 1; it is also more common among cigarette smokers. Clustering of cases has been reported, suggesting an environmental trigger in susceptible individuals. Pathophysiology Immune mechanisms are clearly involved. The condition is closely associated with other autoimmune non-hepatic diseases, such as thyroid disease, and there is a genetic association with HLA-DR8, together with polymorphisms in a number of other genes regulating the nature of the immune response (e.g. IL-12 and its receptor). AMA is directed at pyruvate dehydrogenase complex, a mitochondrial enzyme complex that plays a key role in cellular energy generation. PBC-specific ANAs (such as those directed at the nuclear pore antigen gp210) have a characteristic staining pattern in immunofluorescence assays (selectively binding to the nuclear rim or nuclear dots), which means that they should not be mistaken for the homogenously staining ANA seen in autoimmune hepatitis. Increases in serum immunoglobulin levels are frequent but, unlike in autoimmune hepatitis, it is typically IgM that is elevated. Pathologically, chronic granulomatous inflammation destroys the interlobular bile ducts; progressive lymphocyte-mediated inflammatory damage causes fibrosis, which spreads from the portal tracts to the liver parenchyma and eventually leads to cirrhosis. A model of the natural history of the disease process is shown in Figure 22.32. Clinical features Systemic symptoms such as fatigue are common and may precede diagnosis by years. Pruritus, which can be a feature of any cholestatic disease, is a common presenting complaint and may precede jaundice by months or years. Jaundice is rarely a presenting feature. The itching is usually worse on the limbs. Although there may be right upper abdominal discomfort, fever and rigors do not occur. Bone pain or fractures can rarely result from osteomalacia (fat-soluble vitamin malabsorption) or, more commonly, from osteoporosis (hepatic osteodystrophy). Initially, patients are well nourished but weight loss can occur as the disease progresses. Scratch marks may be found in Fig. 22.32 Natural history of primary biliary cholangitis. (AMA = antimitochondrial antibody; LFTs = liver function tests) Genetic susceptibility Latent disease (antimitochondrial Ab-positive, normal LFTs) Environmental trigger factor(s) Early disease AMA-positive (abnormal LFTs) Late disease (liver scarring/cirrhosis) Liver decompensation Genetic factors Genetic factors Death Liver transplant 30% disease recurrence

888 • HEPATOLOGY Bone disease Osteopenia and osteoporosis are common and normal post- menopausal bone loss is accelerated. Baseline bone density should be measured (p. 989) and treatment started with replacement calcium and vitamin D3. Bisphosphonates should be used if there is evidence of osteoporosis. Osteomalacia is rare. Overlap syndromes AMA-negative PBC (‘autoimmune cholangitis’) A few patients demonstrate the clinical, biochemical and histological features of PBC but do not have detectable AMA in the serum. Serum transaminases, serum immunoglobulin levels and titres of ANA tend to be higher than in AMA-positive PBC. The clinical course mirrors classical PBC, however, and these patients should be considered as having a variant of PBC. PBC/autoimmune hepatitis overlap A few patients with AMA and cholestatic LFTs have elevated transaminases, high serum immunoglobulins and interface hepatitis on liver histology. In such individuals, a trial of glucocorticoid therapy may be beneficial. Primary sclerosing cholangitis Primary sclerosing cholangitis (PSC) is a cholestatic liver disease caused by diffuse inflammation and fibrosis; it can involve the entire biliary tree and leads to the gradual obliteration of intrahepatic and extrahepatic bile ducts, and ultimately biliary cirrhosis, portal hypertension and hepatic failure. Although considered as an autoimmune disease, evidence for an autoimmune pathophysiology is weaker than is the case for PBC and autoimmune hepatitis. The incidence is about 6.3/100 000 in Caucasians. Cholangiocarcinoma develops in about 10–30% of patients during the course of the disease. PSC is twice as common in young men. Most patients present at age 25–40 years, although the condition may be diagnosed at any age and is an important cause of chronic liver disease in children. The generally accepted diagnostic criteria are: • generalised beading and stenosis of the biliary system on cholangiography (Fig. 22.33) • absence of choledocholithiasis (or history of bile duct surgery) • exclusion of bile duct cancer, by prolonged follow-up. The term ‘secondary sclerosing cholangitis’ is used to describe the typical changes described above when a clear predisposing factor for duct fibrosis can be identified. The causes of secondary sclerosing cholangitis are shown in Box 22.51. Pathophysiology The cause of PSC is unknown but there is a close association with inflammatory bowel disease, particularly ulcerative colitis (Box 22.52). About two-thirds of patients have coexisting ulcerative colitis, and PSC is the most common form of chronic liver disease in ulcerative colitis. Between 3% and 10% of patients with ulcerative colitis develop PSC, particularly those with extensive colitis or pancolitis. The prevalence of PSC is lower in patients with Crohn’s colitis (about 1%). Patients with PSC and ulcerative colitis are at greater risk of colorectal neoplasia than those with ulcerative colitis alone, and individuals who develop colorectal neoplasia are at greater risk of cholangiocarcinoma. It is currently believed that PSC is an immunologically mediated disease, triggered in genetically susceptible individuals by toxic the clinical features; portal hypertension can develop before the histological onset of cirrhosis. Management The hydrophilic bile acid ursodeoxycholic acid (UDCA), at a dose of 13–15 mg/kg/day, improves bile flow, replaces toxic hydrophobic bile acids in the bile acid pool, and reduces apoptosis of the biliary epithelium. Clinically, UDCA improves LFTs, may slow down histological progression and has few side-effects; it is therefore widely used in the treatment of PBC and should be regarded as the optimal first-line treatment. Its use is recommended in all clinical guidelines. A significant minority of patients either fail to normalise their LFTs with UDCA or show an inadequate response, and such individuals have an increased risk of developing end-stage liver disease compared to those showing a full response. Obeticholic acid (OCA) is a second-generation bile acid therapeutic that acts as an agonist for the nuclear farnesoid X receptor. It reduces hepatocyte synthesis of bile acids and was approved in 2016 for use in patients showing an inadequate response to UDCA. Immunosuppressants, such as glucocorticoids, azathioprine, penicillamine and ciclosporin, have all been trialled in PBC. None shows overall benefit when given to unselected patients. It is unclear whether these drugs offer benefit to the specific subgroup of patients who do not respond to UDCA and require second-line approaches to treatment. Liver transplantation should be considered once liver failure has developed and may be indicated in patients with intractable pruritus. Serum bilirubin remains the most reliable marker of declining liver function. Transplantation is associated with an excellent 5-year survival of over 80%, although the disease will recur in over one-third of patients at 10 years. Pruritus This is the main symptom requiring treatment. The cause is unknown, but up-regulation of opioid receptors and increased levels of endogenous opioids may play a role. First-line treatment is with the anion-binding resin colestyramine, which probably acts by binding potential pruritogens in the intestine and increasing their excretion in the stool. A dose of 4–16 g/day orally is used. The powder is mixed in orange juice and the main dose (8 g) taken before and after breakfast, when maximal duodenal bile acid concentrations occur. Colestyramine may bind other drugs in the gut (most obviously UDCA) and adequate spacing should be used between drugs. Colestyramine is sometimes ineffective, especially in complete biliary obstruction, and can be difficult for some patients to tolerate. Alternative treatments include rifampicin (150 mg/day, titrated up to a maximum of 600 mg/day as required and contingent on there being no deterioration in LFTs), naltrexone (an opioid antagonist; 25 mg/day initially, increasing up to 300 mg/day), plasmapheresis and a liver support device (e.g. a molecular adsorbent recirculating system, MARS). Fatigue Fatigue affects about one-third of patients with PBC. The cause is unknown but it may reflect intracerebral changes due to cholestasis. Unfortunately, once depression, hypothyroidism and coeliac disease have been excluded, there is currently no specific treatment. The impact on patients’ lives can be substantial. Malabsorption Prolonged cholestasis is associated with steatorrhoea and malabsorption of fat-soluble vitamins, which should be replaced as necessary. Coeliac disease should be excluded since its incidence is increased in PBC.

Autoimmune liver and biliary disease • 889

Clinical features The diagnosis is often made incidentally when persistently raised serum ALP is discovered in an individual with ulcerative colitis. Common symptoms include fatigue, intermittent jaundice, weight loss, right upper quadrant abdominal pain and pruritus. Attacks of acute cholangitis are uncommon and usually follow biliary instrumentation. Physical examination is abnormal in about 50% of symptomatic patients; the most common findings are jaundice and hepatomegaly/splenomegaly. The condition may be associated with many other diseases (Box 22.52). Investigations Biochemical screening usually reveals a cholestatic pattern of LFTs but ALP and bilirubin levels may vary widely in individual patients during the course of the disease. For example, ALP and bilirubin values increase during acute cholangitis, decrease after therapy, and sometimes fluctuate for no apparent reason. Modest elevations in serum transaminases are usually seen, whereas hypoalbuminaemia and clotting abnormalities are found at a late stage only. In addition to ANCA, low titres of serum ANA and anti-smooth muscle antibodies may be found in PSC but have no diagnostic significance; serum AMA is absent. The key investigation is now MRCP, which is usually diagnostic and reveals multiple irregular stricturing and dilatation (Fig. 22.33). ERCP should be reserved for when therapeutic intervention is likely to be necessary and should follow MRCP. On liver biopsy, the characteristic early features of PSC are periductal ‘onion skin’ fibrosis and inflammation, with portal oedema and bile ductular proliferation resulting in expansion of the portal tracts (Fig. 22.34). Later, fibrosis spreads, progressing inevitably to biliary cirrhosis; obliterative cholangitis leads to the so-called ‘vanishing bile duct syndrome’. Management There is no cure for PSC but management of cholestasis and its complications and specific treatment of the disease process are indicated. UDCA is widely used, although the evidence to support this is limited. UDCA may have benefit in terms of reducing colon carcinoma risk. The course of PSC is variable. In symptomatic patients, median survival from presentation to death or liver transplantation is about 12 years. About 75% of asymptomatic patients survive 15 years or more. Most patients die from liver failure, about 30% die from bile duct carcinoma, and the remainder die from colonic cancer or complications of colitis. Immunosuppressive agents, including or infectious agents, which may gain access to the biliary tract through a leaky, diseased colon. A close link with HLA haplotype A1-B8-DR3-DRW52A has been identified. This haplotype is commonly found in association with other organ-specific autoimmune diseases (e.g. autoimmune hepatitis). The importance of immunological factors has been emphasised by reports showing humoral and cellular abnormalities in PSC. Perinuclear antineutrophil cytoplasmic antibodies (ANCA) have been detected in the sera of 60–80% of patients with PSC with or without ulcerative colitis, and in 30–40% of patients with ulcerative colitis alone. The antibody is not specific for PSC and is found in other chronic liver diseases (e.g. 50% of patients with autoimmune hepatitis). Fig. 22.33 Magnetic resonance cholangiopancreatogram showing typical changes of primary sclerosing cholangitis. There is intrahepatic bile duct beading, stricturing and dilatation. The extrahepatic bile duct is also diffusely strictured. Courtesy of Dr Dilip Patel, Royal Infirmary of Edinburgh. 22.51 Causes of secondary sclerosing cholangitis • Previous bile duct surgery with stricturing and cholangitis • Bile duct stones causing cholangitis • Intrahepatic infusion of 5-fluorodeoxyuridine • Insertion of formalin into hepatic hydatid cysts • Insertion of alcohol into hepatic tumours • Parasitic infections (e.g. Clonorchis) • Autoimmune pancreatitis/immunoglobulin G4-associated cholangitis • Acquired immunodeficiency syndrome (AIDS; probably infective as a result of cytomegalovirus or Cryptosporidium) 22.52 Diseases associated with primary sclerosing cholangitis • Ulcerative colitis • Crohn’s colitis • Chronic pancreatitis • Retroperitoneal fibrosis • Riedel’s thyroiditis • Retro-orbital tumours • Immune deficiency states • Sjögren’s syndrome • Angio-immunoblastic lymphoma • Histiocytosis X • Autoimmune haemolytic anaemia • Autoimmune pancreatitis/ immunoglobulin G4-associated cholangitis Fig. 22.34 Primary sclerosing cholangitis. Note onion skin scarring (arrows) surrounding a bile duct.

890 • HEPATOLOGY Primary malignant tumours Hepatocellular carcinoma Hepatocellular carcinoma (HCC) is the most common primary liver tumour, and the sixth most frequent cause of cancer worldwide. Cirrhosis is present in 75–90% of individuals with HCC and is an important risk factor for the disease. The risk is between 1% and 5% in cirrhosis caused by hepatitis B and C. There is also an increased risk in cirrhosis due to haemochromatosis, alcohol, NASH and α1-antitrypsin deficiency. In northern Europe, 90% of those with HCC have underlying cirrhosis, compared with 30% in Taiwan, where hepatitis B is the main risk factor. The age-adjusted incidence rates vary from 28 per 100 000 in South-east Asia (reflecting the prevalence of hepatitis B) to 10 per 100 000 in southern Europe and 5 per 100 000 in northern Europe. Chronic hepatitis B infection increases the risk of HCC 100-fold and is the major risk factor worldwide. The risk of HCC is 0.4% per year in the absence of cirrhosis and 2–6% in cirrhosis. The risk is four times higher in HBeAg-positive individuals than in those who are HBeAg-negative. Hepatitis B vaccination has led to a fall in HCC in countries with a high prevalence of hepatitis B. The incidence in Europe and North America has risen recently, probably related to the increased prevalence of hepatitis C and NASH cirrhosis. The risk is higher in men and rises with age. Macroscopically, the tumour usually appears as a single mass in the absence of cirrhosis, or as a single nodule or multiple nodules in the presence of cirrhosis. It takes its blood supply from the hepatic artery and tends to spread by invasion into the portal vein and its radicals. Lymph node metastases are common, while lung and bone metastases are rare. Well-differentiated tumours can resemble normal hepatocytes and can be difficult to distinguish from normal liver. Clinical features Patients typically present with HCC in one of two ways. Commonly, liver function deteriorates in those with underlying cirrhosis, with worsening ascites and/or jaundice or variceal haemorrhage. Other characteristic symptoms can include weight loss, anorexia and abdominal pain. This often-rapid deterioration can, however, be the event that leads to previously occult cirrhosis becoming clinically apparent, meaning that absence of an established diagnosis of cirrhosis does not preclude a diagnosis of HCC complicating cirrhosis. Examination may reveal hepatomegaly or a right hypochondrial mass. Tumour vascularity can lead to an abdominal bruit, and hepatic rupture with intra-abdominal bleeding may occur. The advanced nature of disease that presents in this way makes curative therapy unlikely. The second presentation is through screening of patients at risk of HCC. The disease is typically detected much earlier in its natural history, significantly increasing the treatment options. Investigations Serum markers Alpha-fetoprotein (AFP) is produced by 60% of HCCs. Levels increase with the size of the tumour and are often normal or only minimally elevated in small tumours detected by ultrasound screening. Serum AFP can also rise in the presence of active hepatitis B and C viral replication; very high levels are seen in acute hepatic necrosis, such as that following paracetamol toxicity. AFP is used in conjunction with ultrasound in screening but, in view of low sensitivity and specificity, levels need to prednisolone, azathioprine, methotrexate and ciclosporin, have been tried; results have generally been disappointing. Symptomatic patients often have pruritus. Management is as for PBC. Fatigue appears to be less prominent than in PBC, although it is still present in some patients. Management of complications Broad-spectrum antibiotics (e.g. ciprofloxacin) should be given for acute attacks of cholangitis but have no proven value in preventing attacks. If cholangiography shows a well-defined obstruction to the extrahepatic bile ducts (‘dominant stricture’), mechanical relief can be obtained by placement of a stent or by balloon dilatation performed at ERCP. It is important, in this situation, to give active consideration to the possibility of cholangiocarcinoma (the differential diagnosis for a dominant extrahepatic stricture). Fat-soluble vitamin replacement is necessary in jaundiced patients. Metabolic bone disease (usually osteoporosis) is a common complication that requires treatment (p. 1044). Surgical treatment Surgical resection of the extrahepatic bile duct and biliary reconstruction have a limited role in the management of noncirrhotic patients with dominant extrahepatic disease. Orthotopic transplantation is the only surgical option in patients with advanced liver disease; 5-year survival is 80–90% in most centres. Unfortunately, the condition may recur in the graft and there are no identified therapies able to prevent this. Cholangiocarcinoma is a contraindication to transplantation. Colon carcinoma risk can be increased in patients following transplantation because of the effects of immune suppression, and enhanced surveillance should be instituted. IgG4-associated cholangitis This disease (as well as its nomenclature) is closely related to autoimmune pancreatitis (which is present in more than 90% of the patients; p. 841). IgG4-associated cholangitis (IAC) often presents with obstructive jaundice (due to either hilar stricturing/ intrahepatic sclerosing cholangitis or a low bile duct stricture), and cholangiographic appearances suggest PSC with or without hilar cholangiocarcinoma. The serum IgG4 is often raised and liver biopsy shows a lymphoplasmacytic infiltrate, with IgG4-positive plasma cells. An important observation is that, compared to PSC, IAC appears to respond well to glucocorticoid therapy. Liver tumours and other focal liver lesions Identification of a hepatic mass lesion is common, both in patients with known pre-existing liver disease and as a primary presentation. Although primary and secondary malignant tumours are important potential diagnoses, benign disease is frequent. The finding of a liver mass, with its association in the minds of patients with metastatic malignant disease, creates a high level of anxiety, a factor that should always be borne in mind. The critical steps to be taken in diagnosing hepatic mass lesions are: • determining the presence, nature and severity of any underlying chronic liver disease, as the differential diagnosis is very different in patients with and those without chronic liver disease • using optimal (usually multiple) imaging modalities.

Liver tumours and other focal liver lesions • 891

Screening may also be indicated in those with chronic hepatitis B (who carry an increased risk of HCC, even in the absence of cirrhosis). Although no randomised controlled studies of outcome have been undertaken, screening identifies smaller tumours, often less than 3 cm in size, which are more likely to be cured by surgical resection, local ablative therapy or transplantation. The role of screening in other forms of chronic liver disease, such as autoimmune hepatitis and PBC, is unclear. This is compounded by the fact that disease staging by biopsy is no longer standard practice in conditions such as PBC, so formal documentation of the presence of cirrhosis, which might be the trigger for commencement of HCC screening, rarely takes place. Management This is different for patients with cirrhosis and those without. In the presence of cirrhosis, tumour size, multicentricity, extent of liver disease (Child–Pugh score) and performance status dictate therapy. An algorithm for managing those with cirrhosis is shown in Figure 22.36. Prognosis depends on tumour size, the presence of vascular invasion, and liver function in those with cirrhosis. Screening has improved the outlook through early detection. Hepatic resection This is the treatment of choice for non-cirrhotic patients. The 5-year survival in this group is about 50%. There is a 50% recurrence rate at 5 years, however, which may be due to a second de novo tumour or recurrence of the original tumour. Few patients with cirrhosis are suitable for hepatic resection because of the high risk of hepatic failure; nevertheless, surgery is offered, particularly in the Far East, to some cirrhotic patients with small tumours and good liver function (Child–Pugh A with no portal hypertension). Liver transplantation Transplantation has the benefit of curing underlying cirrhosis and removing the risk of a second, de novo tumour in an at-risk patient. The requirement for immunosuppression creates its own risks of reactivation, however, if residual or metastatic disease is present, and assessment of patients for suitability for liver transplantation focuses on the exclusion of extrahepatic disease and vascular invasion. The 5-year survival following liver transplantation is 75% for patients with single tumours of less than 5 cm in size or three tumours smaller than 3 cm (the Milan criteria). Unfortunately, the underlying liver disease, in particular hepatitis C, may recur in the transplanted liver and can result in recurrent cirrhosis that gives rise to a de novo HCC risk, now complicated by the presence of immunosuppression. Percutaneous therapy Percutaneous ethanol injection into the tumour under ultrasound guidance is efficacious (80% cure rate) for tumours of 3 cm or less. Recurrence rates (50% at 3 years) are similar to those following surgical resection. Radiofrequency ablation, using a single electrode inserted into the tumour under radiological guidance, is an alternative that takes longer to perform but may cause more complete tumour necrosis. Improvements in percutaneous therapy, with the combination of low patient impact, relative efficacy and capacity for repeat treatment, are making these approaches attractive, particularly when major surgery would be inappropriate. Their role in primary therapy as an alternative to curative resection or transplantation is yet to be established. be interpreted with caution. Nevertheless, in the absence of a marked hepatic flare of disease, a progressively rising AFP, or AFP of > 400 ng/mL (330 IU/mL; normal is < 10 ng/mL (8 IU/mL), warrants an aggressive search for HCC. In HCC patients with elevated AFP levels, serial measurements can be a useful biomarker of disease progression or response to treatment. Imaging Ultrasound will detect focal liver lesions as small as 2–3 cm. The use of ultrasound contrast agents has increased sensitivity and specificity but is highly user-dependent. Ultrasound may also show evidence of portal vein involvement and features of coexistent cirrhosis. Multidetector row CT, following intravenous contrast, identifies HCC by its classical hypervascular appearance (Fig. 22.35). Small lesions of less than 2 cm can be difficult to differentiate from hyperplastic nodules in cirrhosis. MRI can be used instead. Angiography is now seldom performed and has been superseded by the above techniques. A combination of imaging modalities more accurately diagnoses and stages the extent of disease, and use of at least two modalities (typically, CT or MRI following initial screening ultrasound identification of a mass lesion) is recommended. Liver biopsy Histological confirmation is advisable in patients with large tumours who do not have cirrhosis or hepatitis B, in order to confirm the diagnosis and exclude metastatic tumour. Biopsy should be avoided in patients who may be eligible for transplantation or surgical resection because there is a small (< 2%) risk of tumour seeding along the needle tract. In all cases of potential HCC where biopsy is being considered, the impact that a confirmed diagnosis will have on therapy must be weighed against the risks of bleeding. If biopsy will not change management, then its appropriateness should be considered carefully. Role of screening Screening for HCC, by ultrasound scanning and AFP measurements at 6-month intervals, is indicated in high-risk patients who would be suitable for therapy if diagnosed with HCC. These include individuals with cirrhosis caused by hepatitis B and C, haemochromatosis, alcohol, NASH and α1-antitrypsin deficiency. Fig. 22.35 Computed tomogram showing a large hepatocellular carcinoma (arrows). Courtesy of Dr D. Redhead, Royal Infirmary of Edinburgh.

892 • HEPATOLOGY malignant hepatocytes surrounded by a dense fibrous stroma. The treatment of choice is surgical resection. This variant of HCC has a better prognosis following surgery than an equivalent-sized HCC, two-thirds of patients surviving beyond 5 years. Other primary malignant tumours These are rare but include haemangio-endothelial sarcomas. Cholangiocarcinoma (bile duct cancer) typically presents with bile duct obstruction rather than as a hepatic mass lesion, although the latter occasionally occurs. Secondary malignant tumours These are common and usually originate from carcinomas in the lung, breast, abdomen or pelvis. They may be single or multiple. Peritoneal dissemination frequently results in ascites. Clinical features The primary neoplasm is asymptomatic in 50% of patients, being detected on either radiological, endoscopic or blood biochemistry screening. There is liver enlargement and weight loss; jaundice may be present. Investigations A raised ALP activity is the most common biochemical abnormality but LFTs may be normal. Ascitic fluid, if present, has a high protein content and may be blood-stained; cytology sometimes reveals malignant cells. Imaging shows filling defects (Fig. 22.37); laparoscopy may reveal the tumour and facilitates liver biopsy. Trans-arterial chemo-embolisation Hepatocellular cancers are not radiosensitive and the response rate to chemotherapy with drugs, such as doxorubicin, is only around 30%. In contrast, hepatic artery embolisation with absorbable gelatin powder (Gelfoam) and doxorubicin is more effective, with survival rates of 60% in cirrhotic patients with unresectable HCC and good liver function (compared with 20% in untreated patients) at 2 years. Unfortunately, any survival benefit is lost at 4 years. Trans-arterial chemo-embolisation (TACE) is contraindicated in decompensated cirrhosis and multifocal HCC. TACE is now most frequently used as a holding first intervention while the tumour is being assessed and the definitive management plan is being developed. Chemotherapy Sorafenib improves survival from 7.9 to 10.7 months in cirrhotic patients. The drug is a multikinase inhibitor with activity against Raf, vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF) signalling, and is the first systemic therapy to prolong survival in HCC. The ultimate role of sorafenib in HCC – in particular, when and how best to use it – is yet to be established. Fibrolamellar hepatocellular carcinoma This rare variant differs from HCC in that it occurs in young adults, equally in males and females, in the absence of hepatitis B infection and cirrhosis. The tumours are often large at presentation and the AFP is usually normal. Histology of the tumour reveals Fig. 22.36 Management of hepatocellular carcinoma complicating cirrhosis. Performance status (PST; see Box 33.3, p. 1322): 0 = fully active, no symptoms; > 2 = limited self-care, confined to bed or chair for 50% of waking hours. Child–Pugh score: see Box 22.29, p. 867. N1, M1: lymph node involvement and metastases (for TNM classification, see Box 33.4, p. 1322) (OS = overall survival; PEI = percutaneous ethanol injection; RFA = radiofrequency ablation; TACE = trans-arterial chemo-embolisation). Based on European Association for the Study of the Liver, European Organisation for Research and Treatment of Cancer. EASL–EORTC clinical practice guidelines: Management of hepatocellular carcinoma. J Hepatol 2012; 56:908–943. Intermediate stage Multinodular; PST 0 PST 0–2, Child–Pugh A–B PST 0, Child–Pugh A Single Portal pressure Normal Resection RFA/PEI Liver transplantation Curative treatment (30–40%) Median OS: > 60 months 5-year survival: 40–70% Target: 20% OS: 20 months (14–45 months) Target: 40% OS: 11 months (6–14 months) Target: 10% OS: < 3 months Sorafenib Best supportive care TACE No Yes Increased Associated diseases 3 nodules < 3 cm PST > 2, Child–Pugh C Hepatocellular carcinoma Advanced stage Portal vein invasion; N1, M1; PST 1–2 Very early stage Single < 2 cm Early stage Single < 5 cm Terminal stage

Drugs and the liver • 893

consist of nodular regeneration of hepatocytes without fibrosis. They may be multiple but only rarely need resection. Cystic liver disease and liver abscess Isolated or multiple simple cysts are common in the liver and are a relatively frequent finding on ultrasound screening. They can be associated with polycystic renal disease (Fig. 22.39). They are intrinsically benign and require no therapy, other than in rare cases where the mass effect of very large or multiple cysts causes abdominal discomfort. In such cases, percutaneous or surgical debulking can be attempted but recurrence is typical. Liver abscesses are discussed on page 879. Drugs and the liver The liver is the primary site of drug metabolism and an important target for drug-induced injury. Pre-existing liver disease may affect the capacity of the liver to metabolise drugs and unexpected toxicity may occur when patients with liver disease are given drugs in normal doses (p. 32). Box 22.53 also shows drugs that should be avoided in patients with cirrhosis, as they can exacerbate known complications of cirrhosis. The possibility of undiagnosed underlying liver injury should always be considered in patients exhibiting unexpected effects following drug exposure. Management Hepatic resection can improve survival for slow-growing tumours, such as colonic carcinomas, and is an approach that should be actively explored in patients who are fit for liver resection and have had the primary tumour resected once extrahepatic disease has been excluded. Patients with neuro-endocrine tumours, such as gastrinomas, insulinomas and glucagonomas, and those with lymphomas may benefit from surgery, hormonal treatment or chemotherapy. Unfortunately, palliative treatment to relieve pain is all that is available for most patients; this may include arterial embolisation of the tumour masses. Benign tumours The increasing use of ultrasound scanning has led to more frequent identification of incidental benign focal liver lesions. Hepatic adenomas These are rare vascular tumours that may present as an abdominal mass, or with abdominal pain or intraperitoneal bleeding. They are more common in women and may be caused by oral contraceptives, androgens and anabolic glucocorticoids. Resection is indicated for the relief of symptoms. Hepatic adenomas can increase in size during pregnancy. Large or rapidly growing adenomas can rarely rupture, causing intraperitoneal bleeding. Haemangiomas These are the most common benign liver tumours and are present in 1–20% of the population. Most are smaller than 5 cm and rarely cause symptoms (Fig. 22.38). The diagnosis is usually made by ultrasound but CT may show a low-density lesion with delayed arterial filling. Surgery is needed only for very large symptomatic lesions or where the diagnosis is in doubt. Focal nodular hyperplasia Focal nodular hyperplasia is common in women under the age of 40. The lesions are usually asymptomatic but can be up to 10 cm in diameter; they can be differentiated from adenoma by a focal central scar seen on CT or MRI. Histologically, they Fig. 22.37 Computed tomogram showing multiple liver metastases (arrows). Fig. 22.38 Magnetic resonance image showing a haemangioma (arrows) in the liver. Courtesy of Dr D. Redhead, Royal Infirmary of Edinburgh. Fig. 22.39 Computed tomogram showing multiple cysts in the liver and kidneys in polycystic disease.

894 • HEPATOLOGY cases (e.g. NSAIDs and cyclo-oxygenase 2 (COX-2) inhibitors), there is overlap with acute hepatocellular injury. Hepatocyte necrosis Many drugs cause an acute hepatocellular necrosis with high serum transaminase concentrations; paracetamol is the best known. Inflammation is not always present but does accompany necrosis in liver injury due to diclofenac (an NSAID) and isoniazid (an anti-tuberculous drug). Granulomas may be seen in liver injury following the use of allopurinol. Acute hepatocellular necrosis has also been described following the use of several herbal remedies, including germander, comfrey and jin bu huan. Recreational drugs, including cocaine and ecstasy, can also cause severe acute hepatitis. Steatosis Microvesicular hepatocyte fat deposition, due to direct effects on mitochondrial beta-oxidation, can follow exposure to tetracyclines and sodium valproate. Macrovesicular hepatocyte fat deposition has been described with tamoxifen, and amiodarone toxicity can produce a similar histological picture to NASH. Vascular/sinusoidal lesions Drugs such as the alkylating agents used in oncology can damage the vascular endothelium and lead to hepatic venous Drug-induced liver injury Drug toxicity should always be considered in the differential diagnosis of patients presenting with acute liver failure, jaundice or abnormal liver biochemistry. Some typical patterns of drug toxicity are listed in Box 22.54; the most common picture is a mixed cholestatic hepatitis. The presence of jaundice indicates more severe liver damage. Although acute liver failure can occur, most drug reactions are self-limiting and chronic liver damage is rare. Abnormal LFTs often take weeks to normalise following a drug-induced hepatitis, and it may be months before they normalise after a cholestatic hepatitis. Occasionally, permanent bile duct loss (ductopenia) follows a cholestatic drug reaction, such as that due to co-amoxiclav, resulting in chronic cholestasis with persistent symptoms such as itching. The key to diagnosing acute drug-induced liver disease is to take a detailed drug history (Box 22.55), looking for temporal relationships between drug exposure and onset of liver abnormality (bearing in mind the fact that liver injury can frequently take weeks or even months to develop following exposure). A liver biopsy should be considered if there is suspicion of pre-existing liver disease or if blood tests fail to improve when the suspect drug is withdrawn. Where drug-induced liver injury is suspected or cannot be excluded, the potential culprit drug should be discontinued unless it is impossible to do so safely. Types of liver injury Different histological patterns of liver injury may occur with drug injury. Cholestasis Pure cholestasis (selective interference with bile flow in the absence of liver injury) can occur with oestrogens; this was common when high concentrations of oestrogens (50 μg/day) were used as contraceptives. Both the current oral contraceptive pill and hormone replacement therapy can be safely used in chronic liver disease. Chlorpromazine and antibiotics such as flucloxacillin are examples of drugs that cause cholestatic hepatitis, which is characterised by inflammation and canalicular injury. Co-amoxiclav is the most common antibiotic to cause abnormal LFTs but, unlike other antibiotics, it may not produce symptoms until 10–42 days after it is stopped. Anabolic glucocorticoids used by body-builders may also cause a cholestatic hepatitis. In some 22.55 Diagnosing acute drug-induced liver disease • Tabulate the drugs taken: Prescribed and self-administered • Establish whether hepatotoxicity is reported in the literature • Relate the time the drugs were taken to the onset of illness: 4 days to 8 weeks (usual) • Establish the effect of stopping the drugs on normalisation of liver biochemistry: Hepatitic liver function tests (2 months) Cholestatic/mixed liver function tests (6 months) N.B. Challenge tests with drugs should be avoided • Exclude other causes: Viral hepatitis Biliary disease • Consider liver biopsy 22.54 Examples of common causes of drug-induced hepatotoxicity Pattern Drug Cholestasis Chlorpromazine High-dose oestrogens Cholestatic hepatitis Non-steroidal anti-inflammatory drugs Co-amoxiclav Statins Acute hepatitis Rifampicin Isoniazid Non-alcoholic steatohepatitis Amiodarone Venous outflow obstruction Busulfan Azathioprine Fibrosis Methotrexate 22.53 Drugs to be avoided in cirrhosis Drug Problem Toxicity Non-steroidal anti-inflammatory drugs Reduced renal blood flow Mucosal ulceration Hepatorenal failure Bleeding varices Angiotensinconverting enzyme inhibitors Reduced renal blood flow Hepatorenal failure Codeine Constipation Hepatic encephalopathy Narcotics Constipation, drug accumulation Hepatic encephalopathy Anxiolytics Drug accumulation Hepatic encephalopathy

Inherited liver diseases • 895

Pathophysiology The disease is caused by increased absorption of dietary iron and is inherited as an autosomal recessive trait. Approximately 90% of patients are homozygous for a single point mutation resulting in a cysteine to tyrosine substitution at position 282 (C282Y) in the HFE protein, which has structural and functional similarity to the HLA proteins. The mechanisms by which HFE regulates iron absorption are unclear. It is believed, however, that HFE normally interacts with the transferrin receptor in the basolateral membrane of intestinal epithelial cells. In HHC, it is thought that the lack of functional HFE causes a defect in uptake of transferrin-associated iron, leading to up-regulation of enterocyte iron-specific divalent metal transporters and excessive iron absorption. A histidine-to-aspartic acid mutation at position 63 (H63D) in HFE causes a less severe form of haemochromatosis that is most commonly found in patients who are compound heterozygotes also carrying a C282Y mutated allele. Fewer than 50% of C282Y homozygotes will develop clinical features of haemochromatosis; therefore other factors must also be important. HHC may promote accelerated liver disease in patients with alcohol excess or hepatitis C infection. Iron loss in menstruation and pregnancy can delay the onset of HHC in females. Clinical features Symptomatic disease usually presents in men over 40 years of age with features of liver disease (often with hepatomegaly), type 2 diabetes or heart failure. Fatigue and arthropathy are early symptoms but are frequently absent. Leaden-grey skin pigmentation due to excess melanin occurs, especially in exposed parts, axillae, groins and genitalia: hence the term ‘bronzed diabetes’. Once again, absence of this feature does not preclude the diagnosis. Impotence, loss of libido and testicular atrophy are recognised complications, as are early-onset osteoarthritis targeting unusual sites such as the metacarpophalangeal joints, chondrocalcinosis and pseudogout. Cardiac failure or cardiac dysrhythmia may occur due to iron deposition in the heart. Investigations Serum iron studies show a greatly increased ferritin, a raised plasma iron and saturated plasma iron-binding capacity. Transferrin saturation of more than 45% is suggestive of iron overload. Significant liver disease is unusual in patients with ferritin lower than 1000 μg/L (100 μg/dL). The differential diagnoses for elevated ferritin are inflammatory disease or excess ethanol consumption for modest elevations (< 1000 μg/L (100 μg/dL)). Very significant ferritin elevation can be seen in adult Still’s disease. In terms of imaging techniques, MRI has high specificity for iron overload but poor sensitivity. Liver biopsy allows assessment of fibrosis and distribution of iron (hepatocyte iron characteristic of haemochromatosis). The Hepatic Iron Index (HII) provides quantification of liver iron (μmol of iron per g dry weight of liver/age in years). An HII of more than 1.9 suggests genetic haemochromatosis (Fig. 22.40). Both the C282Y and the H63D mutations can be identified by genetic testing, which is now in routine clinical use. Management Treatment consists of weekly venesection of 500 mL blood (250 mg iron) until the serum iron is normal; this may take 2 years or more. The aim is to reduce ferritin to under 50 μg/L (5 μg/dL). Thereafter, venesection is continued as required to keep the serum ferritin normal. Liver and cardiac problems 22.56 Causes of haemochromatosis Primary haemochromatosis • Hereditary haemochromatosis • Congenital acaeruloplasminaemia • Congenital atransferrinaemia Secondary iron overload • Parenteral iron loading (e.g. repeated blood transfusion) • Iron-loading anaemia (thalassaemia, sideroblastic anaemia, pyruvate kinase deficiency) • Liver disease Complex iron overload • Juvenile haemochromatosis • Neonatal haemochromatosis • Alcoholic liver disease • Porphyria cutanea tarda • African iron overload (Bantu siderosis) outflow obstruction. Chronic overdose of vitamin A can damage the sinusoids and trigger local fibrosis that can result in portal hypertension. Hepatic fibrosis Most drugs cause reversible liver injury and hepatic fibrosis is very uncommon. Methotrexate, however, as well as causing acute liver injury when it is started, can lead to cirrhosis when used in high doses over a long period of time. Risk factors for drug-induced hepatic fibrosis include pre-existing liver disease and a high alcohol intake. Inherited liver diseases The inherited diseases are an important and probably underdiagnosed group of liver diseases. In addition to the ‘classical’ conditions, such as haemochromatosis and Wilson’s disease, the important role played by the liver in the expression of the inborn errors of metabolism should be remembered, as should the potential for genetic underpinning for intrahepatic cholestasis. Haemochromatosis Haemochromatosis is a condition in which the amount of total body iron is increased; the excess iron is deposited in, and causes damage to, several organs, including the liver. It may be primary or secondary to other diseases (Box 22.56). Hereditary haemochromatosis In hereditary haemochromatosis (HHC), iron is deposited throughout the body and total body iron may reach 20–60 g (normally 4 g). The important organs involved are the liver, pancreatic islets, endocrine glands, joints and heart. In the liver, iron deposition occurs first in the periportal hepatocytes, extending later to all hepatocytes. The gradual development of fibrous septa leads to the formation of irregular nodules, and finally regeneration results in macronodular cirrhosis. An excess of liver iron can occur in alcoholic cirrhosis but this is mild in comparison with haemochromatosis.

896 • HEPATOLOGY Pathophysiology Normally, dietary copper is absorbed from the stomach and proximal small intestine and is rapidly taken into the liver, where it is stored and incorporated into caeruloplasmin, which is secreted into the blood. The accumulation of excessive copper in the body is ultimately prevented by its excretion, the most important route being via bile. In Wilson’s disease, there is almost always a failure of synthesis of caeruloplasmin; however, some 5% of patients have a normal circulating caeruloplasmin concentration and this is not the primary pathogenic defect. The amount of copper in the body at birth is normal but thereafter it increases steadily; the organs most affected are the liver, basal ganglia of the brain, eyes, kidneys and skeleton. The ATP7B gene encodes a member of the copper-transporting P-type adenosine triphosphatase family, which functions to export copper from various cell types. At least 200 different mutations have been described. Most cases are compound heterozygotes with two different mutations in ATP7B. Attempts to correlate the genotype with the mode of presentation and clinical course have not shown any consistent patterns. The large number of culprit mutations means that, in contrast to haemochromatosis, genetic diagnosis is not routine in Wilson’s disease, although it may have a role in screening families following identification of the genotype in an index patient. Clinical features Symptoms usually arise between the ages of 5 and 45 years. Hepatic disease occurs predominantly in childhood and early adolescence, although it can present in adults in their fifties. Neurological damage causes basal ganglion syndromes and dementia, which tends to present in later adolescence. These features can occur alone or simultaneously. Other manifestations include renal tubular damage and osteoporosis, but these are rarely presenting features. Liver disease Episodes of acute hepatitis, sometimes recurrent, can occur, especially in children, and may progress to fulminant liver failure. The latter is characterised by the liberation of free copper into the blood stream, causing massive haemolysis and renal tubulopathy. Chronic hepatitis can also develop insidiously and eventually present with established cirrhosis; liver failure and portal hypertension may supervene. The possibility of Wilson’s disease should be considered in any patient under the age of 40 presenting with recurrent acute hepatitis or chronic liver disease of unknown cause, especially when this is accompanied by haemolysis. Neurological disease Clinical features include a variety of extrapyramidal features, particularly tremor, choreoathetosis, dystonia, parkinsonism and dementia (Ch. 25). Unusual clumsiness for age may be an early symptom. Neurological disease typically develops after the onset of liver disease and can be prevented by effective treatment started following diagnosis in the liver disease phase. This increases the importance of diagnosis in the liver phase beyond just allowing effective management of liver disease. Kayser–Fleischer rings These constitute the most important single clinical clue to the diagnosis and can be seen in 60% of adults with Wilson’s disease (less often in children but almost always in neurological improve after iron removal, but joint pain is less predictable and can improve or worsen after iron removal. Type 2 diabetes does not resolve after venesection. Other therapy includes that for cirrhosis and diabetes. First-degree family members should be investigated, preferably by genetic screening and also by checking the plasma ferritin and iron-binding saturation. Liver biopsy is indicated in asymptomatic relatives only if the LFTs are abnormal and/or the serum ferritin is greater than 1000 μg/L (100 μg/dL) because these features are associated with significant fibrosis or cirrhosis. Asymptomatic disease should also be treated by venesection until the serum ferritin is normal. Pre-cirrhotic patients with HHC have a normal life expectancy, and even cirrhotic patients have a good prognosis compared with other forms of cirrhosis (three-quarters of patients are alive 5 years after diagnosis). This is probably because liver function is well preserved at diagnosis and improves with therapy. Screening for hepatocellular carcinoma (p. 890) is mandatory because this is the main cause of death, affecting one-third of patients with cirrhosis, irrespective of therapy. Venesection reduces but does not abolish the risk of hepatocellular carcinoma in the presence of cirrhosis. Secondary haemochromatosis Many conditions, including chronic haemolytic disorders, sideroblastic anaemia, other conditions requiring multiple blood transfusion (generally over 50 L), porphyria cutanea tarda, dietary iron overload and occasionally alcoholic cirrhosis, are associated with widespread secondary siderosis. The features are similar to those of primary haemochromatosis but the history and clinical findings point to the true diagnosis. Some patients are heterozygotes for the HFE gene and this may contribute to the development of iron overload. Wilson’s disease Wilson’s disease (hepatolenticular degeneration) is a rare but important autosomal recessive disorder of copper metabolism caused by a variety of mutations in the ATP7B gene on chromosome 13. Total body copper is increased, with excess copper deposited in, and causing damage to, several organs. Fig. 22.40 Liver histology: haemochromatosis. This Perls stain shows accumulating iron within hepatocytes, which is stained blue. There is also accumulation of large fat globules in some hepatocytes (macrovesicular steatosis). Iron also accumulates in Kupffer cells and biliary epithelial cells.

Inherited liver diseases • 897

but this is not necessary to make the diagnosis. Occasionally, patients with liver disease and minor reductions of plasma α1-AT concentrations have α1-AT variants other than PiZZ, but the relationship of these to liver disease is uncertain. There is no specific treatment. The risk of severe and earlyonset emphysema means that all patients should be advised to stop smoking. Gilbert’s syndrome Gilbert’s syndrome is by far the most common inherited disorder of bilirubin metabolism (see Box 22.17, p. 860). It is an autosomal recessive trait when caused by a mutation in the promoter region of the gene for UDP-glucuronyl transferase enzyme (UGT1A1), which leads to reduced enzyme expression. It can be inherited in a dominant fashion when there is a missense mutation in the gene. This results in decreased conjugation of bilirubin, which accumulates as unconjugated bilirubin in the blood. The levels of unconjugated bilirubin increase during fasting, as fasting reduces levels of UDP-glucuronyl transferase. Clinical features The typical presentation is with isolated elevation of bilirubin, typically, although not exclusively, in the setting of physical stress or illness. There are no stigmata of chronic liver disease other than jaundice. Increased excretion of bilirubin and hence stercobilinogen leads to normal-coloured or dark stools, and increased urobilinogen excretion causes the urine to turn dark on standing as urobilin is formed. In the presence of haemolysis, pallor due to anaemia and splenomegaly due to excessive reticulo-endothelial activity are usually present. Investigations The plasma bilirubin is usually less than 100 μmol/L (~6 mg/ dL) and the LFTs are otherwise normal. There is no bilirubinuria because the hyperbilirubinaemia is predominantly unconjugated. Hepatic histology is normal and liver biopsy is not recommended for the investigation of patients with possible Gilbert’s syndrome. The condition is not associated with liver injury and thus has an excellent prognosis, needs no treatment, and is clinically important only because it may be mistaken for more serious liver disease. Wilson’s disease), albeit sometimes only by slit-lamp examination. Kayser–Fleischer rings are characterised by greenish-brown discoloration of the corneal margin appearing first at the upper periphery (p. 846). They disappear with treatment. Investigations A low serum caeruloplasmin is the best single laboratory clue to the diagnosis. Advanced liver failure from any cause can, however, reduce the serum caeruloplasmin and occasionally it is normal in Wilson’s disease. Other features of disordered copper metabolism should therefore be sought; these include a high free serum copper concentration, a high urine copper excretion of greater than 0.6 μmol/24 hrs (38 μg/24 hrs) and a very high hepatic copper content. Measuring 24-hour urinary copper excretion while giving D-penicillamine is a useful confirmatory test; more than 25 μmol/24 hrs is considered diagnostic of Wilson’s disease. Management The copper-binding agent penicillamine is the drug of choice. The dose given must be sufficient to produce cupriuresis and most patients require 1.5 μg/day (range 1–4 μg). The dose can be reduced once the disease is in remission but treatment must continue for life, even through pregnancy. Care must be taken to ensure that re-accumulation of copper does not occur. Abrupt discontinuation of treatment must be avoided because this may precipitate acute liver failure. Toxic effects occur in one-third of patients and include rashes, protein-losing nephropathy, lupus-like syndrome and bone marrow depression. If these do arise, trientine dihydrochloride (1.2–2.4 μg/day) and zinc (50 mg 3 times daily) are potential alternatives. Liver transplantation is indicated for fulminant liver failure or for advanced cirrhosis with liver failure. The value of liver transplantation in severe neurological Wilson’s disease is unclear. Prognosis is excellent, provided treatment is started before there is irreversible damage. Siblings and children of patients with Wilson’s disease must be investigated and treatment should be given to all affected individuals, even if they are asymptomatic. Alpha1-antitrypsin deficiency Alpha1-antitrypsin (α1-AT) is a serine protease inhibitor (Pi) produced by the liver. One of its main anti-protease functions is the breakdown of neutrophil elastase. The mutated form of α1-AT (PiZ) cannot be secreted into the blood by liver cells because it is retained within the endoplasmic reticulum of the hepatocyte. Homozygous individuals (PiZZ) have low plasma α1-AT concentrations, although globules containing α1-AT are found in the liver, and these people may develop hepatic and pulmonary disease. Liver manifestations include cholestatic jaundice in the neonatal period (neonatal hepatitis), which can resolve spontaneously; chronic hepatitis and cirrhosis in adults; and, in the long term, HCC. Alpha1-AT deficiency is a not uncommon exacerbating factor for liver disease of other aetiologies, and the possibility of dual pathology should be considered when severity of disease, such as ALD, appears disproportionate to the level of underlying insult. There are no clinical features that distinguish liver disease due to α1-AT deficiency from liver disease due to other causes, and the diagnosis is made from the low plasma α1-AT concentration and genotyping for the presence of the mutation. Alpha1-ATcontaining globules can be demonstrated in the liver (Fig. 22.41) Fig. 22.41 Liver histology in α1-antitrypsin deficiency. Accumulation of periodic acid–Schiff-positive granules (arrows) within individual hepatocytes is shown in this section from a patient with α1-AT deficiency.

898 • HEPATOLOGY Portal vein thrombosis Portal venous thrombosis as a primary event is rare but can occur in any condition predisposing to thrombosis. It may also complicate intra-abdominal inflammatory or neoplastic disease and is a recognised cause of portal hypertension. Acute portal venous thrombosis causes abdominal pain and diarrhoea, and may rarely lead to bowel infarction, requiring surgery. Treatment is otherwise based on anticoagulation, although there are no randomised data that demonstrate efficacy. An underlying thrombophilia needs to be excluded. Subacute thrombosis can be asymptomatic but may subsequently lead to extrahepatic portal hypertension (p. 868). Ascites is unusual in non-cirrhotic portal hypertension, unless the albumin is particularly low. Portal vein thrombosis can arise as a secondary event in patients with cirrhosis and portal hypertension, and is a recognised cause of decompensation in patients with previously stable cirrhosis. In individuals showing such decompensation, portal vein patency should be assessed by ultrasound with Doppler flow studies. Chronic portal vein thrombosis can be a cause of portal hypertension. Hepatopulmonary syndrome This condition is characterised by resistant hypoxaemia (PaO2 < 9.3 kPa (70 mmHg)), intrapulmonary vascular dilatation in patients with cirrhosis, and portal hypertension. Clinical features include finger clubbing, cyanosis, spider naevi and a characteristic reduction in arterial oxygen saturation on standing. The hypoxia is due to intrapulmonary shunting through direct arteriovenous communications. Nitric oxide (NO) over-production may be important in pathogenesis. The hepatopulmonary syndrome can be treated by liver transplantation but, if severe (PaO2 < 6.7 kPa (50 mmHg)), is associated with an increased operative risk. Portopulmonary hypertension This unusual complication of portal hypertension is similar to ‘primary pulmonary hypertension’ (p. 621). It is defined as pulmonary hypertension with increased pulmonary vascular resistance and a normal pulmonary artery wedge pressure in a patient with portal hypertension. The condition is caused by vasoconstriction and obliteration of the pulmonary arterial system and leads to breathlessness and fatigue. Hepatic venous disease Obstruction to hepatic venous blood flow can occur in the small central hepatic veins, the large hepatic veins, the inferior vena cava or the heart (see Fig. 22.20, p. 868). The clinical features depend on the cause and on the speed with which obstruction develops, and can mimic many other forms of chronic liver disease, sometimes leading to delayed diagnosis. Congestive hepatomegaly and ascites are, however, the most consistent features. The possibility of hepatic venous obstruction should always be considered in patients with an atypical liver presentation. Budd–Chiari syndrome This uncommon condition is caused by thrombosis of the larger hepatic veins and sometimes the inferior vena cava. Many patients have haematological disorders such as myelofibrosis, primary proliferative polycythaemia, paroxysmal nocturnal haemoglobinuria, Vascular liver disease Metabolically, the liver is highly active and has large oxygen requirements. This places it at risk of ischaemic injury in settings of impaired perfusion. The risk is mitigated, however, by the dual perfusion of the liver (via the portal vein as well as hepatic artery), with the former representing a low-pressure perfusion system that offers protection against the potential effects of arterial hypotension. The single outflow through the hepatic vein and the low-pressure perfusion system of the portal vein make the liver vulnerable to venous thrombotic ischaemia in the context of Budd–Chiari syndrome and portal vein thrombosis, respectively. Hepatic arterial disease Liver ischaemia Liver ischaemic injury is relatively common during hypotensive or hypoxic events and is under-diagnosed. The characteristic pattern is one of rising transaminase values in the days following such an event (e.g. prolonged seizures). Liver synthetic dysfunction and encephalopathy are uncommon but can occur. Liver failure is very rare. Diagnosis typically rests on clinical suspicion and exclusion of other potential aetiologies. Treatment is aimed at optimising liver perfusion and oxygen delivery. Outcome is dictated by the morbidity and mortality associated with the underlying disease, given that liver ischaemia frequently occurs in the context of other organ ischaemia in high-risk patients. Liver arterial disease Hepatic arterial disease is rare outside the setting of liver transplantation and is difficult to diagnose. It can cause significant liver damage. Hepatic artery occlusion may result from inadvertent injury during biliary surgery or may be caused by emboli, neoplasms, polyarteritis nodosa, blunt trauma or radiation. It usually causes severe upper abdominal pain with or without signs of circulatory shock. LFTs show raised transaminases (AST or ALT usually > 1000 U/L), as in other causes of acute liver damage. Patients usually survive if the liver and portal blood supply are otherwise normal. Hepatic artery aneurysms are extrahepatic in three-quarters of cases and intrahepatic in one-quarter. Atheroma, vasculitis, bacterial endocarditis and surgical or biopsy trauma are the main causes. They usually lead to bleeding into the biliary tree, peritoneum or intestine and are best diagnosed by angiography. Treatment is radiological or surgical. Any of the vasculitides can affect the hepatic artery but this rarely causes symptoms. Hepatic artery thrombosis is a recognised complication of liver transplantation and typically occurs in the early post-transplant period. Clinical features are often related to bile duct rather than liver ischaemia because of the dominant role of the hepatic artery in extrahepatic bile duct perfusion. Manifestations can include bile duct anastomotic failure with bile leak or the development of late bile duct strictures. Diagnosis and initial intervention are radiological in the first instance, with ERCP and biliary stenting being the principal approaches to the treatment of bile duct injury. Portal venous disease Portal hypertension See page 868.

Pregnancy and the liver • 899

by widespread occlusion of the small central hepatic veins. Pyrrolizidine alkaloids in Senecio and Heliotropium plants used to make teas, as well as cytotoxic drugs and hepatic irradiation, are all recognised causes. SOS may develop in 10–20% of patients following haematopoietic stem cell transplantation (usually within the first 20 days) and carries a 90% mortality in severe cases. Pathogenesis involves obliteration and fibrosis of terminal hepatic venules due to deposition of red cells, haemosiderin-laden macrophages and coagulation factors. In this setting, SOS is thought to relate to pre-conditioning therapy with irradiation and cytotoxic chemotherapy. The clinical features are similar to those of the Budd–Chiari syndrome (see above). Investigations show evidence of venous outflow obstruction histologically but, in contrast to Budd–Chiari, the large hepatic veins appear patent radiologically. Transjugular liver biopsy (with portal pressure measurements) may facilitate the diagnosis. Traditionally, treatment has been supportive but defibrotide shows promise (the drug binds to vascular endothelial cells, promoting fibrinolysis and suppressing coagulation). Cardiac disease Hepatic damage, due primarily to congestion, may develop in all forms of right heart failure (p. 461); usually, the clinical features are predominantly cardiac. Very rarely, long-standing cardiac failure and hepatic congestion give rise to cardiac cirrhosis. Severe left ventricular dysfunction is a cause of ischaemic hepatitis. Cardiac causes of acute and chronic liver disease are typically under-diagnosed. Treatment is principally that of the underlying heart disease with supportive treatment for the liver component. Nodular regenerative hyperplasia of the liver This is the most common cause of non-cirrhotic portal hypertension in developed countries; it is characterised by small hepatocyte nodules throughout the liver without fibrosis, which can result in sinusoidal compression. It is believed to be due to damage to small hepatic arterioles and portal venules. It occurs in older people and is associated with many conditions, including connective tissue disease, haematological diseases and immunosuppressive drugs, such as azathioprine. The condition is usually asymptomatic but occasionally presents with portal hypertension or with an abdominal mass. The diagnosis is made by liver biopsy, which, in contrast to cirrhosis, shows nodule formation in the absence of fibrous septa. Liver function is good and the prognosis is very favourable. Management is based on treatment of the portal hypertension. Pregnancy and the liver The inter-relationship between liver disease and pregnancy can be a complex one and a source of real anxiety for both patient and clinician. Three possibilities need to be borne in mind when treating a pregnant woman with a liver abnormality: • This represents a worsening of pre-existing chronic liver or biliary disease (although pregnancy may be the first time a woman’s liver biochemistry has been tested, so this may not have previously been diagnosed). • This represents a genuine first presentation of liver disease that is not intrinsically related to pregnancy. • This represents a genuine pregnancy-associated liver injury process. or antithrombin III, protein C or protein S deficiencies (Ch. 23). Pregnancy and oral contraceptive use, obstruction due to tumours (particularly carcinomas of the liver, kidneys or adrenals), congenital venous webs and occasionally inferior vena caval stenosis are the other main causes. The underlying cause cannot be found in about 50% of patients, although this percentage is falling as molecular diagnostic tools (such as the JAK2 mutation in myelofibrosis) increase our capacity to diagnose underlying haematological disorders. Hepatic congestion affecting the centrilobular areas is followed by centrilobular fibrosis, and eventually cirrhosis supervenes in those who survive long enough. Clinical features Acute venous occlusion causes rapid development of upper abdominal pain, marked ascites and occasionally acute liver failure. More gradual occlusion causes gross ascites and, often, upper abdominal discomfort. Hepatomegaly, frequently with tenderness over the liver, is almost always present. Peripheral oedema occurs only when there is inferior vena cava obstruction. Features of cirrhosis and portal hypertension develop in those who survive the acute event. Investigations The LFTs vary considerably, depending on the presentation, and can show the features of acute hepatitis. Ascitic fluid analysis shows a protein concentration above 25 g/L (2.5 g/dL) (exudate) in the early stages; this often falls later in the disease, however. Doppler ultrasound may reveal obliteration of the hepatic veins and reversed flow or associated thrombosis in the portal vein. CT may show enlargement of the caudate lobe, as this often has a separate venous drainage system that is not involved in the disease. CT and MRI may also demonstrate occlusion of the hepatic veins and inferior vena cava. Liver biopsy demonstrates centrilobular congestion with fibrosis, depending on the duration of the illness. Venography is needed only if CT and MRI are unable to demonstrate the hepatic venous anatomy clearly. Management Predisposing causes should be treated as far as possible; where recent thrombosis is suspected, thrombolysis with streptokinase, followed by heparin and oral anticoagulation, should be considered. Ascites is initially treated medically but often with only limited success. Short hepatic venous strictures can be treated with angioplasty. In the case of more extensive hepatic vein occlusion, many patients can be managed successfully by insertion of a covered TIPSS, followed by anticoagulation. Surgical shunts, such as portacaval shunts, are less commonly performed now that TIPSS is available. Occasionally, a web can be resected or an inferior vena caval stenosis dilated. Progressive liver failure is an indication for liver transplantation and life-long anticoagulation. Prognosis without transplantation or shunting is poor, particularly following an acute presentation with liver failure. A 3-year survival of 50% is reported in those who survive the initial event. The 1- and 10-year survival following liver transplantation is 85% and 69%, respectively, and this compares with a 5- and 10-year survival of 87% and 37%, respectively, following surgical shunting. Sinusoidal obstruction syndrome (veno-occlusive disease) Sinusoidal obstruction syndrome (SOS; previously known as veno-occlusive disease) is a rare condition characterised

900 • HEPATOLOGY LFTs in pregnancy, which include pregnancy-associated liver disease, are shown in Box 22.57. Liver transplantation The outcome following liver transplantation has improved significantly over the last decade so that elective transplantation in low-risk individuals now has a 1-year survival rate of more than 90% and is an effective treatment for end-stage liver disease. The number of procedures is limited by cadaveric donor availability and in many parts of the world this has led to living donor transplant programmes. Despite this, 10% of those listed for liver transplantation will die while awaiting a donor liver. The main complications of liver transplantation relate to rejection, complications of long-term immunosuppression and disease recurrence in the liver graft. Indications and contraindications Currently, around 9500 liver transplants are undertaken in Europe and the USA annually. About 10% are performed for acute liver failure, 6% for metabolic diseases, 71% for cirrhosis and 11% for hepatocellular carcinoma. Most patients are under 60 years of age and only 10% are aged between 60 and 70 years. Indications for elective transplant assessment are listed in Box 22.58. In North America, the most common indication is hepatitis C cirrhosis, about 10–20% of transplants being for alcoholic cirrhosis (Fig. 22.42). Patients with alcoholic liver disease need to show a capacity for abstinence. The main contraindications to transplantation are sepsis, extrahepatic malignancy, active alcohol or other substance misuse, and marked cardiorespiratory dysfunction. Patients are matched for ABO blood group and size but do not require HLA matching with donors, as the liver is a relatively immune-privileged organ compared with the heart or kidneys. In many parts of the world, the MELD score (see Box 22.30, p. 868) is used to identify and prioritise patients for transplantation. In the UK, a similar system that also incorporates serum sodium, the United Kingdom End-stage Liver Disease (UKELD) score, is used to guide recipient selection. To be listed for elective (non-super-urgent) transplantation in the UK, patients must have a greater than 50% projected post-transplant 5-year survival and must fall into one of three categories: • Category 1: estimated 1-year mortality without transplantation of more than 9% (equivalent to a UKELD score of more than 49 points) It is critical to obtain information relating to liver disease risk factors and pre-pregnancy liver status to establish whether any abnormality was present before pregnancy. In general, the earlier in pregnancy that liver abnormality presents, the more likely it is to represent either pre-existing liver disease or non-pregnancy-related acute liver disease. Equally, the best outcome for both mother and baby results from optimising the physical condition of the mother, and in situations of deteriorating liver function (which can be steep in late pregnancy) consideration should always be given to early delivery if the fetus is viable. Joint management between hepatologists and obstetricians is essential. Intercurrent and pre-existing liver disease Acute hepatitis A can occur during pregnancy but has no effect on the fetus. Chronic hepatitis B requires identification in pregnancy because of long-term health implications for the mother and the effectiveness of perinatal vaccination (with or without pre-delivery maternal antiviral therapy) in reducing neonatal acquisition of chronic hepatitis B. Maternal transmission of hepatitis C occurs in 1% of cases and there is no convincing evidence that the mode of delivery affects this. Hepatitis E is reported to progress to acute liver failure much more commonly in pregnancy, with a 20% maternal mortality. Pregnancy may be associated with either worsening or improvement of autoimmune hepatitis, although improvement during pregnancy and rebound post-partum is the most common pattern seen. Complications of portal hypertension may be a particular issue in the second and third trimesters. Gallstones (p. 903) are more common during pregnancy and may present with cholecystitis or biliary obstruction. The diagnosis can usually be made with ultrasound. In biliary obstruction due to gallstones, therapeutic ERCP can be safely performed but lead protection for the fetus is essential and X-ray screening must be kept to a minimum. Pregnancy-associated liver disease Several conditions occur only during pregnancy, may recur in subsequent pregnancies and resolve after delivery of the baby, and these are discussed on page 1283. The causes of abnormal 22.57 Abnormal liver function tests in pregnancy • Liver function tests: alkaline phosphatase (ALP) levels and albumin normally fall in pregnancy. ALP levels can rise due to the contribution of placental ALP. • Pre-existing liver disease: pregnancy is uncommon in cirrhosis because cirrhosis causes relative infertility. Varices can enlarge in pregnancy, and ascites should be treated with amiloride rather than spironolactone. Penicillamine for Wilson’s disease and azathioprine for autoimmune liver disease should be continued during pregnancy. Autoimmune liver disease can flare up post-partum. • Incidental: viral, autoimmune and drug-induced hepatitis must be excluded in the presence of an elevated alanine aminotransferase (ALT). Immunoglobulin/vaccination given to the fetus at birth prevents transmission of hepatitis B to the fetus if the mother is infected. Gallstones are more common in pregnancy and post-partum, and are a cause of a raised ALP level. Biliary imaging with ultrasound and magnetic resonance cholangiopancreatography is safe. Endoscopic retrograde cholangiopancreatography to remove stones can be performed safely with shielding of the fetus from radiation. • Pregnancy-related liver diseases: occur predominantly in the third trimester and resolve post-partum. Maternal and fetal mortality and morbidity are reduced by expediting delivery. 22.58 Indications for liver transplant assessment for cirrhosis Complications • First episode of bacterial peritonitis • Diuretic-resistant ascites • Recurrent variceal haemorrhage • Hepatocellular carcinoma < 5 cm • Persistent hepatic encephalopathy Poor liver function • Bilirubin > 100 μmol/L (5.8 mg/dL) in primary biliary cholangitis • MELD score > 12 (Box 22.30, p. 868) • Child–Pugh grade C (Box 22.29, p. 867) (MELD = Model for End-stage Liver Disease)

Liver transplantation • 901

Technical complications These include hepatic artery thrombosis, which may necessitate re-transplantation. Anastomotic biliary strictures can also occur; these may respond to endoscopic balloon dilatation and stenting, or require surgical reconstruction. Portal vein thrombosis is rare. Rejection Less immunosuppression is needed following liver transplantation than with kidney or heart/lung grafting. Initial immunosuppression is usually with tacrolimus or ciclosporin, prednisolone and azathioprine or mycophenolate. Some patients can eventually be maintained on a single agent. Acute cellular rejection occurs in 60–80% of patients, commonly at 5–10 days post-transplant and usually within the first 6 weeks, but can arise at any point. This normally responds to 3 days of high-dose intravenous methylprednisolone. Infections Bacterial infections, such as pneumonia and wound infections, can occur in the first few weeks after transplantation. Cytomegalovirus (primary infection or reactivation) is a common infection in the 3 months after transplantation and can cause hepatitis. Patients who have never had cytomegalovirus infection but who receive a liver from a donor who has been exposed are at greatest risk of infection and are usually given prophylactic antiviral therapy, such as valganciclovir. Herpes simplex virus reactivation or, rarely, primary infection may occur. Prophylaxis is given to recipients who have had previous exposure to tuberculosis for the first 6 months after transplantation to prevent reactivation. Late complications These include recurrence of the initial disease in the graft and complications due to the immunosuppressive therapy, such as renal impairment from ciclosporin. Metabolic syndrome (p. 730) is common, being described in about 50% of transplant recipients within 6 months in the USA. Chronic vascular rejection is rare, occurring in only 5% of cases. Prognosis The outcome following transplantation for acute liver failure is worse than that for chronic liver disease because most patients have multi-organ failure at the time of transplantation. The 1-year survival is 65% and falls only a little to 59% at 5 years. The 1-year survival for patients with cirrhosis is over 90%, falling to 70–75% at 5 years. • Category 2: HCC diagnosed radiologically by two concordant modalities; based on CT, a single lesion of less than 5 cm maximum diameter, or fewer than three lesions each less than 3 cm in diameter, without macrovascular invasion or metastases. • Category 3: ‘variant syndromes’, including diuretic-resistant ascites, hepatopulmonary syndrome, chronic hepatic encephalopathy, intractable pruritus, familial amyloidosis, primary hyperlipidaemia, polycystic liver disease and recurrent cholangitis. Super-urgent listing is reserved for patients with acute liver failure, according to specific criteria. Two types of transplant are increasingly used because of insufficient cadaveric donors: • Split liver transplantation. A cadaveric donor liver can be split into two, with the larger right lobe used in an adult and the smaller left lobe used in a child. This practice has led to an increase in procedures despite a shortage of donor organs. • Living donor transplantation. This is normally performed using the left lateral segment or the right lobe. The donor mortality is significant at 0.5–1%. Pre-operative assessment includes looking at donor liver size and psychological status. Complications Early complications Primary graft non-function This is a state of hepatocellular dysfunction arising as a consequence of liver paresis, which results from ischaemia following removal from the donor and prior to reperfusion in the recipient. Factors that increase the likelihood of primary non-function include increasing donor age, degree of steatosis in the liver and the length of ischaemia. Treatment is supportive until recovery of function. Occasionally, recovery is not seen and re-transplantation is necessary. Fig. 22.42 Indications for elective adult liver transplantation in the UK, 2016. Hepatitis C Hepatocellular carcinoma Alcohol Hepatitis B Primary biliary cholangitis Primary sclerosing cholangitis Autoimmune liver disease Cryptogenic Other 24% 6% 6% 26% 2% 11% 9% 5% 11% 22.59 Liver disease in old age • Alcoholic liver disease: 10% of cases present over the age of 70 years, when disease is more likely to be severe and has a worse prognosis. • Hepatitis A: causes more severe illness and runs a more protracted course. • Primary biliary cholangitis: one-third of cases are over 65 years. • Liver abscess: more than 50% of all cases in the UK are over 60 years. • Hepatocellular carcinoma: approximately 50% of cases in the UK present over the age of 65 years. • Surgery: older people are less likely to survive liver surgery (including transplantation) because comorbidity is more prevalent.

902 • HEPATOLOGY Caroli’s disease This very rare disease is characterised by segmental saccular dilatations of the intrahepatic biliary tree. The whole liver is usually affected and extrahepatic biliary dilatation occurs in about one-quarter of patients. Recurrent attacks of cholangitis (see Box 22.18, p. 861) may cause hepatic abscesses. Complications include biliary stones and cholangiocarcinoma. Antibiotics are required for episodes of cholangitis. Occasionally, localised disease can be treated by segmental liver resection, and liver transplantation may sometimes be required. Congenital hepatic fibrosis This is characterised by broad bands of fibrous tissue linking the portal tracts in the liver, abnormalities of the interlobular bile ducts and sometimes a lack of portal venules. The renal tubules may show cystic dilatation (medullary sponge kidney; p. 433), and eventually renal cysts may develop. The condition can be inherited as an autosomal recessive trait. Liver involvement causes portal hypertension with splenomegaly and bleeding from oesophageal varices that usually presents in adolescence or in early adult life. The prognosis is good because liver function is preserved. Treatment may be required for variceal bleeding and occasionally cholangitis. Patients can present during childhood with renal failure if the kidneys are severely affected. Cystic fibrosis Cystic fibrosis (p. 580) is associated with biliary cirrhosis in about 5% of individuals. Splenomegaly and an elevated ALP are characteristic. Complications do not normally arise until late adolescence or early adulthood, when bleeding due to variceal haemorrhage may occur. UDCA improves liver blood tests but it is not known whether the drug can prevent progression of liver disease. Deficiency of fat-soluble vitamins (A, D, E and K) may need to be treated in view of both biliary and pancreatic disease. Extrahepatic biliary disease Diseases of the extrahepatic biliary tree typically present with the clinical features of impaired bile flow (obstructive jaundice and fat Cholestatic and biliary disease The concepts of biliary and cholestatic disease, and the important distinctions between them, can be a source of confusion. ‘Cholestasis’ relates to a biochemical abnormality (typically, elevation of ALP and elevation in serum bile acid levels and bilirubin) that results from an abnormality in bile flow. The cause can range from inherited or acquired dysfunction of transporter molecules responsible for the production of canalicular bile to physical obstruction of the extrahepatic bile duct. ‘Biliary disease’ relates to pathology at any level from the small intrahepatic bile ducts to the sphincter of Oddi. Although there is very significant overlap between cholestatic and biliary disease, there are scenarios where cholestasis can exist without biliary disease (transporter disease or pure drug-induced cholestasis) and where biliary disease can exist without cholestasis (when disease of the bile duct does not impact on bile flow). These anomalies should always be borne in mind and cholestasis and biliary disease always effectively distinguished. Chemical cholestasis Pure cholestasis can occur as an inherited condition (p. 895), as a consequence of cholestatic drug reactions (p. 894) or as acute cholestasis of pregnancy (p. 1284). A more frequent, but less recognised, acquired biochemical cholestasis occurs in sepsis (‘cholangitis lente’). This biochemical phenomenon is one of the causes of LFT abnormality in sepsis, does not require specific treatment, and has a prognostic significance conferred by the underlying septic process. Mutations in the biliary transporter proteins on the hepatocyte canalicular membrane (familial intrahepatic cholestasis 1, FIC1), illustrated in Figure 22.7 (p. 851), have been shown to cause an inherited intrahepatic biliary disease in childhood, characterised by raised ALP levels and progression to a biliary cirrhosis. It is also becoming increasingly clear that these proteins contribute to intrahepatic biliary disease in adulthood. Benign recurrent intrahepatic cholestasis This rare condition usually presents in adolescence and is characterised by recurrent episodes of cholestasis, lasting 1–6 months. It is now known to be mediated by mutations in the ATP8B1 gene, which lies on chromosome 18 and encodes FIC1. Episodes start with pruritus, while painless jaundice develops later. LFTs show a cholestatic pattern. Liver biopsy shows cholestasis during an episode but is normal between episodes. Treatment is required to relieve the symptoms of cholestasis, such as pruritus, and the long-term prognosis is good. Intrahepatic biliary disease Inflammatory and immune disease The small intrahepatic bile ducts appear to be specifically vulnerable to immune injury, and ductopenic injury (‘vanishing bile duct syndrome’) can be a feature of a number of chronic conditions, including graft-versus-host disease (GVHD), sarcoidosis and, in the setting of liver transplantation, ductopenic rejection. Intrahepatic small bile duct injury occurs most frequently in primary biliary cholangitis, an autoimmune cholestatic disease, and less frequently in primary sclerosing cholangitis (Box 22.60). 22.60 Comparison of primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) PBC PSC Gender (F : M) 10 : 1 1 : 3 Age Older: median age 50–55 years Younger: median age 20–40 years Disease associations Non-organ-specific autoimmune disease (e.g. Sjögren’s syndrome) and autoimmune thyroid disease Ulcerative colitis Autoantibody profile 90% AMA +ve 65–85% pANCA +ve (but this is non-specific and not diagnostic) Predominant bile-duct injury Intrahepatic Extrahepatic > intrahepatic (AMA = antimitochondrial antibody; pANCA = perinuclear antineutrophil cytoplasmic antibody)

Cholestatic and biliary disease • 903

cholesterol, fat, total calories and refined carbohydrate or lack of dietary fibre has been implicated. Pathophysiology Gallstones are conventionally classified into cholesterol or pigment stones, although the majority are of mixed composition. Gallstones contain varying quantities of calcium salts, including calcium bilirubinate, carbonate, phosphate and palmitate, which are radio-opaque. Gallstone formation is multifactorial and the factors involved are related to the type of gallstone (Boxes 22.61 and 22.62). Cholesterol gallstones Cholesterol is held in solution in bile by its association with bile acids and phospholipids in the form of micelles and vesicles. Biliary lipoproteins may also have a role in solubilising cholesterol. In gallstone disease, the liver produces bile that contains an excess of cholesterol because there is either a relative deficiency of bile salts or a relative excess of cholesterol (‘lithogenic’ bile). Abnormalities of bile salt synthesis and circulation, cholesterol secretion and gallbladder function may make production of lithogenic bile more likely. Pigment stones Brown, crumbly pigment stones are almost always the consequence of bacterial or parasitic biliary infection. They are common in the Far East, where infection allows bacterial β-glucuronidase to hydrolyse conjugated bilirubin to its free form, malabsorption). Obstructive disease is frequently a consequence of stricturing following gallstone passage and associated infection and inflammation or post-surgical intervention. PSC frequently involves the extrahepatic biliary tree and its differential, IgG4 disease, is an important and potentially treatable cause of disease (p. 890). Malignant diseases (cholangiocarcinoma or carcinoma of the head of pancreas) should be considered in all patients with extrahepatic biliary obstruction). Choledochal cysts This term applies to cysts anywhere in the biliary tree (Fig. 22.43). The great majority cause diffuse dilatation of the common bile duct (type I) but others take the form of biliary diverticula (type II), dilatation of the intraduodenal bile duct (type III) and multiple biliary cysts (type IV). The last type merges with Caroli’s disease (see above). In the neonate, they may present with jaundice or biliary peritonitis. Recurrent jaundice, abdominal pain and cholangitis may arise in the adult. Liver abscess and biliary cirrhosis may develop and there is an increased incidence of cholangiocarcinoma. Excision of the cyst with hepatico-jejunostomy is the treatment of choice. Secondary biliary cirrhosis Secondary biliary cirrhosis develops after prolonged large duct biliary obstruction due to gallstones, benign bile duct strictures or sclerosing cholangitis (see below). Carcinomas rarely cause secondary biliary cirrhosis because few patients survive long enough. The clinical features are those of chronic cholestasis with episodes of ascending cholangitis or even liver abscess (p. 879). Cirrhosis, ascites and portal hypertension are late features. Relief of biliary obstruction may require endoscopic or surgical intervention. Cholangitis dictates treatment with antibiotics, which can be given continuously if attacks recur frequently. Gallstones Gallstone formation is the most common disorder of the biliary tree and it is unusual for the gallbladder to be diseased in the absence of gallstones. In developed countries, gallstones occur in 7% of males and 15% of females aged 18–65 years, with an overall prevalence of 11%. In individuals under 40 years there is a 3 : 1 female preponderance, whereas in the elderly the sex ratio is about equal. Gallstones are less frequent in India, the Far East and Africa. There has been much debate over the role of diet in cholesterol gallstone disease; an increase in dietary Fig. 22.43 Classification and frequency of choledochal cysts. From Shearman DC, Finlayson NDC. Diseases of the gastrointestinal tract and liver, 2nd edn. Edinburgh: Churchill Livingstone, Elsevier Ltd; 1989. Type I (87%) Type II (7%) Type III (3%) Type IV (3%) 22.62 Composition of and risk factors for pigment stones Black Brown Composition Polymerised calcium bilirubinates* Calcium bilirubinate crystals* Mucin glycoprotein Mucin glycoprotein Calcium phosphate Cholesterol Calcium carbonate Calcium palmitate/stearate Cholesterol Risk factors Haemolysis Infected bile Age Stasis Hepatic cirrhosis Ileal resection/disease *Major component. 22.61 Risk factors and mechanisms for cholesterol gallstones ↑Cholesterol secretion • Old age • Female gender • Pregnancy • Obesity • Rapid weight loss Impaired gallbladder emptying • Pregnancy • Gallbladder stasis • Fasting • Total parenteral nutrition • Spinal cord injury ↓Bile salt secretion • Pregnancy

904 • HEPATOLOGY 15% of patients and cause biliary colic. Rarely, fistulae develop between the gallbladder and the duodenum, colon or stomach. If this occurs, air will be seen in the biliary tree on plain abdominal X-rays. If a stone larger than 2.5 cm in diameter has migrated into the gut, it may impact either at the terminal ileum or occasionally in the duodenum or sigmoid colon. The resultant intestinal obstruction may be followed by ‘gallstone ileus’. Gallstones impacted in the cystic duct may cause stricturing of the common hepatic duct and the clinical picture of extrahepatic biliary diseases (‘Mirizzi’s syndrome’, with its important differential of malignant bile duct stricture). The more common cause of jaundice due to gallstones is a stone passing from the cystic duct into the common bile duct (choledocholithiasis), which may also result in cholangitis or acute pancreatitis. It is usually very small stones that precipitate acute pancreatitis, due (it is thought) to oedema at the ampulla as the stone passes into the duodenum (no stone is seen within the bile duct in 80% of cases of presumed gallstone pancreatitis, suggesting stone passage). Previous stone passage is also the likely cause of most cases of benign papillary fibrosis, which is most commonly seen in patients with previous or present gallstone disease (it may present with jaundice, obstructive LFTs with biliary dilatation, post-cholecystectomy pain or acute pancreatitis). Cancer of the gallbladder is growing in frequency (p. 907) but in over 95% of cases is associated with the presence of gallstones. Previously, the diagnosis was typically made as an incidental histological finding following cholecystectomy for gallstone disease. Increasing awareness of the risk of gallbladder carcinoma and of the role played by polyps in the natural history has led to an increase in screening activity and prospective diagnosis. Investigations Ultrasound is the investigation of choice for diagnosing gallstones. Most stones are diagnosed by transabdominal ultrasound, which has more than 92% sensitivity and 99% specificity for gallbladder stones (see Fig. 22.8, p. 854). CT, MRCP (Fig. 22.44) and, increasingly, EUS are excellent modalities for detecting complications of gallstones (distal bile duct stone or gallbladder empyema) but are inferior to ultrasound in defining which then precipitates as calcium bilirubinate. The mechanism of black pigment gallstone formation in developed countries is not satisfactorily explained. Haemolysis is important as a contributing factor for the development of black pigment stones that occur in chronic haemolytic disease. Biliary sludge This describes gelatinous bile that contains numerous microspheroliths of calcium bilirubinate granules and cholesterol crystals, as well as glycoproteins; it is an important precursor to the formation of gallstones in the majority of patients. Biliary sludge is frequently formed under normal conditions but then either dissolves or is cleared by the gallbladder; only in about 15% of patients does it persist to form cholesterol stones. Fasting, parenteral nutrition and pregnancy are also associated with sludge formation. Clinical features Only 10% of individuals with gallstones develop clinical evidence of gallstone disease. Symptomatic stones within the gallbladder (Box 22.63) manifest as either biliary pain (‘biliary colic’) or cholecystitis (see below). If a gallstone becomes acutely impacted in the cystic duct, the patient will experience pain. The term ‘biliary colic’ is a misnomer because the pain does not rhythmically increase and decrease in intensity like other forms of colic. Typically, the pain occurs suddenly and persists for about 2 hours; if it continues for more than 6 hours, a complication such as cholecystitis or pancreatitis may be present. Pain is usually felt in the epigastrium (70% of patients) or right upper quadrant (20%) and radiates to the interscapular region or the tip of the right scapula, but other sites include the left upper quadrant and the lower chest. The pain can mimic intrathoracic disease, oesophagitis, myocardial infarction or dissecting aortic aneurysm. Combinations of fatty food intolerance, dyspepsia and flatulence not attributable to other causes have been referred to as ‘gallstone dyspepsia’. These symptoms are not now recognised as being caused by gallstones and are best regarded as functional dyspepsia (p. 779). Acute and chronic cholecystitis is described below. A mucocele may develop if there is slow distension of the gallbladder from continuous secretion of mucus; if this material becomes infected, an empyema supervenes. Calcium may be secreted into the lumen of the hydropic gallbladder, causing ‘limey’ bile, and if calcium salts are precipitated in the gallbladder wall, the radiological appearance of ‘porcelain’ gallbladder results. Gallstones in the gallbladder (cholecystolithiasis) migrate to the common bile duct (choledocholithiasis; p. 906) in approximately 22.63 Clinical features and complications of gallstones Clinical features • Asymptomatic (80%) • Biliary colic • Acute cholecystitis • Chronic cholecystitis Complications • Empyema of the gallbladder • Porcelain gallbladder • Choledocholithiasis • Acute pancreatitis • Fistulae from gallbladder to duodenum/colon • Pressure on/inflammation of the common hepatic duct by a gallstone in the cystic duct (Mirizzi’s syndrome) • Gallstone ileus • Cancer of the gallbladder Fig. 22.44 Magnetic resonance cholangiopancreatogram showing multiple stones in the gallbladder (long arrow) and also within the distal common bile duct (inset, arrow).

Cholestatic and biliary disease • 905

Investigations Peripheral blood leucocytosis is common, except in the elderly patient, in whom the signs of inflammation may be minimal. Minor increases of transaminases and amylase may be encountered. Amylase should be measured to detect acute pancreatitis (p. 837), which may be a potentially serious complication of gallstones. Only when the amylase is higher than 1000 U/L can pain be confidently attributed to acute pancreatitis, since moderately elevated levels of amylase can occur with many other causes of abdominal pain. Plain X-rays of the abdomen and chest may show radio-opaque gallstones, and rarely intrabiliary gas due to fistulation of a gallstone into the intestine; they are important in excluding lower lobe pneumonia and a perforated viscus. Ultrasonography detects gallstones and gallbladder thickening due to cholecystitis but gallbladder empyema or perforation is best assessed by CT. Management Medical Medical management consists of bed rest, pain relief, antibiotics and intravenous fluids. Moderate pain can be treated with NSAIDs but more severe pain should be managed with opiates. A cephalosporin (such as cefuroxime) or piperacillin/tazobactam is the usual antibiotic of choice, but metronidazole is normally added in severely ill patients and local prescribing practice may vary. Nasogastric aspiration is needed only for persistent vomiting. Cholecystitis usually resolves with medical treatment but the inflammation may progress to an empyema or perforation and peritonitis. Surgical Urgent surgery is the optimal treatment when cholecystitis progresses in spite of medical therapy and when complications such as empyema or perforation develop. Operation should be carried out within 5 days of the onset of symptoms. Delayed surgery after 2–3 months is no longer favoured. When cholecystectomy may be difficult due to extensive inflammatory change, percutaneous gallbladder drainage can be performed, with subsequent cholecystectomy 4–6 weeks later. Recurrent biliary colic or cholecystitis is frequent if the gallbladder is not removed. Chronic cholecystitis Chronic inflammation of the gallbladder is almost invariably associated with gallstones. The usual symptoms are those of recurrent attacks of upper abdominal pain, often at night and following a heavy meal. The clinical features are similar to those of acute calculous cholecystitis but milder. Patients may recover spontaneously or following analgesia and antibiotics. They are usually advised to undergo elective laparoscopic cholecystectomy. Acute cholangitis Acute cholangitis is caused by bacterial infection of bile ducts and occurs in patients with other biliary problems, such as choledocholithiasis (see below), biliary strictures or tumours, or after ERCP. Jaundice, fever (with or without rigors) and right upper quadrant pain are the main presenting features (‘Charcot’s triad’). Treatment is with antibiotics, relief of biliary obstruction and removal (if possible) of the underlying cause. 22.64 Treatment of gallstones Gallbladder stones • Cholecystectomy: laparoscopic or open • Oral bile acids: chenodeoxycholic or ursodeoxycholic (low rate of stone dissolution) Bile duct stones • Lithotripsy (endoscopic or extracorporeal shock wave, ESWL) • Endoscopic sphincterotomy and stone extraction • Surgical bile duct exploration their presence in the gallbladder. When recurrent attacks of otherwise unexplained acute pancreatitis occur, they may result from ‘microlithiasis’ in the gallbladder or common bile duct and are best assessed by EUS. Management Asymptomatic gallstones found incidentally should not be treated because the majority will never cause symptoms. Symptomatic gallstones are best treated surgically by laparoscopic cholecystectomy; the severity of symptoms should be balanced against the individual patient surgical risk in order to decide whether surgery is warranted. Various techniques can be used to treat common bile duct stones (Box 22.64). Cholecystitis Acute cholecystitis Pathophysiology Acute cholecystitis is almost always associated with obstruction of the gallbladder neck or cystic duct by a gallstone. Occasionally, obstruction may be by mucus, parasitic worms or a biliary tumour, or may follow endoscopic bile duct stenting. The pathogenesis is unclear but the initial inflammation is possibly chemically induced. This leads to gallbladder mucosal damage, which releases phospholipase, converting biliary lecithin to lysolecithin, a recognised mucosal toxin. At the time of surgery, approximately 50% of cultures of the gallbladder contents are sterile. Infection occurs eventually, and in elderly patients or those with diabetes mellitus a severe infection with gas-forming organisms can cause emphysematous cholecystitis. Acalculous cholecystitis can occur in the intensive care setting and in association with parenteral nutrition, sickle cell disease and diabetes mellitus. Clinical features The cardinal feature is pain in the right upper quadrant but also in the epigastrium, the right shoulder tip or the interscapular region. Differentiation between biliary colic (p. 904) and acute cholecystitis may be difficult; features suggesting cholecystitis include severe and prolonged pain, fever and leucocytosis. Examination shows right hypochondrial tenderness, rigidity worse on inspiration (Murphy’s sign) and occasionally a gallbladder mass (30% of cases). Fever is present but rigors are unusual. Jaundice occurs in less than 10% of patients and is usually due to passage of stones into the common bile duct, or to compression or even stricturing of the common bile duct following stone impaction in the cystic duct (Mirizzi’s syndrome). Gallbladder perforation occurs in 10–15% of cases and gallbladder empyema may arise.

906 • HEPATOLOGY cause of the obstruction in the common bile duct; 50% of bile duct stones are missed on ultrasound, particularly those in the distal common bile duct. EUS is extremely accurate at identifying bile duct stones. MRCP is non-invasive and is indicated when intervention is not necessarily mandatory (e.g. the patient with possible bile duct stones but no jaundice or sepsis). Management Cholangitis should be treated with analgesia, intravenous fluids and broad-spectrum antibiotics, such as cefuroxime and metronidazole (local prescribing practice may vary). Blood cultures should be taken before the antibiotics are administered. Patients also require urgent decompression of the biliary tree and stone removal. ERCP with biliary sphincterotomy and stone extraction is the treatment of choice and is successful in about 90% of patients. If ERCP fails, other approaches include percutaneous transhepatic drainage and combined (‘rendezvous’) endoscopic procedures, extracorporeal shock wave lithotripsy (ESWL) and surgery. Surgical treatment of choledocholithiasis is performed less frequently than ERCP, and before the common bile duct is explored the diagnosis of choledocholithiasis should be confirmed by intraoperative cholangiography. If gallstones are found, the bile duct is explored, either via the cystic duct or by opening it, all stones are removed, clearance is checked by cholangiography or choledochoscopy, and then primary closure of the duct is performed if possible. External drainage of the common bile duct by T-tube is rarely required nowadays. It is now possible to achieve these goals laparoscopically in specialist centres. Recurrent pyogenic cholangitis This disease occurs predominantly in South-east Asia. Biliary sludge, calcium bilirubinate concretions and stones accumulate in the intrahepatic bile ducts, with secondary bacterial infection. Patients present with recurrent attacks of upper abdominal pain, fever and cholestatic jaundice. Investigation of the biliary tree demonstrates that both the intrahepatic and the extrahepatic portions are filled with soft biliary mud. Eventually, the liver becomes scarred and liver abscesses and secondary biliary cirrhosis develop. The condition is difficult to manage and requires Choledocholithiasis Stones in the common bile duct (choledocholithiasis) occur in 10–15% of patients with gallstones (Fig. 22.45), which have usually migrated from the gallbladder. Primary bile duct stones are rare but can develop within the common bile duct many years after a cholecystectomy, and are sometimes related to biliary sludge arising from dysfunction of the sphincter of Oddi. In Far Eastern countries, primary common bile duct stones are thought to follow bacterial infection secondary to parasitic infections with Clonorchis sinensis, Ascaris lumbricoides or Fasciola hepatica (pp. 297 and 289 ). Common bile duct stones can cause bile duct obstruction and may be complicated by cholangitis due to secondary bacterial infection, sepsis, liver abscess and biliary stricture. Clinical features Choledocholithiasis may be asymptomatic, may be found incidentally by operative cholangiography at cholecystectomy, or may manifest as recurrent abdominal pain with or without jaundice. The pain is usually in the right upper quadrant, and fever, pruritus and dark urine may be present. Rigors may be a feature; jaundice is common and usually associated with pain. Physical examination may show the scar of a previous cholecystectomy; if the gallbladder is present, it is usually small, fibrotic and impalpable. Investigations The LFTs show a cholestatic pattern and there is bilirubinuria. If cholangitis is present, the patient usually has a leucocytosis. The most convenient method of demonstrating obstruction to the common bile duct is transabdominal ultrasound. This shows dilated extrahepatic and intrahepatic bile ducts, together with gallbladder stones (Fig. 22.46), but does not always reveal the Fig. 22.45 Endoscopic retrograde cholangiopancreatogram showing common duct stones (arrows). Fig. 22.46 Endoscopic ultrasound image in a patient with cholangitis. The dilated common bile duct (CBD) contains a small stone (arrow), which causes acoustic shadowing. CBD

Cholestatic and biliary disease • 907

tumour is associated with gallstones, primary and secondary sclerosing cholangitis, Caroli’s disease and choledochal cysts (see Fig. 22.43). In the Far East, particularly northern Thailand, chronic liver fluke infection (Clonorchis sinensis) is a major risk factor for the development of CCA in men. Primary sclerosing cholangitis carries a lifetime risk of CCA of approximately 20%, although only 5% of CCAs relate to primary sclerosing cholangitis. Chronic biliary inflammation appears to be a common factor in the development of biliary dysplasia and cancer that is shared by all the predisposing causes. Tumours typically invade the lymphatics and adjacent vessels, with a predilection for spread within perineural sheaths. The presentation is usually with obstructive jaundice. About 50% of patients also have upper abdominal pain and weight loss. The diagnosis is made using a combination of CT and MRI (see Fig. 22.10, p. 855) but can be difficult to confirm in patients with sclerosing cholangitis. Serum levels of the tumour marker CA19-9 are elevated in up to 80% of cases, although this may occur in biliary obstruction of any cause. In the setting of biliary obstruction, ERCP may result in positive biliary cytology. Endoscopic ultrasound–fine needle aspiration (EUS-FNA) of bile duct masses is sometimes possible, and in specialist centres single-operator cholangioscopy with biopsy is now established. CCAs can be treated surgically in about 20% of patients, which improves 5-year survival from less than 5% to 20–40%. Surgery involves excision of the extrahepatic biliary tree with or without a liver resection and a Roux loop reconstruction. However, most patients are treated by stent insertion across the malignant biliary stricture, using endoscopic or percutaneous transhepatic techniques (Fig. 22.47). Combination chemotherapy is increasingly used and palliation with endoscopic photodynamic therapy has provided encouraging results. Carcinoma at the ampulla of Vater Nearly 40% of all adenocarcinomas of the small intestine arise in relationship to the ampulla of Vater and present with pain, anaemia, vomiting and weight loss. Jaundice may be intermittent or persistent. The diagnosis is made by duodenal endoscopy and biopsy of the tumour but staging by CT/MRI and EUS is essential. Ampullary carcinoma must be differentiated from carcinoma of drainage of the biliary tract with extraction of stones, antibiotics and, in certain patients, partial resection of damaged areas of the liver. Tumours of the gallbladder and bile duct Carcinoma of the gallbladder This is an uncommon tumour, occurring more often in females and usually in those over the age of 70 years. More than 90% are adenocarcinomas; the remainder are anaplastic or, rarely, squamous tumours. Gallstones are present in 70–80% of cases and are thought to be important in the aetiology of the tumour. Individuals with a calcified gallbladder (‘porcelain gallbladder’; p. 904) are at high risk of malignant change, and gallbladder polyps over 1 cm in size are associated with increased risk of malignancy; preventative cholecystectomy should be considered in such patients. Chronic infection with Salmonella, especially in areas where typhoid is endemic, is also a risk factor. Carcinoma of the gallbladder may be diagnosed incidentally and is found in 1–3% of gallbladders removed at cholecystectomy for gallstone disease. It may manifest as repeated attacks of biliary pain and, later, persistent jaundice and weight loss. A gallbladder mass may be palpable in the right hypochondrium. LFTs show cholestasis, and porcelain gallbladder may be found on X-ray. The tumour can be diagnosed by ultrasonography and staged by CT. The treatment is surgical excision but local extension of the tumour beyond the wall of the gallbladder into the liver, lymph nodes and surrounding tissues is invariable and palliative management is usually all that can be offered. Survival is generally short, death typically occurring within 1 year in patients presenting with symptoms. Cholangiocarcinoma Cholangiocarcinoma (CCA) is an uncommon tumour that can arise anywhere in the biliary tree, from the intrahepatic bile ducts (20–25% of cases) and the confluence of the right and left hepatic ducts at the liver hilum (50–60%) to the distal common bile duct (20%). It accounts for only 1.5% of all cancers but the incidence is increasing. The cause is unknown but the Fig. 22.47 Cholangiocarcinoma. A Endoscopic retrograde cholangiopancreatogram showing a malignant distal biliary stricture (arrow) and dilated duct above this. B A self-expanding metallic stent (SEMS) has been placed across the stricture to relieve jaundice (arrow). B A

908 • HEPATOLOGY Functional biliary sphincter disorders (‘sphincter of Oddi dysfunction’) The sphincter of Oddi is a small smooth-muscle sphincter situated at the junction of the bile duct and pancreatic duct in the duodenum. It has been believed that sphincter of Oddi dysfunction (SOD) was characterised by an increase in contractility that produces a benign non-calculous obstruction to the flow of bile or pancreatic juice. This may cause pancreaticobiliary pain, deranged LFTs or recurrent pancreatitis. Classification systems, based on clinical history, laboratory results, findings on investigation and response to interventions, are difficult because of the fluctuating nature of symptoms and the well-recognised placebo effect of interventions. SOD was previously classified into types I–III but these have been replaced by newer terminology (Boxes 22.66 and 22.67). Clinical features Patients with functional biliary sphincter disorders, who are predominantly female, present with symptoms and signs suggestive of either biliary or pancreatic disease: • Patients with biliary sphincter disorders experience recurrent, episodic biliary-type pain. They have often had a cholecystectomy but the gallbladder may be intact. • Patients with pancreatic sphincter disorders usually present with unexplained recurrent attacks of pancreatitis. Investigations The diagnosis is established by excluding gallstones, including microlithiasis, and by demonstrating a dilated or slowly draining bile duct. The gold standard for diagnosis is sphincter of Oddi manometry. This is not widely available, however, and is associated with a high rate of procedure-related pancreatitis. Hepatobiliary scintigraphy (e.g. hepatobiliary iminodiacetic acid) may have value in the second-line investigation of post-cholecystectomy syndrome. the head of the pancreas and a CCA because these last two conditions both have a worse prognosis. Imaging may show a ‘double duct sign’ with stricturing of both the common bile duct and pancreatic duct at the ampulla and upstream dilatation of the ducts. EUS is the most sensitive method of assessing and staging ampullary or periampullary tumours. Curative surgical treatment can be undertaken by pancreaticoduodenectomy and the 5-year survival may be as high as 50%. If resection is impossible, palliative surgical bypass or stenting may be necessary. Benign gallbladder tumours These are uncommon, often asymptomatic and usually found incidentally at operation or postmortem. Cholesterol polyps, sometimes associated with cholesterolosis, papillomas and adenomas, are the main types. Miscellaneous biliary disorders Post-cholecystectomy syndrome Dyspeptic symptoms following cholecystectomy (postcholecystectomy syndrome) occur in about 30% of patients, depending on how the condition is defined, how actively symptoms are sought and what the original indication for cholecystectomy was. The syndrome occurs most frequently in women, in patients who have had symptoms for more than 5 years before cholecystectomy, and in cases when the operation was undertaken for non-calculous gallbladder disease. An increase in bowel habit resulting from bile acid diarrhoea occurs in about 5–10% of patients after cholecystectomy and often responds to colestyramine (4–8 g daily). Severe post-cholecystectomy syndrome occurs in only 2–5% of patients. The main causes are listed in Box 22.65. The usual symptoms include right upper quadrant pain, flatulence, fatty food intolerance and occasionally jaundice and cholangitis. The LFTs may be abnormal and sometimes show cholestasis. Ultrasonography is used to detect biliary obstruction, and EUS or MRCP to seek common bile duct stones. If retained bile duct stones are excluded, sphincter of Oddi dysfunction should be considered (see below). Other investigations that may be required include upper gastrointestinal endoscopy, small bowel radiology and pancreatic function tests. The possibility of a functional illness should also be considered. 22.65 Causes of post-cholecystectomy symptoms Immediate post-surgical • Bleeding • Biliary peritonitis • Abscess • Bile duct trauma/transection • Fistula Biliary • Common bile duct stones • Benign stricture • Tumour • Cystic duct stump syndrome • Disorders of the ampulla of Vater (e.g. benign papillary fibrosis; sphincter of Oddi dysfunction) Extrabiliary • Functional dyspepsia • Peptic ulcer • Pancreatic disease • Gastro-oesophageal reflux • Irritable bowel syndrome • Functional abdominal pain 22.67 Criteria for pancreatic sphincter of Oddi dysfunction • Recurrent attacks of acute pancreatitis – pancreatic-type pain with amylase or lipase 3 times normal and/or imaging evidence of acute pancreatitis • Other aetiologies of acute pancreatitis excluded • Normal pancreas at endoscopic ultrasound • Abnormal sphincter manometry 22.66 Classification of biliary sphincter of Oddi dysfunction (SOD) Organic stenosis (formerly SOD type I) • Biliary-type pain • Abnormal liver enzymes (ALT/AST > twice normal on two or more occasions) • Dilated common bile duct (> 12 mm diameter) • Delayed drainage of ERCP contrast beyond 45 mins Functional sphincter of Oddi disorder (formerly SOD type II) • Biliary-type pain with one or two of the above criteria Functional biliary-type pain (formerly SOD type III) • Biliary-type pain with no other abnormalities

Further information • 909

Adenomyomatosis of the gallbladder In this condition, there is hyperplasia of the muscle and mucosa of the gallbladder. The projection of pouches of mucous membrane through weak points in the muscle coat produces Rokitansky– Aschoff sinuses. There is much disagreement over whether adenomyomatosis is a cause of right upper quadrant pain or other gastrointestinal symptoms. It may be diagnosed by oral cholecystography, when a halo or ring of opacified diverticula can be seen around the gallbladder. Other appearances include deformity of the body of the gallbladder or marked irregularity of the outline. Localised adenomyomatosis in the region of the gallbladder fundus causes the appearance of a ‘Phrygian cap’. Most patients are treated by cholecystectomy but only after other diseases in the upper gastrointestinal tract have been excluded. IgG4-associated cholangitis This recently reported disease often presents with obstructive jaundice and is described on page 890. Further information Books and journal articles Anstee QM, Targher G, Day CP. Progression of NAFLD to diabetes mellitus, cardiovascular disease or cirrhosis. Nat Rev Gastroenterol Hepatol 2013; 10:330–344. EASL Clinical practice guidelines: Autoimmune hepatitis. J Hepatol 2015; 63:971–1004. EASL Clinical practice guidelines: Liver transplantation. J Hepatol 2016; 64:433–485. EASL Recommendations on treatment of hepatitis C 2015. J Hepatol 2015; 63:199–236. EASL-EASD-EASO Clinical practice guidelines for the management of non-alcoholic fatty liver disease. J Hepatol 2016; 64:1388–1402. Neuberger J, Gimson A, Davies M, et al. Selection of patients for liver transplantation and allocation of donated livers in the UK. Gut 2008; 57:252–257. Williams R, Aspinall R, Bellis M, et al. Addressing liver disease in the UK: a blueprint for attaining excellence in health care and reducing premature mortality from lifestyle issues of excess consumption of alcohol, obesity, and viral hepatitis. Lancet 2014; 384:1953–1997. Websites aasld.org American Association for the Study of Liver Diseases (guidelines available). bsg.org.uk British Society of Gastroenterology (guidelines available). easl.eu European Association for the Study of the Liver (guidelines available). eltr.org European Liver Transplant Registry. unos.org United Network for Organ Sharing: US transplant register. Management All patients with organic stenosis are treated with endoscopic sphincterotomy. The results are good but patients should be warned that there is a high risk of complications, particularly acute pancreatitis. Manometry should ideally be performed in all suspected functional sphincter of Oddi disorder patients (‘type II’), and results of sphincterotomy in those with high pressures are good, but this should be avoided in patients with functional biliary-type pain (‘type III’), as it is of no benefit. Medical therapy with nifedipine and/or low-dose amitriptyline may be tried. Pancreatic SOD can be treated with biliary sphincterotomy, carried out in specialist centres, but this should be undertaken with caution and careful consideration. Routine prophylactic pancreatic duct stenting in patients undergoing ERCP for sphincter of Oddi disorders is no longer encouraged. Prophylactic administration of rectal NSAIDs (e.g. diclofenac 100 mg) is recommended instead because this significantly reduces the risk of procedure-related acute pancreatitis. Cholesterolosis of the gallbladder In this condition, lipid deposits in the submucosa and epithelium appear as multiple yellow spots on the pink mucosa, giving rise to the description ‘strawberry gallbladder’. Cholesterolosis of the gallbladder is usually asymptomatic but may occasionally present with right upper quadrant pain. Small, fixed filling defects may be visible on ultrasonography; the radiologist can usually differentiate between gallstones and cholesterolosis. The condition is usually diagnosed at cholecystectomy; if the diagnosis is made radiologically, cholecystectomy may be indicated, depending on symptoms. 22.68 Gallbladder disease in old age • Gallstones: by the age of 70 years, prevalence is around 30% in women and 19% in men. • Acute cholecystitis: tends to be severe, may have few localising signs and is associated with a high frequency of empyema and perforation. If such complications supervene, mortality may reach 20%. • Cholecystectomy: mortality after urgent cholecystectomy for acute uncomplicated cholecystitis is not significantly higher than in younger patients. • Endoscopic sphincterotomy and removal of common duct stones: well tolerated by older patients, with lower mortality than surgical common bile duct exploration. • Cancer of the gallbladder: a disease of old age, with a 1-year survival of 10%.

7KLVSDJHLQWHQWLRQDOO\OHIWEODQN

Ch04-3 Clinical Medicine

13-23 Haematology and transfusion medicine

23 Haematology and transfusion medicine

Haematology and transfusion medicine HG Watson DJ Culligan LM Manson Clinical examination in blood disease 912 Functional anatomy and physiology 914 Haematopoiesis 914 Blood cells and their functions 915 Haemostasis 917 Investigation of diseases of the blood 919 The full blood count 919 Blood film examination 920 Bone marrow examination 920 Investigation of coagulation 920 Presenting problems in blood disease 923 Anaemia 923 High haemoglobin 925 Leucopenia (low white cell count) 925 Leucocytosis (high white cell count) 926 Lymphadenopathy 927 Splenomegaly 927 Bleeding 927 Thrombocytopenia (low platelet count) 929 Thrombocytosis (high platelet count) 929 Pancytopenia 930 Infection 930 Principles of management of haematological disease 930 Blood products and transfusion 930 Chemotherapy 936 Haematopoietic stem cell transplantation 936 Anticoagulant and antithrombotic therapy 938 Anaemias 940 Iron deficiency anaemia 940 Anaemia of chronic disease 943 Megaloblastic anaemia 943 Haemolytic anaemia 945 Haemoglobinopathies 951 Sickle-cell anaemia 951 Other abnormal haemoglobins 953 Thalassaemias 953 Haematological malignancies 954 Leukaemias 954 Lymphomas 961 Paraproteinaemias 966 Aplastic anaemias 968 Myeloproliferative neoplasms 969 Bleeding disorders 970 Disorders of primary haemostasis 970 Coagulation disorders 971 Thrombotic disorders 975 Venous thromboembolic disease (venous thromboembolism) 975 Inherited and acquired thrombophilia and prothrombotic states 977

912 • HAEMATOLOGY AND TRANSFUSION MEDICINE Clinical examination in blood disease Insets (Glossitis) From Hoffbrand VA, John E, Pettit JE, Vyas P. Color atlas of clinical hematology, 4th edn. Philadelphia: Mosby, Elsevier Inc.; 2010; (Petechiae) Young NS, Gerson SL, High KA (eds). Clinical hematology. St Louis: Mosby, Elsevier Inc.; 2006. Observation Hands Perfusion Telangiectasia Skin crease pallor Koilonychia Pulse Rate Mouth Lips: angular stomatitis, telangiectasia Gum hypertrophy Tongue: colour, smoothness Buccal mucosa: petechiae Tonsils: size Conjunctivae Pallor Jaundice Lymph nodes (see opposite) Abdomen Masses Ascites Hepatomegaly Splenomegaly Inguinal and femoral lymph nodes Feet Peripheral circulation Toes: gangrene Joints Deformity Swelling Restricted movement • General well-being • Colour: pallor, plethora • Breathlessness Urinalysis Blood Urobilinogen Hereditary haemorrhagic telangiectasia Fundi Hyperviscosity Engorged veins Papilloedema Haemorrhage Fundal haemorrhage in thrombocytopenia Purpura/petechiae in thrombocytopenia Gangrenous toe in thrombocytosis Swollen joint in haemophilia Koilonychia in iron deficiency Skin Purpura Bruising Gum hypertrophy in acute myeloid leukaemia Glossitis and angular stomatitis in iron deficiency

Clinical examination in blood disease • 913

Bleeding Bleeding can be due to congenital or acquired abnormalities in the clotting system. History and examination help to clarify the severity and the underlying cause of the bleeding problem. Abnormalities detected in the blood are caused not only by primary diseases of the blood and lymphoreticular systems but also by diseases affecting other systems of the body. The clinical assessment of patients with haematological abnormalities must include a general history and examination, as well as a search for symptoms and signs of abnormalities of red cells, white cells, platelets, haemostatic systems, lymph nodes and lymphoreticular tissues. Anaemia Symptoms and signs help to indicate the clinical severity of anaemia. A full history and examination is needed to identify the underlying cause. 6 Lymphadenopathy Lymphadenopathy can be caused by benign or malignant disease. The clinical points to clarify are shown in the box. Pre-auricular Parotid Submandibular Submental Posterior cervical Supraclavicular Anterior cervical Supraclavicular Axillary Epitrochlear Inguinal Femoral Popliteal fossa Lymphadenopathy History • Speed of onset, rate of enlargement • Painful or painless • Associated symptoms: weight loss, night sweats, itch Examination • Sites: localised, generalised • Size (cm) • Character: hard, soft, rubbery • Fixed, mobile • Search area that node drains for abnormalities (e.g. dental abscess) • Other general examination (e.g. joints, rashes, finger clubbing) Anaemia Non-specific symptoms • Tiredness • Lightheadedness • Breathlessness • Development/worsening of ischaemic symptoms, e.g. angina or claudication Non-specific signs • Mucous membrane pallor • Tachypnoea • Raised jugular venous pressure • Tachycardia • Flow murmurs • Ankle oedema • Postural hypotension Bleeding History • Site of bleed • Duration of bleed • Precipitating causes, including previous surgery or trauma • Family history • Drug history • Age at presentation • Other medical conditions, e.g. liver disease Examination There are two main patterns of bleeding:

  1. Mucosal bleeding Reduced number or function of platelets (e.g. bone marrow failure or aspirin) or von Willebrand factor (e.g. von Willebrand disease) Skin: petechiae, bruises Gum and mucous membrane bleeding Fundal haemorrhage Post-surgical bleeding
  2. Coagulation factor deficiency (e.g. haemophilia or warfarin/ anticoagulant) Bleeding into joints (haemarthrosis) or muscles Bleeding into soft tissues Retroperitoneal haemorrhage Intracranial haemorrhage Post-surgical bleeding 8 Examination of the spleen Characteristics of the spleen • Notch • Superficial • Dull to percussion • Cannot get examining hand between ribs and spleen • Moves well with respiration • Move your hand up from the right iliac fossa, towards the left upper quadrant on expiration. • Keep your hand still and ask the patient to take a deep breath through the mouth to feel the spleen edge being displaced downwards. • Place your left hand around the patient’s lower ribs and approach the costal margin to pull the spleen forwards. • To help palpate small spleens, roll the patient on to the right side and examine as before.

914 • HAEMATOLOGY AND TRANSFUSION MEDICINE at times of increased demand. Haematopoietic cells interact closely with surrounding connective tissue stroma, made up of reticular cells, macrophages, fat cells, blood vessels and nerve fibres (Fig. 23.1). In normal marrow, nests of red cell precursors cluster around a central macrophage, which provides iron and also phagocytoses nuclei from red cells prior to their release into the circulation. Megakaryocytes are large cells that produce and release platelets into vascular sinuses. White cell precursors are clustered next to the bone trabeculae; maturing cells migrate into the marrow spaces towards the vascular sinuses. Plasma cells are antibody-secreting mature B cells that normally represent less than 5% of the marrow population and are scattered throughout the intertrabecular spaces. Stem cells All blood cells are derived from pluripotent haematopoietic stem cells. These comprise only 0.01% of the total marrow cells, but they can self-renew (i.e. make more stem cells) or differentiate to produce a hierarchy of lineage-committed progenitor cells. The resulting primitive progenitor cells cannot be identified morphologically, so they are named according to the types of cell (or colony) they form during cell culture experiments. CFU–GM (colony-forming unit – granulocyte, monocyte) is a progenitor cell that produces granulocytic and monocytic lines, CFU–E produce erythroid cells, and CFU–Meg produce megakaryocytes and ultimately platelets (Fig. 23.2). Growth factors, produced in bone marrow stromal cells and elsewhere, control the survival, proliferation, differentiation and function of stem cells and their progeny. Some, such as, interleukin-3 (IL-3), stem cell factor (SCF) and granulocyte, macrophage–colony-stimulating factor (GM–CSF), act on a wide number of cell types at various stages of differentiation. Others, such as erythropoietin, granulocyte–colony-stimulating factor (G–CSF) and thrombopoietin (Tpo), are lineage-specific. Many of these growth factors are now synthesised by recombinant DNA technology and used as treatments: for example, erythropoietin to correct renal anaemia and G–CSF to hasten neutrophil recovery after chemotherapy. The bone marrow also contains stem cells that can differentiate into non-haematological cells. Mesenchymal stem cells differentiate Disorders of the blood cover a wide spectrum of illnesses, ranging from some of the most common disorders affecting humans (anaemias) to relatively rare conditions such as leukaemias and congenital coagulation disorders. Although the latter are uncommon, advances in cellular and molecular biology have had major impacts on their diagnosis, treatment and prognosis. Haematological changes occur as a consequence of diseases affecting any system and give important information in the diagnosis and monitoring of many conditions. Functional anatomy and physiology Blood flows throughout the body in the vascular system, and consists of: • red cells, which transport oxygen from the lungs to the tissues • white cells, which defend against infection • platelets, which interact with blood vessels and clotting factors to maintain vascular integrity and prevent bleeding • plasma, which contains proteins with many functions, including antibodies and coagulation factors. Haematopoiesis Haematopoiesis describes the formation of blood cells, an active process that must maintain normal numbers of circulating cells and be able to respond rapidly to increased demands such as bleeding or infection. During development, haematopoiesis occurs in the yolk sac, liver and spleen, and subsequently in red bone marrow in the medullary cavity of all bones. In childhood, red marrow is progressively replaced by fat (yellow marrow) so that, in adults, normal haematopoiesis is restricted to the vertebrae, pelvis, sternum, ribs, clavicles, skull, upper humeri and proximal femora. However, red marrow can expand in response to increased demands for blood cells. Bone marrow contains a range of immature haematopoietic precursor cells and a storage pool of mature cells for release Fig. 23.1 Structural organisation of normal bone marrow. Megakaryocyte Bony trabecula Neutrophil Erythroid 'nest' Vascular sinusoid Fat cell Myelocyte Blast cells and progenitor cells Lymphocyte

Functional anatomy and physiology • 915

deformable, with a lipid bilayer to which a ‘skeleton’ of filamentous proteins is attached via special linkage proteins (Fig. 23.4). Inherited abnormalities of any of these proteins result in loss of membrane as cells pass through the spleen, and the formation of abnormally shaped red cells called spherocytes or elliptocytes (see Fig. 23.8D). Red cells are exposed to osmotic stress in the pulmonary and renal circulation; in order to maintain homeostasis, the membrane contains ion pumps, which control intracellular levels of sodium, potassium, chloride and bicarbonate. In the absence of mitochondria, the energy for these functions is provided by anaerobic glycolysis and the pentose phosphate pathway in the cytosol. Membrane glycoproteins inserted into the lipid bilayer also form the antigens recognised by blood grouping (see Fig. 23.4). The ABO and Rhesus systems are the most commonly recognised (p. 931) but over 400 blood group antigens have been described. Haemoglobin Haemoglobin is a protein specially adapted for oxygen transport. It is composed of four globin chains, each surrounding an iron-containing porphyrin pigment molecule termed haem. Globin chains are a combination of two alpha and two nonalpha chains; haemoglobin A (αα/ββ) represents over 90% of adult haemoglobin, whereas haemoglobin F (αα/γγ) is the predominant type in the fetus. Each haem molecule contains a ferrous ion (Fe2+), to which oxygen reversibly binds; the affinity for oxygen increases as successive oxygen molecules bind. When oxygen is bound, the beta chains ‘swing’ closer together; they move apart as oxygen is lost. In the ‘open’ deoxygenated state, 2,3-bisphosphoglycerate (2,3-BPG), a product of red cell into skeletal muscle, cartilage, cardiac muscle, and fat cells while others differentiate into nerves, liver and blood vessel endothelium. This is termed stem cell plasticity and may have exciting clinical applications in the future (Ch. 3). Blood cells and their functions Red cells Red cell precursors formed in the bone marrow from the erythroid (CFU–E) progenitor cells are called erythroblasts or normoblasts (Fig. 23.3). These divide and acquire haemoglobin, which turns the cytoplasm pink; the nucleus condenses and is extruded from the cell. The first non-nucleated red cell is a reticulocyte, which still contains ribosomal material in the cytoplasm, giving these large cells a faint blue tinge (‘polychromasia’). Reticulocytes lose their ribosomal material and mature over 3 days, during which time they are released into the circulation. Increased numbers of circulating reticulocytes (reticulocytosis) reflect increased erythropoiesis. Proliferation and differentiation of red cell precursors is stimulated by erythropoietin, a polypeptide hormone produced by renal interstitial peritubular cells in response to hypoxia. Failure of erythropoietin production in patients with renal failure (p. 384) causes anaemia, which can be treated with exogenous recombinant erythropoietin or similar pharmacological agents called erythropoiesis-stimulating agents, e.g. darbepoetin. Normal mature red cells circulate for about 120 days. They are 8 μm biconcave discs lacking a nucleus but filled with haemoglobin, which delivers oxygen to the tissues. In order to pass through the smallest capillaries, the red cell membrane is Fig. 23.2 Stem cells and growth factors in haematopoietic cell development. (BFU–E = burst-forming unit – erythroid; CFU–E = colony-forming unit – erythroid; CFU–GM = colony-forming unit – granulocyte, monocyte; CFU–Meg = colony-forming unit – megakaryocyte; Epo = erythropoietin; G–CSF = granulocyte–colony-stimulating factor; GM–CSF = granulocyte, macrophage–colony-stimulating factor; IL = interleukin; M–CSF = macrophage–colonystimulating factor; SCF = stem cell factor; Tpo = thrombopoietin) GM – CSF, M – CSF Pluripotent stem cell IL-3, GM – CSF, SCF, IL-12 SCF IL-6 IL-11 Myeloid progenitor cell Lymphoid progenitor cell SCF IL-3 SCF IL-7 T cells B cells Monocytes Eosinophils Basophils Neutrophils Platelets Red cells IL-3 IL-3, GM – CSF, IL-6 IL-3, GM – CSF IL-3 Thymus Thymocyte Pre-B stem cell CFU – GM CFU – Meg BFU – E Epo Tpo CFU – E Megakaryoblast G – CSF IL-3, SCF GM – CSF, IL-5 IL-4, IL-7 IL-2, IL-4, IL-7

916 • HAEMATOLOGY AND TRANSFUSION MEDICINE Fig. 23.3 Maturation pathway of red cells, granulocytes and platelets. The image on the right is a normal blood film. Myeloblast Promyelocyte Myelocyte Metamyelocyte Neutrophil Pronormoblast Early normoblast Late normoblast Megakaryoblast Megakaryocyte Platelet Reticulocyte Red blood cell Fig. 23.4 Normal structure of red cell membrane. Red cell membrane flexibility is conferred by attachment of cytoskeletal proteins. Important transmembrane proteins include band 3 (an ion transport channel) and glycophorin C (involved in cytoskeletal attachment and gas exchange, and a receptor for Plasmodium falciparum in malaria). Antigens on the red blood cell determine an individual’s blood group. There are about 22 blood group systems (groups of carbohydrate or protein antigens controlled by a single gene or by multiple closely linked loci); the most important clinically are the ABO and Rhesus (Rh) systems (p. 931). The ABO genetic locus has three main allelic forms: A, B and O. The A and B alleles encode glycosyltransferases that introduce N-acetylgalactosamine (open circle) and D-galactose (blue circle), respectively, on to antigenic carbohydrate molecules on the membrane surface. People with the O allele produce an O antigen, which lacks either of these added sugar groups. Rh antigens are transmembrane proteins. RhD antigen Blood group O antigen Blood group A antigen Blood group B antigen Alpha spectrin Beta spectrin Ankyrin Band 3 Protein 4.1 Adducin Glycophorin C Membrane 40% lipid 50% protein 10% carbohydrate Cytoskeleton metabolism, binds to the haemoglobin molecule and lowers its oxygen affinity. These complex interactions produce the sigmoid shape of the oxygen dissociation curve (Fig. 23.5). The position of this curve depends on the concentrations of 2,3-BPG, H+ ions and CO2; increased levels shift the curve to the right and cause oxygen to be released more readily, e.g. when red cells reach hypoxic tissues. Haemoglobin F is unable to bind 2,3-BPG and has a left-shifted oxygen dissociation curve, which, together with the low pH of fetal blood, ensures fetal oxygenation. Strong oxidising agents, such as dapsone, can convert ferrous iron in haemoglobin to its ferric state (Fe3+). The resultant methaemoglobin also has a left-shifted oxygen dissociation curve, which can result in tissue hypoxia (p. 135). Genetic mutations affecting the haem-binding pockets of globin chains or the ‘hinge’ interactions between globin chains result in haemoglobinopathies or unstable haemoglobins. Alpha globin chains are produced by two genes on chromosome 16, and beta globin chains by a single gene on chromosome 11; imbalance in the production of globin chains results in the thalassaemias (p. 951). Defects in haem synthesis cause the porphyrias (p. 378).

Functional anatomy and physiology • 917

containing 2–5 segments and granules in their cytoplasm. Their main function is to recognise, ingest and destroy foreign particles and microorganisms (p. 64). A large storage pool of mature neutrophils exists in the bone marrow. Every day, some 1011 neutrophils enter the circulation, where cells may be circulating freely or attached to endothelium in the marginating pool. These two pools are equal in size; factors such as exercise or catecholamines increase the number of cells flowing in the blood. Neutrophils spend 6–10 hours in the circulation before being removed, principally by the spleen. Alternatively, they pass into the tissues and either are consumed in the inflammatory process or undergo apoptotic cell death and phagocytosis by macrophages. Eosinophils Eosinophils represent 1–6% of the circulating white cells. They are a similar size to neutrophils but have a bilobed nucleus and prominent orange granules on Romanowsky staining. Eosinophils are phagocytic and their granules contain a peroxidase capable of generating reactive oxygen species and proteins involved in the intracellular killing of protozoa and helminths (p. 233). They are also involved in allergic reactions (e.g. atopic asthma, p. 567; see also p. 84). Basophils These cells are less common than eosinophils, representing less than 1% of circulating white cells. They contain dense black granules that obscure the nucleus. Mast cells resemble basophils but are found only in the tissues. These cells are involved in hypersensitivity reactions (p. 66). Monocytes Monocytes are the largest of the white cells, with a diameter of 12–20 μm and an irregular nucleus in abundant pale blue cytoplasm containing occasional cytoplasmic vacuoles. These cells circulate for a few hours and then migrate into tissue, where they become macrophages, Kupffer cells or antigen-presenting dendritic cells. The former phagocytose debris, apoptotic cells and microorganisms (see Box 4.1, p. 64). Lymphocytes Lymphocytes are derived from pluripotent haematopoietic stem cells in the bone marrow. There are two main types: T cells (which mediate cellular immunity) and B cells (which mediate humoral immunity) (p. 68). Lymphoid cells that migrate to the thymus develop into T cells, whereas B cells develop in the bone marrow. The majority (about 80%) of lymphocytes in the circulation are T cells. Lymphocytes are heterogeneous, the smallest being the size of red cells and the largest the size of neutrophils. Small lymphocytes are circular with scanty cytoplasm but the larger cells are more irregular with abundant blue cytoplasm. Lymphocyte subpopulations have specific functions and lifespan can vary from a few days to many years. Cell surface antigens (‘cluster of differentiation’ (CD) antigens), which appear at different points of lymphocyte maturation and indicate the lineage and maturity of the cell, are used to classify lymphomas and lymphoid leukaemias. Haemostasis Blood must be maintained in a fluid state in order to function as a transport system, but must be able to solidify to form a clot following vascular injury in order to prevent excessive bleeding, a process known as haemostasis. Successful haemostasis Destruction Red cells at the end of their lifespan of approximately 120 days are phagocytosed by the reticulo-endothelial system. Amino acids from globin chains are recycled and iron is removed from haem for reuse in haemoglobin synthesis. The remnant haem structure is degraded to bilirubin and conjugated with glucuronic acid before being excreted in bile. In the small bowel, bilirubin is converted to stercobilin; most of this is excreted, but a small amount is reabsorbed and excreted by the kidney as urobilinogen. Increased red cell destruction due to haemolysis or ineffective haematopoiesis results in jaundice and increased urinary urobilinogen. Free intravascular haemoglobin is toxic and is normally bound by haptoglobins, which are plasma proteins produced by the liver. White cells White cells or leucocytes in the blood consist of granulocytes (neutrophils, eosinophils and basophils), monocytes and lymphocytes (see Fig. 23.12). Granulocytes and monocytes are formed from bone marrow CFU–GM progenitor cells during myelopoiesis. The first recognisable granulocyte in the marrow is the myeloblast, a large cell with a small amount of basophilic cytoplasm and a primitive nucleus with open chromatin and nucleoli. As the cells divide and mature, the nucleus segments and the cytoplasm acquires specific neutrophilic, eosinophilic or basophilic granules (see Fig. 23.3). This takes about 14 days. The cytokines G–CSF, GM–CSF and M–CSF are involved in the production of myeloid cells, and G–CSF can be used clinically to hasten recovery of blood neutrophil counts after chemotherapy. Myelocytes or metamyelocytes are normally found only in the marrow but may appear in the circulation in infection or toxic states. The appearance of more primitive myeloid precursors in the blood is often associated with the presence of nucleated red cells and is termed a ‘leucoerythroblastic’ picture; this indicates a serious disturbance of marrow function. Neutrophils Neutrophils, the most common white blood cells in the blood of adults, are 10–14 μm in diameter, with a multilobular nucleus Fig. 23.5 The haemoglobin–oxygen dissociation curve. Factors are listed that shift the curve to the right (more oxygen released from blood) and to the left (less oxygen released) at given PO2. To convert kPa to mmHg, multiply by 7.5. (2,3-BPG = 2,3-bisphosphoglycerate) PO2 (kPa or mmHg) Haemoglobin saturation (SO2) % kPa mmHg

9 10 11 12 13 14

Normal arterial PO2 Normal venous PO2 2,3-BPG H+ CO2 Temperature Shift to left 2,3-BPG H+ CO2 Temperature Shift to right

918 • HAEMATOLOGY AND TRANSFUSION MEDICINE Fig. 23.6 The stages of normal haemostasis. A Stage 1. Pre-injury conditions encourage flow. The vascular endothelium produces substances (including nitric oxide, prostacyclin and heparans) to prevent adhesion of platelets and white cells to the vessel wall. Platelets and coagulation factors circulate in a non-activated state. B Stage 2. Early haemostatic response: platelets adhere; coagulation is activated. At the site of injury, the endothelium is breached, exposing subendothelial collagen. Small amounts of tissue factor (TF) are released. Platelets bind to collagen via a specific receptor, glycoprotein Ia (GPIa), causing a change in platelet shape and its adhesion to the area of damage by the binding of other receptors (GPIb and GPIIb/IIIa) to von Willebrand factor and fibrinogen, respectively. Coagulation is activated by the tissue factor (extrinsic) pathway, generating small amounts of thrombin. C and D Stage 3. Fibrin clot formation: platelets become activated and aggregate; fibrin formation is supported by the platelet membrane; stable fibrin clot forms. The adherent platelets are activated by many pathways, including binding of adenosine diphosphate (ADP), collagen, thrombin and adrenaline (epinephrine) to surface receptors. The cyclo-oxygenase pathway converts arachidonic acid from the platelet membrane into thromboxane A2, which causes aggregation of platelets. Activation of the platelets results in release of the platelet granule contents, enhancing coagulation further (see Fig. 23.7). Thrombin plays a key role in the control of coagulation: the small amount generated via the TF pathway massively amplifies its own production; the ‘intrinsic’ pathway becomes activated and large amounts of thrombin are generated. Thrombin directly causes clot formation by cleaving fibrinopeptides (FPs) from A B Thrombin Vascular endothelium Heparans Red cell Nitric oxide Prostacyclin Platelet Activated platelet Tissue factor GPIIb/IIIa binds fibrinogen GPIa binds collagen GPIb binds von Willebrand factor Coagulation activation by tissue factor pathway Subendothelial collagen A B C A B A B Thrombin Thrombin receptor Platelet activation Inhibition of fibrinolysis Clot stabilisation Cleavage of fibrinogen TAFI XIII FPs XIIIa TAFIa Intrinsic pathway Activation of protein C pathway Activation of tissue factor pathway Tissue factor is localised to the area of tissue damage and is followed by removal of the clot and tissue repair. This is achieved by complex interactions between the vascular endothelium, platelets, von Willebrand factor, coagulation factors, natural anticoagulants and fibrinolytic enzymes (Fig. 23.6). Dysfunction of any of these components may result in haemorrhage or thrombosis. Platelets Platelets are formed in the bone marrow from megakaryocytes. Megakaryocytic progenitor cells (CFU–Meg) divide to form megakaryoblasts, which undergo a process called ‘endomitotic reduplication’, in which there is division of the nucleus but not the cell. This creates mature megakaryocytes, large cells with several nuclei and cytoplasm containing platelet granules. Large numbers of platelets then fragment off from each megakaryocyte into the circulation. The formation and maturation of megakaryocytes is stimulated by thrombopoietin produced in the liver. Platelets circulate for 8–10 days before they are destroyed in the reticuloendothelial system. Some 30% of peripheral platelets are normally pooled in the spleen and do not circulate. Under normal conditions, platelets are discoid, with a diameter of 2–4 μm (Fig. 23.7). The surface membrane invaginates to form a tubular network, the canalicular system, which provides a conduit for the discharge of the granule content following platelet activation. Drugs that inhibit platelet function and thrombosis include aspirin (cyclo-oxygenase inhibitor), clopidogrel, prasugrel and ticagrelor (adenosine diphosphate (ADP)-mediated activation inhibitors), dipyridamole (phosphodiesterase inhibitor), and the glycoprotein IIb/IIIa inhibitors abciximab, tirofiban and eptifibatide (which prevent fibrinogen binding; p. 500). Clotting factors The coagulation system consists of a cascade of soluble inactive zymogen proteins designated by Roman numerals.

Investigation of diseases of the blood • 919

Investigation of diseases of the blood The full blood count To obtain a full blood count (FBC), anticoagulated blood is processed through automated blood analysers that use a variety of technologies (particle-sizing, radiofrequency and laser instrumentation) to measure the haematological parameters. These include numbers of circulating cells, the proportion of whole blood volume occupied by red cells (the haematocrit, Hct), and the red cell indices that give information about the size of red cells (mean cell volume, MCV) and the amount of haemoglobin present in the red cells (mean cell haemoglobin, MCH). Blood analysers can differentiate types of white blood cell and give automated counts of neutrophils, lymphocytes, monocytes, eosinophils and basophils. It is important to appreciate, however, that a When proteolytically cleaved and activated, each is capable of activating one or more components of the cascade. Activated factors are designated by the suffix ‘a’. Some of these reactions require phospholipid and calcium. Coagulation occurs by two pathways: it is initiated by the extrinsic (or tissue factor) pathway and amplified by the ‘intrinsic pathway’ (see Fig. 23.6D). Clotting factors are synthesised by the liver, although factor V is also produced by platelets and endothelial cells. Factors II, VII, IX and X require post-translational carboxylation to allow them to participate in coagulation. The carboxylase enzyme responsible for this in the liver is vitamin K-dependent. Vitamin K is converted to an epoxide in this reaction and must be reduced to its active form by a reductase enzyme. This reductase is inhibited by warfarin, and this is the basis of the anticoagulant effect of coumarins (p. 939). Congenital (e.g. haemophilia) and acquired (e.g. liver failure) causes of coagulation factor deficiency are associated with bleeding. Tissue factor X Xa Va VIIIa −ve −ve −ve −ve −ve −ve Thrombin Antithrombin Actions of thrombin Intrinsic pathway Activated protein C, protein S Plasmin Inhibitors of plasmin Inhibitors of plasminogen activators Activators of plasminogen Plasminogen t-PA Urokinase Fibrin degradation products (FDP) PAI-1, PAI-2 Tissue factor pathway Natural anticoagulant actions Tissue factor pathway inhibitor (TFPI) Tissue factor E D F Tissue factor (extrinsic) pathway Common pathway Tissue injury Tissue factor VII VIIa X Xa Va V Prothrombin Prothrombin Thrombin Amplification of coagulation by thrombin Intrinsic pathway XI XIa IXa IX VIIIa VIII –ve –ve –ve TAFI α2-antiplasmin α2-macroglobulin fibrinogen to produce fibrin. Fibrin monomers are cross-linked by factor XIII, which is also activated by thrombin. Having had a key role in clot formation and stabilisation, thrombin then starts to regulate clot formation in two main ways: (a) activation of the protein C (PC) pathway (a natural anticoagulant), which reduces further coagulation; (b) activation of thrombin-activatable fibrinolysis inhibitor (TAFI), which inhibits fibrinolysis (see E and F). E Stage 4. Limiting clot formation: natural anticoagulants reverse activation of coagulation factors. Once haemostasis has been secured, the propagation of clot is curtailed by anticoagulants. Antithrombin is a serine protease inhibitor synthesised by the liver, which destroys activated factors such as XIa, Xa and thrombin (IIa). Its major activity against thrombin and Xa is enhanced by heparin and fondaparinux, explaining their anticoagulant effect. Tissue factor pathway inhibitor (TFPI) binds to and inactivates VIIa and Xa. Activation of PC occurs following binding of thrombin to membranebound thrombomodulin; activated protein C (aPC) binds to its co-factor, protein S (PS), and cleaves Va and VIIIa. PC and PS are vitamin K-dependent and are depleted by coumarin anticoagulants such as warfarin. F Stage 5. Fibrinolysis: plasmin degrades fibrin to allow vessel recanalisation and tissue repair. The insoluble clot needs to be broken down for vessel recanalisation. Plasmin, the main fibrinolytic enzyme, is produced when plasminogen is activated, e.g. by tissue plasminogen activator (t-PA) or urokinase in the clot. Plasmin hydrolyses the fibrin clot, producing fibrin degradation products, including the D-dimer. This process is highly regulated; the plasminogen activators are controlled by an inhibitor called plasminogen activator inhibitor (PAI), the activity of plasmin is inhibited by α2-antiplasmin and α2-macroglobulin, and fibrinolysis is further inhibited by the thrombinactivated TAFI. Fig. 23.6, cont’d

920 • HAEMATOLOGY AND TRANSFUSION MEDICINE 23.1 Spurious full blood count results from autoanalysers Result Explanation Increased haemoglobin Lipaemia, jaundice, very high white cell count Reduced haemoglobin Improper sample mixing, blood taken from vein into which an infusion is flowing Increased red cell volume (mean cell volume, MCV) Cold agglutinins, non-ketotic hyperosmolarity Increased white cell count Nucleated red cells present Reduced platelet count Clot in sample, platelet clumping Fig. 23.7 Normal platelet structure. The platelet surface is populated by glycoproteins, which bind to key structures including fibrinogen, collagen and von Willebrand factor and cell surface receptors for thrombin, ADP and adrenaline (epinephrine). Through internal signalling pathways, platelet activation causes degranulation of alpha and dense granules, which ultimately results in platelet aggregation. Blockade of these pathways by drugs such as aspirin, clopidogrel, ticagrelor, tirofiban and abcixamab forms the basis of antiplatelet therapy. (ADP = adenosine diphosphate; GP = glycoprotein) Cell surface receptors Platelet glycoproteins ADP Mitochondrion Dense tubule Alpha granule Dense granule Lysosome Actin and myosin filaments Glycocalyx membrane Open canalicular system GPIIb/IIIa GPIb/V/IX GPIa/IIa GPVI Adrenaline (epinephrine) Thrombin number of conditions can lead to spurious results (Box 23.1). The reference ranges for a number of common haematological parameters in adults are given in Chapter 35. Blood film examination Although technical advances in full blood count analysers have resulted in fewer blood samples requiring manual examination, scrutiny of blood components prepared on a microscope slide (the ‘blood film’) can often yield valuable information (Box 23.2 and Fig. 23.8). Analysers cannot identify abnormalities of red cell shape and content (e.g. Howell–Jolly bodies, basophilic stippling, malaria parasites) or fully define abnormal white cells such as blasts. Bone marrow examination In adults, bone marrow for examination is usually obtained from the posterior iliac crest. After a local anaesthetic, marrow can be sucked out from the medullary space, stained and examined under the microscope (bone marrow aspirate). In addition, a core of bone may be removed (trephine biopsy), fixed and decalcified before sections are cut for staining (Fig. 23.9). A bone marrow aspirate is used to assess the composition and morphology of haematopoietic cells or abnormal infiltrates. Further investigations may be performed, such as cell surface marker analysis (immunophenotyping), chromosome and molecular studies to assess malignant disease, or marrow culture for suspected tuberculosis. A trephine biopsy is superior for assessing marrow cellularity, marrow fibrosis, and infiltration by abnormal cells such as metastatic carcinoma. Investigation of coagulation Bleeding disorders In patients with clinical evidence of a bleeding disorder (p. 913), there are recommended screening tests (Box 23.3). Physiological activation of coagulation is predominantly by tissue factor, with amplification of the process by the small amounts of thrombin formed as a result. For ease of description, the terms extrinsic, intrinsic and common pathways are still used (see Fig. 23.6D). Coagulation tests measure the time to clot formation in vitro in a plasma sample after the clotting process is initiated by activators and calcium. The result of the test sample is compared with normal controls. The tissue factor (‘extrinsic’) pathway (see Fig. 23.6D) is assessed by the prothrombin time (PT), and the ‘intrinsic’ pathway by the activated partial thromboplastin time (APTT), sometimes known as the partial thromboplastin time with kaolin (PTTK). Coagulation is delayed by deficiencies of coagulation factors and by the presence of inhibitors of coagulation, such as heparin. The approximate reference ranges and causes of abnormalities are shown in Box 23.3. If both the PT and APTT are prolonged, this indicates either deficiency or inhibition of the

Investigation of diseases of the blood • 921

Platelet function has historically been assessed by the bleeding time, measured as the time to stop bleeding after a standardised incision. However, most centres have abandoned the use of this test. Platelet function can be assessed in vitro by measuring aggregation in response to various agonists, such as adrenaline (epinephrine), collagen, thrombin, arachidonic acid and ADP, agglutination in response to ristocetin or by measuring the constituents of the intracellular granules, e.g. adenosine triphosphate, adenosine diphosphate and their ratio to each other (ATP/ADP). Coagulation screening tests are also performed in patients with suspected DIC, when clotting factors and platelets are consumed, resulting in thrombocytopenia and prolonged PT and APTT. In addition, there is evidence of active coagulation with final common pathway (which includes factors X, V, prothrombin and fibrinogen) or global coagulation factor deficiency involving more than one factor, as occurs in disseminated intravascular coagulation (DIC, pp. 196 and 978). Further specific tests may be performed based on interpretation of the clinical scenario and results of these screening tests. A mixing test with normal plasma allows differentiation between a coagulation factor deficiency (the prolonged time corrects) and the presence of an inhibitor of coagulation (the prolonged time does not correct); the latter may be a chemical (heparins) or an antibody (most often a lupus anticoagulant but occasionally a specific inhibitor of one of the coagulation factors, typically factor VIII). Von Willebrand disease may present with a normal APTT; further investigation of suspected cases is detailed on page 974. Microcytosis (reduced average cell size, MCV < 76 fL) A • Iron deficiency • Thalassaemia • Sideroblastic anaemia Macrocytosis (increased average cell size, MCV > 100 fL) B • Vitamin B12 or folate deficiency • Liver disease, alcohol • Hypothyroidism • Myelodysplastic syndromes • Drugs (e.g. zidovudine, trimethoprim, phenytoin, methotrexate, hydroxycarbamide) Target cells (central area of haemoglobinisation) C • Liver disease • Thalassaemia • Post-splenectomy • Haemoglobin C disease Spherocytes (dense cells, no area of central pallor) D • Autoimmune haemolytic anaemia • Post-splenectomy • Hereditary spherocytosis Red cell fragments (intravascular haemolysis) E • Microangiopathic haemolysis, e.g. haemolytic uraemic syndrome (HUS), thrombotic thrombocytopenic purpura (TTP) • Disseminated intravascular coagulation (DIC) Nucleated red blood cells (normoblasts) F • Marrow infiltration • Severe haemolysis • Myelofibrosis • Acute haemorrhage Howell–Jolly bodies (small round nuclear remnants) G • Hyposplenism • Post-splenectomy • Dyshaematopoiesis Polychromasia (young red cells – reticulocytes present) H • Haemolysis, acute haemorrhage • Increased red cell turnover Basophilic stippling (abnormal ribosomal RNA appears as blue dots) I • Dyshaematopoiesis • Lead poisoning Fig. 23.8 Appearance of red blood cells. A Microcytosis. B Macrocytosis. C Target cells. D Spherocytes. E Red cell fragments. F Nucleated red blood cells. G Howell–Jolly bodies. H Polychromasia. I Basophilic stippling. A B C D E F G H I 23.2 How to interpret red cell appearances

922 • HAEMATOLOGY AND TRANSFUSION MEDICINE warfarin. INR is the ratio of the patient’s PT to that of a normal control, raised to the power of the international sensitivity index of the thromboplastin used in the test (ISI, derived by comparison with an international reference standard material). Concentrations of the direct oral anticoagulants (DOACs) cannot be accurately assessed from the PT or the APTT, with which they have a variable and generally poor correlation. Monitoring of heparin therapy is, on the whole, required only with unfractionated heparins. Therapeutic anticoagulation prolongs the APTT relative to a control sample by a ratio of approximately 1.5–2.5. Low-molecular-weight heparins have such a predictable dose response that monitoring of the anticoagulant effect is not required, except in patients with renal impairment (glomerular filtration rate less than 30 mL/min). When monitoring is indicated, an anti-Xa activity assay rather than APTT should be used. Thrombotic disorders Measurement of plasma levels of D-dimers derived from fibrin degradation is useful in excluding the diagnosis of active venous thrombosis in some patients (see Fig. 10.6, p. 187). A variety of tests exist that may help to explain an underlying propensity to thrombosis, especially venous thromboembolism (thrombophilia) (Box 23.4). Examples of possible indications for testing are given in Box 23.5. In most patients, the results do not affect clinical management (p. 975) but they may influence the duration of anticoagulation (e.g. antiphospholipid antibodies, p. 977), justify family screening in inherited thrombophilias (p. 975), or suggest additional management strategies to reduce thrombosis risk (e.g. in myeloproliferative disease and paroxysmal nocturnal haemoglobinuria; p. 950). Anticoagulants can interfere with some of these assays; for example, warfarin reduces protein C and S levels and affects measurement of lupus anticoagulant, while heparin interferes with antithrombin and lupus anticoagulant Fig. 23.9 Bone marrow aspirate and trephine. A Trephine biopsy needle. B Macroscopic appearance of a trephine biopsy. C Microscopic appearance of stained section of trephine. D Bone marrow aspirate needle. E Stained macroscopic appearance of marrow aspirate: smear (left) and squash (right). F Microscopic appearance of stained marrow particles and trails of haematopoietic cells. C B D E F A 23.3 Coagulation screening tests1 Investigation Reference range2 Situations in which tests may be abnormal Platelet count 150–400 × 109/L Thrombocytopenia Prothrombin time (PT) 9–12 secs Deficiencies of factors II, V, VII or X Severe fibrinogen deficiency Activated partial thromboplastin time (APTT) 26–36 secs Deficiencies of factors II, V, VIII, IX, X, XI, XII Severe fibrinogen deficiency Unfractionated heparin therapy Antibodies against clotting factors Lupus anticoagulant Multiple factor deficiency (e.g. DIC) Fibrinogen concentration 1.5–4.0 g/L Hypofibrinogenaemia, e.g. liver failure, DIC 1N.B. International normalised ratio (INR) is used only to monitor coumarin therapy and is not a coagulation screening test. 2Ranges are approximate and may vary between laboratories. (DIC = disseminated intravascular coagulation) consumption of fibrinogen and generation of fibrin degradation products (D-dimers). Note, however, that fibrinogen is an acute phase protein that may also be elevated in inflammatory disease (p. 70). Monitoring anticoagulant therapy The international normalised ratio (INR) is validated only to assess the therapeutic effect of coumarin anticoagulants, including

Presenting problems in blood disease • 923

and sex. Other factors, including pregnancy and altitude, also affect haemoglobin levels and must be taken into account when considering whether an individual is anaemic. The clinical features of anaemia reflect diminished oxygen supply to the tissues (p. 912). A rapid onset of anaemia (e.g. due to blood loss) causes more profound symptoms than a gradually developing anaemia. Individuals with cardiorespiratory disease are more susceptible to symptoms of anaemia. The clinical assessment and investigation of anaemia should gauge its severity and define the underlying cause (Box 23.7). Clinical assessment • Iron deficiency anaemia (p. 940) is the most common type of anaemia worldwide. A thorough gastrointestinal history is important, looking in particular for symptoms of blood loss. Menorrhagia is a common cause of anaemia in pre-menopausal females, so women should always be asked about their periods. • A dietary history should assess the intake of iron and folate, which may become deficient in comparison to needs (e.g. in pregnancy or during periods of rapid growth; pp. 712, 945 and 1284). • Past medical history may reveal a disease that is known to be associated with anaemia, such as rheumatoid arthritis (anaemia of chronic disease), or previous surgery (e.g. resection of the stomach or small bowel, which may lead to malabsorption of iron and/or vitamin B12). • Family history and ethnic background may raise suspicion of haemolytic anaemias, such as the haemoglobinopathies and hereditary spherocytosis. Pernicious anaemia may also run in families but is not associated with a clear Mendelian pattern of inheritance. • A drug history may reveal the ingestion of drugs that cause blood loss (e.g. aspirin and anti-inflammatory drugs), haemolysis (e.g. sulphonamides) or aplasia (e.g. chloramphenicol). On examination, as well as the general physical findings of anaemia shown on page 912, there may be specific findings related to the aetiology of the anaemia; for example, a patient may be found to have a right iliac fossa mass due to an underlying caecal carcinoma. Haemolytic anaemias can cause jaundice. Vitamin B12 deficiency may be associated with neurological signs, including peripheral neuropathy, dementia and signs of subacute combined degeneration of the cord (p. 1138). Sickle-cell anaemia (p. 951) may result in leg ulcers, stroke or features of pulmonary hypertension. Anaemia may be multifactorial and the lack of specific symptoms and signs does not rule out silent pathology. Investigations Schemes for the investigation of anaemias are often based on the size of the red cells, which is most accurately indicated by the MCV in the FBC. Commonly, in the presence of anaemia: assays. Therefore these tests, when required, should be performed when the patient is not taking anticoagulants. Presenting problems in blood disease Anaemia Anaemia refers to a state in which the level of haemoglobin in the blood is below the reference range appropriate for age 23.4 Investigation of possible thrombophilia Full blood count Plasma levels • Antithrombin • Protein C • Protein S (free) • Antiphospholipid antibodies, lupus anticoagulant, anticardiolipin antibody/anti-β2GP1 Thrombin/reptilase time (for dysfibrinogenaemia) Genetic testing • Factor V Leiden • Prothrombin G20210A • JAK-2 V617F mutation • CALR mutations Flow cytometry • Screen for GPI-linked cell surface proteins (CD14, 16, 55, 59), deficient in paroxysmal nocturnal haemoglobinuria (CD = cluster of differentiation; GP1 = glycoprotein 1; GPI = glycerol phosphatidyl inositol) 23.5 Possible indications for thrombophilia testing* • Venous thrombosis < 45 years • Recurrent venous thrombosis • Family history of unprovoked or recurrent thrombosis • Combined arterial and venous thrombosis • Venous thrombosis at an unusual site: Cerebral venous thrombosis Hepatic vein (Budd–Chiari syndrome) Portal vein, mesenteric vein *Antiphospholipid antibodies should be sought where clinical criteria for antiphospholipid syndrome (APS) are fulfilled (p. 977). Thrombophilia testing may explain the diagnosis without necessarily affecting management and this limits the clinical value of such an approach. 23.6 Haematological investigations in old age • Blood cell counts and film components: not altered in general by ageing alone, although haemoglobin concentrations fall with increasing age. • Ratio of bone marrow cells to marrow fat: falls. • Neutrophils: maintained throughout life, although leucocytes may be less readily mobilised by bacterial invasion in old age. • Lymphocytes: functionally compromised by age due to a T-cell-related defect in cell-mediated immunity. • Clotting factors: no major changes, although mild congenital deficiencies may be first noticed in old age. • Erythrocyte sedimentation rate (ESR): raised above the reference range but usually in association with chronic or subacute disease. In truly healthy older people, the ESR range is very similar to that in younger people. 23.7 Causes of anaemia Decreased or ineffective marrow production • Lack of iron, vitamin B12 or folate • Hypoplasia/myelodysplasia • Invasion by malignant cells • Renal failure • Anaemia of chronic disease Normal marrow production but increased removal of cells • Blood loss • Haemolysis • Hypersplenism

924 • HAEMATOLOGY AND TRANSFUSION MEDICINE Fig. 23.10 Investigation of anaemia with normal or low mean cell volume (MCV). (Hb = haemoglobin; MCH = mean cell haemoglobin) MCV normal (76–100 fL) or low (< 76 fL) Blood film and reticulocyte count High reticulocyte count Normal or low reticulocyte count Hypochromia (low MCH) Target cells basophilic stippling Hb electrophoresis Increased HbA2 Normal HbA2 Dimorphic Bone marrow Ferritin Consider ferritin Non-specific If Hb < 80 g/L consider bone marrow to establish diagnosis ? Anaemia of chronic disease No obvious cause ?Bleeding ?Haemolysis Normal or high ? Sideroblastic Low Fe deficient Investigate Check family Betathalassaemia trait Alphathalassaemia trait Fig. 23.11 Investigation of anaemia with high mean cell volume (MCV). (LDH = lactate dehydrogenase) ? Bleeding ? Haemolysis Polychromasia/high reticulocyte count MCV high (> 100 fL) Blood film ± reticulocyte count Clinical clues Alcohol, liver disease, family history of pernicious anaemia, hypothyroidism, drugs, previous abdominal surgery etc. Drugs/cytotoxic agents Investigate cause Liver function tests Hypersegmented neutrophils Target cells, stomatocytes Dysplasia/ cytopenia Dimorphic Marrow Marrow Folate, B12 ? Myelodysplasia ? Sideroblastic anaemia Bilirubin ↑ LDH ↑ Spherocytes Fragments +ve Coombs test Low

Presenting problems in blood disease • 925

also have aquagenic pruritus (itching after exposure to water), hepatosplenomegaly and gout (due to high red cell turnover). If the JAK-2 mutation is absent and there is no obvious secondary cause, a measurement of red cell mass is required to confirm an absolute erythrocytosis, followed by further investigations to exclude hypoxia, and causes of inappropriate erythropoietin secretion. Leucopenia (low white cell count) A reduction in the total numbers of circulating white cells is called leucopenia. This may be due to a reduction in all types of white cell or in individual cell types (usually neutrophils or lymphocytes). Leucopenia may occur in isolation or as part of a reduction in all three haematological lineages (pancytopenia; p. 930). Neutropenia A reduction in neutrophil count (usually < 1.5 × 109/L but dependent on age and race) is called neutropenia. The main causes are listed in Box 23.9 and Figure 23.12. Drug-induced neutropenia is not uncommon (Box 23.10). Clinical manifestations range from no symptoms to overwhelming sepsis. The risk of bacterial infection is related to the degree of neutropenia, with counts lower than 0.5 × 109/L considered to be critically low. Fever is the first and often only manifestation of infection. A sore throat, perianal pain or skin inflammation may be present. The lack of neutrophils allows the patient to become septicaemic and shocked within hours if immediate antibiotic therapy is not commenced. Management is discussed on page 224. Lymphopenia This is an absolute lymphocyte count of less than 1 × 109/L. The causes are shown in Box 23.9. Although minor reductions may be asymptomatic, deficiencies in cell-mediated immunity may result in infections (with organisms such as fungi, viruses and mycobacteria) and a propensity to lymphoid and other malignancies (particularly those associated with viral infections such as Epstein–Barr virus (EBV), human papillomavirus (HPV) 23.8 Classification and causes of erythrocytosis Absolute erythrocytosis Relative (low-volume) erythrocytosis Haematocrit High High Red cell mass High Normal Plasma volume Normal Low Causes Primary Myeloproliferative disorder Polycythaemia rubra vera (primary proliferative polycythaemia) Secondary High erythropoietin due to tissue hypoxia: High altitude Cardiorespiratory disease High-affinity haemoglobins Inappropriately increased erythropoietin: Renal disease (hydronephrosis, cysts, carcinoma) Other tumours (hepatoma, bronchogenic carcinoma, uterine fibroids, phaeochromocytoma, cerebellar haemangioblastoma) Exogenous testosterone therapy Exogenous erythropoietin administration: Performance-enhancing drug-taking in athletes Diuretics Smoking Obesity Alcohol excess Gaisböck’s syndrome • A normal MCV (normocytic anaemia) suggests either acute blood loss or the anaemia of chronic disease, also known as the anaemia of inflammation (ACD/AI) (Fig. 23.10). • A low MCV (microcytic anaemia) suggests iron deficiency or thalassaemia or sometimes ACD/AI (Fig. 23.10). • A high MCV (macrocytic anaemia) suggests vitamin B12 or folate deficiency or myelodysplasia (Fig. 23.11). Specific types of anaemia and their management are described later in this chapter (p. 940). High haemoglobin Patients with a persistently raised haematocrit (Hct) (> 0.52 males,

0.48 females) for more than 2 months should be investigated. ‘True’ polycythaemia (or absolute erythrocytosis) indicates an excess of red cells, while ‘relative’, ‘apparent’ or ‘low-volume’ polycythaemia is due to a decreased plasma volume. Causes of polycythaemia are shown in Box 23.8. These involve increased erythropoiesis in the bone marrow, either due to a primary increase in marrow activity, or in response to increased erythropoietin (Epo) levels in chronic hypoxaemia, or due to inappropriate secretion of Epo. Athletes who seek to benefit from increased oxygen-carrying capacity have been known to use Epo to achieve this. Apparent erythrocytosis with a raised Hct, normal red cell mass (RCM) and reduced plasma volume may be associated with hypertension, smoking, alcohol and diuretic use (Gaisböck’s syndrome). Clinical assessment and investigations Males and females with Hct values of over 0.60 and over 0.56, respectively, can be assumed to have an absolute erythrocytosis. A clinical history and examination will identify most patients with polycythaemia secondary to hypoxia. The presence of hypertension, smoking, excess alcohol consumption and/or diuretic use is consistent with low-volume polycythaemia (Gaisböck’s syndrome). In polycythaemia rubra vera (PRV), a mutation in a kinase, JAK-2 V617F, is found in over 90% of cases (p. 970). Patients with PRV have an increased risk of arterial thromboses, particularly stroke, and venous thromboembolism. They may

926 • HAEMATOLOGY AND TRANSFUSION MEDICINE and human herpesvirus 8 (HHV-8)). Lymphopenia without any obvious cause is common with advancing age. Leucocytosis (high white cell count) An increase in the total numbers of circulating white cells is called leucocytosis. This is usually due to an increase in a specific type of cell (see Box 23.9). It is important to realise that an increase in a single type of white cell (e.g. eosinophils or monocytes) may not increase the total white cell count (WCC) above the upper limit of normal and will be apparent only if the ‘differential’ of the white count is examined. Neutrophilia An increase in the number of circulating neutrophils is called a neutrophilia or a neutrophil leucocytosis. It can result from an increased production of cells from the bone marrow or redistribution from the marginated pool. The normal neutrophil count depends on age, race and certain physiological parameters. During pregnancy, not only is there an increase in neutrophils but also earlier forms, such as metamyelocytes, can be found in the blood. The causes of a neutrophilia are shown in Box 23.9. Many drugs can induce cytopenias. In suspected cases check drug summary of product characteristics. 23.10 Drugs that can induce neutropenia Group Examples Analgesics/antiinflammatory agents Gold, penicillamine, naproxen Antithyroid drugs Carbimazole, propylthiouracil Anti-arrhythmics Quinidine, procainamide Antihypertensives Captopril, enalapril, nifedipine Antidepressants/ psychotropics Amitriptyline, dosulepin, mianserin Antimalarials Pyrimethamine, dapsone, sulfadoxine, chloroquine Anticonvulsants Phenytoin, sodium valproate, carbamazepine Antibiotics Sulphonamides, penicillins, cephalosporins Miscellaneous Cimetidine, ranitidine, chlorpropamide, zidovudine Fig. 23.12 Appearance of white blood cells. A Neutrophil. B Eosinophil. C Basophil. D Monocyte. E Lymphocyte. A B C D E Neutrophils A Neutrophilia • Infection: bacterial, fungal • Trauma: surgery, burns • Infarction: myocardial infarct, pulmonary embolus, sickle-cell crisis • Inflammation: gout, rheumatoid arthritis, ulcerative colitis, Crohn’s disease • Malignancy: solid tumours, Hodgkin lymphoma • Myeloproliferative disease: polycythaemia, chronic myeloid leukaemia • Physiological: exercise, pregnancy Neutropenia • Infection: viral, bacterial (e.g. Salmonella), protozoal (e.g. malaria) • Drugs: see Box 23.10 • Autoimmune: connective tissue disease • Alcohol • Bone marrow infiltration: leukaemia, myelodysplasia • Congenital: Kostmann’s syndrome • Constitutional: Afro-Caribbean and Middle Eastern descent Eosinophils B Eosinophilia • Allergy: hay fever, asthma, eczema • Infection: parasitic • Drug hypersensitivity: e.g. gold, sulphonamides • Vasculitis: e.g. eosinophilic granulomatosis with polyangiitis (Churg–Strauss), granulomatosis with polyangiitis (Wegener’s) • Connective tissue disease: polyarteritis nodosa • Malignancy: solid tumours, lymphomas • Primary bone marrow disorders: myeloproliferative disorders, hypereosinophilic syndrome (HES), acute myeloid leukaemia Basophils C Basophilia • Myeloproliferative disease: polycythaemia, chronic myeloid leukaemia • Inflammation: acute hypersensitivity, ulcerative colitis, Crohn’s disease • Iron deficiency Monocytes D Monocytosis • Infection: bacterial (e.g. tuberculosis) • Inflammation: connective tissue disease, ulcerative colitis, Crohn’s disease • Malignancy: solid tumours, chronic myelomonocytic leukaemia Lymphocytes E Lymphocytosis • Infection: viral, bacterial (e.g. Bordetella pertussis) • Lymphoproliferative disease: chronic lymphocytic leukaemia, lymphoma • Post-splenectomy Lymphopenia • Inflammation: connective tissue disease • Lymphoma • Renal failure • Sarcoidosis • Drugs: glucocorticoids, cytotoxics • Congenital: severe combined immunodeficiency • HIV infection 23.9 How to interpret white blood cell results

Presenting problems in blood disease • 927

source of inflammation or primary malignancy in the appropriate drainage area: • the scalp, ear, mouth and throat, face, teeth or thyroid for neck nodes • the breast for axillary nodes • the perineum or external genitalia for inguinal nodes. Generalised lymphadenopathy may be secondary to infection, often viral, connective tissue disease or extensive skin disease (dermatopathic lymphadenopathy) but is more likely to signify underlying haematological malignancy. Weight loss and drenching night sweats that may require a change of nightclothes are associated with haematological malignancies, particularly lymphoma. Initial investigations in lymphadenopathy include an FBC (to detect neutrophilia in infection or evidence of haematological disease), measurement of erythrocyte sedimentation rate (ESR) and a chest X-ray (to detect mediastinal lymphadenopathy). If the findings suggest malignancy, a formal cutting needle or excision biopsy of a representative node is indicated to obtain a histological diagnosis. Splenomegaly The spleen may be enlarged due to involvement by lymphoproliferative disease, the resumption of extramedullary haematopoiesis in myeloproliferative disease, enhanced reticuloendothelial activity in autoimmune haemolysis, expansion of the lymphoid tissue in response to infections, or vascular congestion as a result of portal hypertension (Box 23.12). Hepatosplenomegaly is suggestive of lympho- or myeloproliferative disease, liver disease or infiltration (e.g. with amyloid). Associated lymphadenopathy is suggestive of lymphoproliferative disease. An enlarged spleen may cause abdominal discomfort, accompanied by back pain and abdominal bloating and early satiety due to stomach compression. Splenic infarction produces severe abdominal pain radiating to the left shoulder tip, associated with a splenic rub on auscultation. Rarely, spontaneous or traumatic rupture and bleeding may occur. Investigation should focus on the suspected cause. Imaging of the spleen by ultrasound or computed tomography (CT) will detect variations in density in the spleen, which may be a feature of lymphoproliferative disease; it also allows imaging of the liver and abdominal lymph nodes. Biopsy of enlarged abdominal or superficial lymph nodes may provide the diagnosis, as might a bone marrow biopsy in splenic lymphomas. A chest X-ray or CT of the thorax will detect mediastinal lymphadenopathy. An FBC may show pancytopenia secondary to hypersplenism, when the enlarged spleen has become overactive, destroying blood cells prematurely. If other abnormalities are present, such as abnormal lymphocytes or a leucoerythroblastic blood film, a bone marrow examination is indicated. Screening for infectious or liver disease (p. 852) may be appropriate. If all investigations are unhelpful, splenectomy may be diagnostic but is rarely carried out in these circumstances. Bleeding Normal bleeding is seen following surgery and trauma. Pathological bleeding occurs when structurally abnormal vessels rupture or when a vessel is breached in the presence of a defect in haemostasis. This may be due to a deficiency or dysfunction of platelets, the coagulation factors or von Willebrand factor, or Eosinophilia A high eosinophil count of more than 0.5 × 109/L is usually secondary to infection (especially parasites; p. 233), allergy (e.g. eczema, asthma, reactions to drugs; p. 84), immunological disorders (e.g. polyarteritis, sarcoidosis) or malignancy (e.g. lymphomas) (see Box 23.9). Usually, such eosinophilia is short-lived. In the rarer primary disorders, there is a persistently raised, often clonal, eosinophilia, e.g. in myeloproliferative disorders, subtypes of acute myeloid leukaemia and idiopathic hypereosinophilic syndrome (HES). Recently, specific mutations in receptor tyrosine kinase genes have been found in some primary eosinophilias (e.g. causing rearrangements of platelet-derived growth factor receptors α and β or c-kit), which allow diagnosis and, in some cases, specific therapy with tyrosine kinase inhibitors such as imatinib. Eosinophil infiltration can damage many organs (e.g. heart, lungs, gastrointestinal tract, skin, musculoskeletal system); evaluation of eosinophilia therefore includes not only the identification of any underlying cause and its appropriate treatment but also assessment of any related organ damage. Lymphocytosis A lymphocytosis is an increase in circulating lymphocytes above that expected for the patient’s age. In adults, this is greater than 3.5 × 109/L. Infants and children have higher counts; age-related reference ranges should be consulted. Causes are shown in Box 23.9; the most common is viral infection. Lymphadenopathy Enlarged lymph glands may be an important indicator of haematological disease but they are not uncommon in reaction to infection or inflammation (Box 23.11). The sites of lymph node groups, and symptoms and signs that may help elucidate the underlying cause are shown on page 913. Nodes that enlarge in response to local infection or inflammation (‘reactive nodes’) usually expand rapidly and are painful, whereas those due to haematological disease are more frequently painless. Localised lymphadenopathy should elicit a search for a 23.11 Causes of lymphadenopathy Infective • Bacterial: streptococcal, tuberculosis, brucellosis • Viral: Epstein–Barr virus (EBV), human immunodeficiency virus (HIV) • Protozoal: toxoplasmosis • Fungal: histoplasmosis, coccidioidomycosis Neoplastic • Primary: lymphomas, leukaemias • Secondary: lung, breast, thyroid, stomach, melanoma Connective tissue disorders • Rheumatoid arthritis • Systemic lupus erythematosus (SLE) Sarcoidosis Amyloidosis Drugs • Phenytoin

928 • HAEMATOLOGY AND TRANSFUSION MEDICINE bleeding from superficial cuts, epistaxis, gastrointestinal haemorrhage or menorrhagia is more likely to be due to thrombocytopenia, a platelet function disorder or von Willebrand disease. Recurrent bleeds at a single site suggest a local structural abnormality rather than coagulopathic bleeding. • Duration of history. It may be possible to assess whether the disorder is congenital or acquired. • Precipitating causes. Bleeding arising spontaneously indicates a more severe defect than bleeding that occurs only after trauma. • Surgery. Ask about operations. Dental extractions, tonsillectomy and circumcision are stressful tests of the haemostatic system. Immediate post-surgical bleeding suggests defective platelet plug formation and primary haemostasis; delayed haemorrhage is more suggestive of a coagulation defect. However, in post-surgical patients, persistent bleeding from a single site is more likely to indicate surgical bleeding than a bleeding disorder. • Family history. While a positive family history may be present in patients with inherited disorders, the absence of affected relatives does not exclude a hereditary bleeding diathesis; about one-third of cases of haemophilia arise in individuals without a family history, and deficiencies of factor VII, X and XIII are recessively inherited. Recessive disorders are more common in cultures where there is consanguineous marriage. • Drugs. Use of antithrombotic, anticoagulant and fibrinolytic drugs must be elicited. Drug interactions with warfarin and drug-induced thrombocytopenia should be considered. Some ‘herbal’ remedies may result in a bleeding diathesis. Clinical examination may reveal different patterns of skin bleeding. Petechial purpura is minor bleeding into the dermis that is flat and non-blanching (Fig. 23.13). Petechiae are typically found in patients with thrombocytopenia or platelet dysfunction. occasionally to excessive fibrinolysis, which is most commonly observed following therapeutic thrombolysis (p. 500). Clinical assessment ‘Screening’ blood tests (see Box 23.3) do not reliably detect all causes of pathological bleeding (e.g. von Willebrand disease, scurvy, certain anticoagulant drugs and the causes of purpura listed in Box 23.13) and should not be used indiscriminately. A careful clinical evaluation is the key to diagnosis of bleeding disorders (p. 970). It is important to consider the following: • Site of bleeding. Bleeding into muscle and joints, along with retroperitoneal and intracranial haemorrhage, indicates a likely defect in coagulation factors. Purpura, prolonged 23.13 Causes of non-thrombocytopenic purpura • Senile purpura • Factitious purpura • Henoch–Schönlein purpura (p. 1043) • Vasculitis (p. 1040) • Paraproteinaemias • Purpura fulminans, e.g. in disseminated intravascular coagulation secondary to sepsis 23.12 Causes of splenomegaly Congestive Portal hypertension • Cirrhosis • Hepatic vein occlusion • Portal vein thrombosis • Stenosis or malformation of portal or splenic vein Cardiac • Chronic congestive cardiac failure • Constrictive pericarditis Infective Bacterial • Endocarditis • Sepsis • Tuberculosis • Brucellosis • Salmonella Viral • Hepatitis • Epstein–Barr • Cytomegalovirus Protozoal • Malaria* • Leishmaniasis (kala-azar)* • Trypanosomiasis Fungal • Histoplasmosis Inflammatory/granulomatous disorders • Felty’s syndrome in rheumatoid arthritis • Sarcoidosis • Systemic lupus erythematosus Haematological Red cell disorders • Megaloblastic anaemia • Haemoglobinopathies • Hereditary spherocytosis Autoimmune haemolytic anaemias Myeloproliferative disorders • Chronic myeloid leukaemia* • Myelofibrosis* • Polycythaemia rubra vera • Essential thrombocythaemia Neoplastic • Leukaemias, including chronic myeloid leukaemia* • Lymphomas Other malignancies • Metastatic cancer – rare Lysosomal storage diseases • Gaucher’s disease • Niemann–Pick disease Miscellaneous • Cysts, amyloid, thyrotoxicosis, haemophagocytic syndromes *Causes of massive splenomegaly. Fig. 23.13 Petechial purpura.

Presenting problems in blood disease • 929

Palpable purpura occurs in vasculitis. Ecchymosis, or bruising, is more extensive bleeding into deeper layers of the skin. The lesions are initially dark red or purple but become yellow as haemoglobin is degraded. Retroperitoneal bleeding presents with a flank or peri-umbilical haematoma. Telangiectasia of lips and tongue points to hereditary haemorrhagic telangiectasia (p. 970). Joints should be examined for evidence of haemarthroses. A full examination is important, as it may give clues to an underlying associated systemic illness such as a haematological or other malignancy, liver disease, renal failure, connective tissue disease and possible causes of splenomegaly. Investigations Screening investigations and their interpretation are described on page 920. If the patient has a history that is strongly suggestive of a bleeding disorder and all the preliminary screening tests give normal results, further investigations, such as measurement of von Willebrand factor and assessment of platelet function, should be performed (p. 921). Thrombocytopenia (low platelet count) A reduced platelet count may arise by one of two mechanisms: • decreased or abnormal production (bone marrow failure and hereditary thrombocytopathies) • increased consumption following release into the circulation (immune-mediated, DIC or sequestration). Spontaneous bleeding does not usually occur until the platelet count falls below 20 × 109/L, unless their function is also compromised. Purpura and spontaneous bruising are characteristic but there may also be oral, nasal, gastrointestinal or genitourinary bleeding. Severe thrombocytopenia (< 10 × 109/L) may result in retinal haemorrhage and potentially fatal intracranial bleeding, but this is rare. Investigations are directed at the possible causes listed in Box 23.14. A blood film is the single most useful initial investigation. Examination of the bone marrow may reveal increased megakaryocytes in consumptive causes of thrombocytopenia, or the underlying cause of bone marrow failure in leukaemia, hypoplastic anaemia or myelodysplasia. Treatment (if required) depends on the underlying cause. Platelet transfusion is rarely required and is usually confined to patients with bone marrow failure and platelet counts below 10 × 109/L, or to clinical situations with actual or predicted serious haemorrhage. Thrombocytosis (high platelet count) The most common reason for a raised platelet count is that it is reactive to another process, such as infection, inflammation, connective tissue disease, malignancy, iron deficiency, acute haemolysis or gastrointestinal bleeding (Box 23.15). The presenting clinical features are usually those of the underlying disorder and haemostasis is rarely affected. Reactive thrombocytosis is distinguished from the myeloproliferative disorders by the presence of uniform small platelets, lack of splenomegaly, and the presence of an associated disorder. The key to diagnosis is the clinical history and examination, combined with observation of the platelet count over time (reactive thrombocytosis gets better with resolution of the underlying cause). The platelets are a product of an abnormally expanding clone of cells in the myeloproliferative disorders, chronic myeloid leukaemia 23.14 Causes of thrombocytopenia Decreased production Marrow hypoplasia • Childhood bone marrow failure syndromes, e.g. Fanconi’s anaemia, dyskeratosis congenita, amegakaryocytic thrombocytopenia • Idiopathic aplastic anaemia • Drug-induced: cytotoxics, antimetabolites • Transfusion-associated graft-versus-host disease Marrow infiltration • Leukaemia • Myeloma • Carcinoma (rare) • Myelofibrosis • Osteopetrosis • Lysosomal storage disorders, e.g. Gaucher’s disease Haematinic deficiency • Vitamin B12 and/or folate deficiency Familial (macro-)thrombocytopathies • Myosin heavy chain abnormalities, e.g. Alport’s syndrome, Fechtner’s syndrome, May–Hegglin anomaly • Bernard–Soulier syndrome • Montreal platelet syndrome • Wiskott–Aldrich syndrome (small platelets) • Mediterranean macrothrombocytopathy Increased consumption Immune mechanisms • Idiopathic thrombocytopenic purpura* • Neonatal alloimmune thrombocytopenia • Post-transfusion purpura • Drug-associated, especially quinine, vancomycin and heparin Coagulation activation • Disseminated intravascular coagulation (see Box 23.68, p. 978) Mechanical pooling • Hypersplenism Thrombotic microangiopathies • Haemolytic uraemic syndrome (HUS) and atypical HUS • Liver disease • Thrombotic thrombocytopenic purpura • Pre-eclampsia Others • Gestational thrombocytopenia • Type 2B von Willebrand disease *Associated conditions include collagen vascular diseases (particularly systemic lupus erythematosus), B-cell malignancy, HIV infection and antiphospholipid syndrome. 23.15 Causes of a raised platelet count Reactive thrombocytosis • Acute and chronic inflammatory disorders • Infection • Malignant disease • Tissue damage • Haemolytic anaemias • Post-splenectomy • Post-haemorrhage Clonal thrombocytosis • Primary thrombocythaemia • Polycythaemia rubra vera • Chronic myeloid leukaemia • Myelofibrosis • Myelodysplastic syndromes (MDSs; refractory anaemia with ring sideroblasts and thrombocytosis (RARS-T), MDS with isolated deletion of 5q)

930 • HAEMATOLOGY AND TRANSFUSION MEDICINE 23.16 Causes of pancytopenia Bone marrow failure • Hypoplastic/aplastic anaemia (p. 968): inherited, idiopathic, viral, drugs Bone marrow infiltration • Acute leukaemia • Myeloma • Lymphoma • Carcinoma • Haemophagocytic syndrome • Myelodysplastic syndromes Ineffective haematopoiesis • Megaloblastic anaemia • Acquired immunodeficiency syndrome (AIDS) Peripheral pooling/destruction • Hypersplenism: portal hypertension, Felty’s syndrome, malaria, myelofibrosis • Systemic lupus erythematosus and some forms of myelodysplasia. As with PRV, patients with essential thrombocythaemia may present with thrombosis or, rarely, bleeding. Stroke, transient ischaemic attacks, amaurosis fugax, digital ischaemia or gangrene, aquagenic pruritus, splenomegaly and systemic upset are also features. Patients with myeloproliferative disorders may also present with features such as aquagenic pruritus, splenomegaly and systemic upset. Pancytopenia Pancytopenia refers to the combination of anaemia, leucopenia and thrombocytopenia. It may be due to reduced production of blood cells as a consequence of bone marrow suppression or infiltration, or there may be peripheral destruction or splenic pooling of mature cells. Causes are shown in Box 23.16. A bone marrow aspirate and trephine are usually required to establish the diagnosis. allogeneic transfusion may be avoided by following protocols that recommend the use of low haemoglobin thresholds for red cell transfusion, perioperative blood salvage and antifibrinolytic drugs. Blood products Blood components are prepared from whole blood or specific blood constituents collected from individual donors and include red cells, platelets, plasma and cryoprecipitate (Box 23.17). Plasma derivatives are licensed pharmaceutical products produced on a factory scale from large volumes of human plasma obtained from many people and treated to remove transmissible infection. Examples include: • Coagulation factors. Concentrates of factors VIII and IX are used for the treatment of conditions such as haemophilia A, haemophilia B and von Willebrand disease. Coagulation factors made by recombinant DNA technology are now preferred due to perceived lack of infection risk but plasma-derived products are still used in many countries. • Immunoglobulins. Intravenous immunoglobulin G (IVIgG) is administered as regular replacement therapy to reduce infective complications in patients with primary and secondary immunodeficiency. A short, high-dose course of IVIgG may also be effective in some immunological disorders, including immune thrombocytopenia (p. 971) and Guillain–Barré syndrome (p. 1140). IVIgG can cause acute reactions and must be infused strictly according to the manufacturer’s product information. There is a risk of renal dysfunction in susceptible patients and, in these circumstances, immunoglobulin products containing low or no sucrose are preferred. Anti-zoster immunoglobulin has a role in the prophylaxis of varicella zoster (p. 239). Anti-Rhesus D immunoglobulin is used in pregnancy to prevent haemolytic disease of the newborn (see Box 23.19 below). • Human albumin. This is available in two strengths. The 5% solution can be used as a colloid resuscitation fluid but it is no more effective and is more expensive than crystalloid solutions. Human albumin 20% solution is used in the management of hypoproteinaemic oedema in nephrotic syndrome (p. 395) and ascites in chronic liver disease (p. 864). It is hyperoncotic and expands plasma volume by more than the amount infused. Blood components and their use are summarised in Box 23.17. Blood donation A safe supply of blood components depends on a well-organised system with regular donation by healthy individuals who have no excess risk of infections transmissible in blood (Fig. 23.14). Blood donations are obtained by either venesection of a unit of whole blood or collection of a specific component, such as platelets, by apheresis. During apheresis, the donor’s blood is drawn via a closed system into a machine that separates the components by centrifugation and collects the desired fraction into a bag, returning the rest of the blood to the donor. Each donation must be tested for hepatitis B virus (HBV), hepatitis C virus (HCV), HIV and human T-cell lymphotropic virus (HTLV) nucleic acid and/ or antibodies. Platelet concentrates may be tested for bacterial contamination. The need for other microbiological tests depends on local epidemiology. For example, testing for Trypanosoma cruzi (Chagas’ disease; p. 279) is necessary in areas of South America and the USA where infection is prevalent. Tests for West Nile virus have been required in the USA since this agent became Infection Infection is a major complication of haematological disorders. It relates to the immunological deficit caused by the disease itself, or its treatment with chemotherapy and/or immunotherapy (pp. 224 and 925). Principles of management of haematological disease Blood products and transfusion Blood transfusion from an unrelated donor to a recipient inevitably carries some risk, including adverse immunological interactions between the host and infused blood (p. 931), and transmission of infectious agents. Although there are many compelling clinical indications for blood component transfusion, there are also many clinical circumstances in which transfusion is conventional but the evidence for its effectiveness is limited. In these settings,

Principles of management of haematological disease • 931

Red cell incompatibility Red blood cell membranes contain numerous cell surface molecules that are potentially antigenic (see Fig. 23.4). The ABO and Rhesus D antigens are the most important in routine transfusion and antenatal practice. ABO blood groups The frequency of the ABO antigens varies among different populations. The ABO blood group antigens are oligosaccharide chains that project from the red cell surface. These chains are attached to proteins and lipids that lie in the red cell membrane. The ABO gene encodes a glycosyltransferase that catalyses the final step in the synthesis of the chain, which has three common alleles: A, B and O. The O allele encodes an inactive enzyme, leaving the ABO antigen precursor (called the H antigen) unmodified. The A and B alleles encode enzymes that differ by prevalent. Components for use in specific patient groups are prepared from hepatitis E virus-negative donors in the UK, and plasma donated in the UK is not used at present for producing pooled plasma derivatives in view of concerns about transmission of variant Creutzfeldt–Jakob disease (vCJD; p. 1127). Adverse effects of transfusion Death directly attributable to transfusion is rare, at less than 0.3 per 100 000 transfusions. Relatively minor symptoms of transfusion reactions (fever, itch or urticaria) occur in up to 3% of transfusions, and usually in patients who have had repeated transfusions. Any symptoms or signs that arise during a transfusion must be taken seriously, as they may be the first warnings of a serious reaction. Figure 23.16 below outlines the symptoms and signs, management and investigation of acute reactions to blood components. 23.17 Blood components and their use Component Major haemorrhage Other indications Red cell concentrate1 Most of the plasma is removed and replaced with a solution of glucose and adenine in saline to maintain viability of red cells ABO compatibility with recipient essential Replace acute blood loss: increase circulating red cell mass to relieve clinical features caused by insufficient oxygen delivery. Order 4–6 U initially to allow high red cell to FFP transfusion ratios of (at least) 2 : 1 Severe anaemia If no cardiovascular disease, transfuse to maintain Hb at 70 g/L If known or likely to have cardiovascular disease, maintain Hb at 90 g/L Platelet concentrate One adult dose is made from four donations of whole blood, or from a single platelet apheresis donation ABO compatibility with recipient preferable Maintain platelet count > 50 × 109/L, or in multiple or central nervous system trauma

100 × 109/L If ongoing bleeding, order when platelets < 100 × 109/L to allow for delivery time Each adult dose has a minimum of 2.4 × 1011 platelets, which raises platelet count by 40 × 109/L unless there is consumptive coagulopathy, e.g. disseminated intravascular coagulation Thrombocytopenia, e.g. in acute leukaemia Maintain platelet count > 10 × 109/L if not bleeding Maintain platelet count > 20 × 109/L if minor bleeding or at risk (sepsis, concurrent use of antibiotics, abnormal coagulation) Increase platelet count > 50 × 109/L for minor invasive procedure (e.g. lumbar puncture, gastroscopy and biopsy, insertion of indwelling lines, liver biopsy, laparotomy) or in acute, major blood loss Increase platelet count > 100 × 109/L for operations in critical sites such as brain or eyes Fresh frozen plasma2 150–300 mL plasma from one donation of whole blood ABO compatibility with recipient recommended Dilutional coagulopathy with a PT prolonged 50% is likely after replacement of 1–1.5 blood volumes with red cell concentrate Give initially in (at least) a ratio of 1 FFP:2 red cell concentrate; order 15–20 mL/kg and allow for thawing time. Further doses only if bleeding continues and guided by PT and APTT Replacement of coagulation factor deficiency If no virally inactivated or recombinant product is available Thrombotic thrombocytopenic purpura Plasma exchange (using virus-inactivated plasma if available) is frequently effective Cryoprecipitate2 Fibrinogen and coagulation factor concentrated from plasma by controlled thawing 10–20 mL pack contains: Fibrinogen 150–300 mg Factor VIII 80–120 U von Willebrand factor 80–120 U In UK supplied as pools of 5 U Aim to keep fibrinogen > 1.5 g/L. Pooled units (of 10 donations) will raise fibrinogen by 1 g/L von Willebrand disease and haemophilia If virus-inactivated or recombinant products are not available 1Whole blood is an alternative to red cell concentrate. ABO compatibility with recipient essential. 2Pooled plasma can be treated with solvent and detergent or single units treated with methylene blue as an additional viral inactivation step. Virus-inactivated plasma is indicated for large-volume exposure, as in treatment of thrombotic thrombocytopenic purpura, and for treatment of children in the UK born after 1995. (APTT = activated partial thromboplastin time; FFP = fresh frozen plasma; Hb = haemoglobin; PT = prothrombin time)

932 • HAEMATOLOGY AND TRANSFUSION MEDICINE ABO-incompatible red cell transfusion If red cells of an incompatible ABO group are transfused (especially if a group O recipient is transfused with group A, B or AB red cells), the recipient’s IgM anti-A, anti-B or anti-AB binds to the transfused red cells. This activates the full complement pathway (p. 66), creating pores in the red cell membrane and destroying four amino acids and hence attach different sugars to the end of the chain. Individuals are tolerant to their own ABO antigens, but do not suppress B-cell clones producing antibodies against ABO antigens that they do not carry themselves (Box 23.18). They are, therefore, capable of mounting a humoral immune response to these ‘foreign’ antigens. Fig. 23.14 Blood donation, processing and storage. 1Platelet apheresis involves circulating the donor’s blood through a cell separator to remove platelets before returning other blood components to the donor. 2In the UK, plasma for fractionation is imported as a precautionary measure against vCJD. (vCJD = variant Creutzfeldt–Jakob disease; HIV = human immunodeficiency virus; HTLV = human T-cell lymphotropic virus) A A A Donor Education Recruitment Selection Donation Process into blood components Filter to remove leucocytes Test for: HIV HTLV Hepatitis B Hepatitis C Hepatitis E Syphilis ABO + RhD Other blood groups Red cell antibodies Platelet apheresis1 450 mL whole blood collected into 63 mL anticoagulant/preservative Pooled/apheresis platelets Red cells Fresh frozen plasma Plasma2 4°C 22°C –30°C Storage Fractionation Plasma derivatives, e.g. albumin, immunoglobulin Patient 35 days 5 days (agitate) 36 months Confirm compatibility Thaw

Principles of management of haematological disease • 933

(TA GVHD). The latter occurs when there is sharing of a human leucocyte antigen (HLA) haplotype between donor and recipient, which allows transfused lymphocytes to engraft, proliferate and recognise the recipient as foreign, resulting in acute GVHD (p. 937). Prevention is by gamma- or X-ray irradiation of blood components before their administration to prevent lymphocyte proliferation. Those at risk of TA GVHD, who must receive irradiated blood components, include patients with congenital T-cell immunodeficiencies or Hodgkin lymphoma, patients with aplastic anaemia receiving immunosuppressive therapy with antithymocyte globulin (ATG), recipients of haematopoietic stem cell transplants or of blood from a family member, neonates who have received an intrauterine transfusion, and patients taking T-lymphocyte-suppressing drugs, such as fludarabine and other purine analogues. Transfusion-transmitted infection Over the past 30 years, HBV, HIV-1 and HCV have been identified and effective tests introduced to detect and exclude infected donations. Where blood is from ‘safe’ donors and correctly tested, the current risk of a donated unit being infectious is very small. By 2013 in the UK, the estimated chance that a unit of blood from a ‘safe’ donor might transmit one of the viruses for which blood is tested was 1 in 6.6 million units for HIV-1, 1 in 51.5 million for HCV and 1 in 2.6 million for HBV. However, some patients who received transfusions before these tests were available suffered serious consequences from infection; this serves as a reminder to avoid non-essential transfusion, since it is impossible to exclude the emergence of new or currently unrecognised transfusion-transmissible infection. Licensed plasma derivatives that have been virus-inactivated do not transmit HIV, HTLV, HBV, HCV, cytomegalovirus or other lipid-enveloped viruses. Variant CJD is a human prion disease linked to bovine spongiform encephalitis (BSE; p. 1127). The risk of a recipient acquiring the agent of vCJD from a transfusion is uncertain, but of 16 recipients of blood from donors who later developed the disease, 3 have died with clinical vCJD and 1 other had postmortem immunohistological features of infection. Bacterial contamination of a blood component – usually platelets – is extremely rare (1 proven case in the UK in 2015) but can result in severe bacteraemia/sepsis in the recipient. the transfused red cells in the circulation (intravascular haemolysis). The anaphylatoxins C3a and C5a, released by complement activation, liberate cytokines such as tumour necrosis factor (TNF), interleukin 1 (IL-1) and IL-8, and stimulate degranulation of mast cells with release of vasoactive mediators. All these substances may lead to inflammation, increased vascular permeability and hypotension, which may, in turn, cause shock and renal failure. Inflammatory mediators can also cause platelet aggregation, lung peribronchial oedema and smooth muscle contraction. About 20–30% of ABO-incompatible transfusions cause some degree of morbidity, and 5–10% cause or contribute to a patient’s death. The main reason for this relatively low morbidity is the lack of potency of ABO antibodies in group A or B subjects; even if the recipient is group O, those who are very young or very old usually have weaker antibodies that do not lead to the activation of large amounts of complement. The Rhesus D blood group and haemolytic disease of the newborn About 15% of Caucasians are Rhesus-negative: that is, they lack the Rhesus D (RhD) red cell surface antigen (see Fig. 23.4). In other populations (e.g. in Chinese and Bengalis), only 1–5% are Rhesus-negative. RhD-negative individuals do not normally produce substantial amounts of anti-RhD antibodies. However, if RhD-positive red cells enter the circulation of an RhD-negative individual, IgG antibodies are produced. This can occur during pregnancy if the mother is exposed to fetal cells via fetomaternal haemorrhage, or following transfusion. If a woman is so sensitised, during a subsequent pregnancy anti-RhD antibodies can cross the placenta; if the fetus is RhD-positive, haemolysis with severe fetal anaemia and hyperbilirubinaemia can result. This can cause severe neurological damage or death due to haemolytic disease of the newborn (HDN). Therefore, an RhD-negative female who may subsequently become pregnant should never be transfused with RhD-positive blood. In RhD-negative women, administration of anti-RhD immunoglobulin (anti-D) perinatally can block the immune response to RhD antigen on fetal cells and is the only effective product for preventing the development of Rhesus antibodies (Box 23.19). HDN can also be caused by other alloantibodies against red cell antigens, usually after previous pregnancies or transfusions. These antigens include Rhc, RhC, RhE, Rhe, and the Kell, Kidd and Duffy antigen systems. HDN can also occur if there is fetomaternal ABO incompatibility, most commonly seen in a group O mother with a group A fetus. The fetus is generally less severely affected by ABO incompatibility than by RhD, Rhc or Kell antigen mismatch, and the incompatibility is often picked up coincidentally after birth. Other immunological complications of transfusion Rare but serious complications include transfusion-associated lung injury (TRALI) and transfusion-associated graft-versus-host disease 23.19 Rhesus D blood groups in pregnancy • Haemolytic disease of the newborn (HDN): occurs when the mother has anti-red cell immunoglobulin G (IgG) antibodies that cross the placenta and haemolyse fetal red cells. • Screening for HDN in pregnancy: at the time of booking (12–16 weeks) and again at 28–34 weeks’ gestation, every pregnant woman should have a blood sample sent for determination of ABO and Rhesus D (RhD) group and testing for red cell alloantibodies that may be directed against paternal blood group antigens present on fetal red cells. • Anti-D immunoglobulin prophylaxis in a pregnant woman who is RhD-negative: antenatal anti-D prophylaxis is offered at 28–34 weeks to RhD-negative pregnant women who have no evidence of immune anti-D. This prevents the formation of antibodies that could cause HDN. Following delivery of an RhD-positive baby, the mother is given further anti-D within 72 hours; a maternal sample is checked for remaining fetal red cells and additional anti-D is given if indicated. Additional anti-D is also given after potential sensitising events antenatally (e.g. early bleeding). Doses vary according to national recommendations. 23.18 ABO blood group antigens and antibodies ABO blood group Red cell A or B antigens Antibodies in plasma UK frequency (%) O None Anti-A and anti-B

A A Anti-B

B B Anti-A

AB A and B None

934 • HAEMATOLOGY AND TRANSFUSION MEDICINE antibody screen is negative. This allows group-specific units to be issued quickly and safely, for elective and emergency transfusion. Bedside procedures for safe transfusion Errors leading to patients receiving the wrong blood are an important avoidable cause of mortality and morbidity. Most incompatible transfusions result from failure to adhere to standard procedures for taking correctly labelled blood samples from the patient and ensuring that the correct pack of blood component is transfused into the intended patient. In the UK in 2015, there were 280 reports of transfusion of an incorrect blood component (11 per 100 000 units transfused). Every hospital where blood is transfused should have a written transfusion policy used by all staff who order, check or administer blood products (Fig. 23.15). Management of suspected transfusion reactions is shown in Figure 23.16. Transfusion in major haemorrhage The successful management of a patient with major haemorrhage requires frontline clinical staff to be trained to recognise significant blood loss early and to intervene before shock is established. Hospitals should have local major haemorrhage protocols and all clinical staff must be familiar with their content. Good team working and communication are essential to prevent poor clinical outcome, suboptimal or inappropriate transfusion practice and component wastage. Fresh frozen plasma (FFP) should be given as part of initial resuscitation in (at least) a 1 : 2 ratio with red cell concentrate (RCC) until coagulation results are available. If the patient is bleeding, a ratio of FFP to RCC of 1 : 1 should be given until laboratory results are available and use of cryoprecipitate should be considered. Once the bleeding is under control, further Safe transfusion procedures The proposed transfusion and any alternatives should be discussed with the patient or, if that is not possible, with a relative, and this should be documented in the case record. Some patients, e.g. Jehovah’s Witnesses, may refuse transfusion and require specialised management to survive profound anaemia following blood loss. Pre-transfusion testing To ensure that red cells supplied for transfusion are compatible with the intended recipient, the transfusion laboratory will perform either a ‘group and screen’ procedure or a ‘cross-match’. In the group and screen procedure, the red cells from the patient’s blood sample are tested to determine the ABO and RhD type, and the patient’s serum is also tested against an array of red cells expressing the most important antigens to detect any red cell antibodies. Any antibody detected can be identified by further testing, so that red cell units that lack the corresponding antigen can be selected. The patient’s sample can be held in the laboratory for up to a week, so that the hospital blood bank can quickly prepare compatible blood without the need for a further patient sample. Conventional cross-matching consists of the group and antibody screen, followed by direct confirmation of the compatibility of individual units of red cells with the patient’s serum. Full cross-matching takes about 45 minutes if no red cell antibodies are present, but may require hours if a patient has multiple antibodies. Blood can be supplied by ‘electronic issue’, without the need for compatibility cross-matching, if the laboratory’s computer system shows that the patient’s ABO and RhD groups have been identified and confirmed on two separate occasions and their Fig. 23.15 Bedside procedures for safe blood transfusion. The patient’s safety depends on adherence to standard procedures for taking samples for compatibility testing, administering blood, record-keeping and observations. MORAG MACDONALD HOSPITAL No. 100198E DOB: 11/07/1956 SEX: Female • Positively identify the patient at the bedside • Label the sample tube and complete the request form clearly and accurately after identifying the patient • Do not write forms and labels in advance Taking blood for pre-transfusion testing Administering blood • Positively identify the patient at the bedside • Ensure that the identification of each blood pack matches the patient’s identification • Check that the ABO and RhD groups of each pack are compatible with the patient’s • Check each pack for evidence of damage • If in doubt, do not use and return to the blood bank • Complete the forms that document the transfusion of each pack • Check the compatibility label on the pack against the patient’s wristband • Always involve the patient by asking them to state their name and date of birth, where possible Surname Forename Date of birth Unique identifier/ hospital number Patient’s wristband Blood pack Observations • Transfusions should only be given when the patient can be observed • Blood pressure, pulse and temperature should be monitored before and 15 minutes after starting each pack • In conscious patients, further observations are only needed if the patient has symptoms or signs of a reaction • In unconscious patients, check pulse and temperature at intervals during transfusion • Signs of abnormal bleeding during the transfusion could be due to disseminated intravascular coagulation resulting from an acute haemolytic reaction Record-keeping • Record in the patient’s notes, the reason for transfusion, the product given, dose, any adverse effects and the clinical respons

Principles of management of haematological disease • 935

Fig. 23.16 Investigation and management of acute transfusion reactions. Use size-appropriate dose in children. (ARDS = acute respiratory distress syndrome; BP = blood pressure; CVP = central venous pressure; DIC = disseminated intravascular coagulation; FBC = full blood count; IV = intravenous) Bacterial infection of unit • Take down unit and giving set/return intact to blood bank with all other used/unused units • Take blood cultures, repeat blood group/cross-match/ FBC, coagulation screen, biochemistry, urinalysis • Monitor urine output • Commence broad-spectrum antibiotics if suspected bacterial infection (Ch. 6) • Commence oxygen and fluid support • Seek advice Severe allergic reaction • Discontinue transfusion • Give chlorphenamine 10 mg slowly IV • Commence O2 and fluid support • Give salbutamol nebuliser • If severe hypotension or bronchospasm, give adrenaline (epinephrine) 0.5 mg IM* • Send clotted blood sample to transfusion laboratory • Take down unit and giving set, and return intact to blood bank with all other used/unused units Bacterial contamination? • Blood pack discoloured or damaged • Rapid onset of hyper- or hypotension, rigors or collapse • Temperature ≥ 39°C or rise of ≥ 2°C Fluid overload • Give oxygen and furosemide 40–80 mg IV* Transfusion-related acute lung injury (TRALI) • Typically within 6–24 hrs of transfusion • Breathlessness, non-productive cough • Chest X-ray bilateral nodular infiltration • Discontinue transfusion • Give 100% oxygen • Treat as ARDS – ventilate if severely hypoxaemic If acute dyspnoea/hypotension • Monitor blood gases • Perform chest X-ray • Measure central venous/pulmonary capillary pressure No Raised CVP Yes Normal CVP Severe allergic reaction? • Bronchospasm, angioedema, abdominal pain, hypotension Yes No Suspected ABO incompatibility? • Wrong blood pack infused • Haemoglobinuria Yes ABO incompatibility • Take down unit and giving set; return intact to blood bank • Commence IV saline infusion • Monitor urine output/catheterise Maintain urine output at > 100 mL/hr Give furosemide if urine output falls* • Treat DIC with appropriate blood components • Inform hospital transfusion department immediately No Reaction involves mild fever or urticarial rash only? Fever No Febrile non-haemolytic transfusion reaction If isolated temperature ≥ 38°C, or rise of 1–2°C, observations are stable and patient is otherwise well • Give paracetamol* • Restart infusion at a slower rate and observe more frequently Urticaria Mild pruritus/rash • Give chlorphenamine 10 mg slowly IV* • Restart the transfusion at a slower rate and observe more frequently Stop the transfusion • Undertake rapid clinical assessment, including temperature, pulse, BP, respiratory rate and O2 saturation • Check the identity of recipient details on the unit and compatibility form Symptoms/signs of possible acute transfusion reaction • Fever, chills, tachycardia, hyper- or hypotension, collapse, rigors, flushing, urticaria, bone, muscle, chest and/or abdominal pain, shortness of breath, nausea, generally feeling unwell, respiratory distress

936 • HAEMATOLOGY AND TRANSFUSION MEDICINE targeting of the chemotherapy drug to the specific cancer cell. Examples of such antibody–drug conjugates (ADCs) include the linking of the intercalating antibiotic calicheamicin to anti-CD33 (gemtuzumab ozogamicin) to treat acute myeloid leukaemia, and to anti-CD22 (inotuzumab ozogamicin) to treat acute lymphoblastic leukaemia. Small molecules targeted at the mechanisms causing cancer are replacing chemotherapy in some disease situations, such as tyrosine kinase inhibitors in chronic myeloid leukaemia and inhibitors of B-cell signalling in relapsed chronic lymphocytic leukaemia and lymphomas. More details of specific chemotherapies are given later in the chapter. Haematopoietic stem cell transplantation Transplantation of haematopoietic stem cells (HSCT) has offered the only hope of ‘cure’ in a variety of haematological and non-haematological disorders (Box 23.22). As standard treatment improves, the indications for HSCT are being refined and extended, although its use remains most common in haematological malignancies. The type of HSCT is defined according to the donor and source of stem cells: • In allogeneic HSCT, the stem cells come from a donor – either a related donor (usually an HLA-identical sibling) or a closely HLA-matched volunteer unrelated donor (VUD). • In an autologous transplant, the stem cells are harvested from the patient and stored in the vapour phase of liquid nitrogen until required. Stem cells can be harvested from the bone marrow or from the blood. FFP transfusion should be guided by laboratory results with transfusion triggers of PT and/or APTT above 1⋅5 times normal for a standard dose of FFP (15–20 mL/kg). Cryoprecipitate should be given if the fibrinogen level falls below 1.5 g/L. Platelets should be kept above 50 × 109/L; to allow for delivery time, platelets should be requested if there is ongoing bleeding and the platelet count has fallen below 100 × 109/L. Blood component use in major haemorrhage is summarised in Box 23.17 and key points in transfusion medicine in Box 23.20. Chemotherapy Chemotherapy refers to the use of drugs to treat cancer (Box 23.21; see also Fig. 33.2, p. 1317). Many haematological malignancies are sensitive to the effects of chemotherapy drugs and, as such, chemotherapy is the mainstay of treatment for most haematological cancers. There is a wide range of drugs available that work by damaging DNA or disrupting cellular metabolism, in such a way that natural apoptosis mechanisms, such as TP53, are activated and the cell dies. Despite cancer cells being more sensitive, chemotherapy is largely non-specific and kills some normal cells as well as cancer cells. This leads to common side-effects of treatment, such as transient bone marrow failure, mucositis and infertility. The supportive care of patients undergoing chemotherapy is critical in overcoming these side-effects. It is this supportive care, including blood product support, antibiotics, antifungal drugs, growth factors and antiemetics, that has allowed specialist haematology units to achieve the best possible results from intensive chemotherapy: for example, when treating acute leukaemia. The basic principles of chemotherapy include combining several non-cross-reacting drugs in a regimen that kills a fixed proportion of cancer cells with a given dose. Several cycles of the combination are given to achieve gradual reduction of the tumour burden, to induce remission and, in some instances, to produce a cure (p. 1330). In recent years, chemotherapy has been improved by the addition of treatments that are more targeted to the cancer cell, particularly monoclonal antibodies; for example, rituximab (anti-CD20) has been added to CHOP (cyclophosphamide doxorubicin, vincristine, prednisolone) and other regimens, significantly improving the outcome in a range of CD20-positive B-cell lymphomas, including diffuse large B-cell lymphoma, follicular lymphoma and mantle cell lymphoma. Chemotherapy drugs can also be linked to a monoclonal antibody to allow 23.21 Examples of commonly used groups of cancer drugs in haematology Alkylating agents • Cross-link double-stranded DNA by adding an alkyl group, e.g. cyclophosphamide, melphalan, chlorambucil Anthracyclines • Intercalate between base pairs in the DNA molecule, e.g. daunorubicin, doxorubicin, idarubicin Antimetabolites • Inhibit DNA and RNA synthesis, e.g. cytosine arabinoside, fludarabine, methotrexate Vinca alkaloids • Cause disruption of tubulin, e.g. vincristine, vinblastine Topoisomerase II inhibitors • Prevent DNA repair, e.g. etoposide, daunorubicin, mitoxantrone An example of a common combination regimen is CHOP, used in lymphoma: cyclophosphamide, hydroxydaunorubicin (doxorubicin), oncovin (vincristine) and prednisolone, given every 21 days for six cycles 23.20 Key points in transfusion medicine • A restrictive strategy for red cell transfusion (Hb < 70 g/L) is at least as effective as a liberal strategy (< 100 g/L). • The majority of reports in haemovigilance schemes such as SHOT relate to errors in the process of transfusion. • Although transfusion-transmitted infection is a major concern for patients receiving transfusion, it is rare. • In patients with trauma or burns or those who have had surgery, there is no evidence that resuscitation with albumin or other colloid solutions reduces the risk of death compared to resuscitation with crystalloid solutions. • It is recommended that transfusion should be carried out at night time only in unavoidable circumstances. (SHOT = Serious Hazards of Transfusion) 23.22 Indications for allogeneic haematopoietic stem cell transplantation • Neoplastic disorders affecting stem cell compartments (e.g. leukaemias) • Failure of haematopoiesis (e.g. aplastic anaemia) • Major inherited defects in blood cell production (e.g. thalassaemia, immunodeficiency diseases) • Inborn errors of metabolism with missing enzymes or cell lines

Principles of management of haematological disease • 937

remains a significant risk of the haematological malignancy relapsing. The long-term survival for patients undergoing allogeneic HSCT in acute leukaemia is around 50%. Graft-versus-host disease GVHD is caused by the cytotoxic activity of donor T lymphocytes that become sensitised to their new host, regarding it as foreign. This may cause either an acute or a chronic form of GVHD. Acute GVHD occurs in the first 100 days after transplant in about one-third of patients. It can affect the skin, causing rashes, the liver, causing jaundice, and the gut, causing diarrhoea, and may vary from mild to lethal. Prevention includes HLA-matching of the donor, immunosuppressant drugs, including methotrexate, ciclosporin, alemtuzumab or ATG. Severe presentations are very difficult to control and, despite high-dose glucocorticoids, may result in death. Chronic GVHD may follow acute GVHD or arise independently; it occurs later than acute GVHD. It often resembles a connective tissue disorder, although in mild cases a rash may be the only manifestation. Chronic GVHD is usually treated with glucocorticoids and prolonged immunosuppression with, for example, ciclosporin. Chronic GVHD results in an increased infection risk. However, associated with chronic GVHD are the graft-versus-disease effect and a lower relapse rate of the underlying malignancy. Autologous HSCT This procedure can also be used in haematological malignancies. The patient’s own stem cells from blood or marrow are first harvested and frozen. After conditioning myeloablative therapy, the autologous stem cells are reinfused into the blood stream in order to rescue the patient from the marrow damage and aplasia caused by chemotherapy. Autologous HSCT may be used for disorders that do not primarily involve the haematopoietic tissues, or for patients in whom very good remissions have been achieved. The most common indications are lymphomas and myeloma. The preferred source of stem cells for autologous transplants is peripheral blood (PBSCT). These stem cells engraft more Allogeneic HSCT Healthy bone marrow or blood stem cells from a donor are infused intravenously into the recipient, who has been suitably ‘conditioned’. The conditioning treatment (chemotherapy with or without radiotherapy) is ‘myeloablative’ or, increasingly, ‘nonmyeloablative’. Myeloablative conditioning destroys malignant cells and immunosuppresses the recipient, as well as ablating the recipient’s haematopoietic tissues. Reduced intensity conditioning (non-myeloablative) relies on intense immunosuppression to provide ‘immunological space’ for transplanted stem cells. The infused donor cells ‘home’ to the marrow, engraft and produce enough erythrocytes, granulocytes and platelets for the patient’s needs after about 3–4 weeks. During this period of aplasia, patients are at risk of infection and bleeding, and require intensive supportive care as described on page 957. It may take several years to regain normal immunological function and patients remain at risk from opportunistic infections, particularly in the first year. An advantage of receiving allogeneic donor stem cells is that the donor’s immune system can recognise residual recipient malignant cells and destroy them. This immunological ‘graft-versus-disease’ effect is a powerful tool against many haematological tumours and can be boosted post-transplantation by the infusion of T cells taken from the donor: so-called donor lymphocyte infusion (DLI). Considerable morbidity and mortality are associated with HSCT. The best results are obtained in patients with minimal residual disease, and in those under 20 years of age who have an HLA-identical sibling donor. Reduced-intensity conditioning has enabled treatment of older or less fit patients. In this form of transplantation, rather than using very intensive myeloablative conditioning, which causes morbidity from organ damage, relatively low doses of chemotherapy drugs, such as fludarabine and cyclophosphamide or busulfan, are used in combination with antibodies such as alemtuzumab (which targets CD52 on mature lymphoid cells) or anti-thymocyte globulin (ATG) to immunosuppress the recipient and allow donor stem cells to engraft. The emerging donor immune system then eliminates malignant cells via the ‘graft-versus-disease’ effect, which may be boosted by the elective use of donor T-cell infusions posttransplant. Such transplants have produced long-term remissions in some patients with acute leukaemia and myelodysplastic syndromes aged 40–65 years, who would not previously have been considered for a myeloablative allograft. Complications These are outlined in Boxes 23.23 and 23.24. The risks and outcomes of transplantation depend upon several patient- and disease-related factors. In general, 25% die from procedurerelated complications, such as infection and GVHD, and there 23.23 Complications of allogeneic haematopoietic stem cell transplantation Early • Anaemia • Infections • Bleeding • Acute GVHD • Mucositis – pain, nausea, diarrhoea • Liver veno-occlusive disease Late • Chronic GVHD • Infertility • Cataracts • Second malignancy (GVHD = graft-versus-host disease) 23.24 Infections during recovery from haematopoietic stem cell transplantation (HSCT) Infection Time after HSCT Management Herpes simplex (p. 247) 0–4 weeks (aplastic phase) Aciclovir prophylaxis and therapy Bacterial, fungal 0–4 weeks (aplastic phase) As for acute leukaemia (p. 956) – antibiotic and antifungal prophylaxis and therapy Cytomegalovirus (p. 242) 5–21 weeks (cell-mediated immune deficiency) Antigen screening in blood (PCR) and pre-emptive therapy (e.g. ganciclovir) Varicella zoster (p. 238) After 13 weeks Aciclovir prophylaxis and therapy Pneumocystis jirovecii (p. 318) 8–26 weeks Co-trimoxazole Encapsulated bacteria 8 weeks to years (immunoglobulin deficiency, prolonged with GVHD) Prophylaxis and revaccination (GVHD = graft-versus-host disease; PCR = polymerase chain reaction)

938 • HAEMATOLOGY AND TRANSFUSION MEDICINE disease, while warfarin and other anticoagulants are favoured in VTE (p. 975) and management of atrial fibrillation (p. 471). In some extremely prothrombotic situations, such as coronary artery stenting, a combination of anticoagulant and antiplatelet drugs is used (p. 491). A wide range of anticoagulant and antithrombotic drugs is used in clinical practice. These drugs and their modes of action are given in Box 23.26. Newer agents allow predictable anticoagulation without the need for frequent monitoring and dose titration. Although warfarin remains the mainstay for oral anticoagulation, newer oral anticoagulants (dabigatran, rivaroxaban, edoxaban and apixaban), which can be given at fixed doses with predictable effects and no need for monitoring, have now been approved for the prevention of perioperative VTE, the treatment of established VTE and the prevention of cardioembolic stroke in patients with atrial fibrillation. Heparins Unfractionated heparin (UFH) and low-molecular-weight heparins (LMWHs) act by binding via a specific pentasaccharide in the heparin molecule to antithrombin. Fondaparinux is a synthetic pentasaccharide, which also binds antithrombin and has similar properties to LMWH. These agents enhance the natural anticoagulant activity of antithrombin (see Fig. 23.6E). Increased cleavage of activated proteases, particularly factor Xa and thrombin (IIa), accounts for the anticoagulant effect. LMWHs preferentially augment antithrombin activity against factor Xa. For the licensed indications, LMWHs are at least as efficacious as UFH but have several advantages: • LMWHs are nearly 100% bioavailable and so produce reliable dose-dependent anticoagulation. • LMWHs do not require monitoring of their anticoagulant effect (except possibly in patients with very low body quickly, marrow recovery occurring within 2–3 weeks. There is no risk of GVHD and no immunosuppression is required. Thus autologous stem cell transplantation carries a lower procedurerelated mortality rate than allogeneic HSCT at around 5%, but there is a higher rate of recurrence of malignancy because the anti-malignancy effect is solely dependent on the conditioning chemotherapy with no ‘graft-versus-disease’ effect. Anticoagulant and antithrombotic therapy There are numerous indications for anticoagulant and antithrombotic medications (Box 23.25). The guiding principles are outlined here but management in specific indications is discussed elsewhere in the book. Broadly speaking, antiplatelet medications are of greater efficacy in the prevention of arterial thrombosis and of less value in the prevention of venous thromboembolism (VTE). Thus, antiplatelet agents, such as aspirin, clopidogrel and, increasingly, ticagrelor, are the drugs of choice in acute coronary events (p. 498) and in ischaemic cerebrovascular 23.26 Modes of action of anticoagulant and antithrombotic drugs Mode of action Drug Antiplatelet drugs Cyclo-oxygenase (COX) inhibition Aspirin Adenosine diphosphate (ADP) receptor inhibition Clopidogrel Prasugrel Ticagrelor Glycoprotein IIb/IIIa inhibition Abciximab Tirofiban Eptifibatide Phosphodiesterase inhibition Dipyridamole Oral anticoagulants Vitamin K antagonism Warfarin/coumarins Direct thrombin inhibition Dabigatran Direct Xa inhibition Rivaroxaban Apixaban Edoxaban Injectable anticoagulants Antithrombin-dependent inhibition of thrombin and Xa Heparin LMWH Antithrombin-dependent inhibition of Xa Fondaparinux Danaparoid Direct thrombin inhibition Argatroban Bivalirudin Heparin/LMWH/Fondaparinux • Prevention and treatment of VTE • Percutaneous coronary intervention • Post-thrombolysis for MI • Unstable angina pectoris • Non-Q wave MI • Acute peripheral arterial occlusion • Cardiopulmonary bypass • Haemodialysis and haemofiltration Coumarins (warfarin etc.) • Prevention and treatment of VTE • Arterial embolism • Atrial fibrillation with specific risk factors for stroke (p. 472) • Mobile mural thrombus post-MI • Extensive anterior MI • Dilated cardiomyopathy • Cardioversion • Ischaemic stroke in antiphospholipid syndrome • Mitral stenosis and mitral regurgitation with atrial fibrillation • Recurrent venous thrombosis while on warfarin • Mechanical prosthetic cardiac valves Rivaroxaban • Prevention and treatment of VTE • Atrial fibrillation with risk factors for stroke Dabigatran etexilate • Prevention of VTE • Atrial fibrillation with risk factors for stroke Apixaban • Prevention of VTE • Atrial fibrillation with risk factors for stroke Edoxaban • Treatment of VTE • Atrial fibrillation with risk factors for stroke Therapeutic INR 2.5 INR 3.5 23.25 Indications for anticoagulation (INR = international normalised ratio; LMWH = low-molecular-weight heparin; MI = myocardial infarction; VTE = venous thromboembolism)

Principles of management of haematological disease • 939

baseline. The count may still be in the reference range. The patient may be asymptomatic, or develop venous or arterial thrombosis and skin lesions, including overt skin necrosis. Affected patients may complain of pain or itch at injection sites and of systemic symptoms, such as shivering, following heparin injections. Patients who have received heparin in the preceding 100 days and who have preformed antibodies may develop acute systemic symptoms and an abrupt fall in platelet count in the first 24 hours after re-exposure. Investigations The pre-test probability of the diagnosis is assessed using the 4Ts scoring system. This assigns a score based on: • the thrombocytopenia • the timing of the fall in platelet count • the presence of new thrombosis • the likelihood of another cause for the thrombocytopenia. Individuals at low risk need no further test. Those with intermediate and high likelihood scores should have the diagnosis confirmed or refuted using an anti-PF4 enzyme-linked immunosorbent assay (ELISA). Management Heparin should be discontinued as soon as HIT is diagnosed and an alternative anticoagulant that does not cross-react with the antibody should be substituted. Argatroban (a direct thrombin inhibitor) and danaparoid (a heparin analogue) are licensed for use in the UK. In asymptomatic patients with HIT who do not receive an alternative anticoagulant, around 50% will sustain a thrombosis in the subsequent 30 days. Patients with established thrombosis have a poorer prognosis. Coumarins Although several coumarin anticoagulants are used around the world, warfarin is the most common. Coumarins inhibit the vitamin K-dependent post-translational carboxylation of factors II (prothrombin), VII, IX and X in the liver (see Fig. 23.6D). This results in anticoagulation due to an effective deficiency of these factors. This is monitored by the INR, a standardised test based on measurement of the prothrombin time (p. 922). Recommended target INR values for specific indications are given in Box 23.25. Warfarin anticoagulation typically takes more than 3–5 days to become established, even using loading doses. Patients who require rapid initiation of therapy may receive higher initiation doses of warfarin. A typical regime in this situation is to give 10 mg warfarin on the first and second days, with 5 mg on the third day; subsequent doses are titrated against the INR. Patients without an urgent need for anticoagulation (e.g. atrial fibrillation) can have warfarin introduced slowly using lower doses. Low-dose regimens are associated with a lower risk of the patient developing a supratherapeutic INR, and hence a lower bleeding risk. The duration of warfarin therapy depends on the clinical indication, and while treatment of deep vein thrombosis (DVT) or preparation for cardioversion may require a limited duration, anticoagulation to prevent cardioembolic stroke in atrial fibrillation or from heart valve disease is long-term. The major problems with warfarin are: • a narrow therapeutic window • metabolism that is affected by many factors • numerous drug interactions. weight and with a glomerular filtration rate below 30 mL/min). • LMWHs have a half-life of around 4 hours when given subcutaneously, compared with 1 hour for UFH. This permits once-daily dosing by the subcutaneous route, rather than the therapeutic continuous intravenous infusion or twice-daily subcutaneous administration required for UFH. • While rates of bleeding are similar between products, the risk of osteoporosis and heparin-induced thrombocytopenia is much lower for LMWH. UFH is, however, more completely reversed by protamine sulphate in the event of bleeding and at the end of cardiopulmonary bypass, for which UFH remains the drug of choice (Box 23.27). LMWHs are widely used for the prevention and treatment of VTE, the management of acute coronary syndromes and for most other scenarios listed in Box 23.25. In some situations, UFH is still favoured by some clinicians, though there is little evidence that it is advantageous, except when rapid reversibility is required. UFH is useful in patients with a high risk of bleeding, e.g. those who have peptic ulceration or who may require urgent surgery. It is also favoured in the treatment of life-threatening thromboembolism, e.g. major pulmonary embolism with significant hypoxaemia, hypotension and right-sided heart strain. In this situation, UFH is started with a loading intravenous dose of 80 U/ kg, followed by a continuous infusion of 18 U/kg/hr initially. The level of anticoagulation should be assessed by the APTT after 6 hours and, if satisfactory, twice daily thereafter. It is usual to aim for a patient APTT that is 1.5–2.5 times the control time of the test. Monitoring of UFH treatment by APTT is not without difficulties and other assays, such as the specific anti-Xa assay, may provide more accurate guidance. Heparin-induced thrombocytopenia Heparin-induced thrombocytopenia (HIT) is a rare complication of heparin therapy, caused by induction of anti-heparin/PF4 antibodies that bind to and activate platelets via an Fc receptor. This results in platelet activation and a prothrombotic state, with a paradoxical thrombocytopenia. HIT is more common in surgical than medical patients (especially cardiac and orthopaedic patients), with use of UFH rather than LMWH, and with higher doses of heparin. Clinical features Patients present, typically 5–14 days after starting heparin treatment, with a fall in platelet count of more than 30% from 23.27 Treatments for emergencies in haematological practice • Reversal of life- and limb-threatening haemorrhage in anticoagulated patients: Warfarin: prothrombin complex concentrate and IV vitamin K1 Unfractionated heparin: protamine sulphate Dabigatran: idarucizumab • Recognition of thrombotic thrombocytopenic purpura and treatment with plasma exchange • Recognition of coagulopathy associated with acute promyelocytic leukaemia and treatment with all-trans-retinoic acid and fibrinogen replacement • Recognition of chest syndrome and stroke in patients with sickle-cell anaemia and red cell transfusion or exchange transfusion • Recognition of neutropenic sepsis in patients receiving chemotherapy and early treatment with empirical broad-spectrum antibiotics

940 • HAEMATOLOGY AND TRANSFUSION MEDICINE 2–4 hours after oral intake, have very few drug interactions and are all moderately dependent on renal function for their excretion. An initial perceived drawback was the lack of specific reversal agents for these drugs but idarucizumab is a monoclonal antibody now available for the reversal of dabigatran, and andexanet alfa, a site-inactivated Xa molecule, is close to licensing for the reversal of apixaban and rivaroxaban (see Box 23.27). DOACs are now licensed for the prevention of VTE following high-risk orthopaedic surgery (except edoxaban), the acute management and prevention of recurrence of VTE, and the prevention of stroke and systemic embolism in patients with atrial fibrillation with risk factors. The general perception at present is that in these indications they are at least as efficacious as dose-adjusted coumarin and probably associated with less clinically significant bleeding. Anaemias Around 30% of the total world population is anaemic and half of these, some 600 million people, have iron deficiency. The classification of anaemia by the size of the red cells (MCV) indicates the likely cause (see Figs 23.10 and 23.11). Red cells in the bone marrow must acquire a minimum level of haemoglobin before being released into the blood stream (Fig. 23.17). While in the marrow compartment, red cell precursors undergo cell division, driven by erythropoietin. If red cells cannot acquire haemoglobin at a normal rate, they will undergo more divisions than normal and will have a low MCV when finally released into the blood. The MCV is low because component parts of the haemoglobin molecule are not fully available: that is, iron in iron deficiency, globin chains in thalassaemia, haem ring in congenital sideroblastic anaemia and, occasionally, poor iron utilisation in the anaemia of chronic disease/anaemia of inflammation. In megaloblastic anaemia, the biochemical consequence of vitamin B12 or folate deficiency is an inability to synthesise new bases to make DNA. A similar defect of cell division is seen in the presence of cytotoxic drugs or haematological disease in the marrow, such as myelodysplasia. In these states, cells haemoglobinise normally but undergo fewer cell divisions, resulting in circulating red cells with a raised MCV. The red cell membrane is composed of a lipid bilayer that will freely exchange with the plasma pool of lipid. Conditions such as liver disease, hypothyroidism, hyperlipidaemia and pregnancy are associated with raised lipids and may also cause a raised MCV. Reticulocytes are larger than mature red cells, so when the reticulocyte count is raised – e.g. in haemolysis – this may also increase the MCV. Iron deficiency anaemia This occurs when iron losses or physiological requirements exceed absorption. Blood loss The most common explanation in men and post-menopausal women is gastrointestinal blood loss (p. 780). This may result from occult gastric or colorectal malignancy, gastritis, peptic ulceration, inflammatory bowel disease, diverticulitis, polyps and angiodysplastic lesions. Worldwide, hookworm and schistosomiasis are the most common causes of gut blood loss (pp. 288 and 294). Gastrointestinal blood loss may be exacerbated Drug interactions are common through protein binding and metabolism by the cytochrome P450 system. Inter-individual differences in warfarin doses required to achieve a therapeutic INR are mostly accounted for by naturally occurring polymorphisms in the CYP2C9 and the VKORC1 genes (which predict the metabolism and function of warfarin, respectively) and dietary intake of vitamin K. Major bleeding is the most common serious side-effect of warfarin and occurs in 1–2% of patients each year. Fatal haemorrhage, which is most commonly intracranial, occurs in about 0.25% per annum. There are scoring systems that predict the annual bleeding risk and these can be used to help compare the risks and benefits of warfarin for an individual patient (Box 23.28). There are also some specific contraindications to anticoagulation (Box 23.28). Management of warfarin includes strategies for over-anticoagulation and for bleeding: • If the INR is above the therapeutic level, warfarin should be withheld or the dose reduced. If the patient is not bleeding, it may be appropriate to give a small dose of vitamin K either orally or intravenously (1–2.5 mg), especially if the INR is greater than 8. • In the event of bleeding, withhold further warfarin. Minor bleeding can be treated with 1–2.5 mg of vitamin K IV. Major haemorrhage should be treated as an emergency with vitamin K 5–10 mg slowly IV, combined with coagulation factor replacement (see Box 23.27). This should optimally be a prothrombin complex concentrate (30–50 U/kg) that contains factors II, VII, IX and X; if that is not available, fresh frozen plasma (15–30 mL/kg) should be given. Direct oral anticoagulants The direct oral anticoagulants (DOACs) offer an alternative to coumarins in the management of VTE and the prevention of stroke and systemic embolism in patients with atrial fibrillation. The DOACs are direct specific inhibitors of key proteases in the common pathway. Dabigatran inhibits thrombin while rivaroxaban, apixaban and edoxaban inhibit Xa. The key features of these drugs include the fact that they are efficacious in fixed oral doses, have a short half-life of around 10 hours, achieve peak plasma levels 23.28 How to assess risks of anticoagulation Contraindications • Recent surgery, especially to eye or central nervous system • Pre-existing haemorrhagic state, e.g. advanced liver disease, haemophilia, thrombocytopenia • Pre-existing structural lesions, e.g. peptic ulcer • Recent cerebral or gastrointestinal haemorrhage • Uncontrolled hypertension • Cognitive impairment • Frequent falls Bleeding risk score • Several bleeding risk scores exist for different indications for anticoagulation • The validation of most bleeding risk scores has been poor • Many risk factors for thrombosis are also risk factors for bleeding • Following anticoagulant-related bleeding, reassessment of bleeding and thrombosis risk is indicated • In many cases, patients benefit from recommencing anticoagulants after bleeding

Anaemias • 941

very specific test; a subnormal level is due to iron deficiency or, very rarely, hypothyroidism or vitamin C deficiency. Ferritin levels can be raised in liver disease and in the acute phase response; in these conditions, a ferritin level of up to 100 μg/L may still be compatible with low bone marrow iron stores. by the chronic use of aspirin or non-steroidal anti-inflammatory drugs (NSAIDs), which cause intestinal erosions and impair platelet function. In women of child-bearing age, menstrual blood loss, pregnancy and breastfeeding contribute to iron deficiency by depleting iron stores; in developed countries, one-third of pre-menopausal women have low iron stores but only 3% display iron-deficient haematopoiesis. Very rarely, chronic haemoptysis or haematuria may cause iron deficiency. Malabsorption A dietary assessment should be made in all patients to ascertain their iron intake (p. 716). Gastric acid is required to release iron from food and helps to keep iron in the soluble ferrous state (Fig. 23.18). Achlorhydria in the elderly or that due to drugs such as proton pump inhibitors may contribute to the lack of iron availability from the diet, as may previous gastric surgery. Iron is absorbed actively in the upper small intestine and hence can be affected by coeliac disease (p. 805). Physiological demands At times of rapid growth, such as infancy and puberty, iron requirements increase and may outstrip absorption. In pregnancy, iron is diverted to the fetus, the placenta and the increased maternal red cell mass, and is lost with bleeding at parturition (Box 23.29). Investigations Confirmation of iron deficiency Serum ferritin is a measure of iron stores in tissues and is the best single test to confirm iron deficiency (Box 23.30). It is a Fig. 23.17 Factors that influence the size of red cells in anaemia. In microcytosis, the MCV is < 76 fL. In macrocytosis, the MCV is > 100 fL. (MCV = mean cell volume; RBC = red blood cell) Normal Defective haemoglobinisation Defective DNA synthesis Normal DNA synthesis e.g. Iron deficiency Thalassaemia Sideroblastic anaemia Reticulocyte e.g. ↓ B12 ↓ Folate Cytotoxic drugs Myelodysplasia Marked reticulocytosis Normal-sized RBC Elevated plasma lipid Liver disease Hypothyroidism Alcohol Hyperlipidaemia Pregnancy Normal haemoglobinisation Macrocytosis (↑ MCV) Microcytosis (↓ MCV) Marrow Blood 23.29 Haematological physiology in pregnancy • Full blood count: increased plasma volume (40%) lowers normal haemoglobin (reference range reduced to > 105 g/L at 28 weeks). The mean cell volume (MCV) may increase by 5 fL. A progressive neutrophilia occurs. Gestational thrombocytopenia (rarely < 60 × 109/L) is a benign phenomenon. • Depletion of iron stores: iron deficiency is a common cause of anaemia in pregnancy and, if present, should be treated with oral iron supplement. • Vitamin B12: serum levels are physiologically low in pregnancy but deficiency is uncommon. • Folate: tissue stores may become depleted, and folate supplementation is recommended in all pregnancies (see Box 19.29, p. 712). • Coagulation factors: from the second trimester, procoagulant factors increase approximately threefold, particularly fibrinogen, von Willebrand factor and factor VIII. This causes activated protein C resistance and a shortened activated partial thromboplastin time (APTT), and contributes to a prothrombotic state. • Anticoagulants: levels of protein C increase from the second trimester, while levels of free protein S fall as C4b binding protein increases.

942 • HAEMATOLOGY AND TRANSFUSION MEDICINE can now be measured by immunoassay and used to distinguish storage iron depletion in the presence of an acute phase response or liver disease, when a raised level indicates iron deficiency. In difficult cases, it may still be necessary to examine a bone marrow aspirate for iron stores. Investigation of the cause This will depend on the age and sex of the patient, as well as the history and clinical findings. In men and in post-menopausal women with a normal diet, the upper and lower gastrointestinal tract should be investigated by endoscopy or radiological studies. Serum anti-transglutaminase antibodies and possibly a duodenal biopsy are indicated (p. 806) to detect coeliac disease. Current guidelines suggest exclusion of coeliac disease by antibody testing at an early stage of investigation. In the tropics, stool and urine should be examined for parasites (p. 233). Plasma iron and total iron binding capacity (TIBC) are measures of iron availability; hence they are affected by many factors besides iron stores. Plasma iron has a marked diurnal and day-to-day variation and becomes very low during an acute phase response but is raised in liver disease and haemolysis. Levels of transferrin, the binding protein for iron, are lowered by malnutrition, liver disease, the acute phase response and nephrotic syndrome, but raised by pregnancy and the oral contraceptive pill. A transferrin saturation (i.e. iron/TIBC × 100) of less than 16% is consistent with iron deficiency but is less specific than a ferritin measurement. All proliferating cells express membrane transferrin receptors to acquire iron; a small amount of this receptor is shed into blood, where it can be detected in a free soluble form. At times of poor iron stores, cells up-regulate transferrin receptor expression and the levels of soluble plasma transferrin receptor increase. This Fig. 23.18 The regulation of iron absorption, uptake and distribution in the body. The transport of iron is regulated in a similar fashion to enterocytes in other iron-transporting cells such as macrophages. < 10% Non-haem iron Haem iron

90% Iron available for absorption or Amino acids Vitamin C Phytates Tannins Phosphates Dietary iron 7 mg/1000 kcal < 5% ~30% Iron binds to transferrin for delivery to tissues Maximum iron absorption 3.5 mg/day Tissue iron Enzymes (2%) Myoglobin (4%) Ferritin (29%) Haemoglobin (65%) High hepcidin state Low hepcidin state Ferroportin internalised Ferroportin available Gut lumen Fe Fe Fe Fe Fe Fe Fe Fe Blood Enterocyte Ferroportin Hepcidin Inflammatory cytokines induce hepcidin secretion from liver Anaemia Hypoxia Low iron stores suppress hepcidin secretion from liver 23.30 Investigations to differentiate anaemia of chronic disease from iron deficiency anaemia Ferritin Iron TIBC Transferrin saturation Soluble transferrin receptor Iron deficiency anaemia ↓ ↓ ↑ ↓ ↑ Anaemia of chronic disease ↑/Normal ↓ ↓ ↓ ↓/Normal (TIBC = total iron binding capacity)

Anaemias • 943

Megaloblastic anaemia This results from a deficiency of vitamin B12 or folic acid, or from disturbances in folic acid metabolism. Folate is an important substrate of, and vitamin B12 a co-factor for, the generation of the essential amino acid methionine from homocysteine. This reaction produces tetrahydrofolate, which is converted to thymidine monophosphate for incorporation into DNA. Deficiency of either vitamin B12 or folate will therefore produce high plasma levels of homocysteine and impaired DNA synthesis. The end result is cells with arrested nuclear maturation but normal cytoplasmic development: so-called nucleocytoplasmic asynchrony. All proliferating cells will exhibit megaloblastosis; hence changes are evident in the buccal mucosa, tongue, small intestine, cervix, vagina and uterus. The high proliferation rate of bone marrow results in striking changes in the haematopoietic system in megaloblastic anaemia. Cells become arrested in development and die within the marrow; this ineffective erythropoiesis results in an expanded hypercellular marrow. The megaloblastic changes are most evident in the early nucleated red cell precursors, and haemolysis within the marrow results in a raised bilirubin and lactate dehydrogenase (LDH), but without the reticulocytosis characteristic of other forms of haemolysis (p. 945). Iron stores are usually raised. The mature red cells are large and oval, and sometimes contain nuclear remnants. Nuclear changes are seen in the immature granulocyte precursors and a characteristic appearance is that of ‘giant’ metamyelocytes with a large ‘sausage-shaped’ nucleus. The mature neutrophils show hypersegmentation of their nuclei, with cells having six or more nuclear lobes. If severe, a pancytopenia may be present in the peripheral blood. Vitamin B12 deficiency, but not folate deficiency, is associated with neurological disease in up to 40% of cases, although advanced neurological disease due to B12 deficiency is now uncommon in the developed world. The main pathological finding is focal demyelination affecting the spinal cord, peripheral nerves, optic nerves and cerebrum. The most common manifestations are sensory, with peripheral paraesthesiae and ataxia of gait. The clinical and diagnostic features of megaloblastic anaemia are summarised in Boxes 23.31 and 23.32, and the neurological features of B12 deficiency in Box 23.33. Vitamin B12 Vitamin B12 absorption The average daily diet contains 5–30 μg of vitamin B12, mainly in meat, fish, eggs and milk – well in excess of the 1 μg daily Management Unless the patient has angina, heart failure or evidence of cerebral hypoxia, transfusion is not necessary and oral iron replacement is appropriate. Ferrous sulphate 200 mg 3 times daily (195 mg of elemental iron per day) is adequate and should be continued for 3–6 months to replete iron stores. Many patients suffer gastrointestinal side-effects with ferrous sulphate, including dyspepsia and altered bowel habit. When this occurs, reduction in dose to 200 mg twice daily or a switch to ferrous gluconate 300 mg twice daily (70 mg of elemental iron per day) or another alternative oral preparation should be tried. Delayed-release preparations are not useful, since they release iron beyond the upper small intestine, where it cannot be absorbed. The haemoglobin should rise by around 10 g/L every 7–10 days and a reticulocyte response will be evident within a week. A failure to respond adequately may be due to non-adherence, continued blood loss, malabsorption or an incorrect diagnosis. Patients with malabsorption, chronic gut disease or inability to tolerate any oral preparation may need parenteral iron therapy. Previously, iron dextran or iron sucrose was used, but new preparations of iron isomaltose and iron carboxymaltose have fewer allergic effects and are preferred. Doses required can be calculated based on the patient’s starting haemoglobin and body weight. Observation for anaphylaxis following an initial test dose is recommended. Anaemia of chronic disease Anaemia of chronic disease (ACD), also known as anaemia of inflammation (AI), is a common type of anaemia, particularly in hospital populations. It occurs in the setting of chronic infection, chronic inflammation or neoplasia. The anaemia is not related to bleeding, haemolysis or marrow infiltration, is mild, with haemoglobin in the range of 85–115 g/L, and is usually associated with a normal MCV (normocytic, normochromic), though this may be reduced in long-standing inflammation. The serum iron is low but iron stores are normal or increased, as indicated by the ferritin or stainable marrow iron. Pathogenesis It has recently become clear that the key regulatory protein that accounts for the findings characteristic of ACD/AI is hepcidin, which is produced by the liver (see Fig. 23.18). Hepcidin production is induced by pro-inflammatory cytokines, especially IL-6. Hepcidin binds to ferroportin on the membrane of iron-exporting cells, such as small intestinal enterocytes and macrophages, internalising the ferroportin and thereby inhibiting the export of iron from these cells into the blood. The iron remains trapped inside the cells in the form of ferritin, levels of which are therefore normal or high in the face of significant anaemia. Inhibition or blockade of hepcidin is a potential target for treatment of this form of anaemia. Diagnosis and management It is often difficult to distinguish ACD associated with a low MCV from iron deficiency. Box 23.30 summarises the investigations and results. Examination of the marrow may ultimately be required to assess iron stores directly. A trial of oral iron can be given in difficult situations. A positive response occurs in true iron deficiency but not in ACD. Measures that reduce the severity of the underlying disorder generally help to improve the ACD. Trials of higher-dose intravenous iron are under way to try to bypass the hepcidin-induced blockade. 23.31 Clinical features of megaloblastic anaemia Symptoms • Malaise (90%) • Breathlessness (50%) • Paraesthesiae (80%) • Sore mouth (20%) • Weight loss • Impotence • Poor memory • Depression • Personality change • Hallucinations • Visual disturbance Signs • Smooth tongue • Angular cheilosis • Vitiligo • Skin pigmentation • Heart failure • Pyrexia

944 • HAEMATOLOGY AND TRANSFUSION MEDICINE not add much in most clinical situations. Levels of cobalamins fall in normal pregnancy. Reference ranges vary between laboratories but levels below 150 ng/L are common and, in the last trimester, 5–10% of women have levels below 100 ng/L. Spuriously low B12 values occur in women using the oral contraceptive pill and in patients with myeloma, in whom paraproteins can interfere with vitamin B12 assays. Causes of vitamin B12 deficiency Dietary deficiency This occurs only in strict vegans but the onset of clinical features can occur at any age between 10 and 80 years. Less strict vegetarians often have slightly low vitamin B12 levels but are not tissue vitamin B12-deficient. Gastric pathology Release of vitamin B12 from food requires normal gastric acid and enzyme secretion, and this is impaired by hypochlorhydria in elderly patients or following gastric surgery. Total gastrectomy invariably results in vitamin B12 deficiency within 5 years, often combined with iron deficiency; these patients need life-long 3-monthly vitamin B12 injections. After partial gastrectomy, vitamin B12 deficiency only develops in 10–20% of patients by 5 years; an annual injection of vitamin B12 should prevent deficiency in this group. Pernicious anaemia This is an organ-specific autoimmune disorder in which the gastric mucosa is atrophic, with loss of parietal cells causing intrinsic factor deficiency. In the absence of intrinsic factor, less than 1% of dietary vitamin B12 is absorbed. Pernicious anaemia has an incidence of 25/100 000 population over the age of 40 years in developed countries, but an average age of onset of 60 years. It is more common in individuals with other autoimmune disease (Hashimoto’s thyroiditis, Graves’ disease, vitiligo or Addison’s disease; Ch. 18) or a family history of these or pernicious anaemia. The finding of anti-intrinsic factor antibodies in the context of B12 deficiency is diagnostic of pernicious anaemia without further investigation. Antiparietal cell antibodies are present in over 90% of cases but are also present in 20% of normal females over the age of 60 years; a negative result makes pernicious anaemia less likely but a positive result is not diagnostic. The Schilling test, involving measurement of absorption of radio-labelled B12 after oral administration before and after replacement of intrinsic factor, has fallen out of favour with the availability of autoantibody tests, greater caution in the use of radioactive tracers, and limited availability of intrinsic factor. Small bowel pathology One-third of patients with pancreatic exocrine insufficiency fail to transfer dietary vitamin B12 from R protein to intrinsic factor. This usually results in slightly low vitamin B12 values but no tissue evidence of vitamin B12 deficiency. Motility disorders or hypogammaglobulinaemia can result in bacterial overgrowth, and the ensuing competition for free vitamin B12 can lead to deficiency. This is corrected to some extent by appropriate antibiotics. A small number of people heavily infected with the fish tapeworm (p. 297) develop vitamin B12 deficiency. Inflammatory disease of the terminal ileum, such as Crohn’s disease, may impair the absorption of vitamin B12–intrinsic factor complex, as may surgery on that part of the bowel. requirement. In the stomach, gastric enzymes release vitamin B12 from food and at gastric pH it binds to a carrier protein termed R protein. The gastric parietal cells produce intrinsic factor, a vitamin B12-binding protein that optimally binds vitamin B12 at pH 8. As gastric emptying occurs, pancreatic secretion raises the pH and vitamin B12 released from the diet switches from the R protein to intrinsic factor. Bile also contains vitamin B12 that is available for reabsorption in the intestine. The vitamin B12–intrinsic factor complex binds to specific receptors in the terminal ileum, and vitamin B12 is actively transported by the enterocytes to plasma, where it binds to transcobalamin II, a transport protein produced by the liver, which carries it to the tissues for utilisation. The liver stores enough vitamin B12 for 3 years and this, together with the enterohepatic circulation, means that vitamin B12 deficiency takes years to become manifest, even if all dietary intake is stopped or severe B12 malabsorption supervenes. Blood levels of vitamin B12 (cobalamin) provide a reasonable indication of tissue stores, are usually diagnostic of deficiency and remain the first-line tests for most laboratories. Additional tests have been evaluated, including measurement of methylmalonic acid, holotranscobalamin and plasma homocysteine levels, but do 23.33 Neurological findings in B12 deficiency Peripheral nerves • Glove and stocking paraesthesiae • Loss of ankle reflexes Spinal cord • Subacute combined degeneration of the cord Posterior columns – diminished vibration sensation and proprioception Corticospinal tracts – upper motor neuron signs Cerebrum • Dementia • Optic atrophy Autonomic neuropathy 23.32 Investigations in megaloblastic anaemia Investigation Result Haemoglobin Often reduced, may be very low Mean cell volume Usually raised, commonly > 120 fL Erythrocyte count Low for degree of anaemia Blood film Oval macrocytosis, poikilocytosis, red cell fragmentation, neutrophil hypersegmentation Reticulocyte count Low for degree of anaemia Leucocyte count Low or normal Platelet count Low or normal Bone marrow Increased cellularity, megaloblastic changes in erythroid series, giant metamyelocytes, dysplastic megakaryocytes, increased iron in stores, pathological non-ring sideroblasts Serum ferritin Elevated Plasma lactate dehydrogenase Elevated, often markedly

Anaemias • 945

results are available, that treatment should always include both folic acid and vitamin B12. The use of folic acid alone in the presence of vitamin B12 deficiency may result in worsening of neurological features. Rarely, if severe angina or heart failure is present, transfusion can be used in megaloblastic anaemia. The cardiovascular system is adapted to the chronic anaemia present in megaloblastosis, and the volume load imposed by transfusion may result in decompensation and severe cardiac failure. In such circumstances, exchange transfusion or slow administration of 1 U of red cells with diuretic cover may be given. Vitamin B12 deficiency Vitamin B12 deficiency is treated with hydroxycobalamin. In cases of uncomplicated deficiency, 1000 μg IM for 6 doses 2 or 3 days apart, followed by maintenance therapy of 1000 μg every 3 months for life, is recommended. In the presence of neurological involvement, a dose of 1000 μg on alternate days until there is no further improvement, followed by maintenance as above, is recommended. The reticulocyte count will peak by the 5th–10th day after starting replacement therapy. The haemoglobin will rise by 10 g/L every week until normalised. The response of the marrow is associated with a fall in plasma potassium levels and rapid depletion of iron stores. If an initial response is not maintained and the blood film is dimorphic (i.e. shows a mixture of microcytic and macrocytic cells), the patient may need additional iron therapy. A sensory neuropathy may take 6–12 months to correct; long-standing neurological damage may not improve. Folate deficiency Oral folic acid (5 mg daily for 3 weeks) will treat acute deficiency and 5 mg once weekly is adequate maintenance therapy. Prophylactic folic acid in pregnancy prevents megaloblastosis in women at risk, and reduces the risk of fetal neural tube defects (p. 712). Prophylactic supplementation is also given in chronic haematological disease associated with reduced red cell lifespan (e.g. haemolytic anaemias). There is some evidence that supraphysiological supplementation (400 μg/day) can reduce the risk of coronary and cerebrovascular disease by lowering plasma homocysteine levels. This has led the US Food and Drug Administration to introduce fortification of bread, flour and rice with folic acid. Haemolytic anaemia Haemolysis indicates that there is shortening of the normal red cell lifespan of 120 days. There are many causes, as shown in Figure 23.19. To compensate, the bone marrow may increase its output of red cells six- to eightfold by increasing the proportion of red cells produced, expanding the volume of active marrow, and releasing reticulocytes prematurely. Anaemia occurs only if the rate of destruction exceeds this increased production rate. There are some general features of haemolysis and other specific features that help to identify the reason for haemolysis. Results of investigations that establish the presence of haemolysis are shown in Box 23.36. Red cell destruction overloads pathways for haemoglobin breakdown in the liver (p. 850), causing a modest rise in unconjugated bilirubin in the blood and mild jaundice. Increased reabsorption of urobilinogen from the gut results in an increase in urinary urobilinogen (pp. 860 and 915). Red cell destruction releases LDH into the serum. The bone Folate Folate absorption Folates are produced by plants and bacteria; hence dietary leafy vegetables (spinach, broccoli, lettuce), fruits (bananas, melons) and animal protein (liver, kidney) are a rich source. An average Western diet contains more than the minimum daily intake of 50 μg but excess cooking destroys folates. Most dietary folate is present as polyglutamates; these are converted to monoglutamate in the upper small bowel and actively transported into plasma. Plasma folate is loosely bound to plasma proteins such as albumin and there is an enterohepatic circulation. Total body stores of folate are small and deficiency can occur in a matter of weeks. Folate deficiency The causes and diagnostic features of folate deficiency are shown in Boxes 23.34 and 23.35. The edentulous elderly or psychiatric patient is particularly susceptible to dietary deficiency and this is exacerbated in the presence of gut disease or malignancy. Pregnancy-induced folate deficiency is the most common cause of megaloblastosis worldwide and is more likely in the context of twin pregnancies, multiparity and hyperemesis gravidarum. Serum folate measurement is very sensitive to dietary intake; a single folate-rich meal can normalise it in a patient with true folate deficiency, whereas anorexia, alcohol and anticonvulsant therapy can reduce it in the absence of megaloblastosis. For this reason, red cell folate levels are a more accurate indicator of folate stores and tissue folate deficiency. Management of megaloblastic anaemia If a patient with a severe megaloblastic anaemia is very ill and treatment must be started before vitamin B12 and red cell folate 23.35 Investigation of folic acid deficiency Diagnostic findings • Serum folate levels may be low but are difficult to interpret • Low red cell folate levels indicate prolonged folate deficiency and are probably the most relevant measure Corroborative findings • Macrocytic dysplastic blood picture • Megaloblastic marrow Usually only a problem in patients deficient in folate from another cause. 23.34 Causes of folate deficiency Diet • Poor intake of vegetables Malabsorption • e.g. Coeliac disease, small bowel surgery Increased demand • Cell proliferation, e.g. haemolysis • Pregnancy Drugs • Certain anticonvulsants (e.g. phenytoin) • Contraceptive pill • Certain cytotoxic drugs (e.g. methotrexate)

946 • HAEMATOLOGY AND TRANSFUSION MEDICINE the red cells may give an indication of the likely cause of the haemolysis: • Spherocytes are small, dark red cells that suggest autoimmune haemolysis or hereditary spherocytosis. • Sickle cells suggest sickle-cell disease. • Red cell fragments indicate microangiopathic haemolysis. • Bite cells (normal-sized red cells that look as if they have been partially eaten) suggest oxidative haemolysis. The compensatory erythroid hyperplasia may give rise to folate deficiency, with megaloblastic blood features. The differential diagnosis of haemolysis is determined by the clinical scenario in combination with the results of blood film examination and Coombs testing for antibodies directed against red cells (see below and Fig. 23.19). Extravascular haemolysis Physiological red cell destruction occurs in the reticulo-endothelial cells in the liver or spleen, so avoiding free haemoglobin in the marrow compensation results in a reticulocytosis, and sometimes nucleated red cell precursors appear in the blood. Increased proliferation of the bone marrow can result in a thrombocytosis, neutrophilia and, if marked, immature granulocytes in the blood, producing a leucoerythroblastic blood film. The appearances of Fig. 23.19 Causes and classification of haemolysis. A Inherited causes. B Acquired causes. (CLL = chronic lymphocytic leukaemia; DIC = disseminated intravascular coagulation; EBV = Epstein–Barr virus; G6PD = glucose-6-phosphate dehydrogenase; HUS = haemolytic uraemic syndrome; PK = pyruvate kinase; RA = rheumatoid arthritis; SLE = systemic lupus erythematosus; TTP = thrombotic thrombocytopenic purpura) A B Primary idiopathic Secondary •Autoimmune, e.g. SLE, RA •Drugs, e.g. L-dopa, methyldopa, mefenamic acid, penicillin, quinidine, fludarabine •Lymphoid malignancy, e.g. CLL, myeloma, lymphoma •Other malignancy, e.g. lung, colon, kidney, ovary, thymoma •Others, e.g. ulcerative colitis, HIV Primary idiopathic Secondary •Infection, e.g. mycoplasma, EBV, syphilis •Lymphoprolifer- ative disorders, e.g. lymphoma Red cell antigeninduced •Transfusion reaction •Haemolytic disease of the newborn Immune Acquired Inherited Non-immune Autoantibodies Alloantibodies Warm antibodies Cold antibodies Mechanical •Prosthetic valves •Microangiopathic, e.g. DIC, HUS, TTP •March haemoglobinuria Infection •Intracellular organisms, e.g. malaria •Toxins, e.g. C. perfringens Chemical/physical •Oxidative drugs, e.g. dapsone, maloprim •Copper (Wilson’s disease) •Burns •Drowning

Acquired abnormal membrane •Paroxysmal nocturnal haemoglobinuria Red cell membrane abnormality •Hereditary spherocytosis •Hereditary elliptocytosis Haemoglobin •Deficiency, e.g. thalassaemias •Abnormality, e.g. sickle-cell disease Red cell enzyme deficiency •Glycolytic pathway, e.g. PK •Hexose monophosphate shunt, e.g. G6PD •Pyrimidine 5´ nucleotidase 23.36 Investigation results indicating active haemolysis Hallmarks of haemolysis • ↓Haemoglobin • ↑Unconjugated bilirubin • ↑Lactate dehydrogenase • ↑Reticulocytes • ↑Urinary urobilinogen Additional features of intravascular haemolysis • ↓Haptoglobin • ↑Methaemalbumin • Positive urinary haemosiderin • Haemoglobinuria

Anaemias • 947

Hereditary spherocytosis This is usually inherited as an autosomal dominant condition, although 25% of cases have no family history and represent new mutations. The incidence is approximately 1 : 5000 in developed countries but this may be an under-estimate, since the disease may present de novo in patients aged over 65 years and is often discovered as a chance finding on a blood count. The most common abnormalities are deficiencies of beta spectrin or ankyrin (see Fig. 23.4). The severity of spontaneous haemolysis varies. Most cases are associated with an asymptomatic compensated chronic haemolytic state with spherocytes present on the blood film, a reticulocytosis and mild hyperbilirubinaemia. Pigment gallstones are present in up to 50% of patients and may cause symptomatic cholecystitis. Occasional cases are associated with more severe haemolysis; these may be due to coincidental polymorphisms in alpha spectrin or co-inheritance of a second defect involving a different protein. These cases tend to present earlier in life with symptomatic, sometimes transfusion-dependent anaemia. The clinical course may be complicated by crises: • A haemolytic crisis occurs when the severity of haemolysis increases; this is rare, and usually associated with infection. • A megaloblastic crisis follows the development of folate deficiency; this may occur as a first presentation of the disease in pregnancy. • An aplastic crisis occurs in association with parvovirus (erythrovirus) infection (p. 237). Parvovirus causes a common exanthem in children, but if individuals with chronic haemolysis become infected, the virus directly invades red cell precursors and temporarily switches off red cell production. Patients present with severe anaemia and a low reticulocyte count. Investigations The patient and other family members should be screened for features of compensated haemolysis (see Box 23.36). This may be all that is required to confirm the diagnosis. Haemoglobin levels are variable, depending on the degree of compensation. The blood film will show spherocytes but the direct Coombs test (Fig. 23.20) is negative, excluding immune haemolysis. An osmotic fragility test may show increased sensitivity to lysis in hypotonic saline solutions but is limited by lack of sensitivity and specificity. More specific flow cytometric tests, detecting binding of eosin-5-maleimide to red cells, are recommended in borderline cases. Management Folic acid prophylaxis, 5 mg daily, should be given for life. In severe cases, consideration may be given to splenectomy, which improves but does not normalise red cell survival. Potential indications for splenectomy include moderate to severe haemolysis with complications (anaemia and gallstones), although splenectomy should be delayed where possible until after 6 years of age in view of the risk of sepsis. Guidelines for the management of patients after splenectomy are presented in Box 23.37. Acute, severe haemolytic crises require transfusion support, but blood must be cross-matched carefully and transfused slowly as haemolytic transfusion reactions may occur (p. 935). Hereditary elliptocytosis This term refers to a heterogeneous group of disorders that produce an increase in elliptocytic red cells on the blood film and a variable degree of haemolysis. This is due to a functional plasma. In most haemolytic states, haemolysis is predominantly extravascular. To confirm the haemolysis, patients’ red cells can be labelled with 51chromium. When re-injected, they can be used to determine red cell survival; when combined with body surface radioactivity counting, this test may indicate whether the liver or the spleen is the main source of red cell destruction. However, it is seldom performed in clinical practice. Intravascular haemolysis Less commonly, red cell lysis occurs within the blood stream due to membrane damage by complement (ABO transfusion reactions, paroxysmal nocturnal haemoglobinuria), infections (malaria, Clostridium perfringens), mechanical trauma (heart valves, DIC) or oxidative damage (e.g. enzymopathies such as glucose6-phosphate dehydrogenase deficiency, which may be triggered by drugs such as dapsone and maloprim). When intravascular red cell destruction occurs, free haemoglobin is released into the plasma. Free haemoglobin is toxic to cells and binding proteins have evolved to minimise this risk. Haptoglobin is an α2-globulin produced by the liver, which binds free haemoglobin, resulting in a fall in its levels during active haemolysis. Once haptoglobins are saturated, free haemoglobin is oxidised to form methaemoglobin, which binds to albumin, in turn forming methaemalbumin, which can be detected spectrophotometrically in Schumm’s test. Methaemoglobin is degraded and any free haem is bound to a second binding protein called haemopexin. If all the protective mechanisms are saturated, free haemoglobin may appear in the urine (haemoglobinuria). When fulminant, this gives rise to black urine, as in severe falciparum malaria infection (p. 274). In smaller amounts, renal tubular cells absorb the haemoglobin, degrade it and store the iron as haemosiderin. When the tubular cells are subsequently sloughed into the urine, they give rise to haemosiderinuria, which is always indicative of intravascular haemolysis (Box 23.36). Causes of haemolytic anaemia These can be classified as inherited or acquired (Fig. 23.19). • Inherited red cell abnormalities resulting in chronic haemolytic anaemia may arise from pathologies of the red cell membrane (hereditary spherocytosis or elliptocytosis), haemoglobin (haemoglobinopathies), or protective enzymes that prevent cellular oxidative damage, such as glucose-6-phosphate dehydrogenase (G6PD). • Acquired causes include auto- and alloantibody-mediated destruction of red blood cells and other mechanical, toxic and infective causes. Red cell membrane defects The structure of the red cell membrane is shown in Figure 23.4. The basic structure is a cytoskeleton ‘stapled’ on to the lipid bilayer by special protein complexes. This structure ensures great deformability and elasticity; the red cell diameter is 8 μm but the narrowest capillaries in the circulation are in the spleen, measuring just 2 μm in diameter. When the normal red cell structure is disturbed, usually by a quantitative or functional deficiency of one or more proteins in the cytoskeleton, cells lose their elasticity. Each time such cells pass through the spleen, they lose membrane relative to their cell volume. This results in an increase in mean cell haemoglobin concentration (MCHC), abnormal cell shape (see Box 23.2) and reduced red cell survival due to extravascular haemolysis.

948 • HAEMATOLOGY AND TRANSFUSION MEDICINE A characteristic variant of hereditary elliptocytosis occurs in South-east Asia, particularly Malaysia and Papua New Guinea, with stomatocytes and ovalocytes in the blood. This has a prevalence of up to 30% in some communities because it offers relative protection from malaria and thus has sustained a high gene frequency. The blood film is often very abnormal and immediate differential diagnosis is broad. Red cell enzymopathies The mature red cell must produce energy via ATP to maintain a normal internal environment and cell volume while protecting itself from the oxidative stress presented by oxygen carriage. ATP is generated by glycolysis, while the hexose monophosphate shunt produces nicotinamide adenine dinucleotide phosphate (NADPH) and glutathione to protect against oxidative stress. The impact of functional or quantitative defects in the enzymes in these pathways depends on the importance of the steps affected and the presence of alternative pathways. In general, defects in the hexose monophosphate shunt pathway result in periodic haemolysis precipitated by episodic oxidative stress, while those in the glycolysis pathway result in shortened red cell survival and chronic haemolysis. Glucose-6-phosphate dehydrogenase deficiency The enzyme glucose-6-phosphate dehydrogenase (G6PD) is pivotal in the hexose monophosphate shunt pathway. Deficiencies result in the most common human enzymopathy, affecting 10% of the world’s population, with a geographical distribution that parallels the malaria belt because heterozygotes are protected from malarial parasitisation. The enzyme is a heteromeric structure made of catalytic subunits that are encoded by a gene on the X chromosome. The deficiency therefore affects males and rare abnormality of one or more anchor proteins in the red cell membrane, e.g. alpha spectrin or protein 4.1 (see Fig. 23.4). Inheritance may be autosomal dominant or recessive. Hereditary elliptocytosis is less common than hereditary spherocytosis in Western countries, with an incidence of 1/10 000, but is more common in equatorial Africa and parts of South-east Asia. The clinical course is variable and depends on the degree of membrane dysfunction caused by the inherited molecular defect(s); most cases present as an asymptomatic blood film abnormality but occasional cases result in neonatal haemolysis or a chronic compensated haemolytic state. Management of the latter is the same as for hereditary spherocytosis. 23.37 Management of the splenectomised patient • Vaccinate with pneumococcal, Haemophilus influenzae type B, meningococcal group C and influenza vaccines at least 2–3 weeks before elective splenectomy. Vaccination should be given after emergency surgery but may be less effective • Pneumococcal re-immunisation should be given at least 5-yearly and influenza annually. Vaccination status must be documented • Life-long prophylactic penicillin V (500 mg twice daily) is recommended. In penicillin-allergic patients, consider a macrolide • Patients should be educated regarding the risks of infection and methods of prophylaxis • A card or bracelet should be carried to alert health professionals to the risk of overwhelming sepsis • In sepsis, patients should be resuscitated and given IV antibiotics to cover pneumococcus, Haemophilus and meningococcus, according to local resistance patterns • The risk of cerebral malaria is increased in the event of infection • Animal bites should be promptly treated with local disinfection and antibiotics, to prevent serious soft tissue infection and sepsis Fig. 23.20 Direct and indirect antiglobulin tests. Direct antiglobulin test (DAT) (Coombs test) Detects the presence of antibody bound to the red cell surface, e.g.

  1. Autoimmune haemolytic anaemia
  2. Haemolytic disease of newborn
  3. Transfusion reactions Antibodies to human globulin Red cell agglutination Indirect antiglobulin test (IAT) (indirect Coombs test) Detects antibodies in the plasma, e.g.
  4. Antibody screen in pre-transfusion testing
  5. Screening in pregnancy for antibodies that may cause

haemolytic disease of newborn Red cells with known antigen expression Red cell agglutination Patient’s plasma Stage 1 Red cells with Ag – Ab complex on cell surface Stage 2 Antibodies to human globulin Key Red blood cells Red cell antigen Antibody bound to red cell antigen A B

Anaemias • 949

Pyrimidine 5′ nucleotidase deficiency The pyrimidine 5′ nucleotidase enzyme catalyses the dephosphorylation of nucleoside monophosphates and is important during the degradation of RNA in reticulocytes. It is inherited as an autosomal recessive trait and is as common as pyruvate kinase deficiency in Mediterranean, African and Jewish populations. The accumulation of excess ribonucleoprotein results in coarse basophilic stippling (see Box 23.2), associated with a chronic haemolytic state. The enzyme is very sensitive to inhibition by lead and this is the reason why basophilic stippling is a feature of lead poisoning. Autoimmune haemolytic anaemia This results from increased red cell destruction due to red cell autoantibodies. The antibodies may be IgG or IgM, or more rarely IgE or IgA. If an antibody avidly fixes complement, it will cause intravascular haemolysis, but if complement activation is weak, the haemolysis will be extravascular (in the reticulo-endothelial system). Antibody-coated red cells lose membrane to macrophages in the spleen and hence spherocytes are present in the blood. The optimum temperature at which the antibody is active (thermal specificity) is used to classify immune haemolysis: • Warm antibodies bind best at 37°C and account for 80% of cases. The majority are IgG and often react against Rhesus antigens. • Cold antibodies bind best at 4°C but can bind up to 37°C in some cases. They are usually IgM and bind complement. To be clinically relevant, they must act within the range of normal body temperatures. They account for the other 20% of cases. Warm autoimmune haemolysis The incidence of warm autoimmune haemolysis is approximately 1/100 000 population per annum; it occurs at all ages but is more common in middle age and in females. No underlying cause is identified in up to 50% of cases. The remainder are secondary to a wide variety of other conditions (see Fig. 23.19B). Investigations There is evidence of haemolysis, spherocytes and polychromasia on the blood film. The diagnosis is confirmed by the direct Coombs or antiglobulin test (see Fig. 23.20). The patient’s red cells are mixed with Coombs reagent, which contains antibodies against human IgG/IgM/complement. If the red cells have been coated by antibody in vivo, the Coombs reagent will induce their agglutination and this can be detected visually. The relevant antibody can be eluted from the red cell surface and tested against a panel of typed red cells to determine against which red cell antigen it is directed. The most common specificity is for Rhesus antigens and most often anti-e; this is helpful when choosing blood to cross-match. The direct Coombs test can be negative in the presence of brisk haemolysis. A positive test requires about 200 antibody molecules to attach to each red cell; with a very avid complement-fixing antibody, haemolysis may occur at lower levels of antibody-binding. The standard Coombs reagent will miss IgA or IgE antibodies. Around 10% of all warm autoimmune haemolytic anaemias are Coombs test-negative. Management If the haemolysis is secondary to an underlying cause, this must be treated and any implicated drugs stopped. homozygous females (p. 48), but it is carried by females. Carrier heterozygous females are usually only affected in the neonatal period or in the presence of skewed X-inactivation (p. 49). Over 400 subtypes of G6PD are described. The most common types associated with normal activity are the B+ enzyme present in most Caucasians and 70% of Afro-Caribbeans, and the A+ variant present in 20% of Afro-Caribbeans. The two common variants associated with reduced activity are the A− variety in approximately 10% of Afro-Caribbeans, and the Mediterranean or B− variety in Caucasians. In East and West Africa, up to 20% of males and 4% of females (homozygotes) are affected and have enzyme levels of about 15% of normal. The deficiency in Caucasian and East Asian populations is more severe, with enzyme levels as low as 1%. Clinical features and investigation findings are shown in Box 23.38. Management aims to stop the intake of any precipitant drugs or foods and treat any underlying infection. Favism due to the consumption of fava beans is the classically described precipitant of haemolysis in patients with G6PD deficiency. Acute transfusion support may be life-saving. Pyruvate kinase deficiency This is the second most common red cell enzyme defect. It results in deficiency of ATP production and a chronic haemolytic anaemia. It is inherited as an autosomal recessive trait. The extent of anaemia is variable; the blood film shows characteristic ‘prickle cells’ that resemble holly leaves. Enzyme activity is only 5–20% of normal. Transfusion support may be necessary during periods of haemolysis. 23.38 Glucose-6-phosphate dehydrogenase deficiency Clinical features • Acute drug-induced haemolysis to (e.g.): Analgesics: aspirin, phenacetin Antimalarials: primaquine, quinine, chloroquine, pyrimethamine Antibiotics: sulphonamides, nitrofurantoin, ciprofloxacin Miscellaneous: quinidine, probenecid, vitamin K, dapsone • Chronic compensated haemolysis • Infection or acute illness • Neonatal jaundice: may be a feature of the B− enzyme • Favism, i.e. acute haemolysis after ingestion of broad beans (Vicia fava) Laboratory features Non-spherocytic intravascular haemolysis during an attack The blood film will show: • Bite cells (red cells with a ‘bite’ of membrane missing) • Blister cells (red cells with surface blistering of the membrane) • Irregularly shaped small cells • Polychromasia reflecting the reticulocytosis • Denatured haemoglobin visible as Heinz bodies within the red cell cytoplasm with a supravital stain such as methyl violet G6PD level • Can be indirectly assessed by screening methods that usually depend on the decreased ability to reduce dyes • Direct assessment of G6PD is made in those with low screening values • Care must be taken close to an acute haemolytic episode because reticulocytes may have higher enzyme levels and give rise to a false normal result

950 • HAEMATOLOGY AND TRANSFUSION MEDICINE antibody is termed the Donath–Landsteiner antibody and has specificity against the P antigen on the red cells. Alloimmune haemolytic anaemia Alloimmune haemolytic anaemia is caused by antibodies against non-self red cells. It has two main causes, occurring after: • unmatched blood transfusion (p. 935) • maternal sensitisation to paternal antigens on fetal cells (haemolytic disease of the newborn, p. 933). Non-immune haemolytic anaemia Endothelial damage Disruption of red cell membrane may occur in a number of conditions and is characterised by the presence of red cell fragments on the blood film and markers of intravascular haemolysis: • Mechanical heart valves. High flow through incompetent valves or periprosthetic leaks through the suture ring holding a valve in place result in shear stress damage. • March haemoglobinuria. Vigorous exercise, such as prolonged marching or marathon running, can cause red cell damage in the capillaries in the feet. • Thermal injury. Severe burns cause thermal damage to red cells, characterised by fragmentation and the presence of microspherocytes in the blood. • Microangiopathic haemolytic anaemia. Fibrin deposition in capillaries can cause severe red cell disruption. It may occur in a wide variety of conditions: disseminated carcinomatosis, malignant or pregnancy-induced hypertension, haemolytic uraemic syndrome (p. 408), thrombotic thrombocytopenic purpura (p. 979) and disseminated intravascular coagulation (p. 978). Infection Plasmodium falciparum malaria (p. 274) may be associated with intravascular haemolysis; when severe, this is termed blackwater fever because of the associated haemoglobinuria. Clostridium perfringens sepsis (p. 227), usually in the context of ascending cholangitis or necrotising fasciitis, may cause severe intravascular haemolysis with marked spherocytosis due to bacterial production of a lecithinase that destroys the red cell membrane. Chemicals or drugs Dapsone and sulfasalazine cause haemolysis by oxidative denaturation of haemoglobin. Denatured haemoglobin forms Heinz bodies in the red cells, visible on supravital staining with brilliant cresyl blue. Arsenic gas, copper, chlorates, nitrites and nitrobenzene derivatives may all cause haemolysis. Paroxysmal nocturnal haemoglobinuria Paroxysmal nocturnal haemoglobinuria (PNH) is a rare acquired, non-malignant clonal expansion of haematopoietic stem cells deficient in glycosylphosphatidylinositol (GPI) anchor protein. GPI anchors several key molecules to cells and its absence results in clinical outcomes that reflect this, causing intravascular haemolysis and anaemia because of increased sensitivity of red cells to lysis by complement. This happens because key defence mechanisms that protect cells from complement-mediated lysis (CD55 and CD59) are GPI-anchored to red cells under normal circumstances. Episodes of intravascular haemolysis result in haemoglobinuria, most noticeable in early morning urine, which It is usual to treat patients initially with prednisolone (1 mg/kg orally). A response is seen in 70–80% of cases but may take up to 3 weeks; a rise in haemoglobin will be matched by a fall in bilirubin, LDH and reticulocyte levels. Once the haemoglobin has normalised and the reticulocytosis resolved, the glucocorticoid dose can be reduced slowly over several weeks. Glucocorticoids probably work by decreasing macrophage destruction of antibodycoated red cells and reducing antibody production. Transfusion support may be required for life-threatening problems, such as the development of heart failure or rapid unabated falls in haemoglobin. The least incompatible blood should be used but this may still give rise to transfusion reactions or the development of alloantibodies. If the haemolysis fails to respond to glucocorticoids or can only be stabilised by large doses, then second-line therapies should be considered. These include immunomodulation/suppression and splenectomy. Currently, there are fewer splenectomies than previously and the second-line drug of choice in current UK guidance is the anti-CD20 monoclonal antibody rituximab. Splenectomy is associated with a good response in 50–60% of cases. The operation can be performed laparoscopically with reduced morbidity. If splenectomy is not appropriate, alternative immunosuppressive therapy with azathioprine, ciclosporin, mycophenolate or cyclophosphamide may be considered. There are concerns about all modes of second-line therapy, as long-term immunosuppression carries a risk of malignancy, while splenectomy is associated with an excess of severe infection due to the capsulate organisms pneumococcus and meningococcus (see Box 23.40). Cold agglutinin disease This is mediated by antibodies, usually IgM, which bind to the red cells at low temperatures and cause them to agglutinate. It may cause intravascular haemolysis if complement fixation occurs. This can be chronic when the antibody is monoclonal, or acute or transient when the antibody is polyclonal. Chronic cold agglutinin disease This typically affects elderly patients and may be associated with an underlying low-grade B-cell lymphoma. It causes a low-grade intravascular haemolysis with cold, painful and often blue fingers, toes, ears or nose (so-called acrocyanosis). The latter is due to red cell agglutination in the small vessels in these colder, exposed areas. The blood film shows red cell agglutination and the MCV may be spuriously high because the automated analysers detect red cell aggregates as single cells. Monoclonal IgM usually has anti-I or, less often, anti-i specificity. Treatment is primarily by transfusion support but may also be directed at any underlying lymphoma. Patients must keep extremities warm, especially in winter. Some patients respond to glucocorticoid therapy and rituximab. Two considerations for patients requiring blood transfusion is that the cross-match sample must be placed in a transport flask at a temperature of 37°C and blood administered via a blood-warmer. All patients should receive folic acid supplementation. Other causes of cold agglutination Cold agglutination can occur in association with Mycoplasma pneumoniae or with infectious mononucleosis. Paroxysmal cold haemoglobinuria is a very rare cause seen in children, in association with viral or bacterial infection. An IgG antibody binds to red cells in the peripheral circulation but lysis occurs in the central circulation when complement fixation takes place. This

Haemoglobinopathies • 951

haemoglobin. These substitutions often change the charge of the globin chains, producing different electrophoretic mobility, and this forms the basis for the diagnostic use of haemoglobin electrophoresis to identify haemoglobinopathies. Quantitative abnormalities – thalassaemias In quantitative abnormalities (the thalassaemias), there are mutations causing a reduced rate of production of one or other of the globin chains, altering the ratio of alpha to non-alpha chains. In alpha-thalassaemia excess beta chains are present, while in beta-thalassaemia excess alpha chains are present. The excess chains precipitate, causing red cell membrane damage and reduced red cell survival due to haemolysis. Sickle-cell anaemia Sickle-cell disease results from a single glutamic acid to valine substitution at position 6 of the beta globin polypeptide chain. It is inherited as an autosomal recessive trait (p. 48). Homozygotes only produce abnormal beta chains that make haemoglobin S (HbS, termed SS), and this results in the clinical syndrome of sickle-cell disease. Heterozygotes produce a mixture of normal and abnormal beta chains that make normal HbA and HbS (termed AS), and this results in sickle-cell trait; although this was previously thought of as asymptomatic, it may be associated with an increased risk of sudden and cardiovascular death. Epidemiology The heterozygote frequency is over 20% in tropical Africa (see Fig. 23.21). In black American populations, sickle-cell trait has a frequency of 8%. Individuals with sickle-cell trait are relatively resistant to the lethal effects of falciparum malaria in early childhood; the high prevalence in equatorial Africa can be explained by the survival advantage it confers in areas where falciparum malaria is endemic. However, homozygous patients with sickle-cell anaemia do not have correspondingly greater resistance to falciparum malaria. Pathogenesis When haemoglobin S is deoxygenated, the molecules of haemoglobin polymerise to form pseudocrystalline structures known as ‘tactoids’. These distort the red cell membrane and has a characteristic red–brown colour. The disease is associated with an increased risk of venous and arterial thrombosis in unusual sites, such as the liver or abdomen. PNH clones are also associated with hypoplastic bone marrow failure, aplastic anaemia and myelodysplastic syndrome (pp. 960 and 969). Management is supportive with transfusion and folate supplements and prophylaxis or treatment of thrombosis. Standard care now includes the anti-complement C5 monoclonal antibody eculizimab. This has been shown to be effective in reducing haemolysis, transfusion requirements and thrombotic risk. Eculizumab carries a risk of infection, particularly for Neisseria meningitidis, and all treated patients must be vaccinated against this organism. Haemoglobinopathies These diseases are caused by mutations affecting the genes encoding the globin chains of the haemoglobin molecule. Normal haemoglobin is composed of two alpha and two non-alpha globin chains. Alpha globin chains are produced throughout life, including in the fetus, so severe mutations may cause intrauterine death. Production of non-alpha chains varies with age; fetal haemoglobin (HbF-αα/γγ) has two gamma chains, while the predominant adult haemoglobin (HbA-αα/ββ) has two beta chains. Thus, disorders affecting the beta chains do not present until after 6 months of age. A constant small amount of haemoglobin A2 (HbA2-αα/δδ, usually less than 2%) is made from birth. The geographical distribution of the common haemoglobinopathies is shown in Figure 23.21. The haemoglobinopathies can be classified into qualitative or quantitative abnormalities. Qualitative abnormalities – abnormal haemoglobins In qualitative abnormalities (called the abnormal haemoglobins), there is a functionally important alteration in the amino acid structure of the polypeptide chains of the globin chains. Several hundred such variants are known; they were originally designated by letters of the alphabet, e.g. S, C, D or E, but the more recently described ones are known by names that usually taken from the town or district in which they were first described. The best-known example is haemoglobin S, found in sickle-cell anaemia. Mutations around the haem-binding pocket cause the haem ring to fall out of the structure and produce an unstable Fig. 23.21 The geographical distribution of the haemoglobinopathies. From Hoffbrand AV, Pettit JE. Essential haematology, 3rd edn. Edinburgh: Blackwell Science; 1992. Thalassaemia Sickle-cell anaemia HbC HbD HbE

952 • HAEMATOLOGY AND TRANSFUSION MEDICINE • Stroke. The single most devastating consequence of sickle-cell disease is stroke. Stroke or silent stroke occurs in 10–15% of children with sickle-cell disease. Children at risk of stroke can be identified by screening with transcranial Doppler ultrasound, with fast flow associated with increased stroke risk. These children may be offered strategies such as transfusion or treatment with hydroxycarbamide to reduce the risk of stroke. • Sickle chest syndrome. This may follow a vaso-occlusive crisis and is the most common cause of death in adult sickle-cell disease. Bone marrow infarction results in fat emboli to the lungs, which cause further sickling and infarction, leading to ventilatory failure if not treated. • Sequestration crisis. Thrombosis of the venous outflow from an organ causes loss of function and acute painful enlargement. In children, the spleen is the most common site. Massive splenic enlargement may result in severe anaemia, circulatory collapse and death. Recurrent sickling in the spleen in childhood results in infarction and adults may have no functional spleen. In adults, the liver may undergo sequestration with severe pain due to capsular stretching. Priapism is a complication seen in affected men. • Aplastic crisis. Infection of adult sicklers with human parvovirus B19 (erythrovirus) may result in a severe but produce characteristic sickle-shaped cells (Fig. 23.22). The polymerisation is reversible when re-oxygenation occurs. The distortion of the red cell membrane, however, may become permanent and the red cell ‘irreversibly sickled’. The greater the concentration of sickle-cell haemoglobin in the individual cell, the more easily tactoids are formed, but this process may be enhanced or retarded by the presence of other haemoglobins. Thus the abnormal haemoglobin C variant participates in polymerisation more readily than haemoglobin A, whereas haemoglobin F strongly inhibits polymerisation. Clinical features Sickling is precipitated by hypoxia, acidosis, dehydration and infection. Irreversibly sickled cells have a shortened survival and plug vessels in the microcirculation. This results in a number of acute syndromes, termed ‘crises’, and chronic organ damage (Fig. 23.22): • Painful vaso-occlusive crisis. Plugging of small vessels in the bone produces acute severe bone pain. This affects areas of active marrow: the hands and feet in children (so-called dactylitis) or the femora, humeri, ribs, pelvis and vertebrae in adults. Patients usually have a systemic response with tachycardia, sweating and a fever. This is the most common form of crisis. Fig. 23.22 Clinical and laboratory features of sickle-cell disease. CNS Subarachnoid bleed Fits Cardiac Sickle myocardium Cardiomegaly Transfusional iron overload Vertebral collapse Osteoporosis Splenic infarction Avascular necrosis Cerebrovascular event Priapism Leg ulceration Background retinopathy Proliferative retinopathy Vitreous bleeds Ocular Sickle chest syndrome Infection Pulmonary hypertension Pulmonary Osteomyelitis Cholelithiasis Hepatic sequestration Dactylitis Enuresis Haematuria Papillary necrosis Chronic renal failure Renal Arthropathy Blood film Electrophoresis gel Nucleated red cell Sickle cell Normal HbC trait HbS trait HbC HbS HbA HbF Autosomal recessive inheritance

Haemoglobinopathies • 953

children or chest syndromes in adults. Exchange transfusion, in which a patient is simultaneously venesected and transfused to replace HbS with HbA, may be used in life-threatening crises or to prepare patients for surgery. A high HbF level inhibits polymerisation of HbS and reduces sickling. Patients with sickle-cell disease and high HbF levels have a mild clinical course with few crises. Some agents are able to increase synthesis of HbF and this has been used to reduce the frequency of severe crises. The oral cytotoxic agent hydroxycarbamide has been shown to have clinical benefit with acceptable side-effects in children and adults who have recurrent severe crises. Relatively few allogeneic stem cell transplants from HLAmatched siblings have been performed but this procedure appears to be potentially curative (p. 937). Prognosis In Africa, few children with sickle-cell anaemia survive to adult life without medical attention. Even with standard medical care, approximately 15% die by the age of 20 years and 50% by the age of 40 years. Other abnormal haemoglobins Another beta-chain haemoglobinopathy, haemoglobin C (HbC) disease, is clinically silent but associated with microcytosis and target cells on the blood film. Compound heterozygotes inheriting one HbS gene and one HbC gene from their parents have haemoglobin SC disease, which behaves like a mild form of sickle-cell disease. SC disease is associated with a reduced frequency of crises but is not uncommonly associated with complications in pregnancy and retinopathy. Thalassaemias Thalassaemia is an inherited impairment of haemoglobin production, in which there is partial or complete failure to synthesise a specific type of globin chain. In alpha-thalassaemia, disruption of one or both alleles on chromosome 16 may occur, with production of some or no alpha globin chains. In betathalassaemia, defective production usually results from disabling point mutations causing no (β0) or reduced (β–) beta chain production. Beta-thalassaemia Failure to synthesise beta chains (beta-thalassaemia) is the most common type of thalassaemia, most prevalent in the Mediterranean area. Heterozygotes have thalassaemia minor, a condition in which there is usually mild microcytic anaemia and little or no clinical disability, which may be detected only when iron therapy for a mild microcytic anaemia fails. Homozygotes (thalassaemia major) either are unable to synthesise haemoglobin A or, at best, produce very little; after the first 4–6 months of life, they develop profound transfusion-dependent hypochromic anaemia. The diagnostic features are summarised in Box 23.40. Intermediate grades of severity occur. Management and prevention See Box 23.41. Cure is now a possibility for selected children, with allogeneic HSCT (p. 937). It is possible to identify a fetus with homozygous betathalassaemia by obtaining chorionic villous material for DNA self-limiting red cell aplasia. This results in profound anaemia, which may cause heart failure. Unlike in all other sickle crises, the reticulocyte count is low. • Pregnancy. Pregnancy in sickle-cell disease requires planning and multidisciplinary management. Women with sickle-cell disease have increased pregnancy-related morbidity, which includes painful crisis, placental failure and thrombosis (Box 23.39). Investigations Patients with sickle-cell disease have a compensated anaemia, usually around 60–80 g/L. The blood film shows sickle cells, target cells and features of hyposplenism from a young age. A reticulocytosis is present. The presence of HbS can be demonstrated by exposing red cells to a reducing agent such as sodium dithionite; HbA gives a clear solution, whereas HbS polymerises to produce a turbid solution. This forms the basis of emergency screening tests before surgery in appropriate ethnic groups but cannot distinguish between sickle-cell trait and disease. The definitive diagnosis requires haemoglobin electrophoresis to demonstrate the absence of HbA, 2–20% HbF and the predominance of HbS. Both parents of the affected individual will have sickle-cell trait. Management All patients with sickle-cell disease should receive prophylaxis with daily folic acid, and appropriate management of the hyposplenic state that is uniformly found in these patients from an early age (see Box 23.37). Seasonal vaccination against influenza is also advised in these patients. Vaso-occlusive crises are managed by aggressive rehydration, oxygen therapy, adequate analgesia (which often requires opiates) and antibiotics. Transfusion should be with fully genotyped blood wherever possible. Simple top-up transfusion may be used in a sequestration or aplastic crisis. A regular transfusion programme to suppress HbS production and maintain the HbS level below 30% may be indicated in patients with recurrent severe complications, such as cerebrovascular accidents in 23.39 Sickle-cell disease in pregnancy • Pre-conceptual counselling: advice on the effect of sickle-cell disease on pregnancy, and vice versa, should be offered. • Vaccination status: should be updated before conception. • Testing of partner: testing for haemoglobinopathy status is advised. • Folic acid: should be taken in high dose (5 mg daily) prior to and throughout pregnancy. • Hydroxycarbamide: should be discontinued 3 months prior to conception. • Angiotensin-converting enzyme (ACE) inhibitors: should be discontinued prior to conception. • Pulmonary hypertension: should be excluded prior to conception. • Placental failure: women with sickle-cell disease have increased rates, resulting in pre-eclampsia and intrauterine growth retardation. • Aspirin 75 mg: should be given throughout pregnancy. • Thromboprophylaxis after delivery: all women with sickle-cell disease should receive thromboprophylaxis with low-molecularweight heparin for at least 10 days post vaginal delivery and for 6 weeks post caesarean section. Antenatal thromboprophylaxis should be considered for women with additional risk factors for venous thromboembolism (see Box 23.65). • Transfusion: extended cross-matched blood for Rhesus and Kell status should be provided. Blood should be cytomegalovirus- negative.

954 • HAEMATOLOGY AND TRANSFUSION MEDICINE analysis sufficiently early in pregnancy to allow termination. This examination is appropriate only if both parents are known to be carriers (beta-thalassaemia minor) and will accept a termination. Alpha-thalassaemia Reduced or absent alpha-chain synthesis is common in Southeast Asia. There are two alpha gene loci on chromosome 16 and therefore each individual carries four alpha gene alleles. • If one is deleted, there is no clinical effect. • If two are deleted, there may be a mild hypochromic anaemia. • If three are deleted, the patient has haemoglobin H disease. • If all four are deleted, the baby is stillborn (hydrops fetalis). Haemoglobin H is a beta-chain tetramer, formed from the excess of beta chains, which is functionally useless, so that patients rely on their low levels of HbA for oxygen transport. Treatment of haemoglobin H disease is similar to that of beta-thalassaemia of intermediate severity, involving folic acid supplementation, transfusion if required and avoidance of iron therapy. Haematological malignancies Haematological malignancies arise when the processes controlling proliferation or apoptosis are corrupted in blood cells because of acquired mutations in key regulatory genes. If mature differentiated cells are involved, the cells will have a low growth fraction and produce indolent neoplasms, such as the low-grade lymphomas or chronic leukaemias, when patients have an expected survival of many years. In contrast, if more primitive stem or progenitor cells are involved, the cells can have the highest growth fractions of all human neoplasms, producing rapidly progressive, lifethreatening illnesses such as the acute leukaemias or high-grade lymphomas. Involvement of pluripotent stem cells produces the most aggressive acute leukaemias. In general, haematological neoplasms are diseases of elderly patients, the exceptions being acute lymphoblastic leukaemia, which predominantly affects children, and Hodgkin lymphoma, which affects people aged 20–40 years. Management of young patients with haematological malignancy is particularly challenging (Box 23.43). Leukaemias Leukaemias are malignant disorders of the haematopoietic stem cell compartment, characteristically associated with increased numbers of white cells in the bone marrow and/or peripheral blood. The course of leukaemia may vary from a few days or weeks to many years, depending on the type. Epidemiology and aetiology The incidence of leukaemia of all types in the population is approximately 10/100 000 per annum, of which just under half are cases of acute leukaemia. Males are affected more frequently than females, the ratio being about 3 : 2 in acute leukaemia, 2 : 1 in chronic lymphocytic leukaemia and 1.3 : 1 in chronic myeloid leukaemia. Geographical variation in incidence does occur, the most striking being the rarity of chronic lymphocytic leukaemia in Chinese and related races. Acute leukaemia occurs at all ages. Acute lymphoblastic leukaemia shows a peak of incidence in children aged 1–5 years. All forms of acute myeloid leukaemia 23.41 Treatment of beta-thalassaemia major Problem Management Erythropoietic failure Allogeneic HSCT from HLA-compatible sibling Transfusion to maintain Hb

100 g/L Folic acid 5 mg daily Iron overload Iron therapy contraindicated Iron chelation therapy Splenomegaly causing mechanical problems, excessive transfusion needs Splenectomy; see Box 23.37 (Hb = haemoglobin; HLA = human leucocyte antigen; HSCT = haematopoietic stem cell transplantation) 23.40 Diagnostic features of beta-thalassaemia Beta-thalassaemia major (homozygotes) • Profound hypochromic anaemia • Evidence of severe red cell dysplasia • Erythroblastosis • Absence or gross reduction of the amount of haemoglobin A • Raised levels of haemoglobin F • Evidence that both parents have thalassaemia minor Beta-thalassaemia minor (heterozygotes) • Mild anaemia • Microcytic hypochromic erythrocytes (not iron-deficient) • Some target cells • Punctate basophilia • Raised haemoglobin A2 fraction 23.42 Anaemia in old age • Mean haemoglobin: falls with age in both sexes but remains well within the reference range. When a low haemoglobin does occur, it is generally due to disease. • Anaemia can never be considered ‘normal’ in old age. • Symptoms: may be subtle and insidious. Cardiovascular features such as dyspnoea and oedema, and cerebral features such as dizziness and apathy, tend to predominate. • Ferritin: if lower than 45 μg/L in older people, is highly predictive of iron deficiency. Conversely, ferritin may be raised by chronic disease and so a normal ferritin does not exclude iron deficiency. • Serum iron and transferrin: fall with age because of the prevalence of other disorders, and are not reliable indicators of deficiency. • Most common cause of iron deficiency: gastrointestinal blood loss. • Most common cause of vitamin B12 deficiency: pernicious anaemia, as the prevalence of chronic atrophic gastritis rises in old age. • Neuropsychiatric symptoms associated with vitamin B12 deficiency: well-established association but a causal relationship has not been clearly shown. Dementia associated with vitamin B12 deficiency in the absence of haematological abnormalities is rare. • Anaemia of chronic disease: frequent in old age because of the rising prevalence of diseases that inhibit iron transport.

Haematological malignancies • 955

Myeloid refers to the other lineages: that is, precursors of red cells, granulocytes, monocytes and platelets (see Fig. 23.2). The diagnosis of leukaemia is usually suspected from an abnormal blood count, often a raised white count, and is confirmed by examination of the bone marrow. This includes the morphology of the abnormal cells, analysis of cell surface markers (immunophenotyping), clone-specific chromosome abnormalities and molecular changes. These results are incorporated in the World Health Organisation (WHO) classification of tumours of haematopoietic and lymphoid tissues; the subclassification of acute leukaemias is shown in Box 23.45. The features in the bone marrow not only provide an accurate diagnosis but also give valuable prognostic information, increasingly allowing therapy to be tailored to the patient’s disease. Acute leukaemia There is a failure of cell maturation in acute leukaemia. Proliferation of cells that do not mature leads to an accumulation of primitive cells that take up more and more marrow space at the expense of the normal haematopoietic elements. Eventually, this proliferation spills into the blood. Acute myeloid leukaemia (AML) is about four times more common than acute lymphoblastic leukaemia (ALL) in adults. In children, the proportions are reversed, the lymphoblastic variety being more common. The clinical features are usually those of bone marrow failure (anaemia, bleeding or infection; pp. 923, 927 and 930). Investigations Blood examination usually shows anaemia with a normal or raised MCV. The leucocyte count may vary from as low as 1 × 109/L to as high as 500 × 109/L or more. In the majority of patients, have their lowest incidence in young adult life and there is a striking rise over the age of 50. Chronic leukaemias occur mainly in middle and old age. The cause of the leukaemia is unknown in the majority of patients. Several risk factors have been identified (Box 23.44). Terminology and classification Leukaemias are traditionally classified into four main groups: • acute lymphoblastic leukaemia (ALL) • acute myeloid leukaemia (AML) • chronic lymphocytic leukaemia (CLL) • chronic myeloid leukaemia (CML). In acute leukaemia, there is proliferation of primitive stem cells, with limited accompanying differentiation, leading to an accumulation of blasts, predominantly in the bone marrow, which causes bone marrow failure. In chronic leukaemia, the malignant clone is able to differentiate, resulting in an accumulation of more mature cells. Lymphocytic and lymphoblastic cells are those derived from the lymphoid stem cell (B cells and T cells). 23.44 Risk factors for leukaemia Ionising radiation • After atomic bombing of Japanese cities (myeloid leukaemia) • Radiotherapy • Diagnostic X-rays of the fetus in pregnancy Cytotoxic drugs • Especially alkylating agents (myeloid leukaemia, usually after a latent period of several years) • Industrial exposure to benzene Retroviruses • Adult T-cell leukaemia/lymphoma (ATLL) caused by human T-cell lymphotropic virus 1(HTLV-1), most prevalent in Japan, the Caribbean and some areas of Central and South America and Africa Genetic • Identical twin of patients with leukaemia • Down’s syndrome and certain other genetic disorders Immunological • Immune deficiency states (e.g. hypogammaglobulinaemia) 23.43 Consequences of haematological malignancy in adolescence • Tailored management protocols: the most effective treatment schedules for leukaemia and lymphoma differ between children and adults. Adolescent patients may be most appropriately managed in specialist centres. • Psychosocial effects: adolescents undergoing treatment for haematological malignancy may suffer significant consequences for their schooling and social development, and require support from a multidisciplinary team. • ‘Late effects’: adolescents who have been treated with chemotherapy and/or radiotherapy in childhood may be at risk of a wide range of complications, depending on the region irradiated, radiation dose and the drugs used. Particularly relevant complications in this age group include short stature, growth hormone deficiency, delayed puberty, and cognitive dysfunction affecting schooling (after cranial irradiation). Life-long follow-up is often undertaken to detect and manage these late effects and to deal with consequences such as infertility and second malignancy. 23.45 WHO classification of acute leukaemia* Acute myeloid leukaemia (AML) with recurrent genetic abnormalities • AML with t(8;21)(q22;q22.1), gene product RUNX1-RUNX1T1 • AML with inv(16)(p13.1;q22), gene product CBFB-MYHL1 • Acute promyelocytic leukaemia t(15;17), gene product PML-RARA • AML with t(9;11)(p21.3;q23.3), gene product MLLT3-KMT2A • AML with t(6;9)(p23;q34), gene product DEK-NUP214 • AML with inv(3)(q21.3;q26.2) or t(3;3)(q21.3;q26.2), gene products GATA2, MECOM • AML (megakaryoblastic) with t(1;22)(p13.3;q13.3), gene product RBM15-MKL1 • AML with mutated NPM1 • AML with biallelic mutations of CEBPA Acute myeloid leukaemia with myelodysplasia-related changes • e.g. Following a myelodysplastic syndrome Therapy-related myeloid neoplasms • e.g. Alkylating agent or topoisomerase II inhibitor Myeloid sarcoma Myeloid proliferations related to Down’s syndrome Acute myeloid leukaemia not otherwise specified • e.g. AML with or without differentiation, acute myelomonocytic leukaemia, erythroleukaemia, megakaryoblastic leukaemia Acute lymphoblastic leukaemia (ALL) • B-lymphoblastic leukaemia/lymphoma • T-lymphoblastic leukaemia/lymphoma *Updated 2016; major subtypes.

956 • HAEMATOLOGY AND TRANSFUSION MEDICINE of leukaemia. Classification and prognosis are determined by immunophenotyping and chromosome and molecular analysis, as shown in Figure 23.24. Management The first decision must be whether or not to give specific treatment to attempt to achieve remission. This is generally aggressive, has numerous side-effects, and may not be appropriate for the very elderly or patients with serious comorbidities (Chs 32 and 33). In these patients, supportive treatment can effect considerable improvement in well-being. Low-intensity chemotherapy, such as low-dose cytosine arabinoside or, recently, azacitidine, is frequently used in elderly and more frail patients but only induces remission in less than 20% of patients. Specific therapy Ideally, whenever possible, patients with acute leukaemia should be treated within a clinical trial. If a decision to embark on specific therapy has been taken, the patient should be prepared as recommended in Box 23.46. It is unwise to attempt aggressive management of acute leukaemia unless adequate services are available for the provision of supportive therapy. The aim of treatment is to destroy the leukaemic clone of cells without destroying the residual normal stem cell compartment from which repopulation of the haematopoietic tissues will occur. There are three phases: • Remission induction. In this phase, a fraction of the tumour is destroyed by combination chemotherapy. The patient goes through a period of severe bone marrow hypoplasia lasting 3–4 weeks and requires intensive support and inpatient care from a specially trained multidisciplinary team. The aim is to achieve remission, a state in which the blood counts return to normal and the marrow blast count is less than 5%. Quality of life is highly dependent on achieving remission. • Remission consolidation. If remission has been achieved, residual disease is attacked by therapy during the consolidation phase. This consists of a number of courses of chemotherapy, again resulting in periods of marrow hypoplasia. In poor-prognosis leukaemia, this may include allogeneic HSCT. • Remission maintenance. If the patient is still in remission after the consolidation phase for ALL, a period of maintenance therapy is given, with the individual as an outpatient and treatment consisting of a repeating cycle of drug administration. This may extend for up to 3 years if relapse does not occur. the count is below 100 × 109/L. Severe thrombocytopenia is usual but not invariable. Frequently, blast cells are seen in the blood film but sometimes the blast cells may be infrequent or absent. A bone marrow examination will confirm the diagnosis. The bone marrow is usually hypercellular, with replacement of normal elements by leukaemic blast cells in varying degrees (but more than 20% of the cells) (Fig. 23.23). The presence of Auer rods in the cytoplasm of blast cells indicates a myeloblastic type Fig. 23.23 Acute myeloid leukaemia. Bone marrow aspirate showing infiltration with large blast cells, which display nuclear folding and prominent nucleoli. Fig. 23.24 Investigation of acute lymphoblastic leukaemia (ALL). A Flow cytometric analysis of blasts labelled with the fluorescent antibodies anti-CD19 (y axis) and anti-CD10 (x axis). ALL blasts are positive for both CD19 and CD10 (arrow). B Chromosome analysis (karyotype) of blasts showing additional chromosomes X, 4, 6, 7, 14, 18 and 21. A

CD10

CD19

CD19- and CD10positive cells B 23.46 Preparation for specific therapy in acute leukaemia • Existing infections identified and treated (e.g. urinary tract infection, oral candidiasis, dental, gingival and skin infections) • Anaemia corrected by red cell concentrate transfusion • Thrombocytopenic bleeding controlled by platelet transfusions • If possible, central venous catheter (e.g. Hickman line) inserted to facilitate access to the circulation for delivery of chemotherapy, fluids, blood products and other supportive drugs • Tumour lysis risk assessed and prevention started: fluids with allopurinol or rasburicase • Therapeutic regimen carefully explained to the patient and informed consent obtained • Consideration of entry into clinical trial

Haematological malignancies • 957

should be given to maintain the platelet count above 10 × 109/L. Coagulation abnormalities occur and need accurate diagnosis and treatment (p. 971). Infection Fever (> 38°C) lasting over 1 hour in a neutropenic patient indicates possible sepsis (see also p. 218). Parenteral broad-spectrum antibiotic therapy is essential. Empirical therapy is given according to local bacteriological resistance patterns, such as with a combination of an aminoglycoside (e.g. gentamicin) and a broad-spectrum penicillin (e.g. piperacillin/tazobactam) or a single-agent beta-lactam (e.g. meropenem). The organisms most commonly associated with severe neutropenic sepsis are Gram-positive bacteria, such as Staphylococcus aureus and Staphylococcus epidermidis, which are present on the skin and gain entry via cannulae and central lines. Gram-negative infections often originate from the gastrointestinal tract, which is affected by chemotherapy-induced mucositis; organisms such as Escherichia coli, Pseudomonas and Klebsiella spp. are likely to cause rapid clinical deterioration and must be covered with initially empirical antibiotic therapy. Gram-positive infection may require vancomycin or teicoplanin therapy. If fever has not resolved after 3–5 days and there is evidence on CT scanning or sensitive blood tests for a disseminated fungal infection, empirical antifungal therapy (e.g. a liposomal amphotericin B preparation, voriconazole or caspofungin) is added. Patients with ALL are susceptible to infection with Pneumocystis jirovecii (p. 318), which causes a severe pneumonia. Prophylaxis with co-trimoxazole is given during chemotherapy. Diagnosis may require either induced sputum, bronchoalveolar lavage or open lung biopsy. Treatment is with high-dose co-trimoxazole, initially intravenously, changing to oral treatment as soon as possible. Oral and pharyngeal Candida infection is common. Fluconazole is effective for the treatment of established local infection and for prophylaxis against systemic candidaemia. Prophylaxis against other systemic fungal infections, including Aspergillus, using itraconazole or posaconazole, for example, is usual practice during high-risk intensive chemotherapy. This is often used along with sensitive markers of early fungal infection to guide treatment initiation (a ‘pre-emptive approach’). For systemic fungal infection with Candida or aspergillosis, intravenous liposomal amphotericin, caspofungin or voriconazole is required for at least 3 weeks. In systemic Candida infection intravenous catheters should be removed. Reactivation of herpes simplex infection (p. 247) occurs frequently around the lips and nose during ablative therapy for acute leukaemia, and is treated with aciclovir. This may also be prescribed prophylactically to patients with a history of cold sores or elevated antibody titres to herpes simplex. Herpes zoster manifesting as chickenpox or, after reactivation, as shingles (p. 239) should be treated in the early stage with high-dose aciclovir, as it can be fatal in immunocompromised patients. The value of isolation facilities, such as laminar flow rooms, is debatable but may contribute to staff awareness of careful reverse barrier nursing practice. The isolation can be psychologically stressful for the patient. Metabolic problems Frequent monitoring of fluid balance and renal, hepatic and haemostatic function is necessary. Patients are often severely anorexic and diarrhoea is common as a consequence of the side-effects of therapy; they may find drinking difficult and hence require intravenous fluids and electrolytes. Renal toxicity occurs with some antibiotics (e.g. aminoglycosides) and antifungal agents (amphotericin). Cellular breakdown during induction therapy In patients with ALL, it is necessary to give prophylactic treatment to the central nervous system, as this is a sanctuary site where standard therapy does not penetrate. This usually consists of a combination of cranial irradiation, intrathecal chemotherapy and high-dose methotrexate, which crosses the blood–brain barrier. Thereafter, specific therapy is discontinued and the patient observed. The detail of the schedules for these treatments can be found in specialist texts. The drugs most commonly employed are listed in Box 23.47. Generally, if a patient fails to go into remission with induction treatment, alternative drug combinations may be tried, but the outlook is poor unless remission can be achieved. Disease that relapses during treatment or soon after the end of treatment carries a poor prognosis and is difficult to treat. The longer after the end of treatment that relapse occurs, the more likely it is that further treatment will be effective. In some patients, alternative palliative chemotherapy, not designed to achieve remission, may be used to curb excessive leucocyte proliferation. Drugs used for this purpose include hydroxycarbamide and mercaptopurine. The aim is to reduce the blast count without inducing bone marrow failure. Supportive therapy Aggressive and potentially curative therapy, which involves periods of severe bone marrow failure, would not be possible without appropriate supportive care. The following problems commonly arise. Anaemia Anaemia is treated with red cell concentrate transfusions. Bleeding Thrombocytopenic bleeding requires platelet transfusions, unless the bleeding is trivial. Recent trials have confirmed that in acute leukaemia prophylactic platelet transfusion 23.47 Drugs commonly used in the treatment of acute leukaemia Phase Acute lymphoblastic leukaemia Acute myeloid leukaemia Induction Vincristine (IV) Prednisolone (oral) L-Asparaginase (IM) Daunorubicin (IV) Methotrexate (intrathecal) Imatinib (oral)* Daunorubicin (IV) Cytarabine (IV) Etoposide (IV and oral) Gentuzumab ozogamicin (IV) All-trans retinoic acid (ATRA) (oral) Arsenic trioxide (ATO) Consolidation Daunorubicin (IV) Cytarabine (IV) Etoposide (IV) Methotrexate (IV) Imatinib (oral)* Cytarabine (IV) Amsacrine (IV) Mitoxantrone (IV) Maintenance Prednisolone (oral) Vincristine (IV) Mercaptopurine (oral) Methotrexate (oral) Imatinib (oral)* Relapse Fludarabine Cytarabine Idarubicin Fludarabine Cytarabine Arsenic trioxide (ATO) Idarubicin *If Philadelphia chromosome-positive.

958 • HAEMATOLOGY AND TRANSFUSION MEDICINE in acute promyelocytic leukaemia, which has greatly reduced induction deaths from bleeding in this good-risk leukaemia. A chemotherapy-free schedule of ATRA and ATO has recently produced cure rates of 90% in patients with low-risk acute promyelocytic leukaemia. Current trials aim to improve survival, especially in standard and poor-risk disease, with strategies that include better use of allogeneic HSCT and targeted therapies such as anti-CD33 monoclonal antibodies (Mylotarg) and FLT3 inhibitors. FLT3 is a cytokine receptor often expressed on AML blast cells and whose expression is associated with a poorer prognosis. Chronic myeloid leukaemia Chronic myeloid leukaemia (CML) is a myeloproliferative stem cell disorder resulting in proliferation of all haematopoietic lineages but manifesting predominantly in the granulocytic series. Maturation of cells proceeds fairly normally. The disease occurs chiefly between the ages of 30 and 80 years, with a peak incidence at 55 years. It is rare, with an annual incidence in the UK of 1.8/100 000, and accounts for 20% of all leukaemias. It is found in all races. The defining characteristic of CML is the chromosome abnormality known as the Philadelphia (Ph) chromosome. This is a shortened chromosome 22 resulting from a reciprocal translocation of material with chromosome 9. The break on chromosome 22 occurs in the breakpoint cluster region (BCR). The fragment from chromosome 9 that joins the BCR carries the abl oncogene, which forms a fusion gene with the remains of the BCR. This BCR ABL fusion gene codes for a 210 kDa protein with tyrosine kinase activity, which plays a causative role in the disease as an oncogene (p. 1318), influencing cellular proliferation, differentiation and survival. In some patients in whom conventional chromosomal analysis does not detect a Ph chromosome, the BCR ABL gene product is detectable by molecular techniques. Natural history The disease has three phases: • A chronic phase, in which the disease is responsive to treatment and is easily controlled, which used to last 3–5 years. With the introduction of imatinib therapy, this phase has been prolonged to encompass a normal life expectancy in many patients. • An accelerated phase (not always seen), in which disease control becomes more difficult. • Blast crisis, in which the disease transforms into an acute leukaemia, either myeloblastic (70%) or lymphoblastic (30%), which is relatively refractory to treatment. This is the cause of death in the majority of patients; survival is therefore dictated by the timing of blast crisis, which cannot be predicted. Prior to imatinib therapy (see below), approximately 10% of patients per year would transform. In those treated with imatinib for up to 10 years, only between 0.5 and 2.5% have transformed each year. Clinical features Symptoms at presentation may include lethargy, weight loss, abdominal discomfort, gout and sweating, but about 25% of patients are asymptomatic at diagnosis. Splenomegaly is present in 90%; in about 10%, the enlargement is massive, extending to over 15 cm below the costal margin. A friction rub may be heard in cases of splenic infarction. Hepatomegaly occurs in about 50%. Lymphadenopathy is unusual. (tumour lysis syndrome; p. 1328) releases intracellular ions and nucleic acid breakdown products, causing hyperkalaemia, hyperuricaemia, hyperphosphataemia and hypocalcaemia. This may lead to renal failure. Allopurinol and intravenous hydration are given to try to prevent this. In patients at high risk of tumour lysis syndrome, prophylactic rasburicase (a recombinant urate oxidase enzyme) is used. Occasionally, dialysis may be required. Psychological problems Psychological support is a key aspect of care. Patients should be kept informed, and their questions answered and fears allayed as far as possible. A multidisciplinary approach to patient care involves input from many services, including psychology. Key members of the team include haematology specialist nurses, who are often the central point of contact for patients and families throughout the illness. Haematopoietic stem cell transplantation This is described on page 936. In patients with high-risk acute leukaemia, allogeneic HSCT can improve 5-year survival from 20% to around 50%. Reduced-intensity conditioning has allowed HSCT to be delivered to a higher proportion of patients with acute leukaemias, up to the age of about 65 years. Prognosis Without treatment, the median survival of patients with acute leukaemia is about 5 weeks. This may be extended to a number of months with supportive treatment. Patients who achieve remission with specific therapy have a better outlook. Around 80% of adult patients under 60 years of age with ALL or AML achieve remission, although remission rates are lower for older patients. However, the relapse rate continues to be high. Box 23.48 shows the survival in ALL and AML and the influence of prognostic features. The level of detectable leukaemia cells, called minimal residual disease (MRD), measured after induction therapy in ALL by sensitive laboratory techniques, has been shown to be a powerful prognostic tool that is now used routinely to direct subsequent consolidation therapy. Advances in treatment have led to steady improvement in survival from leukaemia. They include the introduction of drugs such as all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) 23.48 Outcome in adult acute leukaemia Disease/risk Risk factors 5-year overall survival Acute myeloid leukaemia (AML) Good risk Promyelocytic leukaemia t(15;17) 90% t(8;21) 65% inv 16 or t(16;16) 70% Poor risk Cytogenetic abnormalities 21% −5, −7, del 5q, abn(3q), complex (> 5) Intermediate risk AML with none of the above 48% Acute lymphoblastic leukaemia (ALL) Poor risk Philadelphia chromosome 20% High white count > 100 × 109/L Abnormal short arm of chromosome 11 t(1;19) Standard ALL with none of the above 37%

Haematological malignancies • 959

to stop TKI therapy and this is being investigated in clinical trials. For those failing to respond or who lose their response and progress on first-line therapy, options include switching to a different TKI (Box 23.49). Some patients develop detectable mutations in the BCR ABL gene, which renders them resistant to one or more of the TKIs. The T315I mutation has been particularly problematic, as this provides wide-ranging resistance. The third-generation TKI ponatinib is effective, however. Allogeneic HSCT (p. 937) is now reserved for patients who fail TKI therapy. Hydroxycarbamide and interferon were previously used for control of disease. Hydroxycarbamide is still useful in palliative situations and interferon is used in women planning pregnancy. Accelerated phase and blast crisis Management is more difficult. For patients in accelerated phase, TKI therapy is indicated, most commonly with nilotinib or dasatinib. When blast transformation occurs, the type of blast cell should be determined. Response to appropriate acute leukaemia treatment (see Box 23.49) is better if disease is lymphoblastic than if myeloblastic. Second- or third-generation TKIs such as dasatinib are used in combination with chemotherapy to try and achieve remission. In younger and fitter patients an allogeneic HSCT is appropriate therapy if a return to chronic phase is achieved. Hydroxycarbamide can be an effective single agent and low-dose cytarabine can also be used palliatively in older patients. Chronic lymphocytic leukaemia Chronic lymphocytic leukaemia (CLL) is the most common variety of leukaemia, accounting for 30% of cases. The male-to-female ratio is 2 : 1 and the median age at presentation is 65–70 years. In this disease, B lymphocytes, which would normally respond to antigens by transformation and antibody formation, fail to do so. An ever-increasing mass of immuno-incompetent cells accumulates, to the detriment of immune function and normal bone marrow haematopoiesis. Clinical features The onset is usually insidious. Indeed, in around 70% of patients, the diagnosis is made incidentally on a routine FBC. Presenting problems may be anaemia, infections, painless lymphadenopathy, and systemic symptoms such as night sweats or weight loss; these more often occur later in the course of the disease. Investigations The diagnosis is based on the peripheral blood findings of a mature lymphocytosis (> 5 × 109/L) with characteristic morphology and cell surface markers. Immunophenotyping reveals the lymphocytes to be monoclonal B cells expressing the B-cell antigens CD19 and CD23, with either kappa or lambda immunoglobulin light chains and, characteristically, an aberrant T-cell antigen CD5. On flow cytometry, some people are shown to have circulating CLL cells at a level less than 5 × 109/L. This is known as monoclonal B lymphocytosis of uncertain significance. Other useful investigations in CLL include a reticulocyte count and a direct Coombs test, as autoimmune haemolytic anaemia may occur (p. 949). Serum immunoglobulin levels should be estimated to establish the degree of hypogammaglobulinaemia, which is common and progressive. Bone marrow examination by aspirate and trephine is not essential for the diagnosis of CLL, but may be helpful in difficult cases, for prognosis (patients with diffuse marrow involvement have a poorer prognosis) and to monitor response to therapy. The main prognostic factor is Investigations FBC results are variable between patients. There is usually a normocytic, normochromic anaemia. The leucocyte count can vary from 10 to 600 × 109/L. In about one-third of patients, there is a very high platelet count, sometimes as high as 2000 × 109/L. In the blood film, the full range of granulocyte precursors, from myeloblasts to mature neutrophils, is seen but the predominant cells are neutrophils and myelocytes (see Fig. 23.3). Myeloblasts usually constitute less than 10% of all white cells. There is often an absolute increase in eosinophils and basophils, and nucleated red cells are common. If the disease progresses through an accelerated phase, the percentage of more primitive cells increases. Blast transformation is characterised by a dramatic increase in the number of circulating blasts. In patients with thrombocytosis, very high platelet counts may persist during treatment, in both chronic and accelerated phases, but usually drop dramatically at blast transformation. Basophilia tends to increase as the disease progresses. Bone marrow should be obtained to confirm the diagnosis and phase of disease by morphology, chromosome analysis to demonstrate the presence of the Ph chromosome, and RNA analysis to demonstrate the presence of the BCR ABL gene product. Blood LDH levels are elevated and the uric acid level may be high due to increased cell breakdown. Management Chronic phase There are now five available tyrosine kinase inhibitors (TKIs) for the treatment of CML (Box 23.49). These specifically inhibit BCR ABL tyrosine kinase activity. Imatinib, nilotinib and dasatinib are recommended as first-line therapy in chronic phase CML; they usually normalise the blood count within a month and within 3–6 months produce complete cytogenetic response (disappearance of the Ph chromosome) in some 90% of patients. A sample of bone marrow is taken at 6 months to confirm complete cytogenetic response, and patients are subsequently monitored by 3-monthly real-time quantitative polymerase chain reaction (PCR) for BCR ABL mRNA transcripts in blood. The aim is to reduce the BCR ABL transcript levels by 3–5 logs from baseline and this is called major molecular response (MR3–MR5). A proportion of patients achieve a complete molecular response where the transcripts are not detectable by PCR. It may be possible for patients with a complete or major molecular response 23.49 Tyrosine kinase inhibition in chronic myeloid leukaemia Agents First-line • Imatinib • Nilotinib • Dasatinib Second-line • Imatinib • Nilotinib • Dasatinib • Bosutinib • Ponatinib* Outcomes • 90% achieve complete cytogenetic response • Responses faster with nilotinib and dasatinib • Median survival comparable to normal population *For patients with T315I kinase domain mutations use ponatinib.

960 • HAEMATOLOGY AND TRANSFUSION MEDICINE Prognosis The majority of clinical stage A patients have a normal life expectancy but patients with advanced CLL are more likely to die from their disease or infectious complications. Survival is influenced by prognostic features of the leukaemia, particularly TP53 mutation status, and whether patients can tolerate and respond to fludarabine-based treatment. In those able to be treated with chemotherapy and rituximab, 90% are alive 4 years later. Rarely, CLL transforms to an aggressive high-grade lymphoma, called Richter’s transformation. Prolymphocytic leukaemia Prolymphocytic leukaemia (PLL) is a variant of chronic lymphocytic leukaemia found mainly in males over the age of 60 years; 25% of cases are of the T-cell variety. There is typically massive splenomegaly with little lymphadenopathy and a very high leucocyte count, often in excess of 400 × 109/L. The characteristic cell is a large lymphocyte with a prominent nucleolus. Treatment is generally unsuccessful and the prognosis very poor. Leukapharesis, splenectomy and chemotherapy may be tried. The anti-CD52 antibody alemtuzumab, when given intravenously, has produced responses in some 90% of patients with T-PLL. Hairy cell leukaemia This is a rare chronic B-cell lymphoproliferative disorder. The male-to-female ratio is 6 : 1 and the median age at diagnosis is 50 years. Presenting symptoms are general ill health and recurrent infections. Splenomegaly occurs in 90% but lymph node enlargement is unusual. Severe neutropenia, monocytopenia and the characteristic hairy cells in the blood and bone marrow are typical. These cells usually have a B-lymphocyte immunotype but they also characteristically express CD25 and CD103. Recently, all patients with hairy cell leukaemia have been found to have a mutation in the BRAF gene. Over recent years, a number of treatments, including cladribine and deoxycoformycin, have been shown to produce long-lasting remissions. Myelodysplastic syndromes Myelodysplastic syndromes (MDSs) constitute a group of clonal haematopoietic disorders with the common features of ineffective blood cell production and a tendency to progress to AML. As such, they are pre-leukaemic and represent genetic steps in the development of leukaemia. These genetic abnormalities have been identified and are present as a manifestation of clonal haematopoiesis in about 3% of patients over the age of 80, at a time when their blood counts are normal (clonal haematopoiesis of indeterminate potential, CHIP). MDS presents with consequences of bone marrow failure (anaemia, recurrent infections or bleeding), usually in older people (median age at diagnosis is 73 years). The overall incidence is 4/100 000 in the population, rising to more than 30/100 000 in the over-seventies. The blood film is characterised by cytopenias and abnormal-looking (dysplastic) blood cells, including macrocytic red cells and hypogranular neutrophils with nuclear hyper- or hyposegmentation. The bone marrow is hypercellular, with dysplastic changes in at least 10% of cells of one or more cell lines. Blast cells may be increased but do not reach the 20% level that indicates acute leukaemia. Chromosome analysis frequently reveals abnormalities, particularly stage of disease (Box 23.50); however, loss of chromosome 17p or mutation in the TP53 gene, which resides at this genetic locus, is a powerful prognostic marker and predictor of response to therapy. A mutation in TP53 is present in < 10% of patients at presentation but rises to 30% of cases at relapse. This test should be performed in all patients prior to the initiation of therapy. Management No specific treatment is required for most clinical stage A patients, unless progression occurs. Life expectancy is usually normal in older patients. The patient should be offered clear information about CLL and be reassured about the indolent nature of the disease, as the diagnosis of leukaemia inevitably causes anxiety. Treatment is required only if there is evidence of bone marrow failure, massive or progressive lymphadenopathy or splenomegaly, systemic symptoms such as weight loss or night sweats, a rapidly increasing lymphocyte count, autoimmune haemolytic anaemia or thrombocytopenia. Initial therapy for those requiring treatment (progressive stage A and stages B and C) is based on the age and fitness of the patient and the TP53 mutation status. For patients who are under 70 years, fit and TP53 mutationnegative, fludarabine in combination with the alkylating agent cyclophosphamide and the anti-CD20 monoclonal antibody rituximab (FCR) is standard care. For older, less fit patients, rituximab is combined with gentler chemotherapy: bendamustine or oral chlorambucil. Recently, a more potent type 2 anti-CD20 antibody, obinutuzumab, has become available and produces better responses in combination with chlorambucil than rituximab. CLL cells are dependent on abnormal and persistent signalling through the B-cell receptor (BCR) pathway. Drugs that can inhibit this pathway are now available and show great promise. Ibrutinib inhibits Bruton’s tyrosine kinase and idelalisib inhibits PI3 kinase, both components of the BCR pathway. Ibrutinib and idelalisib are licensed for relapsed CLL but crucially are licensed and effective in TP53-mutated disease at all stages and are quickly becoming standard care in TP53-mutated CLL. Bone marrow failure or autoimmune cytopenias may respond to glucocorticoid treatment. Supportive care is increasingly required in progressive disease, such as transfusions for symptomatic anaemia or thrombocytopenia, prompt treatment of infections and, for some patients with hypogammaglobulinaemia, immunoglobulin replacement. Radiotherapy may be used for lymphadenopathy that is causing discomfort or local obstruction, and for symptomatic splenomegaly. Splenectomy may be required to improve low blood counts due to autoimmune destruction or to hypersplenism, and can relieve massive splenomegaly. 23.50 Staging of chronic lymphocytic leukaemia Clinical stage A (60% patients) • No anaemia or thrombocytopenia and fewer than three areas of lymphoid enlargement Clinical stage B (30% patients) • No anaemia or thrombocytopenia, with three or more involved areas of lymphoid enlargement Clinical stage C (10% patients) • Anaemia and/or thrombocytopenia, regardless of the number of areas of lymphoid enlargement

Haematological malignancies • 961

with isolated del(5q) responds well to the immunomodulatory drug lenalidomide, with two-thirds of anaemic patients becoming transfusion-independent for up to 2 years. Allogeneic stem cell transplantation may afford a cure in patients with a good performance status and is considered in high-risk patients (IPSS-R high and very high) and some low-risk patients. More recently, the hypomethylating agent azacytidine has improved survival by a median of 9 months for high-risk patients, and in the UK is a recommended standard of care for those not eligible for transplantation. Lymphomas These neoplasms arise from lymphoid tissues, and are diagnosed from the pathological findings on biopsy as Hodgkin or nonHodgkin lymphoma. The majority are of B-cell origin. Non-Hodgkin lymphomas are classified as low- or high-grade tumours on the basis of their proliferation rate. The normal architecture of the lymph node is outlined in Figure 23.25. • High-grade tumours divide rapidly, are typically present for a matter of weeks before diagnosis, and may be lifethreatening with frequent risk of extranodal involvement. • Low-grade tumours divide slowly, may be present for many months before diagnosis, and typically behave in an indolent fashion. Hodgkin lymphoma The histological hallmark of Hodgkin lymphoma (HL) is the presence of Reed–Sternberg cells: large, malignant lymphoid cells of B-cell origin (Fig. 23.26). They are often present only in small numbers but are surrounded by large numbers of reactive non-malignant T cells, plasma cells and eosinophils. The epidemiology of HL is shown in Box 23.53 and its histological WHO classification in Box 23.54. Nodular lymphocyte-predominant HL is slow-growing, localised and rarely fatal. It has biological features, such as CD20-positive Hodgkin cells, and clinical features that make it more akin to a low-grade B-cell non-Hodgkin lymphoma. Classical HL is divided into four histological subtypes from the appearance of the of chromosome 5 or 7. The WHO classification of MDS is shown in Box 23.51. Prognosis The natural history of MDS is progressive worsening of dysplasia leading to fatal bone marrow failure or progression to AML in 30% of cases. The time to progression varies (from months to years) with the subtype of MDS, being slowest in MDS with ring sideroblasts and single-lineage dysplasia and most rapid in MDS with excess blasts. The revised International Prognostic Scoring System (IPSS-R) predicts clinical outcome based on karyotype and cytopenias in blood, as well as percentage of bone marrow blasts (Box 23.52). There are five prognostic groups. The median survival for low-risk patients (IPSS-R very low and low) is 5–9 years, that for the intermediate group is 3 years and that for high-risk patients (IPSS-R high and very high) is 1–1.5 years. Management For the vast majority of patients who are elderly, the disease is incurable, and supportive care with red cell and platelet transfusions is the mainstay of treatment. A trial of erythropoiesis stimulating agents (ESA) and granulocyte–colony-stimulating factor (G–CSF) is recommended in some patients with lowrisk MDS (IPSS-R very low, low and intermediate) to improve haemoglobin or neutrophil counts. A rare subtype called MDS 23.51 WHO classification of myelodysplastic syndromes (MDSs) Disease Bone marrow findings MDS with single-lineage dysplasia < 5% blasts and single-lineage dysplasia only MDS with ring sideroblasts (MDS-RS)

15% ring sideroblasts, or 6–14% and presence of SF3B1 gene mutation MDS with multilineage dysplasia < 5% blasts and dysplasia in 2 or more lineages MDS with excess blasts 5–19% blasts MDS with isolated del(5q) Myelodysplastic syndrome associated with a del(5q) cytogenetic abnormality < 5% blasts Often normal or increased blood platelet count MDS, unclassifiable None of the above or inadequate material The IPSS-R is based on three prognostic factors: the blast percentage in bone marrow; karyotype; and number and degree of blood cytopenias. A score is derived from which patients can be stratified into five risk categories for survival and leukaemic transformation. 23.52 Revised International Prognostic Scoring System and outcomes in myelodysplasia Risk category Overall score Median survival (years) 25% progression to acute myeloid leukaemia (years) Very low ≤ 1.5 8.8 Not reached Low 1.5–3 5.3 10.8 Intermediate 3–4.5 3.0 3.2 High 4.5–6 1.6 1.4 Very high 6 0.8 0.73 Fig. 23.25 Schema of lymph node architecture. Different lymphocyte populations reside in different areas of the node: B cells in the follicles, T cells in the paracortex and plasma cells in the medulla. B cells are selected for antigen in the follicle centre. Errors during this process result in B-cell lymphomas, which are by far the most common type. Germinal centre B-cell follicle Mantle zone Marginal zone Afferent lymph Paracortex Cortex Efferent lymph Medulla Blood vessels Capsule

962 • HAEMATOLOGY AND TRANSFUSION MEDICINE but may cause dry cough and some breathlessness. Isolated subdiaphragmatic nodes occur in fewer than 10% at diagnosis. Hepatosplenomegaly may be present but does not always indicate disease in those organs. Spread is contiguous from one node to the next, and extranodal disease, such as bone, brain or skin involvement, is rare. Investigations Treatment of HL depends on the stage at presentation; investigations therefore aim not only to diagnose lymphoma but also to determine the extent of disease (Box 23.55). • FBC may be normal. If a normochromic, normocytic anaemia or lymphopenia is present, this is a poor prognostic factor. An eosinophilia or a neutrophilia may be present. • ESR may be raised. • Renal function tests are required to ensure function is normal prior to treatment. • Liver function may be abnormal in the absence of disease or may reflect hepatic infiltration. An obstructive pattern may be caused by nodes at the porta hepatis. • LDH measurements showing raised levels are an adverse prognostic factor. • Chest X-ray may show a mediastinal mass. • CT scan of chest, abdomen and pelvis permits staging. Bulky disease (> 10 cm in a single node mass) is an adverse prognostic feature. • Positron emission tomography (PET) scanning identifies nodes involved with HL, which are 18fluorodeoxyglucose (FDG)-avid, and this allows more accurate staging and monitoring of response (Fig. 23.27). • Lymph node biopsy may be undertaken surgically or by percutaneous needle biopsy under radiological guidance (Fig. 23.28). Management Clinical trials have shown that patients with early-stage disease (stages IA and IIA) have better outcomes if limited cycles of chemotherapy are combined with radiotherapy, rather than using radiotherapy alone. 23.55 Clinical stages of Hodgkin lymphoma (Ann Arbor classification) Stage Definition I Involvement of a single lymph node region (I) or extralymphatic* site (IE) II Involvement of two or more lymph node regions (II) or an extralymphatic site and lymph node regions on the same side of (above or below) the diaphragm (IIE) III Involvement of lymph node regions on both sides of the diaphragm with (IIIE) or without (III) localised extralymphatic involvement or involvement of the spleen (IIIs), or both (IIISE) IV Diffuse involvement of one or more extralymphatic tissues, e.g. liver or bone marrow Each stage is subclassified: A No systemic symptoms B Weight loss > 10%, drenching sweats, fever *The lymphatic structures are defined as the lymph nodes, spleen, thymus, Waldeyer’s ring, appendix and Peyer’s patches. 23.54 WHO pathological classification of Hodgkin lymphoma (HL) Type Histology classification Proportion of HL Nodular lymphocytepredominant HL 5% Classical HL Nodular sclerosing 70% Mixed cellularity 20% Lymphocyte-rich 5% Lymphocyte-depleted Rare 23.53 Epidemiology and aetiology of Hodgkin lymphoma Incidence • Approximately 4 new cases/100 000 population/year Sex ratio • Slight male excess (1.5 : 1) Age • Median age 31 years; first peak at 20–35 years and second at 50–70 years Aetiology • Unknown • More common in patients from well-educated backgrounds and small families • Three times more likely with a past history of infectious mononucleosis but no definitive causal link to Epstein–Barr virus infection proven Fig. 23.26 Hodgkin lymphoma. In the centre of this lymph node biopsy is a large typical Reed–Sternberg cell with two nuclei containing a prominent eosinophilic nucleolus. Reed–Sternberg cells and surrounding reactive cells. The nodular sclerosing type is more common in young patients and in women. Mixed cellularity is more common in the elderly. Lymphocyte-rich HL usually presents in men. Lymphocyte-depleted HL is rare and probably represents large-cell or anaplastic non-Hodgkin lymphoma. Clinical features There is painless, rubbery lymphadenopathy, usually in the neck or supraclavicular fossae; the lymph nodes may fluctuate in size. Young patients with nodular sclerosing disease may have large mediastinal masses that are surprisingly asymptomatic

Haematological malignancies • 963

rate and decades of life ahead of them. Recent randomised trial data from the UK RAPID study have suggested that early-stage patients without bulk disease who have a negative PET scan after three cycles of ABVD can safely omit radiotherapy. Young women receiving breast irradiation during the treatment of chest disease have an increased risk of breast cancer and should participate in a screening programme. Patients continuing to smoke after lung irradiation are at particular risk of lung cancer. ABVD chemotherapy can cause cardiac and pulmonary toxicity, due to doxorubicin and bleomycin, respectively. The incidence of infertility and secondary myelodysplasia/AML is low with this regimen. Patients with advanced-stage disease are most commonly managed with chemotherapy alone. Standard treatment in the UK is 6–8 cycles of ABVD, followed by an assessment of response. The recent UK RATHL trial has confirmed previous data showing that achieving a PET-negative response after two cycles of ABVD (interim PET-2 response) predicts a very good outcome from continuing with up to six cycles of ABVD. Indeed, the same outcome can be achieved by omitting the bleomycin from the last four cycles and using just AVD, thus reducing the risk of lung toxicity. Patients who are PET-positive after two cycles, however, have a very high relapse risk if they continue with ABVD, only 13% being relapse-free at 2 years. The RATHL and other studies have demonstrated that changing to a more intensive regimen, BEACOPP (bleomycin, etoposide, adriamycin, cyclophosphamide, vincristine (oncovin), procarbazine, prednisolone), in these patients improves the relapse-free survival to approximately 65%. Patients with relapsed disease that responds to salvage chemotherapy and ideally becomes PET-negative should be considered for autologous stem cell transplantation (p. 937). Those with resistant disease might benefit from an allogeneic A Fig. 23.27 Positron emission tomography (PET) scans in Hodgkin lymphoma, demonstrating response to treatment. A Chest X-ray from a young man with Hodgkin lymphoma at presentation, showing a left-sided anterior–superior mediastinal mass with tracheal deviation to the right. B Fused PET-CT image showing intense fluorodeoxyglucose (FDG) uptake (avidity) in the mass at presentation. C Fused PET-CT image showing no FDG uptake (PET negativity), representing complete response at the end of treatment. B C Fig. 23.28 CT-guided percutaneous needle biopsy of retroperitoneal nodes involved by lymphoma. Biopsy needle Enlarged lymph nodes The ABVD regimen (doxorubicin, bleomycin, vinblastine and dacarbazine) is widely used in the UK. Standard therapy for early-stage patients without additional risk factors, such as bulk disease or high ESR, is two cycles of ABVD combined with 20 Gy radiotherapy to the involved sites of disease. Standard therapy for early-stage patients with additional risk factors is four cycles of ABVD combined with 30 Gy radiotherapy. Careful planning of radiotherapy is required to limit the doses delivered to normal tissues and new planning techniques continue to improve targeting of radiotherapy. Nevertheless, the long-term risks of second cancers and heart and lung disease within the radiation fields remain a concern, especially for young people with a high cure

964 • HAEMATOLOGY AND TRANSFUSION MEDICINE even years before presentation, runs an indolent course, but is not curable by conventional therapy. Of all cases of NHL in the developed world, over two-thirds are either diffuse large B-cell NHL (high-grade) or follicular NHL (low-grade) (Fig. 23.29). Other forms of NHL, including Burkitt lymphoma, mantle cell lymphoma, mucosa-associated lymphoid tissue (MALT) lymphomas and T-cell lymphomas, are less common. Clinical features Unlike Hodgkin lymphoma, NHL is often widely disseminated at presentation, including in extranodal sites. Patients present with lymph node enlargement (Fig. 23.30), which may be associated with systemic upset: weight loss, sweats, fever and itching. Hepatosplenomegaly may be present. Sites of extranodal involvement include the bone marrow, gut, thyroid, lung, skin, testis, brain and, more rarely, bone. Bone marrow involvement is more common in low-grade (50–60%) than high-grade (10%) disease. Compression syndromes may occur, including gut obstruction, ascites, superior vena cava obstruction and spinal cord compression. The same staging system (see Box 23.55) is used for both HL and NHL, but NHL is more likely to be stage III or IV at presentation. Investigations These are as for HL, but in addition the following should be performed: • Bone marrow aspiration and trephine to identify bone marrow involvement. • Immunophenotyping of surface antigens to distinguish T-cell from B-cell tumours. This may be done on blood, marrow or nodal material. stem cell transplant. Brentuximab vedotin is an antibody–drug conjugate directed against CD30 on the Reed–Sternberg cell surface. This antibody delivers the antimitotic toxin monomethyl auristatin E to the Hodgkin cells and, as a single agent, can produce good responses in patients who have failed, or are not suitable for, an autologous transplant and can be a ‘bridge’ to an allogeneic transplant. Prognosis Over 90% of patients with early-stage HL achieve complete remission when treated with chemotherapy followed by involved field radiotherapy, and the great majority are cured. The major challenge is how to reduce treatment intensity, and hence long-term toxicity, without reducing the excellent cure rates in this group. Omitting radiotherapy in the majority of PET-negative patients is one major step forward in this regard. Historically, between 50 and 70% of those with advanced-stage HL were cured. The Hasenclever index (Box 23.56) can be helpful in assigning approximate chances of cure when discussing treatment plans with patients. More recent data using the PET scanner to direct therapy suggests that long-term survival is improving to beyond 80%. Patients who fail to respond to initial chemotherapy or relapse within a year of initial therapy have a poor prognosis but some may achieve long-term survival after autologous HSCT. Patients relapsing after 1 year may obtain long-term survival with further chemotherapy alone, but fit patients frequently proceed to autologous HSCT. Non-Hodgkin lymphoma Non-Hodgkin lymphoma (NHL) represents a monoclonal proliferation of lymphoid cells of B-cell (90%) or T-cell (10%) origin. The incidence of these tumours increases with age, to 62.8/million population per annum at age 75 years, and the overall rate is increasing at about 3% per year. The epidemiology of NHL is shown in Box 23.57. Previous classifications were based principally on histological appearances. The current WHO classification stratifies according to cell lineage (T or B cells) and incorporates clinical features, histology, chromosomal abnormalities and concepts related to the biology of the lymphoma. Clinically, the most important factor is grade, which is a reflection of proliferation rate. High-grade NHL has high proliferation rates, rapidly produces symptoms, is fatal if untreated, but is potentially curable. Low-grade NHL has low proliferation rates, may be asymptomatic for many months or 23.57 Epidemiology and aetiology of non-Hodgkin lymphoma Incidence • 12 new cases/100 000 people/year Sex ratio • Slight male excess Age • Median age 65–70 years Aetiology • No single causative abnormality described • Lymphoma is a late manifestation of HIV infection (p. 322) • Specific lymphoma types are associated with viruses: e.g. Epstein–Barr virus (EBV) with post-transplant NHL, human herpesvirus 8 (HHV8) with a primary effusion lymphoma, and human T-cell lymphotropic virus (HTLV-1) with adult T-cell leukaemia lymphoma • Gastric lymphoma can be associated with Helicobacter pylori infection • Some lymphomas are associated with specific chromosomal translocations: The t(14;18) in follicular lymphoma results in the dysregulated expression of the BCL-2 gene product, which inhibits apoptotic cell death The t(8;14) found in Burkitt lymphoma and the t(11;14) in mantle cell lymphoma alter function of c-myc and cyclin D1, respectively, resulting in malignant proliferation • Lymphoma occurs in congenital immunodeficiency states and in immunosuppressed patients after organ transplantation 23.56 The Hasenclever prognostic index for advanced Hodgkin lymphoma Score 1 for each of the following risk factors present at diagnosis: • Age > 45 years • Male gender • Serum albumin < 40 g/L • Hb < 105 g/L • Stage IV disease • White blood cell count > 15 × 109/L • Lymphopenia < 0.6 × 109/L Score 5-year rate of freedom from progression (%) 5-year rate of overall survival (%) 0–1

2

3

4

Haematological malignancies • 965

Fig. 23.29 Histology of non-Hodgkin lymphoma. A (Low-grade) follicular or nodular pattern. B (High-grade) diffuse pattern. A B Fig. 23.30 Bulky axillary lymphadenopathy with distended superficial veins in a patient presenting with high-grade lymphoma. From Howard MR, Hamilton PJ. Haematology: An illustrated colour text, 4th edn. Edinburgh: Elsevier Ltd; 2013. • Cytogenetic analysis to detect chromosomal translocations and molecular testing for T-cell receptor or immunoglobulin gene rearrangements. • Immunoglobulin determination. Some lymphomas are associated with IgG or IgM paraproteins, which serve as markers for treatment response. • Measurement of uric acid levels. Some very aggressive high-grade NHLs are associated with very high urate levels, which can precipitate renal failure when treatment is started. • HIV testing. HIV is a risk factor for some lymphomas and affects treatment decisions. • Hepatitis B and C testing. This should be done prior to therapy with rituximab. Management Low-grade NHL The majority of patients (80%) present with advanced stage disease and will run a relapsing and remitting course over several years. Asymptomatic patients may not require therapy and are managed by ‘watching and waiting’. Indications for treatment include marked systemic symptoms, lymphadenopathy causing discomfort or disfigurement, bone marrow failure or compression syndromes. In follicular lymphoma, the options are: • Radiotherapy. This can be used for localised stage I disease, which is rare. • Chemotherapy. Most patients will respond to oral therapy with chlorambucil, which is well tolerated but not curative. More intensive intravenous chemotherapy in younger patients produces better quality of life but no survival benefit. • Monoclonal antibody therapy. Humanised monoclonal antibodies (‘biological therapy’; p. 960) can be used to target surface antigens on tumour cells and to induce tumour cell apoptosis directly. The anti-CD20 antibody rituximab has been shown to induce durable clinical responses in up to 60% of patients when given alone, and acts synergistically when given with chemotherapy. Rituximab (R) in combination with cyclophosphamide, vincristine and prednisolone (R-CVP), cyclophosphamide, doxorubicin, vincristine, prednisolone (R-CHOP) or bendamustine (R-bendamustine) is commonly used as first-line therapy. Randomised trials have also confirmed that 2 years of maintenance therapy with single-agent rituximab, following achievement of first or second response, delays relapse and the time to next treatment. As yet, however, rituximab maintenance has not shown a survival benefit. New and more potent monoclonal antibodies are also in development and trials of obinutuzumab (p. 960) have been completed. • Kinase inhibitors. Idelalisib is approved for relapsed follicular lymphoma and ibrutinib (p. 960) is approved for relapsed mantle cell lymphoma, a poor-prognosis lymphoma with low-grade histology but aggressive clinical behaviour. These targeted therapies are likely to become more widely used in low-grade lymphomas in the near future. • Transplantation. High-dose chemotherapy and autologous HSCT can produce long remissions in patients with relapsed disease. Decisions on the timing of such treatment are complex in the context of rituximab maintenance and newer targeted therapies. However, younger patients with short first or second remissions or who relapse during rituximab maintenance should be considered.

966 • HAEMATOLOGY AND TRANSFUSION MEDICINE present in the blood but there are no other features of myeloma, Waldenström macroglobulinaemia (see below), lymphoma or related disease. It is a common condition associated with increasing age; a paraprotein can be found in 1% of the population aged over 50 years, increasing to 5% over 80 years. Clinical features and investigations Patients are usually asymptomatic, and the paraprotein is found on blood testing for other reasons. The routine blood count and biochemistry are normal, the paraprotein is usually present in small amounts with no associated immune paresis, and there are no lytic bone lesions. The bone marrow may have increased plasma cells but these usually constitute less than 10% of nucleated cells. Prognosis After follow-up of 20 years, only one-quarter of cases will progress to myeloma or a related disorder (i.e. around 1% per annum). There is no certain way of predicting progression in an individual patient. However, an abnormal ratio of kappa to lambda light chains (serum free light chain ratio, SFLR) increases the risk of progression. Patients with an abnormal ratio should be monitored for progression on an annual basis. Waldenström macroglobulinaemia This is a low-grade lymphoplasmacytic lymphoma associated with an IgM paraprotein, causing clinical features of hyperviscosity syndrome. It is a rare tumour occurring in the elderly and more commonly affects males. Patients classically present with features of hyperviscosity, such as nosebleeds, bruising, delirium and visual disturbance. However, presentation may be with anaemia, systemic symptoms, splenomegaly or lymphadenopathy, or may be asymptomatic, with an IgM paraprotein detected on routine screening. Patients are found on investigation to have an IgM paraprotein associated with a raised plasma viscosity. The bone marrow has a characteristic appearance, with infiltration of lymphoid cells, plasma cells and sometimes prominent mast cells. A high proportion of patients have a mutation in the MYD88 gene. Management If patients show symptoms of hyperviscosity and anaemia, plasmapheresis is required to remove IgM and make blood transfusion possible. Chemotherapy with alkylating agents, such as chlorambucil, has been the mainstay of treatment, controlling disease in over 50%. Fludarabine may be more effective in this disease but has more side-effects. Rituximab in combination with chemotherapy is most commonly used; ibrutinib is very effective and has recently been licensed for use. Rituximab alone can cause a rapid release of IgM and increase in viscosity. The median survival is 5 years. Multiple myeloma This is a malignant proliferation of plasma cells. Normal plasma cells are derived from B cells and produce immunoglobulins that contain heavy and light chains. Normal immunoglobulins are polyclonal, which means that a variety of heavy chains are produced and each may be of kappa or lambda light chain type (p. 68). In myeloma, plasma cells produce immunoglobulin of a single heavy and light chain, a monoclonal protein commonly referred to as a paraprotein. In most cases an excess of light chain is produced, and in some cases only light chain is produced; High-grade NHL Patients with diffuse large B-cell NHL need treatment at initial presentation: • Chemotherapy. The majority (> 90%) are treated with intravenous combination chemotherapy, typically with the CHOP regimen (cyclophosphamide, doxorubicin, vincristine and prednisolone). • Monoclonal antibody therapy. When combined with CHOP chemotherapy, rituximab (R) increases the complete response rates and improves overall survival. R-CHOP is currently recommended as first-line therapy for those with stage II or higher diffuse large B-cell lymphoma. • Radiotherapy. Stage I patients without bulky disease are treated with four cycles of CHOP or R-CHOP, followed by involved site radiotherapy. Radiotherapy is also indicated for a residual localised site of bulk disease after chemotherapy, and for spinal cord and other compression syndromes. • HSCT. Autologous HSCT (p. 937) benefits patients with relapsed disease that is sensitive to salvage immunochemotherapy. As with HL, achieving PET negativity prior to autologous transplantation is desirable. Prognosis Low-grade NHL runs an indolent remitting and relapsing course, with an overall median survival of 12 years. Transformation to a high-grade NHL occurs in 3% per annum and is associated with poor survival. In diffuse large B-cell NHL treated with R-CHOP, some 75% of patients overall respond initially to therapy and 50% will have disease-free survival at 5 years. The prognosis for patients with NHL is further refined according to the international prognostic index (IPI). For high-grade NHL, 5-year survival ranges from over 75% in those with low-risk scores (age < 60 years, stage I or II, one or fewer extranodal sites, normal LDH and good performance status) to 25% in those with high-risk scores (increasing age, advanced stage, concomitant disease and a raised LDH). Relapse is associated with a poor response to further chemotherapy (< 10% 5-year survival), but in patients under 65 years HSCT improves survival. Paraproteinaemias A gammopathy refers to over-production of one or more classes of immunoglobulin. It may be polyclonal in association with acute or chronic inflammation, such as infection, sarcoidosis, autoimmune disorders or some malignancies. Alternatively, a monoclonal increase in a single immunoglobulin class may occur in association with normal or reduced levels of the other immunoglobulins. Such monoclonal proteins (also called M-proteins, paraproteins or monoclonal gammopathies) occur as a feature of myeloma, lymphoma and amyloidosis, in connective tissue disease such as rheumatoid arthritis or polymyalgia rheumatica, in infection such as HIV, and in solid tumours. In addition, they may be present with no underlying disease. Gammopathies are detected by plasma immunoelectrophoresis. Monoclonal gammopathy of uncertain significance In monoclonal gammopathy of uncertain significance (MGUS, also known as benign monoclonal gammopathy), a paraprotein is

Haematological malignancies • 967

60–70 years and the disease is more common in Afro-Caribbeans. The clinical features are demonstrated in Figure 23.31. Diagnosis of myeloma requires two of the following criteria to be fulfilled: • increased malignant plasma cells in the bone marrow • serum and/or urinary M-protein • skeletal lytic lesions. Bone marrow aspiration, plasma and urine electrophoresis, and a skeletal survey are thus required. Normal immunoglobulin levels, i.e. the absence of immunoparesis, should cast doubt on the diagnosis. Paraproteinaemia can cause an elevated ESR but this is a non-specific test; only approximately 5% of patients with a persistently elevated ESR above 100 mm/hr have underlying myeloma. Management If patients are asymptomatic with no evidence of end-organ damage (e.g. to kidneys, bone marrow or bone), treatment may not be required. So-called asymptomatic myeloma should be monitored closely for the development of end-organ damage. Immediate support • High fluid intake to treat renal impairment and hypercalcaemia (p. 661). • Analgesia for bone pain. this appears in the urine as Bence Jones proteinuria and can be measured in the urine or serum as free light chain. The frequency of different isotypes of monoclonal protein in myeloma is shown in Box 23.58. Although a small number of malignant plasma cells are present in the circulation, the majority are present in the bone marrow. The malignant plasma cells produce cytokines, which stimulate osteoclasts and result in net bone reabsorption. The resulting lytic lesions cause bone pain, fractures and hypercalcaemia. Marrow involvement can result in anaemia or pancytopenia. Clinical features and investigations The incidence of myeloma is 4/100 000 new cases per annum, with a male-to-female ratio of 2 : 1. The median age at diagnosis is Fig. 23.31 Clinical and laboratory features of multiple myeloma. (ESR = erythrocyte sedimentation rate; NSAIDs = non-steroidal anti-inflammatory drugs) Spinal cord compression Bony collapse Extradural mass Amyloid ‘Panda’ eyes Nephrotic syndrome Carpal tunnel syndrome Abnormal blood tests Bone pain/fracture Retinal bleeds Bruising Heart failure Cerebral ischaemia Engorged retinal veins in hyperviscosity Hyperviscosity Renal failure due to: Paraprotein deposition Hypercalcaemia Infection NSAIDs Amyloid Lytic lesions Lytic lesions in skull Anaemia Normo- or macrocytic Pancytopenia Raised ESR Bone marrow Plasmacytosis > 10% Bence Jones proteinuria Serum free light chains Paraproteinaemia Immune paresis Plasma cells in bone marrow Lytic lesion eroding right superior pubic ramus and acetabulum Hypercalcaemia Renal impairment 23.58 Classification of multiple myeloma Type of monoclonal (M)-protein Relative frequency (%) IgG

IgA

Light chain only

Others (D, E, non-secretory)

968 • HAEMATOLOGY AND TRANSFUSION MEDICINE emergency treatment of spinal cord compression complicating extradural plasmacytomas. Bisphosphonates Long-term bisphosphonate therapy reduces bone pain and skeletal events. These drugs protect bone (p. 1047) and may cause apoptosis of malignant plasma cells. There is evidence that intravenous zoledronate in combination with anti-myeloma therapy confers a survival advantage over oral bisphosphonates. Osteonecrosis of the jaw may be associated with long-term use or poor oral hygiene and gum sepsis; regular dental review, including a check before starting therapy, is therefore important. Prognosis The international staging system (ISS) identifies poor prognostic features, including a high β2-microglobulin and low albumin at diagnosis (ISS stage 3, median survival 29 months). Those with a normal albumin and a low β2-microglobulin (ISS stage 1) have a median survival of 62 months. Increasingly, cytogenetic analysis is used to identify poor-risk patients, e.g. t(4;14), del(17/17p), t(14;16), t(14;20), non-hyperdiploidy and gain(1q). Use of autologous HSCT and advances in drug therapy with the newer agents have increased survival. Over one-third of patients are now surviving for 5 years, compared with only one-quarter 10 years ago. The outlook may improve further with new drugs and combinations of treatments. Aplastic anaemias Primary idiopathic acquired aplastic anaemia This is a rare disorder in Europe and North America, with 2–4 new cases per million population per annum. The disease is much more common in certain other parts of the world, e.g. east Asia. The basic problem is failure of the pluripotent stem cells because of an autoimmune attack, producing hypoplasia of the bone marrow with a pancytopenia in the blood. The diagnosis rests on exclusion of other causes of secondary aplastic anaemia (see below) and rare congenital causes, such as Fanconi’s anaemia. Clinical features and investigations Patients present with symptoms of bone marrow failure, usually anaemia or bleeding, and less commonly, infections. An FBC demonstrates pancytopenia, low reticulocytes and often macrocytosis. Bone marrow aspiration and trephine reveal hypocellularity. The severity of aplastic anaemia is graded according to the Camitta criteria (Box 23.60). • Bisphosphonates for hypercalcaemia and to delay other skeletal related events (p. 1047). • Allopurinol to prevent urate nephropathy. • Plasmapheresis, if necessary, for hyperviscosity. Chemotherapy with or without HSCT Myeloma therapy has improved with the addition of novel agents, initially thalidomide and more recently the proteasome inhibitor bortezomib and the second-generation immunomodulatory drug lenalidomide. For first-line therapy in older patients, thalidomide combined with the alkylating agent melphalan and prednisolone (MPT) has increased the median overall survival to more than 4 years. Lenalidomide is approved first-line treatment for patients not eligible for transplantation and who are intolerant of, or unsuitable for, thalidomide. Thalidomide and lenalidomide both have anti-angiogenic effects against tumour blood vessels and immunomodulatory effects. Both can cause somnolence, constipation, peripheral neuropathy and thrombosis, though lenalidomide has a better side-effect profile. It is vital that females of child-bearing age use adequate contraception, as thalidomide and lenalidomide are teratogenic. Treatment is administered until paraprotein levels have stopped falling. This is termed ‘plateau phase’ and can last for weeks or years. In younger, fitter patients, standard treatment includes firstline therapies, such as cyclophosphamide, thalidomide and dexamethasone (CTD) or bortezomib (Velcade), thalidomide and dexamethasone (VTD) to maximum response, and then autologous HSCT, which improves quality of life and prolongs survival but does not cure myeloma. In all patients who have achieved maximal response, lenalidomide maintenance has been shown to prolong the response. When myeloma progresses, treatment is given to induce a further plateau phase. In the UK, the proteosome inhibitor bortezomib and lenalidomide have been used as second- and third-line therapy, as appropriate. As they have been used more frequently in the first or second line with prognostic benefit, however, subsequent relapses are more difficult to treat. A second-generation proteasome inhibitor, carfilzomib, and the anti-CD38 antibody daratumumab show promise in relapsed/ refractory disease. Responding patients may benefit from a second autologous HSCT. Radiotherapy This is effective for localised bone pain not responding to simple analgesia and for pathological fractures. It is also useful for the 23.59 Haematological malignancy in old age • Median age: approximately 70 years for most haematological malignancies. • Poor-risk biological features: adverse cytogenetics or the presence of a multidrug resistance phenotype are more frequent. • Prognosis: increasing age is an independent adverse variable in acute leukaemia and aggressive lymphoma. • Chemotherapy: may be less well tolerated. Older people are more likely to have antecedent cardiac, pulmonary or metabolic problems, tolerate systemic infection less well and metabolise cytotoxic drugs differently. • Cure rates: similar to those in younger patients, in those who do tolerate treatment. • Decision to treat: should be based on the individual’s biological status, the level of social support available, and the patient’s wishes and those of the immediate family, but not on chronological age alone. 23.60 Camitta criteria Severe AA (SAA) • Marrow cellularity < 25% (or 25–50% with < 30% residual haematopoietic cells), plus at least two of: Neutrophils < 0.5 × 109/L Platelets < 20 × 109/L Reticulocyte count < 20 × 109/L Very severe AA (VSAA) • As for SAA but neutrophils < 0.2 × 109/L Non-severe AA (NSAA) • AA not fulfilling the criteria for SAA or VSAA

Myeloproliferative neoplasms • 969

rubra vera (PRV), essential thrombocythaemia and myelofibrosis are the non-leukaemic myeloproliferative neoplasms. Although the majority of patients are classifiable as having one of these disorders, some have overlapping features and there is often progression from one to another, e.g. PRV to myelofibrosis. The recent discovery of the molecular basis of these disorders will lead to changes in classification and treatment; a mutation in the gene on chromosome 9 encoding the signal transduction molecule JAK-2 has been found in more than 90% of PRV cases and 50% of those with essential thrombocythaemia and myelofibrosis. Mutations in the calreticulin gene (CALR), which produces a chaperone protein that protects proteins moving from the endoplasmic reticulin to the cytoplasm, have been found in a further 25% of patients with essential thrombocythaemia. Less commonly, mutations can be detected in the thrombopoietin receptor gene MPL. Myelofibrosis In myelofibrosis, the marrow is initially hypercellular, with an excess of abnormal megakaryocytes that release growth factors, such as platelet-derived growth factor, to the marrow microenvironment, resulting in a reactive proliferation of fibroblasts. As the disease progresses, the marrow becomes fibrosed. Most patients present over the age of 50 years, with lassitude, weight loss and night sweats. The spleen can be massively enlarged due to extramedullary haematopoiesis (blood cell formation outside the bone marrow), and painful splenic infarcts may occur. The characteristic blood picture is leucoerythroblastic anaemia, with circulating immature red blood cells (increased reticulocytes and nucleated red blood cells) and granulocyte precursors (myelocytes). The red cells are shaped like teardrops (teardrop poikilocytes), and giant platelets may be seen in the blood. The white count varies from low to moderately high and the platelet count may be high, normal or low. Urate levels may be high due to increased cell breakdown, and folate deficiency is common. The marrow is often difficult to aspirate and a trephine biopsy shows an excess of megakaryocytes, increased reticulin and fibrous tissue replacement. The presence of a JAK-2 mutation supports the diagnosis. Management and prognosis Median survival is 4 years from diagnosis, but ranges from 1 year to over 20 years. Treatment is directed at control of symptoms, e.g. red cell transfusions for anaemia. Folic acid should be given to prevent deficiency. Cytotoxic therapy with hydroxycarbamide may help control spleen size, the white cell count or systemic symptoms. Splenectomy may be required for a grossly enlarged spleen or symptomatic pancytopenia secondary to splenic pooling of cells and hypersplenism. HSCT may be considered for younger patients. Ruxolitinib, an inhibitor of JAK-2, is now licensed in myelofibrosis and is effective at reducing systemic symptoms and splenomegaly. Essential thrombocythaemia Uncontrolled proliferation of megakaryocytes results in a raised level of circulating platelets that are often dysfunctional. Prior to a diagnosis of essential thrombocythaemia being made, reactive causes of thrombocytosis must be excluded (see Box 23.15). The presence of a JAK-2, CALR or, rarely, MPL mutation supports the diagnosis but is not universal. Patients present at a median age of 60 years with vascular occlusion or bleeding, or with an asymptomatic isolated raised platelet count. A small Management All patients will require blood product support and aggressive management of infection. The prognosis of severe aplastic anaemia managed with supportive therapy only is poor and more than 50% of patients die, usually in the first year. The curative treatment for patients under 35 years of age with severe idiopathic aplastic anaemia is allogeneic HSCT if there is an available sibling donor (p. 937). Older patients (35–50) may be candidates if they have no comorbidities (p. 937). Those with a compatible sibling donor should proceed to transplantation as soon as possible; they have a 75–90% chance of long-term cure. In older patients and those without a suitable donor, immunosuppressive therapy (IST) with anti-thymocyte globulin (ATG) and ciclosporin is the treatment of choice and gives 5-year survival rates of 75%. Unrelated donor allografts are considered for suitable patients who fail IST. The thrombopoietin receptor agonist eltrombopag (p. 971) has produced trilineage responses in patients who fail IST and is licensed for this indication. Non-transplanted patients may relapse or other clonal disorders of haematopoiesis may evolve, such as paroxysmal nocturnal haemoglobinuria (p. 950), myelodysplastic syndrome (p. 960) and AML (p. 955). Patients with aplastic anaemia must be followed up long-term. Secondary aplastic anaemia Causes of this condition are listed in Box 23.61. It is not practical to list all the drugs that have been suspected of causing aplasia. It is important to check the reported side-effects of all drugs taken over the preceding months. In some instances, the cytopenia is more selective and affects only one cell line, most often the neutrophils. Frequently, this is an incidental finding, with no ill health. It probably has an immune basis but this is difficult to prove. 23.61 Causes of secondary aplastic anaemia • Drugs: Cytotoxic drugs Antibiotics – chloramphenicol, sulphonamides Antirheumatic agents – penicillamine, gold, phenylbutazone, indometacin Antithyroid drugs – carbimazole, propylthiouracil Anticonvulsants Immunosuppressants – azathioprine • Chemicals: Benzene, toluene solvent misuse – glue-sniffing Insecticides – chlorinated hydrocarbons (DDT), organophosphates and carbamates (pp. 145 and 146) • Radiation • Viral hepatitis • Pregnancy • Paroxysmal nocturnal haemoglobinuria The clinical features and methods of diagnosis are the same as for primary idiopathic aplastic anaemia. An underlying cause should be treated or removed, but otherwise management is as for the idiopathic form. Myeloproliferative neoplasms These make up a group of chronic conditions characterised by clonal proliferation of marrow precursor cells. Polycythaemia

970 • HAEMATOLOGY AND TRANSFUSION MEDICINE (p. 929), von Willebrand disease (p. 974), and also in platelet function disorders and diseases affecting the vessel wall. Vessel wall abnormalities Vessel wall abnormalities may be: • congenital, such as hereditary haemorrhagic telangiectasia • acquired, as in a vasculitis (p. 1040) or scurvy. Hereditary haemorrhagic telangiectasia Hereditary haemorrhagic telangiectasia (HHT) is a dominantly inherited condition caused by mutations in the genes encoding endoglin and activin receptor-like kinase, which are endothelial cell receptors for transforming growth factor-beta (TGF-β), a potent angiogenic cytokine. Telangiectasia and small aneurysms are found on the fingertips, face and tongue, and in the nasal passages, lung and gastrointestinal tract. A significant proportion of these patients develop larger pulmonary arteriovenous malformations (PAVMs) that cause arterial hypoxaemia due to a right-to-left shunt. These predispose to paradoxical embolism, resulting in stroke or cerebral abscess. All patients with HHT should be screened for PAVMs; if these are found, ablation by percutaneous embolisation should be considered. Patients present either with recurrent bleeds, particularly epistaxis, or with iron deficiency due to occult gastrointestinal bleeding. Treatment can be difficult because of the multiple bleeding points but regular iron therapy often allows the marrow to compensate for blood loss. Local cautery or laser therapy may prevent single lesions from bleeding. A variety of medical therapies have been tried but none has been found to be universally effective. Ehlers–Danlos disease Vascular Ehlers–Danlos syndrome (type 4) is a rare autosomal dominant disorder (1/100 000) caused by a defect in type 3 collagen that results in fragile blood vessels and organ membranes, leading to bleeding and organ rupture. Classical joint hypermobility (p. 1059) is often limited in this form of the disease but skin changes and facial appearance are typical. The diagnosis should be considered when there is a history of bleeding with normal laboratory tests. Scurvy Vitamin C deficiency affects the normal synthesis of collagen and results in a bleeding disorder characterised by perifollicular and petechial haemorrhage, bruising and subperiosteal bleeding. The key to diagnosis is the dietary history (p. 715). Platelet function disorders Bleeding may result from thrombocytopenia (see Box 23.14, p. 929) or from congenital or acquired abnormalities of platelet function. The most common acquired disorders are iatrogenic, resulting from the use of aspirin, clopidogrel, ticagrelor, dipyridamole and the glycoprotein IIb/IIIa inhibitors to prevent arterial thrombosis (see Box 23.26, p. 938). Inherited platelet function abnormalities are relatively rare. Congenital abnormalities may be due to deficiency of the membrane glycoproteins, e.g. Glanzmann’s thrombasthenia (IIb/IIIa) or Bernard–Soulier syndrome (Ib), or due to the presence of defective platelet granules, e.g. a deficiency of dense (delta) granules (see Fig. 23.7, p. 920) giving rise to storage pool disorders. The congenital macrothrombocytopathies that are due to mutations in the myosin heavy chain gene MYH-9 are characterised by large platelets, percentage (around 5%) will transform to acute leukaemia and others to myelofibrosis. It is likely that most patients with essential thrombocythaemia benefit from low-dose aspirin to reduce the risk of occlusive vascular events. Low-risk patients (age < 40 years, platelet count < 1500 × 109/L and no bleeding or thrombosis) may not require treatment to reduce the platelet count. For those with a platelet count above 1500 × 109/L, with symptoms, or with other risk factors for thrombosis such as diabetes or hypertension, treatment to control platelet counts should be given. Agents include oral hydroxycarbamide or anagrelide, an inhibitor of megakaryocyte maturation. Intravenous radioactive phosphorus (32P) may be useful in old age and interferon-alfa has a role in younger patients. Polycythaemia rubra vera PRV occurs mainly in patients over the age of 40 years and presents either as an incidental finding of a high haemoglobin, or with symptoms of hyperviscosity, such as lassitude, loss of concentration, headaches, dizziness, blackouts, pruritus and epistaxis. Some patients present with manifestations of peripheral arterial or cerebrovascular disease. Venous thromboembolism may also occur. Peptic ulceration is common, sometimes complicated by bleeding. Patients are often plethoric and many have a palpable spleen at diagnosis. Investigation of polycythaemia is discussed on page 925. The diagnosis of PRV now rests on the demonstration of a high haematocrit and the presence of the JAK-2 V617F mutation (positive in 95% of cases). In the occasional JAK-2-negative cases, a raised red cell mass and absence of causes of a secondary erythrocytosis must be established. The spleen may be enlarged and neutrophil and platelet counts are frequently raised, an abnormal karyotype may be found in the marrow, and in vitro culture of the marrow can be used to demonstrate autonomous growth in the absence of added growth factors. Management and prognosis Aspirin reduces the risk of thrombosis. Venesection gives prompt relief of hyperviscosity symptoms. Between 400 and 500 mL of blood (less if the patient is elderly) are removed and the venesection is repeated every 5–7 days until the haematocrit is reduced to below 45%. Less frequent but regular venesection will maintain this level until the haemoglobin remains reduced because of iron deficiency. Suppression of marrow proliferation with hydroxycarbamide or interferon-alfa may reduce the risk of vascular occlusion, control spleen size and reduce transformation to myelofibrosis. Intravenous 32P, which is reserved for older patients as it increases the risk of transformation to acute leukaemia by 6–10-fold, is rarely used now in Europe and North America. Median survival after diagnosis in treated patients exceeds 10 years. Some patients survive more than 20 years; however, cerebrovascular or coronary events occur in up to 60% of patients. The disease may convert to another myeloproliferative disorder, with about 15% developing acute leukaemia or myelofibrosis. Bleeding disorders Disorders of primary haemostasis The initial formation of the platelet plug (see Fig. 23.6A, p. 918; also known as ‘primary haemostasis’) may fail in thrombocytopenia

Bleeding disorders • 971

phagocytosis of sensitised platelets by reticulo-endothelial cells. Administration of intravenous immunoglobulin can raise the platelet count by blocking antibody receptors on reticulo-endothelial cells, and is combined with glucocorticoid therapy if there is severe haemostatic failure, especially with evidence of significant mucosal bleeding or a slow response to glucocorticoids alone. Persistent or potentially life-threatening bleeding should be treated with platelet transfusion in addition to the other therapies. The condition may become chronic, with remissions and relapses. Relapses should be treated by re-introducing glucocorticoids. If a patient has two relapses or primary refractory disease, second-line therapies are considered. The options for second-line therapy include the thrombopoietin receptor agonists (TPO-RA) eltrombopag and romiplostim, splenectomy and immunosuppression. Where splenectomy is considered, the precautions shown in Box 23.40 need to be in place. Splenectomy produces complete remission in about 70% of patients and improvement in a further 20–25% in favourable cases. The TPO-RAs induce response in around 75% of cases, usually within 10–14 days. Low-dose glucocorticoid therapy and immunosuppressants such as rituximab, ciclosporin, mycophenolate and tacrolimus may also produce remissions. The order in which therapies should be used is not entirely clear, although the TPO-RAs are licensed for this indication while the immunosuppressive agents are not. Coagulation disorders Normal coagulation is explained in Figure 23.6 (p. 918). Coagulation factor deficiency may be congenital or acquired, and may affect one or several of the coagulation factors (Box 23.62). Inherited disorders are almost uniformly related to decreased synthesis, as a result of mutation in the gene encoding a key protein in coagulation. Von Willebrand disease is the most common inherited bleeding disorder. Haemophilia A and B are the most common single coagulation factor deficiencies but inherited deficiencies of all the other coagulation factors are seen. Acquired disorders may be due to under-production (e.g. in liver failure), increased consumption (e.g. in DIC) or inhibition of function of coagulation factors (such as heparin therapy or immune inhibitors of coagulation, e.g. acquired haemophilia A). Haemophilia A Factor VIII deficiency resulting in haemophilia A affects 1/10 000 individuals. It is the most common congenital coagulation factor deficiency. Factor VIII is primarily synthesised by the liver and endothelial cells and has a half-life of about 12 hours. It is protected from proteolysis in the circulation by binding to von Willebrand factor (vWF). Genetics The factor VIII gene is located on the X chromosome. Haemophilia is associated with a range of mutations in the factor VIII gene; these include major inversions, large deletions and missense, nonsense and splice site abnormalities. As the factor VIII gene is on the X chromosome, haemophilia A is a sex-linked disorder (p. 48). Thus all daughters of a patient with haemophilia are obligate carriers and they, in turn, have a 1 in 4 chance of each pregnancy resulting in the birth of an affected male baby, a normal male baby, a carrier female or a normal female. Antenatal diagnosis by chorionic villous sampling is possible in families with a known mutation. inclusion bodies in the neutrophils (Döhle bodies) and a variety of other features, including sensorineural deafness and renal abnormalities. Other familial thrombocytopathies are important, as they can be associated with somatic features, and some are associated with a propensity for development of bone marrow failure or dysplasia (e.g. RUNX-1-associated thrombocytopenia). Apart from Glanzmann’s thrombasthenia, these conditions are mild disorders, with bleeding typically occurring after trauma or surgery, but rarely spontaneous. Glanzmann’s thrombasthenia is an autosomal recessive condition associated with a variable but often severe bleeding disorder. These conditions are usually managed by local mechanical measures, but antifibrinolytics, such as tranexamic acid, may be useful and, in severe bleeding, platelet transfusion may be required. Recombinant VIIa is licensed for the treatment of resistant bleeding in Glanzmann’s thrombasthenia. Thrombocytopenia Thrombocytopenia occurs in many disease processes, as listed in Box 23.14 (p. 929), many of which are discussed elsewhere in this chapter. Idiopathic thrombocytopenic purpura Idiopathic thrombocytopenic purpura (ITP) is immune-mediated with involvement of autoantibodies, most often directed against the platelet membrane glycoprotein IIb/IIIa, which sensitise the platelet, resulting in premature removal from the circulation by cells of the reticulo-endothelial system. It is not a single disorder; some cases occur in isolation while others are associated with underlying immune dysregulation in conditions such as connective tissue diseases, HIV infection, B-cell malignancies, pregnancy and certain drug therapies. The clinical presentation and pathogenesis are similar, however, whatever the cause of ITP. Clinical features and investigations The presentation depends on the degree of thrombocytopenia. Spontaneous bleeding typically occurs only when the platelet count is below 20 × 109/L. At higher counts, the patient may complain of easy bruising or sometimes epistaxis or menorrhagia. Many cases with counts of more than 50 × 109/L are discovered by chance. In adults, ITP more commonly affects females and may have an insidious onset. Unlike ITP in children, it is unusual for there to be a history of a preceding viral infection. Symptoms or signs of a connective tissue disease may be apparent at presentation or emerge several years later. Patients aged over 65 years should be considered for a bone marrow examination to look for an accompanying B-cell malignancy, and appropriate autoantibody testing performed if a diagnosis of connective tissue disease is likely. HIV testing should be considered because a positive result will have major implications for appropriate therapy. The peripheral blood film is normal, apart from a greatly reduced platelet number, while the bone marrow reveals an obvious increase in megakaryocytes. Management Many patients with stable compensated ITP and a platelet count of more than 30 × 109/L do not require treatment to raise the platelet count, except at times of increased bleeding risk, such as surgery and biopsy. First-line therapy for patients with spontaneous bleeding is with high doses of glucocorticoids, either prednisolone (1 mg/kg daily) or dexamethasone (40 mg daily for 4 days), to suppress antibody production and inhibit

972 • HAEMATOLOGY AND TRANSFUSION MEDICINE (factor VIII levels < 0.01 U/mL) present with spontaneous bleeding into skin, muscle and joints. Retroperitoneal and intracranial bleeding is also a feature. Babies with severe haemophilia have an increased risk of intracranial haemorrhage and, although there is insufficient evidence to recommend routine caesarean section for these births, it is appropriate to avoid head trauma and to perform imaging of the newborn within the first 24 hours of life. Individuals with moderate and mild haemophilia (factor VIII levels 0.01–0.4 U/mL) present with the same pattern of bleeding but usually after trauma or surgery, when bleeding is disproportionate to the severity of the insult. The major morbidity of recurrent bleeding in severe haemophilia is musculoskeletal. Bleeding is typically into large joints, especially knees, elbows, ankles and hips. Muscle haematomas are also characteristic, most commonly in the calf and psoas muscles. If early treatment is not given to arrest bleeding, a hot, swollen and very painful joint or muscle haematoma develops. Recurrent bleeding into joints leads to synovial hypertrophy, destruction of the cartilage and chronic haemophilic arthropathy (Fig. 23.32). Complications of muscle haematomas depend on their location. A large psoas bleed may extend to compress the femoral nerve; calf haematomas may increase pressure within the inflexible fascial sheath, causing a compartment syndrome with ischaemia, necrosis, fibrosis, and subsequent contraction and shortening of the Achilles tendon. Management The key to the management of severe haemophilia A (and B; p. 974) in more affluent countries is prophylactic coagulation factor replacement. The aim of this treatment is to maintain trough levels of factor VIII (or IX in the case of haemophilia B) above 0.02 U/mL. Doing this substantially reduces the number of bleeding episodes for men with severe haemophilia and so reduces the rate of deterioration of joints, which is the major long-term morbidity. Prophylaxis can be provided in many different ways: daily, on alternate days, or on information from pharmacokinetic studies that inform on the best way of scheduling prophylaxis. Practice in haemophilia A and B is in the process of changing somewhat due to the introduction of a variety of recombinant factor concentrates that have been manipulated to alter their half-life. In addition to standard half-life recombinant factor VIII, there are new products produced by Fc fusion and pegylation/ glycopegylation that extend the half-life of factor VIII to the degree that it can be used to alter dosing schedules for prophylaxis. The alternative approach, which still needs to be used in less affluent countries, is to treat on demand. In severe haemophilia A, bleeding episodes should be treated by raising the factor VIII level, usually by intravenous infusion of factor VIII concentrate. Factor VIII concentrates are freeze-dried and stable at 4°C and can therefore be stored in domestic refrigerators, allowing patients to treat themselves at home at the earliest indication of bleeding. Factor VIII concentrate prepared from blood donor plasma is now screened for HBV, HCV and HIV, and undergoes two separate virus inactivation processes during manufacture; these preparations have a good safety record. However, factor VIII concentrates prepared by recombinant technology are now widely available and, although more expensive, are perceived as being safer than those derived from human plasma in relation to infection risk. In addition to raising factor VIII concentrations, resting of the bleeding site with either bed rest or a splint reduces continuing haemorrhage. Once bleeding has settled, the patient should be mobilised and physiotherapy used to restore strength to the surrounding muscles. All non-immune potential recipients Haemophilia ‘breeds true’ within a family; all members have the same factor VIII gene mutation and a similarly severe or mild phenotype. Female carriers of haemophilia may have reduced factor VIII levels because of random inactivation of their normal X chromosome in the developing fetus (p. 49). This can result in a mild bleeding disorder; thus all known or suspected carriers of haemophilia A should have their factor VIII level measured. Clinical features The extent and patterns of bleeding are closely related to residual factor VIII levels (Box 23.63). Patients with severe haemophilia 23.63 Severity of haemophilia (ISTH criteria) Severity Factor VIII or IX level Clinical presentation Severe < 0.01 U/mL Spontaneous haemarthroses and muscle haematomas Moderate 0.01–0.05 U/mL Mild trauma or surgery causes bleeding Mild

0.05–0.4 U/mL Major injury or surgery results in excess bleeding (ISTH = International Society on Thrombosis and Haemostasis) 23.62 Causes of coagulopathy Congenital X-linked • Haemophilia A and B Autosomal • Von Willebrand disease • Factor II, V, VII, X, XI and XIII deficiencies • Combined II, VII, IX and X deficiency • Combined V and VIII deficiency • Hypofibrinogenaemia • Dysfibrinogenaemia Acquired Under-production • Liver failure • Vitamin K deficiency Increased consumption • Coagulation activation: Disseminated intravascular coagulation (DIC) • Immune-mediated: Acquired haemophilia and von Willebrand disease • Others: Acquired factor X deficiency (in amyloid) Acquired von Willebrand disease in Wilms’ tumour Acquired factor VII deficiency in sepsis Drug-induced • Inhibition of function: Heparins Argatroban Bivalirudin Fondaparinux Rivaroxaban Apixaban Dabigatran Edoxaban • Inhibition of post-translational modification: Warfarin

Bleeding disorders • 973

have evidence of HBV exposure, and 60% became HIV-positive. Management is described in Chapters 22 and 12. Concern that the infectious agent that causes vCJD (p. 1127) might be transmissible by blood and blood products has been confirmed in recipients of red cell transfusion (p. 931), and in one recipient of factor VIII. Pooled plasma products, including factor VIII concentrate, are now manufactured from plasma collected in countries with a low incidence of bovine spongiform encephalopathy. Another serious complication of factor VIII infusion is the development of anti-factor VIII antibodies, which arise in about 20% of those with severe haemophilia. Such antibodies rapidly neutralise therapeutic infusions, making treatment relatively ineffective. Infusions of activated clotting factors, e.g. VIIa or factor VIII inhibitor bypass activity (FEIBA), may stop bleeding. Haemophilia B (Christmas disease) Aberrations of the factor IX gene, which is also present on the X chromosome, result in a reduction of the plasma factor IX level, giving rise to haemophilia B. This disorder is clinically indistinguishable from haemophilia A but is less common. The of pooled blood products should be offered hepatitis A and B immunisation. The vasopressin receptor agonist desmopressin (p. 688) raises the vWF and factor VIII levels 3–4-fold, which is useful in arresting bleeding in patients with mild or moderate haemophilia A. The dose required for this purpose is higher than that used in diabetes insipidus, usually 0.3 μg/kg, and is given intravenously or subcutaneously. Alternatively, the same effect can be achieved by intranasal administration of 300 μg. Following repeated administration of desmopressin, patients need to be monitored for evidence of water retention, which can result in significant hyponatraemia. Desmopressin is contraindicated in patients with a history of severe arterial disease because of a propensity to provoke a thrombotic event, and in young children where hyponatraemia can result in fits. Complications of coagulation factor therapy Before 1986, coagulation factor concentrates from human plasma were not virally inactivated and many patients became infected with HIV and HBV/HCV. In patients with haemophilia treated with pooled concentrates that were not virally inactivated before 1988, infection with HCV is almost universal, 80–90% Fig. 23.32 Clinical manifestations of haemophilia. On the knee X-ray, repeated bleeds have led to broadening of the femoral epicondyles, and there is no cartilage present, as evidenced by the close proximity of the femur and tibia (A); sclerosis (B), osteophyte (C) and bony cysts (D) are present. (HCV = hepatitis C virus) Inset (Massive bruising) From Hoffbrand VA. Color atlas of clinical hematology, 3rd edn. Philadelphia: Mosby, Elsevier Inc.; 2000. D B C A Haemophilia B in the descendants of Queen Victoria Albert Victoria

56 4

Numerical value = age at death Affected with haemophilia (male) Carrier for haemophilia (female) Chronic haemophilic arthropathy with joint swelling and muscle wasting on left Left thigh muscle haematoma in severe haemophilia Massive bruising X-ray of advanced haemophilic arthropathy Massive retroperitoneal haemorrhage Hepatoma in cirrhotic liver secondary to HCV infection contracted from coagulation factor concentrate X-linked inheritance of haemophilia B

974 • HAEMATOLOGY AND TRANSFUSION MEDICINE assays that include functional and antigenic measures of vWF, multimeric analysis of the protein, and specific tests of function to determine binding to platelet glycoprotein Ib (RIPA) and factor VIII (Box 23.64). In addition, analysis for mutations in the vWF gene is informative in most cases. Management Many episodes of mild haemorrhage can be successfully treated by local means or with desmopressin, which raises the vWF level, resulting in a secondary increase in factor VIII. Tranexamic acid may be useful in mucosal bleeding. For more serious or persistent bleeds, haemostasis can be achieved with selected factor VIII concentrates, which contain considerable quantities of vWF in addition to factor VIII. Young children and patients with severe arterial disease should not receive desmopressin, and patients with type 2B disease develop thrombocytopenia that may be troublesome following desmopressin. Bleeding in type 3 patients responds only to factor VIII/vWF concentrate. Rare inherited bleeding disorders Severe deficiencies of factor VII, X and XIII occur as autosomal recessive disorders. They are rare but are associated with severe bleeding. Typical features include haemorrhage from the umbilical stump and intracranial haemorrhage. Factor XIII deficiency in women is typically associated with recurrent fetal loss. Factor XI deficiency may occur in heterozygous or homozygous individuals. Bleeding is very variable and is not accurately predicted by coagulation factor levels. In general, severe bleeding is confined to patients with levels below 15% of normal. Acquired bleeding disorders DIC is an important cause of bleeding that begins with exaggerated and inappropriate intravascular coagulation. It is discussed under thrombotic disease on page 978. frequency of bleeding episodes is related to the severity of the deficiency of the plasma factor IX level. Treatment is with a factor IX concentrate, used in much the same way as factor VIII for haemophilia A. The new extended half-life recombinant factor IX products made by Fc fusion, albumin fusion and pegylation offer the possibility of prophylaxis on a once-weekly or even two-weekly schedule. Although factor IX concentrates shared the problems of virus transmission seen with factor VIII, they do not commonly induce inhibitor antibodies (< 1% patients); when this does occur, however, it may be heralded by the development of a severe allergic-type reaction. Von Willebrand disease Von Willebrand disease is a common but usually mild bleeding disorder caused by a quantitative (types 1 and 3) or qualitative (type 2) deficiency of von Willebrand factor (vWF). This protein is synthesised by endothelial cells and megakaryocytes, and is involved in both platelet function and coagulation. It normally forms a multimeric structure that is essential for its interaction with subendothelial collagen and platelets (see Fig. 23.7, p. 920). vWF acts as a carrier protein for factor VIII, to which it is non-covalently bound; deficiency of vWF lowers the plasma factor VIII level. vWF also forms bridges between platelets and subendothelial components (e.g. collagen; see Fig. 23.6B, p. 918), allowing platelets to adhere to damaged vessel walls; deficiency of vWF therefore leads to impaired platelet plug formation. Blood group antigens (A and B) are expressed on vWF, reducing its susceptibility to proteolysis; as a result, people with blood group O have lower circulating vWF levels than individuals with non-O groups. This needs to be borne in mind when making a diagnosis of von Willebrand disease. Most patients with von Willebrand disease have a type 1 disorder, characterised by a quantitative decrease in a normal functional protein. Patients with type 2 disorders inherit vWF molecules that are functionally abnormal. The type of abnormality depends on the site of the mutation in the vWD gene and how it affects binding to platelets, collagen and factor VIII. Patients with type 2A disease have abnormalities in vWF-dependent platelet adhesion; those with mutations in the platelet glycoprotein Ib binding site, resulting in increased affinity for glycoprotein 1b, have type 2B disease; those with mutations in the factor VIII binding site have type 2N disease; and those with other abnormalities in platelet binding but with normal vWF multimeric structure have type 2M disease. The patterns of laboratory abnormality accompanying these types are described in Box 23.64. The gene for vWF is located on chromosome 12 and the disease is usually autosomal dominantly inherited, except in type 2N and type 3, where inheritance is autosomal recessive. Clinical features Patients present with haemorrhagic manifestations similar to those in individuals with reduced platelet function. Superficial bruising, epistaxis, menorrhagia and gastrointestinal haemorrhage are common. Bleeding episodes are usually much less frequent than in severe haemophilia, and excessive haemorrhage may be observed only after trauma or surgery. Within a single family, the disease has variable penetrance, so that some members may have quite severe and frequent bleeds, whereas others are relatively asymptomatic. Investigations The disorder is characterised by reduced activity of vWF and factor VIII. The disease can be classified using a combination of 23.64 Classification of von Willebrand disease Type Defect Inheritance Investigations/patterns

Partial quantitative AD Parallel decrease in vWF:Ag, RiCoF and Vlll:c 2A Qualitative AD Absent HWM of vWF Ratio of vWF activity to antigen < 0.7 2B Qualitative AD Reduced HWM of vWF Enhanced platelet agglutination (RIPA) 2M Qualitative AD Ratio of vWF activity to antigen ԟ 0.7 Normal multimers of vWF Abnormal vWF/platelet interactions 2N Qualitative AR Defective binding of vWF to VIII Low VIII

Severe quantitative AR or CH Very low vWF and VIII:c activity Absent multimers (AD = autosomal dominant; AR = autosomal recessive; CH = compound heterozygote; HWM = high-weight multimers of vWF; RiCoF = ristocetin co-factor; RIPA = ristocetin-induced platelet agglutination; VIII:c = coagulation factor VIII activity in functional assay; vWF = von Willebrand factor; vWF:Ag = vWF antigen measured by ELISA)

Thrombotic disorders • 975

Management of VTE The mainstay of treatment for all forms of VTE is anticoagulation. This can be achieved in several ways. One option is to use LMWH followed by a coumarin anticoagulant, such as warfarin. Treatment of acute VTE with LMWH should continue for a minimum of 5 days. Patients treated with warfarin should achieve a target INR of 2.5 (range 2–3; pp. 922 and 938) with LMWH continuing until the INR is above 2. Alternatively, patients may be treated with a DOAC. Rivaroxaban and apixaban may be used immediately from diagnosis without the need for LMWH, while the licences for dabigatran and edoxaban include initial treatment with LMWH for a minimum of 5 days before commencing the DOAC. In patients with active cancer and VTE, there is evidence that maintenance anticoagulation with LMWH is associated with a lower recurrence rate than warfarin. Patients who have had VTE and have a strong contraindication to anticoagulation and those who continue to have new pulmonary emboli despite therapeutic anticoagulation should have an inferior vena cava (IVC) filter inserted to prevent life-threatening PE (p. 619). The optimal initial period of anticoagulation is between 6 weeks and 6 months. Patients with a provoked VTE in the Liver disease Although, traditionally, severe parenchymal liver disease (Ch. 22) has been described as a state associated with an excess of bleeding, it is now clear that these patients also have an increased risk of venous thrombosis. Although there is reduced hepatic synthesis of procoagulant factors, this is balanced to a degree by the reduced production of natural anticoagulant proteins and reduced fibrinolytic activity in patients with advanced liver disease. In severe parenchymal liver disease, bleeding may arise from many different causes. Pathological sources of potential major bleeding, such as oesophageal varices or peptic ulcer, are common. There is reduced hepatic synthesis, for example, of factors V, VII, VIII, IX, X, XI, prothrombin and fibrinogen. Clearance of plasminogen activator is reduced. Thrombocytopenia may occur secondary to hypersplenism in portal hypertension. In cholestatic jaundice, there is reduced vitamin K absorption, leading to deficiency of factors II, VII, IX and X, but also of proteins C and S. Treatment with plasma products or platelet transfusion should be reserved for acute bleeds or to cover interventional procedures such as liver biopsy. Vitamin K deficiency can be readily corrected with parenteral administration of vitamin K. Renal failure The severity of the haemorrhagic state in renal failure is proportional to the plasma urea concentration. Bleeding manifestations are those of platelet dysfunction, with gastrointestinal haemorrhage being particularly common. The causes are multifactorial and include anaemia, mild thrombocytopenia and the accumulation of low-molecular-weight waste products, normally excreted by the kidney, that inhibit platelet function. Treatment is by dialysis to reduce the urea concentration. Rarely, in severe or persistent bleeding, platelet concentrate infusions and red cell transfusions are indicated. Increasing the concentration of vWF, either by cryoprecipitate or by desmopressin, may promote haemostasis. Thrombotic disorders Venous thromboembolic disease (venous thromboembolism) While the most common presentations of venous thromboembolism (VTE) are deep vein thrombosis (DVT) of the leg (p. 186) and/or pulmonary embolism (PE; see also p. 619), similar management principles apply to rarer manifestations such as jugular vein thrombosis, upper limb DVT, cerebral sinus thrombosis (p. 1128) and intra-abdominal venous thrombosis (e.g. Budd– Chiari syndrome; p. 898). VTE has an annual incidence of approximately 1 : 1000 in Western populations. The relative incidence of DVT:PE is approximately 2 : 1. Mortality 30 days after DVT is approximately 10%, compared to 15% for PE. All forms of VTE are increasingly common with age and many of the deaths are related to coexisting medical conditions, such as active cancer or inflammatory disease, which predispose the patient to thrombosis in the first place. Risk factors for VTE are often present (Box 23.65) and it is appropriate to seek evidence of these risk factors in determining the long-term management strategy. Figure 23.33 illustrates some of the causes and consequences of VTE. The diagnosis of DVT and PE are discussed on pages 187 and 619, respectively. 23.65 Factors predisposing to venous thrombosis Patient factors • Increasing age • Obesity • Varicose veins • Previous deep vein thrombosis • Family history, especially of unprovoked venous thromboembolism when young • Transient additional risk factors: Pregnancy/puerperium Oestrogen-containing oral contraceptives and hormone replacement therapy Immobility, e.g. long-distance travel (> 4 hrs) Intravenous drug use involving the femoral vein Surgery (see below) Medical illnesses (see below) Surgical conditions • Major surgery, especially if > 30 mins’ duration • Abdominal or pelvic surgery, especially for cancer • Major lower limb orthopaedic surgery, e.g. joint replacement and hip fracture surgery Medical conditions • Myocardial infarction/heart failure • Inflammatory bowel disease • Malignancy (anti-cancer chemotherapy increases the risk of venous thromboembolism compared with cancer alone) • Nephrotic syndrome • Chronic obstructive pulmonary disease • Pneumonia • Neurological conditions associated with immobility, e.g. stroke, paraplegia, Guillain–Barré syndrome • Any high-dependency admission Haematological disorders • Polycythaemia rubra vera • Essential thrombocythaemia • Deficiency of natural anticoagulants: antithrombin, protein C, protein S • Paroxysmal nocturnal haemoglobinuria • Gain-of-function prothrombotic mutations: factor V Leiden, prothrombin gene G20210A • Myelofibrosis Antiphospholipid syndrome

976 • HAEMATOLOGY AND TRANSFUSION MEDICINE The management of DVT of the leg should also include elevation and analgesia; in limb-threatening DVT, thrombolysis may also be considered. Thrombolysis for PE is discussed on page 621. Post-thrombotic syndrome is due to damage of venous valves by the thrombus. It occurs in around 30% of patients who sustain a proximal lower limb DVT and results in persistent leg swelling, heaviness and discoloration. The most severe complication of this syndrome is ulceration around the medial malleolus (Fig. 23.33). Recent trial evidence suggests that use of elastic compression stockings following a DVT does not reduce the incidence of post-thrombotic syndrome. Prophylaxis of VTE All patients admitted to hospital should be assessed for their risk of developing VTE and appropriate prophylactic measures should be put in place. Both medical and surgical patients are at increased risk. A summary of the risk categories is given in Box 23.66. Early mobilisation of patients is important to prevent DVT, and those at medium or high risk require additional antithrombotic measures; these may be pharmacological or mechanical. There presence of a temporary risk factor, which is then removed, can usually be treated for short periods (e.g. 3 months), and indeed anticoagulation for more than 6 months does not alter the rate of recurrence following discontinuation of therapy. If there are ongoing risk factors that cannot be alleviated, such as active cancer, long-term anticoagulation is usually recommended, provided that the risk of bleeding is not deemed excessive. For patients with unprovoked VTE, the optimum duration of anticoagulation can be difficult to establish. Recurrence of VTE is about 2–3% per annum in patients who have a temporary medical risk factor at presentation and about 7–10% per annum in those with apparently unprovoked VTE. This plateaus at around 30–40% recurrence at 5 years. As such, many patients who have had unprovoked episodes of VTE will benefit from long-term anticoagulation. Several factors predict risk of recurrence following an episode of unprovoked VTE. The strongest predictors of recurrence are male sex and a positive D-dimer assay measured 1 month after stopping anticoagulant therapy. These factors are incorporated into scoring systems to predict recurrence such as the DASH score and the Vienna prediction model. Fig. 23.33 Causes and consequences of venous thromboembolic disease and its treatment. (DVT = deep vein thrombosis; IVC = inferior vena cava) Lateral sinus thrombosis is an uncommon form of venous thrombosis at an unusual site c i n e g o rt a I l a c i g o l o h t a P Fatal intracerebral haemorrhage is the most common cause of haemorrhagic death in patients on warfarin Postmortem fatal massive pulmonary embolism Absent IVC predisposes to lower limb DVT Inferior vena cava Common iliac vein Common femoral vein Superficial femoral vein Popliteal vein External and internal iliac veins Profunda femoris vein Gastrocnemius vein Anterior tibial vein Soleus muscle sinus Massive haemorrhage may complicate heparin therapy. This is particularly problematic in patients with renal failure on haemodialysis Iliac vein thrombosis IVC filter Post-thrombotic syndrome complicates 30% of cases of lower limb DVT. Severe cases are complicated by ulceration

Thrombotic disorders • 977

anticoagulation, as discussed on page 975. Patients who are deemed to be at high risk of thrombosis, e.g. those with antithrombin deficiency in pregnancy, should receive treatment or prophylactic doses of heparin to cover the period of risk only. Antithrombin deficiency Antithrombin (AT) is a serine protease inhibitor (SERPIN) that inactivates the activated coagulation factors IIa, IXa, Xa and XIa. Heparins and fondaparinux achieve their therapeutic effect by potentiating the activity of AT. Familial deficiency of AT is inherited in an autosomal dominant manner; homozygosity for mutant alleles is not compatible with life. Around 70% of affected individuals will have an episode of VTE before the age of 60 years and the relative risk for thrombosis compared with the background population is 10–20. Pregnancy is a high-risk period for VTE and this requires fairly aggressive management with doses of LMWH that are greater than the usual prophylactic doses (≥ 100 U/kg/day). AT concentrate (either plasma-derived or recombinant) is available; this is required for cardiopulmonary bypass and may be used as an adjunct to heparin in surgical prophylaxis and in the peripartum period. Protein C and S deficiencies Protein C and its co-factor protein S are vitamin K-dependent natural anticoagulants involved in switching off coagulation factor activation (factors Va and VIIIa) and thrombin generation (see Fig. 23.6F, p. 919). Inherited deficiency of either protein C or S results in a prothrombotic state with a fivefold relative risk of VTE compared with the background population. Factor V Leiden Factor V Leiden results from a gain-of-function, single-base-pair mutation which prevents the cleavage and hence inactivation of activated factor V. This results in a relative risk of venous thrombosis of 5 in heterozygotes and 50 or more in rare homozygotes. The mutation is found in about 5% of Northern Europeans, 2% of Hispanics, 1.2% of African–Americans, 0.5% of Asian–Americans and 1.25% of Native Americans, and is rare in Chinese and Malay people. Prothrombin G20210A This gain-of-function mutation in the non-coding 3′ end of the prothrombin gene is associated with an increased plasma level of prothrombin. It is present in about 2% of Northern Europeans but is rare in native populations of Korea, China, India and Africa. In the heterozygous state, it is associated with a 2–3-fold increase in risk of VTE compared with the background population. Antiphospholipid syndrome Antiphospholipid syndrome (APS) is a clinicopathological entity in which a constellation of clinical conditions, alone or in combination, is found in association with a persistently positive test for an antiphospholipid antibody. The antiphospholipid antibodies are heterogeneous and typically are directed against proteins that bind to phospholipids (Box 23.67). Although causal roles for these antibodies have been proposed, the mechanisms underlying the clinical features of APS are not clear. In clinical practice, two types of test are used, which detect: • antibodies that bind to negatively charged phospholipid on an ELISA plate (called an anticardiolipin antibody test). These assays usually contain β2-glycoprotein 1 (β2-GP1) is increasing evidence in high-risk groups, such as patients who have had major lower limb orthopaedic surgery and abdominal or pelvic cancer surgery, for protracted thromboprophylaxis for as long as 30 days or so after the procedure. Particular care should be taken with the use of pharmacological prophylaxis in patients with a high risk of bleeding or with specific risks of haemorrhage related to the site of surgery or the use of spinal or epidural anaesthesia. Inherited and acquired thrombophilia and prothrombotic states Several inherited conditions predispose to VTE (see Box 23.65), and have several points in common that are worth noting: • None of them is strongly associated with arterial thrombosis. • All are associated with a slightly increased incidence of adverse outcome of pregnancy, including recurrent early fetal loss, but there are no data to indicate that any specific intervention changes that outcome. • Apart from in antithrombin deficiency and homozygous factor V Leiden, most carriers of these genes will never have an episode of VTE; if they do, it will be associated with the presence of an additional temporary risk factor. • There is little evidence that detection of these abnormalities predicts recurrence of VTE. • None of these conditions per se requires treatment with anticoagulants. Patients with thrombosis should receive 23.66 Antithrombotic prophylaxis Indications Patients in the following categories should be considered for specific antithrombotic prophylaxis: Moderate risk of DVT • Major surgery: In patients > 40 years or with other risk factor for VTE • Major medical illness, e.g.: Heart failure Myocardial infarction with complications Sepsis Inflammatory conditions, including inflammatory bowel disease Active malignancy Nephrotic syndrome Stroke and other conditions leading to lower limb paralysis High risk of DVT • Major abdominal or pelvic surgery for malignancy or with history of DVT or known thrombophilia (see Box 23.4, p. 923) • Major hip or knee surgery • Neurosurgery Methods of VTE prophylaxis Mechanical • Intermittent pneumatic compression • Mechanical foot pumps • Graduated compression stockings Pharmacological • LMWHs • Unfractionated heparin • Fondaparinux • Dabigatran • Rivaroxaban • Apixaban • Warfarin (DVT = deep vein thrombosis; VTE = venous thromboembolism)

978 • HAEMATOLOGY AND TRANSFUSION MEDICINE • those that interfere with phospholipid-dependent coagulation tests like the APTT or the dilute Russell viper venom time (DRVVT; called a lupus anticoagulant test). The term antiphospholipid antibody encompasses both a lupus anticoagulant and an anticardiolipin antibody/ anti-β2-GP1; individuals may be positive for one, two or all three of these activities. It has been shown that patients who are ‘triple-positive’ have an increased likelihood of thrombotic events. Clinical features and management APS may present in isolation (primary APS) or in association with one of the conditions shown in Box 23.67, most typically systemic lupus erythematosus (secondary APS). Most patients present with a single manifestation and APS is now most frequently diagnosed in women with adverse outcomes of pregnancy. It is extremely important to make the diagnosis in patients with APS, whatever the manifestation, because it affects the prognosis and management of arterial thrombosis, VTE and pregnancy. Arterial thrombosis, typically stroke, associated with APS should probably be treated with warfarin, as opposed to aspirin. APS-associated VTE is one of the situations in which the predicted recurrence rate is high enough to indicate long-term anticoagulation after a first event. In women with obstetric presentations of APS, intervention with heparin and aspirin is almost routinely prescribed, although there is little evidence from clinical trials that it is an effective therapy in increasing the chance of a successful pregnancy outcome. Disseminated intravascular coagulation Disseminated intravascular coagulation (DIC) may complicate a range of illnesses (Box 23.68). It is characterised by systemic activation of the pathways involved in coagulation and its regulation. This may result in the generation of intravascular fibrin clots causing multi-organ failure, with simultaneous coagulation factor and platelet consumption, causing bleeding. The systemic coagulation activation is induced either through cytokine pathways, which are activated as part of a systemic inflammatory 23.67 Antiphospholipid syndrome (APS) Clinical manifestations • Adverse pregnancy outcome Recurrent first trimester abortion (≥ 3) Unexplained death of morphologically normal fetus after 10 weeks’ gestation Severe early pre-eclampsia • Venous thromboembolism • Arterial thromboembolism • Livedo reticularis, catastrophic APS, transverse myelitis, skin necrosis, chorea Conditions associated with secondary APS • Systemic lupus erythematosus • Rheumatoid arthritis • Systemic sclerosis • Behçet’s disease • Temporal arteritis • Sjögren’s syndrome Targets for antiphospholipid antibodies • β2-glycoprotein 1 • Protein C • Annexin V • Prothrombin (may result in haemorrhagic presentation) 23.68 Disseminated intravascular coagulation (DIC) Underlying conditions • Infection/sepsis • Trauma • Obstetric, e.g. amniotic fluid embolism, placental abruption, pre-eclampsia • Severe liver failure • Malignancy, e.g. solid tumours and leukaemias • Tissue destruction, e.g. pancreatitis, burns • Vascular abnormalities, e.g. vascular aneurysms, liver haemangiomas • Toxic/immunological, e.g. ABO incompatibility, snake bites, recreational drugs ISTH scoring system for diagnosis of DIC Presence of an associated disorder Essential Platelets (× 109/L)

100 = 0 < 100 = 1 < 50 = 2 Elevated fibrin degradation products No increase = 0 Moderate = 2 Strong = 3 Prolonged prothrombin time < 3 secs = 0 3 secs but < 6 secs = 1 6 secs = 2 Fibrinogen 1 g/L = 0 < 1 g/L = 1 Total score ≥ 5 = Compatible with overt DIC < 5 = Repeat monitoring over 1–2 days (ISTH = International Society for Thrombosis and Haemostasis) 23.69 Haemostasis and thrombosis in old age • Thrombocytopenia: not uncommon because of the rising prevalence of disorders in which it may be a secondary feature, and also because of the greater use of drugs that can cause it. • ‘Senile’ purpura: presumed to be due to an age-associated loss of subcutaneous fat and the collagenous support of small blood vessels, making them more prone to damage from minor trauma. • Thrombosis: incidence of thromboembolic disease rises with increasing age. This may be due to stasis and concurrent illness, to which older people are prone; some studies show increased platelet aggregation with age, and others age-associated hyperactivity of the haemostatic system, which could contribute to a prothrombotic state. • Thromboprophylaxis: should be considered in all older patients who are immobile as a result of acute illness. Prophylaxis is not required in chronic immobility without a medical cause, as there is no associated increase in thromboembolism. • Anticoagulation: older patients are more sensitive to the anticoagulant effects of warfarin, partly due to the concurrent use of other drugs and the presence of other pathology. Life-threatening or fatal bleeds on warfarin are significantly more common in those over 80 years. response, or by the release of procoagulant substances such as tissue factor. In addition, suboptimal function of the natural anticoagulant pathways and dysregulated fibrinolysis contribute to DIC. There is consumption of platelets, coagulation factors (notably factors V and VIII) and fibrinogen. The lysis of fibrin

Further information • 979

• thrombocytopenia • microangiopathic haemolytic anaemia • neurological sequelae • fever • renal impairment. It is an acute autoimmune disorder mediated by antibodies against ADAMTS-13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif). This enzyme normally cleaves vWF multimers to produce normal functional units, and its deficiency results in large vWF multimers that cross-link platelets. The features are of microvascular occlusion by platelet thrombi affecting key organs, principally brain and kidneys. It is a rare disorder (1 in 750 000 per annum), which may occur alone or in association with drugs (ticlopidine, ciclosporin), HIV, shiga toxins (p. 263) and malignancy. It should be treated by emergency plasma exchange. Glucocorticoids, aspirin and rituximab also have a role in management. Untreated mortality rates are 90% in the first 10 days, and even with appropriate therapy, the mortality rate is 20–30% at 6 months. Further information Websites bcshguidelines.com British Committee for Standards in Haematology guidelines. cibmtr.org International Bone Marrow Transplant Registry. transfusionguidelines.org.uk Contains the UK Transfusion Services’ Handbook of Transfusion Medicine and links to other relevant sites. ukhcdo.org UK Haemophilia Centre Doctors’ Organisation. clot results in production of fibrin degradation products (FDPs), including D-dimers. Investigations DIC should be suspected when any of the conditions listed in Box 23.68 are met. Measurement of coagulation times (APTT and PT; p. 920), along with fibrinogen, platelet count and FDPs, helps in the assessment of prognosis and aids clinical decision-making with regard to both bleeding and thrombotic complications. Management Therapy is primarily aimed at the underlying cause. These patients will often require intensive care to deal with concomitant issues, such as acidosis, dehydration, renal failure and hypoxia. Blood component therapy, such as fresh frozen plasma, cryoprecipitate and platelets, should be given if the patient is bleeding or to cover interventions with a high bleeding risk, but should not be prescribed routinely based on coagulation tests and platelet counts alone. Prophylactic doses of heparin should be given, unless there is a clear contraindication. Established thrombosis should be treated cautiously with therapeutic doses of unfractionated heparin, unless clearly contraindicated. Patients with DIC should not, in general, be treated with antifibrinolytic therapy, e.g. tranexamic acid. Thrombotic thrombocytopenic purpura Like DIC and also heparin-induced thrombocytopenia (p. 938), thrombotic thrombocytopenic purpura (TTP) is a disorder in which thrombosis is accompanied by paradoxical thrombocytopenia. TTP is characterised by a pentad of findings, although few patients have all five components:

7KLVSDJHLQWHQWLRQDOO\OHIWEODQN

Ch04-3 Clinical Medicine

14-24 Rheumatology and bone disease

24 Rheumatology and bone disease

Rheumatology and bone disease GPR Clunie SH Ralston Clinical examination of the musculoskeletal system 982 Functional anatomy and physiology 984 Bone 984 Joints 986 Skeletal muscle 987 Investigation of musculoskeletal disease 988 Joint aspiration 988 Imaging 988 Blood tests 990 Tissue biopsy 992 Electromyography 992 Presenting problems in musculoskeletal disease 992 Acute monoarthritis 992 Polyarthritis 993 Fracture 994 Generalised musculoskeletal pain 995 Back pain 995 Regional musculoskeletal pain 997 Neck pain 997 Shoulder pain 997 Elbow pain 998 Hand and wrist pain 998 Hip pain 998 Knee pain 998 Ankle and foot pain 999 Muscle pain and weakness 1000 Principles of management 1000 Education and lifestyle interventions 1000 Non-pharmacological interventions 1001 Pharmacological treatment 1002 Osteoarthritis 1007 Crystal-induced arthritis 1012 Fibromyalgia 1018 Bone and joint infections 1019 Rheumatoid arthritis 1021 Juvenile idiopathic arthritis 1026 Spondyloarthropathies 1027 Axial spondyloarthropathy 1028 Reactive arthritis 1031 Psoriatic arthritis 1032 Enteropathic (spondylo)arthritis 1034 Autoimmune connective tissue diseases 1034 Vasculitis 1040 Diseases of bone 1044 Osteoporosis 1044 Osteomalacia, rickets and vitamin D deficiency 1049 Paget’s disease of bone 1053 Other bone diseases 1055 Bone and joint tumours 1056 Rheumatological involvement in other diseases 1057 Miscellaneous conditions 1058

982 • RHEUMATOLOGY AND BONE DISEASE Observation Extensor surfaces Rheumatoid nodules Swollen bursa Psoriasis rash Face Rash Alopecia Mouth ulcers Eyes Trunk Kyphosis Scoliosis Tender spots (fibromyalgia, enthesitis) • General appearance • Gait • Deformity • Swelling • Redness • Rash Hands Swelling Deformity Nail changes Tophi Raynaud’s Feet Deformity Swelling (gout, dactylitis) Redness Rheumatoid nodules Heberden and Bouchard nodes in osteoarthritis Synovitis and deformity in rheumatoid arthritis Butterfly rash in systemic lupus erythematosus Scleritis in rheumatoid arthritis Acute gout Legs Deformity Swelling Restricted movement Bone deformity in Paget’s disease Nail dystrophy in psoriatic arthritis

Clinical examination of the musculoskeletal system

Clinical examination of the musculoskeletal system • 983

Ask patient to put hands behind head (tests shoulder movements) Inspect hands for swelling or deformity 2 Arms Ask patient to make a fist and open and close fingers (tests hand function) Squeeze metacarpals (tests for inflammation) 3 Legs Flex each hip with hand on knee. Rotate hips internally and externally (tests hip movements and detects knee crepitus) Inspect ankles and feet. Squeeze forefoot (tests for metatarsophalangeal synovitis) Palpate each knee for warmth and swelling (tests for synovitis and effusion) 4 Spine 5 Schöber’s test Patient slides hand down leg to knee (tests lateral spine flexion) 10 cm 15 cm Ask patient to try to put ear on shoulder (tests lateral flexion cervical spine) Patient looks at ceiling and then puts chin on chest (tests flexion and extension cervical spine) Mark skin with pen in midline about 4 cm below superior iliac crest. Make another mark in midline 10 cm above first. Ask patient to bend forwards. Normally, distance between marks should increase to 15 cm Stand behind patient and hold their pelvis. Ask them to turn from side to side without moving their feet (tests thoracolumbar rotation) Inspect spine from behind and side, looking for scoliosis, kyphosis or localised deformity. Ask patient to touch toes 1 Gait Ask patient to walk for a few steps, then come back. Look for pain or limp Press over supraspinatus (tests for hyperalgesia) Patient turns palms up and down with elbows at side (tests supination and pronation of wrists and elbow) Patient flexes elbows to touch shoulder (tests elbow flexion) General Assessment of Locomotor System (GALS) and Schöber’s test

984 • RHEUMATOLOGY AND BONE DISEASE ossification, in which embryonic fibroblasts differentiate directly into bone within condensations of mesenchymal tissue during early fetal life. Long bones, such as the femur and radius, develop by endochondral ossification from a cartilage template. During development, the cartilage is invaded by vascular tissue containing osteoprogenitor cells and is gradually replaced by bone from centres of ossification situated in the middle and at the ends of the bone. A thin remnant of cartilage called the growth plate or epiphysis remains at each end of long bones, and chondrocyte proliferation here is responsible for skeletal growth during childhood and adolescence. At the end of puberty, the increased levels of sex hormones halt cell division in the growth plate. The cartilage remnant then disappears as the epiphysis fuses and longitudinal bone growth ceases. Two types of bone tissue are present in the normal skeleton (Fig. 24.1). Cortical bone is formed from Haversian systems, comprising concentric lamellae of bone tissue surrounding a central canal that contains blood vessels. Cortical bone is dense and forms a hard envelope around the long bones. Trabecular or cancellous bone fills the centre of the bone and consists of an interconnecting meshwork of trabeculae, separated by spaces filled with bone marrow. The most important cell types in bone are: • Osteoclasts: multinucleated cells of haematopoietic origin, responsible for bone resorption. • Osteoblasts: mononuclear cells of derived from marrow stromal cells responsible for bone formation. Disorders of the musculoskeletal system affect all ages and ethnic groups. In the UK, about 25% of new consultations in general practice are for musculoskeletal symptoms. Musculoskeletal diseases may arise from processes affecting bones, joints, muscles, or connective tissues such as skin and tendon. The principal manifestations are pain and impairment of locomotor function. Diseases of the musculoskeletal system tend to be more common in women and most increase in frequency with increasing age. They are the most common cause of physical disability in older people and account for one-third of physical disability at all ages. Functional anatomy and physiology The musculoskeletal system is responsible for movement of the body, provides a structural framework to protect internal organs, and acts as a reservoir for storage of calcium and phosphate in the regulation of mineral homeostasis. The main components of the musculoskeletal system are depicted in Figure 24.1. Bone Bones fall into two main types, based on their embryonic development. Flat bones, such as the skull, develop by intramembranous Fig. 24.1 Structure of the major musculoskeletal tissues. Osteocytes Osteoblasts Osteoclasts Trabecular bone Haversian system Blood vessels Collagen lamellae Osteocytes Cortical bone Synovium Articular cartilage Growth plate Calcified zone Hypertrophic zone Proliferative zone Bone Synovial lining cells Joint capsule Myofilament Myofibril Fascicle Chondrocytes Calcified cartilage Subchondral bone Muscle Epiphyseal plate

Enthesis Tendon Bone

Functional anatomy and physiology • 985

into mature osteoclasts in response to M-CSF, produced by bone marrow stromal cells, and RANKL, produced by both osteocytes and bone marrow stromal cells. The RANKL binds to and activates a receptor called RANK (receptor activator of nuclear factor kappa B) on osteoclast precursors, promoting osteoclast differentiation and bone resorption. This effect is blocked by osteoprotegerin (OPG), which is a decoy receptor for RANKL that inhibits osteoclast formation. Once formed, mature osteoclasts attach to the bone surface by a tight sealing zone and secrete hydrochloric acid and proteolytic enzymes, including cathepsin K, into the space underneath, which is known as the Howship’s lacuna. The acid dissolves the mineral and cathepsin K degrades collagen. Osteocytes also produce sclerostin (SOST), which is a potent inhibitor of bone formation. Under conditions of mechanical loading, sclerostin production by osteocytes is inhibited, allowing bone formation to proceed, stimulated by members of the Wnt family of signalling proteins. The Wnt molecules stimulate bone formation by activating members of the lipoprotein receptor-related protein (LRP) family, the most important of which are LRP4, LRP5 and LRP6. Sclerostin antagonises the effects of Wnt family members by blocking their interaction with LRP family members. Finally, osteocytes play a critical role in phosphate homeostasis by producing the hormone FGF23, which regulates renal tubular phosphate reabsorption. Key regulators of bone remodelling are summarised in Box 24.1. Mineralisation of bone is critically dependent on the enzyme alkaline phosphatase (ALP), which is produced by osteoblasts and degrades pyrophosphate, an inhibitor of mineralisation. Bone remodelling is predominantly regulated at a local level but can be influenced by circulating hormones or mechanical loading, which can up-regulate or down-regulate remodelling across the whole skeleton (Box 24.1). • Osteocytes: cells that differentiate from osteoblasts that become embedded in bone matrix during bone formation. They are responsible for sensing and responding to mechanical stimuli and for coordinating osteoclast and osteoblast activity. • Bone marrow stromal cells: cells that produce receptor activator of nuclear factor kappa B ligand (RANKL) and macrophage colony-stimulating factor (M-CSF), which stimulate osteoclast formation, and other cytokines that support haematopoiesis (p. 914). • Bone lining cells: flattened cells lining the bone surface that differentiate from osteoblasts when bone formation is complete. Bone matrix and mineral The most abundant protein of bone is type I collagen, which is formed from two α1 peptide chains and one α2 chain wound together in a triple helix. Type I collagen is proteolytically processed inside the cell before being laid down in the extracellular space, releasing propeptide fragments that can be used as biochemical markers of bone formation. Subsequently, the collagen fibrils become ‘cross-linked’ to one another by pyridinium molecules, a process that enhances bone strength. When bone is broken down by osteoclasts, the cross-links are released into the circulation. These can be measured biochemically and are sometimes used clinically to assess levels of bone resorption. Bone is normally laid down in an orderly fashion, but when bone turnover is high, as in Paget’s disease or severe hyperparathyroidism, it is laid down in a chaotic pattern, giving rise to ‘woven bone’ that is mechanically weak. Bone matrix also contains growth factors, other structural proteins and proteoglycans, thought to be involved in helping bone cells attach to bone matrix and in regulating bone cell activity. The other major component of bone is mineral, comprised of calcium and phosphate crystals deposited between the collagen fibrils in the form of hydroxyapatite [Ca10 (PO4)6 (OH)2]. Mineralisation is essential for bone’s rigidity and strength but over-mineralisation causes the bone to become brittle. In clinical practice, increased mineralisation can occur in some types of osteogenesis imperfecta and in response to long-term bisphosphonate therapy. Bone remodelling Bone remodelling is required for renewal and repair of the skeleton throughout life. This is a cyclical process that has four phases; quiescence, resorption, reversal and formation, as illustrated in Figure 24.2. Remodelling starts with the attraction of osteoclast precursors in peripheral blood to the target site, probably by local release of chemotactic factors from areas of microdamage. The osteoclasts resorb bone and, after about 10 days, undergo programmed cell death (apoptosis), heralding the start of the reversal phase, when osteoblast precursors are recruited to the resorption site. The osteoblast precursors differentiate into mature osteoblasts and form new bone during the formation phase. Initially, the matrix is unmineralised (osteoid) but eventually becomes mineralised to form mature bone. Some osteoblasts become trapped in bone matrix and differentiate into osteocytes, which play a key regulatory role in coordinating bone formation and resorption, whereas others differentiate into bone-lining cells. The cellular and molecular mediators of this bone remodelling are shown in more detail in Figure 24.3. Osteoclast precursors are derived from haematopoietic stem cells and differentiate Fig. 24.2 The bone remodelling cycle. Bone is renewed and repaired by the process of bone remodelling. This begins by removal of old and damaged bone by osteoclasts during the phase of bone resorption. After about 10 days, the osteoclasts undergo programmed cell death (apoptosis) and during the reversal phase are replaced by osteoclasts, which begin to fill in the resorbed area with new bone matrix, heralding the start of bone formation. The bone matrix is initially uncalcified (osteoid) but then becomes mineralised to form mature bone. Bone-lining cells Osteoclasts Microdamage Formation Quiescence Resorption Reversal Apoptotic osteoclast Osteoblasts Osteoid Osteocytes Mineralisation

986 • RHEUMATOLOGY AND BONE DISEASE Joints There are three main types of joint: fibrous, fibrocartilaginous and synovial (Box 24.2). Fibrous and fibrocartilaginous joints These comprise a simple bridge of fibrous or fibrocartilaginous tissue joining two bones together where there is little requirement for movement. The intervertebral disc is a special type of fibrocartilaginous joint in which an amorphous area, called the nucleus pulposus, lies in the centre of the fibrocartilaginous bridge. The nucleus has a high water content and acts as a cushion to improve the disc’s shock-absorbing properties. 24.2 Types of joint Type Range of movement Examples Fibrous Minimal Skull sutures Fibrocartilaginous Limited Symphysis pubis Costochondral junctions Intervertebral discs Sacroiliac joints Synovial Large Most limb joints Temporomandibular Costovertebral 24.1 Key regulators of bone remodelling Mediator Source Effects Comment RANKL Osteocytes Stromal cells Activated T cells Stimulates bone resorption Activates RANK Osteoprotegerin Stromal cells Lymphocytes Inhibits bone resorption Acts as decoy receptor for RANKL Wnt Stromal cells Stimulates bone formation Activates LRP receptors Sclerostin Osteocytes Inhibits bone formation Blocks effect of Wnt on LRP receptors Parathyroid hormone Parathyroid glands Increases bone resorption and formation Thyroid hormone Thyroid gland Increases bone resorption and formation Oestrogen Ovary Inhibits bone resorption Glucocorticoid Adrenal gland Exogenous Inhibits bone formation (LRP = lipoprotein receptor-related protein; RANKL = receptor activator of nuclear factor kappa B ligand) Fig. 24.3 Cellular and molecular regulators of bone remodelling Osteoclast precursors are derived from haematopoietic stem cells. They differentiate into mature osteoclasts in response to the receptor activator of nuclear factor kappa B ligand (RANKL), which is produced by osteocytes, bone marrow stromal cells and activated T cells (not shown), and macrophage colony-stimulating factor (M-CSF), which is produced by bone marrow stromal cells. Osteoprotegerin (OPG) is also produced in the bone microenvironment, where it inhibits osteoclastic bone resorption by blocking the effect of RANKL. Osteoblasts, which are derived from bone marrow stromal cells, are responsible for bone formation. Osteoblast activity is stimulated by signalling molecules in the Wnt family but inhibited by sclerostin (SOST), which is produced by osteocytes. In addition to their role in regulating osteoclast and osteoblast activity, osteocytes have an endocrine function in regulating phosphate homeostasis by producing fibroblast growth factor 23 (FGF23), which acts on the kidney to promote phosphate excretion. Osteoclast precursor RANKL FGF23 SOST OPG M-CSF RANKL Wnt Haematopoietic stem cell Bone marrow stromal cells Renal phosphate excretion Osteoblast Osteocyte Osteoclast

Functional anatomy and physiology • 987

in reduced water content and shock-absorbing properties. These changes differ from those found in osteoarthritis (p. 1007), where there is abnormal chondrocyte division, loss of proteoglycan from matrix and an increase in water content. Cartilage matrix is constantly turning over and in health there is a perfect balance between synthesis and degradation. Degradation of cartilage matrix is carried out by aggrecanases and matrix metalloproteinases, responsible for the breakdown of proteins and proteoglycans, and by glycosidases, responsible for the breakdown of GAGs. Pro-inflammatory cytokines, such as interleukin-1 (IL-1) and tumour necrosis factor (TNF), which are released during inflammation, stimulate production of aggrecanase and metalloproteinases, causing cartilage degradation. Synovial fluid The surfaces of articular cartilage are separated by a space filled with synovial fluid (SF), a viscous liquid that lubricates the joint. It is an ultrafiltrate of plasma, into which synovial cells secrete hyaluronan and proteoglycans. Intra-articular discs Some joints contain fibrocartilaginous discs within the joint space that act as shock absorbers. The most clinically important are the menisci of the knee. These are avascular structures that remain viable because of diffusion of oxygen and nutrients from the SF. Synovial membrane, joint capsule and bursae The bones of synovial joints are connected by the joint capsule, a fibrous structure richly supplied with blood vessels, nerves and lymphatics that encases the joint. Ligaments are discrete, regional thickenings of the capsule that act to stabilise joints (see Fig. 24.4). The inner surface of the joint capsule is the synovial membrane, comprising an outer layer of blood vessels and loose connective tissue that is rich in type I collagen, and an inner layer 1–4 cells thick consisting of two main cell types. Type A synoviocytes are phagocytic cells derived from the monocyte/ macrophage lineage and are responsible for removing particulate matter from the joint cavity; type B synoviocytes are fibroblast-like cells that secrete SF. Most inflammatory and degenerative joint diseases associate with thickening of the synovial membrane and infiltration by lymphocytes, polymorphs and macrophages. Bursae are hollow sacs lined with synovium and contain a small amount of SF. They help tendons and muscles move smoothly in relation to bones and other articular structures. Skeletal muscle Skeletal muscles are responsible for body movements and respiration. Muscle consists of bundles of cells (myocytes) embedded in fine connective tissue containing nerves and blood vessels. Myocytes are large, elongated, multinucleated cells formed by fusion of mononuclear precursors (myoblasts) in early embryonic life. The nuclei lie peripherally and the centre of the cell contains actin and myosin molecules, which interdigitate with one another to form the myofibrils that are responsible for muscle contraction. The molecular mechanisms of skeletal muscle contraction are the same as for cardiac muscle (p. 446). Myocytes contain many mitochondria that provide the large amounts of adenosine triphosphate (ATP) necessary for muscle contraction and are rich in the protein myoglobin, which acts as a reservoir for oxygen during contraction. Individual myofibrils are organised into bundles (fasciculi) that are bound together by a thin layer of connective tissue (the Synovial joints These are complex structures containing several cell types. They are found where a wide range of movement is needed (Fig. 24.4). Articular cartilage This avascular tissue covers the bone ends in synovial joints. Cartilage cells (chondrocytes) are responsible for synthesis and turnover of cartilage, which consists of a mesh of type II collagen fibrils that extend through a hydrated ‘gel’ of proteoglycan molecules. The most important proteoglycan is aggrecan, which consists of a core protein to which several glycosaminoglycan (GAG) side chains are attached (Fig. 24.5). The GAGs are polysaccharides that consist of long chains of disaccharide repeats comprising one normal sugar and an amino sugar. The most abundant GAGs in aggrecan are chondroitin sulphate and keratan sulphate. Hyaluronan is another important GAG that binds to aggrecan molecules to form very large complexes with a total molecular weight of more than 100 million. Aggrecan has a strong negative charge and avidly binds water molecules to assume a shape that occupies the maximum possible volume available. The expansive force of the hydrated aggrecan, combined with the restrictive strength of the collagen mesh, gives articular cartilage excellent shock-absorbing properties. With ageing, the concentration of chondroitin sulphate decreases, whereas that of keratan sulphate increases, resulting Fig. 24.4 Structure of a synovial joint. Bone Skin and subcutaneous tissue Fibrocartilage pad Hyaline articular cartilage Joint space Synovium Capsule Bursa Tendon Tendon sheath Ligamentous thickening of capsule Muscle Bursa Fig. 24.5 Ultrastructure of articular cartilage. Aggrecan Core protein Link protein Chondroitin sulphate Keratan sulphate Type II collagen fibrils Hyaluronan

988 • RHEUMATOLOGY AND BONE DISEASE smaller, rhomboid in shape and usually less numerous than urate crystals; they have weak intensity and positive birefringence (Fig. 24.6B). Imaging Plain X-rays X-rays show structural changes that are of value in the differential diagnosis and monitoring of many bone and joint diseases (Box 24.3). perimysium). The surface of the muscle is surrounded by a thicker layer of connective tissue, the epimysium, which merges with the perimysium to form the muscle tendon. Tendons are tough, fibrous structures that attach muscles to a point of insertion on the bone surface called the enthesis. Investigation of musculoskeletal disease Clinical history and examination usually provide sufficient information for the diagnosis and management of many musculoskeletal diseases. Investigations are helpful in confirming the diagnosis, assessing disease activity and indicating prognosis. Joint aspiration Joint aspiration with examination of SF is pivotal in patients suspected of having septic arthritis, crystal arthritis or intra-articular bleeding. It should be carried out in all individuals with acute monoarthritis, and samples should be sent for microbiology and clinical chemistry. It is possible to obtain SF by aspiration from most peripheral joints and only a small amount is required for diagnostic purposes. Normal SF is present in small volume, is clear and either colourless or pale yellow, and has a high viscosity. It contains few cells. With joint inflammation, the volume increases, the cell count and the proportion of neutrophils rise (causing turbidity), and the viscosity reduces (due to enzymatic degradation of hyaluronan and aggrecan). Turbid fluid with a high neutrophil count occurs in sepsis, crystal arthritis and reactive arthritis. High concentrations of urate crystals or cholesterol can make SF appear white. Non-uniform blood-staining usually reflects needle trauma to the synovium. Uniform blood-staining is most commonly due to a bleeding diathesis, trauma or pigmented villonodular synovitis (p. 1059) but can occur in severe inflammatory synovitis. A lipid layer floating above blood-stained fluid is diagnostic of intra-articular fracture and is caused by release of bone marrow fat into the joint. Crystals can be identified by compensated polarised light microscopy of fresh SF (to avoid crystal dissolution and post-aspiration crystallisation). Urate crystals are long and needle-shaped, and show a strong light intensity and negative birefringence (Fig. 24.6A). Calcium pyrophosphate crystals are Fig. 24.6 Compensated polarised light microscopy of synovial fluids (× 400). A Monosodium urate crystals show bright negative birefringence under polarised light and needle-shaped morphology. B Calcium pyrophosphate crystals show weak positive birefringence under polarised light and are few in number. They are more difficult to detect than urate crystals. A B 24.3 Radiographic abnormalities in selected rheumatic diseases Rheumatoid arthritis • Periarticular osteoporosis • Marginal joint erosions • Joint subluxation • Joint space narrowing Osteoporosis • Osteopenia • Vertebral fractures • Non-vertebral fractures • Cortical thinning Paget’s disease • Bone expansion • Abnormal trabecular pattern • Osteosclerosis and lysis • Pseudofractures Psoriatic arthritis • Sacroiliitis • Syndesmophytes • Bone sclerosis • Proliferative enthesis erosions • Enthesophytes • Juxta-articular new bone Osteoarthritis • Joint space narrowing • Osteophytes • Subchondral sclerosis • Joint deformity • Subchondral cysts They are of diagnostic value in osteoarthritis (OA), where they demonstrate joint space narrowing that tends to be focal rather than widespread, as in inflammatory arthritis. Other features of OA detected on X-rays include osteophytes, subchondral sclerosis, bone cysts and calcified loose bodies within the synovium (see Fig. 24.21, p. 1010). Erosions and sclerosis of the sacroiliac joints and syndesmophytes in the spine may be observed in patients with spondyloarthritis (SpA; see Fig. 24.40, p. 1030). In peripheral joints, proliferative erosions, associated with new bone formation and periosteal reaction, occur in SpA. In tophaceous gout, well-defined punched-out erosions may occur (see Fig. 24.27, p. 1015). Calcification of cartilage, tendons and soft tissues or muscle occurs mainly in chondrocalcinosis (see Fig. 24.28, p. 1016), calcium-containing crystal diseases, tumoral calcinosis and autoimmune connective tissue diseases. X-rays are of limited value in the diagnosis of rheumatoid arthritis (RA) because features such as erosions, joint space narrowing and periarticular osteoporosis may be detectable only after several months or even years. The main indication for X-rays in RA is in the assessment of disease over time when structural damage to the joints is suspected. Bone scintigraphy Bone scintigraphy is useful in the diagnosis of metastatic bone disease and Paget’s disease of bone. Abnormalities may also be observed in primary bone tumours, complex regional pain syndrome, osteoarthritis and inflammatory arthritis. It involves

Investigation of musculoskeletal disease • 989

Dual X-ray absorptiometry Estimation of bone mineral density (BMD) has a key role in the diagnosis and management of osteoporosis and is best made using dual X-ray absorptiometry (DXA). Measurements at lumbar spine, hip and sometimes forearm are obtained. DXA works on the principle that calcium in bone attenuates passage of X-rays through the tissue in proportion to the amount of mineral present: the more bone mineral present, the higher the BMD value. gamma-camera imaging following an intravenous injection of 99mTc-labelled bisphosphonate. Early post-injection images reflect blood flow and can show increased perfusion of inflamed synovium, Pagetic bone or primary or secondary bone tumours. Delayed images taken a few hours later reflect bone remodelling as the 99mTc-labelled bisphosphonate localises to sites of active bone turnover. Scintigraphy has a high sensitivity for detecting important bone and joint pathology that is not apparent on X-rays (Box 24.4). Single photon emission computed tomography (SPECT) combines radionuclide imaging with computed tomography. It can provide accurate anatomical localisation of abnormal tracer uptake within the bone and is of particular value in the assessment of patients with chronic low back pain of unknown cause. Magnetic resonance imaging Magnetic resonance imaging (MRI) gives detailed information on anatomy, allowing three-dimensional visualisation of bone and soft tissues that cannot be adequately assessed by plain X-rays. The technique is valuable in the assessment and diagnosis of many musculoskeletal diseases (Box 24.5). T1-weighted sequences are useful for defining anatomy, whereas T2-weighted sequences are useful for assessing tissue water content, which is often increased in synovitis and other inflammatory disorders (Fig. 24.7). MRI sequences that suppress signal from fat, such as short TI inversion recovery (STIR), are helpful when evaluating inflammatory disease. Contrast agents, such as gadolinium, can be administered to increase sensitivity in detecting erosions and synovitis. Ultrasonography Ultrasonography is a useful investigation for confirmation of small joint synovitis and erosions, for anatomical location of periarticular lesions, for characterisation of tendon lesions and for guided injection of joints and bursae. Ultrasound is more sensitive than clinical examination for the detection of early synovitis and is used increasingly in the diagnosis and assessment of patients with suspected inflammatory arthritis. In addition to locating synovial thickening and effusions, ultrasound can detect increased blood flow within synovium using power Doppler imaging, an option that is available on most modern ultrasound machines (Fig. 24.8). Computed tomography Computed tomography (CT) is used selectively for assessing patients with bone and joint disease. CT may be used when skeletal configuration needs defining, when calcific lesions are being assessed (crowned dens syndrome, p. 1017), when MRI is contraindicated, or when articular regions are being evaluated in which an adjacent joint replacement creates signal artefacts on MRI, using specific metal artefact reduction algorithms. Fig. 24.7 Magnetic resonance image showing joint synovitis. Coronal post-contrast T1-weighted image shows extensive enhancement consistent with synovitis (white areas, arrowed) in both wrists, at the second metacarpophalangeal joint and proximal interphalangeal joints of the right hand. Courtesy of Dr I. Beggs. Fig. 24.8 Ultrasound image showing synovitis. Lateral image of a metacarpophalangeal joint in inflammatory arthritis. The periosteum (P) of the phalanx shows as a white line. The dark, hypo-echoic area indicates an effusion. The coloured areas demonstrated by power Doppler indicate increased vascularity. The inset shows a transverse image of the same joint. Courtesy of Dr N. McKay. 24.4 Conditions identified by 99mTc-labelled bisphosphonate bone scintigraphy • Skeletal metastases • Paget’s disease of bone • Stress fractures and osteomalacia (e.g. Looser’s zones) • Complex regional pain syndrome (p. 1055) • Sclerosing bone disorders (e.g. hypertrophic pulmonary osteoarthropathy; p. 1057) • Spondyloarthritides (abnormalities at sacroiliac joints and tendon/ ligament insertions) 24.5 Conditions detected by magnetic resonance imaging • Osteonecrosis • Intervertebral disc disease • Nerve root entrapment • Spinal cord compression • Spinal stenosis • Sepsis • Complex regional pain syndrome • Malignancy • Fractures • Meniscal disease • Synovitis • Sacroiliitis and enthesitides • Inflammatory myositis • Rotator cuff tears, bursitis and tenosynovitis

990 • RHEUMATOLOGY AND BONE DISEASE when the T-score lies between −1.0 and −2.5 (shaded pink). BMD values above −1.0 and below +2.5 are considered normal (yellow/green), whereas values above +2.5 indicate high bone mass, the most common cause being OA. The results need to be interpreted carefully and in reference to coexisting conditions, such as aortic calcification, vertebral fractures, degenerative disc disease and OA, all of which can artefactually raise BMD results. Radiographic correlation is then advisable. Blood tests Haematology Abnormalities in the full blood count (FBC) often occur in inflammatory rheumatic diseases but changes are usually nonspecific. Examples include neutrophilia in crystal arthritides and sepsis; neutropenia in lupus; and lymphopenia in autoimmune rheumatic and connective tissue diseases. Reduced levels of haemoglobin and raised platelets are a common and important finding in active inflammatory rheumatological disorders. Many synthetic and biologic disease-modifying antirheumatic drugs (DMARDs) can cause marrow toxicity and require regular monitoring of the FBC. Additional tests that are useful in assessing rheumatic diseases include the direct antiglobulin test (which can indicate intravascular haemolysis in systemic lupus erythematosus (SLE); p. 948) and the dilute Russell viper venom test (a functional assay for a lupus anticoagulant; p. 978). Biochemistry Routine biochemistry is useful for assessing metabolic bone disease, muscle diseases and gout, and is essential in monitoring DMARDs and biologic drugs (renal and hepatic function). Several bone diseases, including Paget’s disease, renal bone disease and osteomalacia, give a characteristic pattern that can be helpful diagnostically (Box 24.6). Serum levels of uric acid are usually raised in gout but a normal level does not exclude it, especially during an acute attack, when urate levels temporarily fall. Equally, an elevated serum uric acid does not confirm the diagnosis, since most hyperuricaemic people never develop gout. Levels of C-reactive protein (CRP) are a useful marker of infection and inflammation, and are more specific than the erythrocyte sedimentation rate (ESR). An exception is in autoimmune connective tissue diseases, such as SLE and systemic sclerosis, where CRP may be normal but the ESR raised in active disease. Accordingly, an elevated CRP in a patient with lupus or systemic sclerosis suggests an intercurrent illness, such as sepsis, rather than active disease. More detail on the Fig. 24.9 Typical output from a dual X-ray absorptiometry (DXA) scan. A Image from hip DXA scan. B Bone mineral density (BMD) values plotted in g/cm2 (left axis) and as the T-score values (right axis). The solid line represents the population average plotted against age, and the interrupted lines are ± 2 standard deviations. The BMD T-score result from the patient shown aged 70 years (arrow) is −3.0, indicating osteoporosis. Note that, while the patient’s BMD is below average, it lies within the reference range for someone of that age, since BMD normally falls with age. 1.3 +2.0 +1.0 0.0 −1.0 −2.0 −3.0 −4.0 1.0 0.7 0.4

Age (years) T-score BMD (g/cm2)

A B 24.6 Typical biochemical abnormalities in various skeletal diseases (in serum) Calcium Phosphate ALP PTH FGF23 25(OH)D Osteoporosis N N N (↑ after fracture) N or ↑ N N or ↓ Paget’s disease N N ↑↑ N or ↑ N N or ↓ Renal osteodystrophy N or ↓ N or ↑ ↑ ↑↑ ↑↑ N or ↓ Vitamin D-deficient osteomalacia N or ↓ N or ↓ ↑ ↑↑ N or ↓ ↓↓ Hypophosphataemic rickets N ↓↓ ↑ N or ↑ ↑↑ N or ↓ Primary hyperparathyroidism ↑/↑↑ N or ↓ N or ↑ ↑↑ N or ↑ N or ↓ (ALP = alkaline phosphatase; FGF23 = fibroblast growth factor 23; PTH = parathyroid hormone) (N = normal; single arrow = increased or decreased; double arrow = greatly increased or decreased) Bone density measurements are often presented as T-scores, which measure of the number of standard deviations by which the patient’s BMD value differs from that in a young healthy control (Fig. 24.9). Osteoporosis is defined in postmenopausal women and men of more than 50 years old by a T-score of 2.5 or below (shaded red in the figure); osteopenia is diagnosed

Investigation of musculoskeletal disease • 991

and can be detected in asymptomatic patients several years before the development of RA. Their pathological role is still debated but it is likely that they amplify the synovial response to an inflammatory stimulus. Antinuclear antibodies Antinuclear antibodies (ANAs) are directed against one or more components of the cell nucleus, including nucleic acids themselves and the proteins concerned with the processing of DNA or RNA. They occur in many inflammatory rheumatic diseases but are also found at low titre in normal individuals and in other diseases (Box 24.9). ANAs are not associated with disease severity or activity. The most common indication for ANA testing is in patients suspected of having SLE or other autoimmune connective tissue diseases. ANA has high sensitivity for SLE (100%) but low specificity (10–40%). A negative ANA virtually excludes SLE but a positive result does not confirm it. Anti-DNA antibodies bind to double-stranded DNA (dsDNA) and are useful in SLE monitoring as very high titres are associated with more severe disease, including renal or central nervous system (CNS) involvement, and an increase in antibody titre may precede relapse. Anti-DNA antibodies are routinely tested by enzyme-linked immunosorbent assay (ELISA; see also p. 1036). Antibodies to extractable nuclear antigens (ENAs) act as markers for certain autoimmune connective tissue diseases and some complications of SLE but sensitivity and specificity are poor (Box 24.10). For example, antibodies to Sm are found in a minority of patients with SLE but are associated with renal involvement. Antibodies to Ro occur in SLE and in Sjögren’s syndrome (in association with anti-La antibodies), and are associated with a photosensitive rash and congenital heart block. Antibodies to ribonucleoprotein (RNP) occur in SLE and also in mixed connective tissue disease, where features of lupus, myositis and systemic sclerosis coexist. Anti-topoisomerase 1 (also termed Scl-70) antibodies occur in diffuse systemic sclerosis, whereas anti-centromere antibodies are more specific for limited systemic sclerosis. Antiphospholipid antibodies Antiphospholipid antibodies bind to a number of phospholipid binding proteins but the most clinically relevant are those that target beta2-glycoprotein 1 (β2GP1). They may be detected in 24.9 Conditions associated with a positive antinuclear antibody* Condition Approximate frequency (%) Systemic lupus erythematosus 100% Systemic sclerosis 60–80% Sjögren’s syndrome 40–70% Dermatomyositis or polymyositis 30–80% Mixed connective tissue disease 100% Autoimmune hepatitis 100% Rheumatoid arthritis 30–50% Autoimmune thyroid disease 30–50% Malignancy Varies widely Infectious diseases Varies widely *Low-titre positive antinuclear antibody can occur in people without autoimmune disease, without obvious clinical consequences, particularly in the elderly. Normal healthy people can be positive for rheumatoid factor. 24.8 Conditions associated with a positive rheumatoid factor Condition Approximate frequency (%) Rheumatoid arthritis with nodules and extra-articular manifestations

Rheumatoid arthritis (overall)

Sjögren’s syndrome

Mixed essential cryoglobulinaemia

Primary biliary cholangitis

Infective endocarditis

Systemic lupus erythematosus

Tuberculosis

Age > 65 years

interpretation of CRP and ESR changes is given on page 72. Serum creatine phosphokinase levels are useful in the diagnosis of myopathy or myositis, but specificity and sensitivity are poor and raised levels may occur in some conditions (Box 24.7). Immunology Autoantibody tests are widely used in the diagnosis of rheumatic diseases. Whatever test is used, the results must be interpreted in light of the clinical picture and the different detection and assay systems used in different hospitals. Rheumatoid factor Rheumatoid factor (RF) is an antibody directed against the Fc fragment of human immunoglobulin. In routine clinical practice, immunoglobulin M (IgM) RF is usually measured, although different methodologies allow measurement of IgG and IgA RFs too. Positive RF occurs in a wide variety of diseases and some normal adults (Box 24.8), particularly with increasing age. Although the specificity is poor, about 70% of patients with RA test positive. High RF titres are associated with more severe disease and extra-articular disease. Anti-citrullinated peptide antibodies Anti-citrullinated peptide antibodies (ACPAs) recognise peptides in which the amino acid arginine has been converted to citrulline by peptidylarginine deiminase, an enzyme abundant in inflamed synovium and in a variety of mucosal structures. ACPAs have similar sensitivity to RF for RA (70%) but much higher specificity (> 95%), and should be used in preference to RF in the diagnosis of RA. ACPAs are associated with more severe disease progression The CK-MB cardiac-specific isoform is disproportionately elevated compared with total CPK. 24.7 Causes of an elevated serum creatinine phosphokinase (CPK) • Inflammatory myositis ± vasculitis • Muscular dystrophy • Motor neuron disease • Alcohol, drugs (especially statins) • Myocardial infarction • Trauma, strenuous exercise, prolonged immobilisation after a fall • Hypothyroidism, metabolic myopathy • Viral myositis

992 • RHEUMATOLOGY AND BONE DISEASE Synovial biopsy can be useful in selected patients with chronic inflammatory monoarthritis or tenosynovitis to rule out chronic infectious causes, especially mycobacterial infections. Synovial biopsy can be obtained arthroscopically (by conventional means or by use of needle arthroscope) or by using ultrasound guidance under local anaesthetic. Temporal artery biopsy can be of value in patients suspected of having temporal arteritis, especially when the presentation is atypical, but a negative result does not exclude the diagnosis. Biopsies of affected tissues, such as skin, lung, nasopharynx, gut, kidney and muscle, should be sought by default in confirming a diagnosis of systemic vasculitis. Muscle biopsy plays an important role in the investigation of myopathy and inflammatory myositis. It is usually taken from the quadriceps or deltoid through a small skin incision under local anaesthetic. Since myositis can be patchy in nature, MRI is sometimes used to localise the best site for biopsy. Immunohistochemical staining, together with plain histology, gives information on primary and secondary muscle and neuromuscular disease. Repeat biopsies are sometimes used to monitor the response to treatment. Bone biopsy is occasionally required where non-invasive tests give inconclusive results, in the diagnosis of infiltrative disorders, in patients with renal bone disease, suspected chronic infection or malignancy, and rarely to confirm or exclude the presence of osteomalacia. Bone is taken from the iliac crest using a large-diameter (8 mm) trephine needle under local anaesthetic and processed without demineralisation. For focal lesions, the biopsy should be taken under X-ray guidance or at open surgery, from an affected site. Electromyography Electromyography (p. 1076) is of value in the investigation of suspected myopathy and inflammatory myositis, when it shows the diagnostic triad of: • spontaneous fibrillation • short-duration action potentials in a polyphasic disorganised outline • repetitive bouts of high-voltage oscillations on needle contact with diseased muscle. Presenting problems in musculoskeletal disease Acute monoarthritis The most important causes of acute arthritis in a single joint are crystal arthritis, sepsis, SpA and oligoarticular juvenile idiopathic arthritis (JIA; p. 1026). Other potential causes are shown in Box 24.11. Clinical assessment The clinical history, pattern of joint involvement, speed of onset, and age and gender of the patient all give clues to the most likely diagnosis. Gout classically affects the first metatarsophalangeal (MTP) joint, whereas pseudogout, which can be a presenting feature of calcium pyrophosphate dihydrate (CPPD) disease, can affect the hand/wrist, ankle, knee or hip. A very rapid onset (6–12 hours) is suggestive of crystal arthritis; joint sepsis develops more slowly and continues to progress until treated. SLE and other autoimmune connective tissue diseases and are key in diagnosing antiphospholipid antibody syndrome (p. 977). Antineutrophil cytoplasmic antibodies Antineutrophil cytoplasmic antibodies (ANCAs) are IgG antibodies directed against the cytoplasmic constituents of granulocytes and are useful in the diagnosis and monitoring of systemic vasculitis. Two common patterns are described by immunofluorescence: cytoplasmic fluorescence (c-ANCA), which is caused by antibodies to proteinase-3 (PR3); and perinuclear fluorescence (p-ANCA), which is caused by antibodies to myeloperoxidase (MPO) and other proteins, such as lactoferrin and elastase. These antibodies are not specific for vasculitis and positive results may be found in autoimmune liver disease, malignancy, infection (bacterial and human immunodeficiency virus, HIV), inflammatory bowel disease, RA, SLE and pulmonary fibrosis. Complement Low complement C3 is an indicator of active SLE, owing to ‘consumption’ of complement by immune complexes (see Fig. 4.4, p. 66). Low C4 is less specific for SLE activity. High C3 and functional measures of complement activation are non-specific features of inflammation. Tissue biopsy Tissue biopsy is useful in confirming the diagnosis in certain musculoskeletal diseases. 24.10 Conditions associated with antibodies to extractable nuclear antigens Antibody (target/other name) Disease association Anti-centromere antibody Localised cutaneous systemic sclerosis (sensitivity 60%, specificity 98%) Anti-histone antibody Drug-induced lupus (80%) Anti-Jo-1 (anti-histidyl-tRNA synthetase) Polymyositis, dermatomyositis or polymyositis–systemic sclerosis overlap (20–30%) Particularly associated with interstitial lung disease Anti-La antibody (anti-SS-B) Sjögren’s syndrome (60%) SLE (20–60%) Anti-ribonucleoprotein antibody (anti-RNP) Mixed connective tissue disease (100%) SLE (25–50%), usually in conjunction with anti-Sm antibodies Anti-Ro antibody (anti-SS-A) SLE (35–60%): associated with photosensitivity, thrombocytopenia and subacute cutaneous lupus Maternal anti-Ro antibodies associated with neonatal lupus and congenital heart block Sjögren’s syndrome (40–80%) Anti-RNA polymerase Diffuse systemic sclerosis (15%) Anti Sm (anti-Smith antibody) SLE (15–30%); associated with renal disease Anti-Scl-70 (anti-topoisomerase I antibody) Diffuse systemic sclerosis (15%); associated with more severe organ involvement, including pulmonary fibrosis (SLE = systemic lupus erythematosus)

Presenting problems in musculoskeletal disease • 993

underlying cause (Box 24.13). The most important diagnoses to consider are PsA, RA and inflammatory small joint OA. RA is characterised by symmetrical involvement of the small joints of the hands and feet, wrists, ankles and knees. PsA is strongly associated with enthesitis. Viral arthritis (p. 1020), Poncet’s disease (in regions where tuberculosis is highly prevalent; p. 588), polyarticular JIA (in children) and post-streptococcal arthritis should also be considered. The pattern of involvement can be helpful in reaching a diagnosis (Fig. 24.10). Asymmetry, lower limb predominance, enthesitis and greater involvement of large joints are characteristic of the SpAs. In PsA there may be involvement of the proximal and distal interphalangeal (PIP and DIP) joints, as opposed to the metacarpophalangeal (MCP) and PIP joints in RA. Inflammatory OA can appear similar to small-joint PsA in the pattern of joint involvement. In PsA there may be nail pitting or early onycholysis. Psoriasis may not be present. SLE can be associated with polyarthritis but more usually causes polyarthralgia and tenosynovitis, mainly of distal limb joints/tendons (p. 1035). Investigations Blood samples should be taken for routine haematology, biochemistry, ESR, CRP, viral serology and an immunological screen, including ANA, RF and ACPA. Ultrasound examination or MRI may be required to confirm the presence of synovitis, if this is not obvious clinically. 24.12 Common causes of polyarthritis Cause Characteristics Rheumatoid arthritis Symmetrical, small and large joints, upper and lower limbs Viral arthritis Symmetrical, small joints; may be associated with rash and prodromal illness; self-limiting Osteoarthritis Symmetrical, targets PIP, DIP and first CMC joints in hands, knees, hips, back and neck; associated with Heberden’s and Bouchard’s nodes Psoriatic arthritis Asymmetrical, targets all joints and entheses; associated with nail pitting/ onycholysis, dactylitis Axial spondyloarthritis and enteropathic arthritis Tends to affect midsize and large joints and entheses, lower more than upper limbs; history of inflammatory back pain Systemic lupus erythematosus Symmetrical, typically affecting small joints; clinical evidence of synovitis unusual Juvenile idiopathic arthritis Various patterns (p. 1026): polyarticular, oligoarticular and systemic but also enthesitis-predominant Chronic gout Affects distal more than proximal joints; history of acute attacks Chronic sarcoidosis (p. 608) Varies: small and large joints, often involves ankles Calcium pyrophosphate arthritis Chronic polyarthritis with involvement of wrists, ankles, knees and oligoarticular small hand joints (CMC = carpometacarpal; DIP = distal interphalangeal; PIP = proximal interphalangeal) 24.11 Causes of acute monoarthritis Common • Gout • Pseudogout • Trauma • Haemarthrosis • Spondyloarthritis • Psoriatic arthritis • Reactive arthritis • Enteropathic arthritis Less common • Rheumatoid arthritis • Juvenile idiopathic arthritis • Pigmented villonodular synovitis • Foreign body reaction • Tuberculosis • Leukaemia* • Gonococcal infection • Osteomyelitis* *In children, both leukaemia and osteomyelitis may present with monoarthritis. Haemarthrosis typically causes a large effusion, in the absence of periarticular swelling or skin change, in a patient who has suffered an injury. Pigmented villonodular synovitis (p. 1059) also presents with synovial swelling and a large effusion, although the onset is gradual. A previous diarrhoeal illness or genital infection suggests reactive arthritis, whereas intercurrent illness, dehydration or surgery may act as a trigger for crystal-induced arthritis. Rheumatoid arthritis seldom presents with monoarthritis but psoriatic arthritis (PsA) can typically present this way. Osteoarthritis can present with pain and stiffness affecting a single joint, but the onset is gradual and there is usually no evidence of significant joint swelling unless it is complicated by crystal-induced inflammation. Investigations Aspiration of the affected joint is mandatory. If sepsis is suspected in a large joint, arthroscopic washout is advisable. The fluid should be sent for culture and Gram stain to seek the presence of organisms and should be checked by polarised light microscopy for crystals. Blood cultures should also be taken in patients suspected of having septic arthritis. CRP levels and ESR are raised in sepsis, crystal arthritis and reactive arthritis, and this can be useful in assessing the response to treatment. Serum uric acid measurements may be raised in gout but a normal level does not exclude the diagnosis. Ruling out primary hyperparathyroidism is essential if there is pseudogout. Management If there is any suspicion of sepsis, intravenous antibiotics (see Box 24.50, p. 1020) should be given promptly, pending the results of cultures. Unless atypical infections/tuberculosis (requiring prolonged or special culture) are suspected, intra-articular glucocorticoid injection may be considered after 48 hours of negative synovial fluid culture. Otherwise, management should be directed towards the underlying cause. Polyarthritis This term is used to describe pain and swelling affecting five or more joints or joint groups. The possible causes are listed in Box 24.12. Clinical assessment The hallmarks of inflammatory arthritis are early-morning stiffness and worsening of symptoms with inactivity, along with synovial swelling and tenderness on examination. Clinical features in other systems can be helpful in determining the

994 • RHEUMATOLOGY AND BONE DISEASE Management Treatment with non-steroidal anti-inflammatory drugs (NSAIDs) and analgesics will help. Systemic glucocorticoids can be considered if symptoms are very severe or having a great functional impact, but early immunotherapy (DMARDs) is required in RA and in some cases of PsA. An early accurate and specific diagnosis is very important. Fracture Fractures are a common presenting symptom of osteoporosis but they also occur in other bone diseases, in osteopenia and in some patients with normal bone. Clinical assessment The presentation is with localised bone pain, which is worsened by movement of the affected limb or region. There is usually a history of trauma but spontaneous fractures can occur in the absence of trauma in severe osteoporosis. Fractures can be divided into several subtypes, based on the precipitating event and presence or absence of an underlying disease (Box 24.14). The main differential diagnosis is soft tissue injury but fracture should be suspected when there is marked pain and swelling, abnormal movement of the affected limb, crepitus or deformity. Femoral neck fractures typically produce a shortened, externally rotated leg that is painful to move. The pain from vertebral fracture is variable and a high index of suspicion is key to making the diagnosis by imaging, as discussed below. Investigations X-rays of the affected site should be taken in at least two planes and examined for discontinuity of the cortical outline (Box 24.15). In addition to demonstrating the fracture, X-rays may also show evidence of an underlying disorder, such as osteoporosis, Paget’s disease or osteomalacia. If the X-ray fails to show evidence of a fracture but clinical suspicion remains high, MRI should be Fig. 24.10 Patterns of joint involvement in different forms of polyarthritis. A Rheumatoid arthritis typically targets the metacarpophalangeal and proximal interphalangeal joints of the hands and metatarsophalangeal joints of the feet, as well as other joints, in a symmetrical pattern. B Psoriatic arthritis targets proximal and distal interphalangeal joints of the hands, entheses and larger joints in an asymmetrical pattern. Sacroiliitis (often asymmetrical) may occur. C Axial spondyloarthritis/ankylosing spondylitis targets the spine, sacroiliac joints, entheses and large peripheral joints in an asymmetrical pattern. D Osteoarthritis targets the proximal and distal interphalangeal joints of the hands, first carpometacarpal joint at the base of the thumb, knees, hips, lumbar and cervical spine. A B C D 24.13 Extra-articular features of inflammatory arthritis Clinical feature Disease association Skin, nails and mucous membranes Psoriasis, nail pitting and dystrophy Psoriatic arthritis Raynaud’s phenomenon Systemic sclerosis, antiphospholipid syndrome, SLE Photosensitivity SLE Livedo reticularis SLE, antiphospholipid syndrome Splinter haemorrhages, nail-fold infarcts, purpuric lesions Vasculitis Urticaria and erythemas SLE, adult-onset Still’s disease, systemic JIA, rheumatic fever Oral ulcers SLE, reactive arthritis, Behçet’s disease Nodules RA (mainly extensor surfaces), gout (tophi; eccentric, white deposits within), rheumatic fever Xerostomia, dry skin, various rashes Primary Sjögren’s syndrome Eyes Uveitis SpA, sarcoid, JIA, Behçet’s disease Conjunctivitis Reactive arthritis Episcleritis, scleritis RA, vasculitis Heart, lungs Pleuro-pericarditis SLE, RA, rheumatic fever Aortic valve/root disease HLA-B27-related SpA Interstitial lung disease RA, SLE, primary Sjögren’s syndrome Abdominal organs Hepatosplenomegaly RA, SLE Haematuria, proteinuria SLE, vasculitis, systemic sclerosis Urethritis Reactive arthritis and SpA (sterile) Fever, lymphadenopathy Infection, systemic JIA, rheumatic fever (HLA = human leucocyte antigen; JIA = juvenile idiopathic arthritis; RA = rheumatoid arthritis; SLE = systemic lupus erythematosus; SpA = spondyloarthritis)

Presenting problems in musculoskeletal disease • 995

in association with hypermobility, most notably Ehlers–Danlos syndrome hypermobility subtype (hEDS; p. 1059). Investigations Bone scintigraphy is of value in patients suspected of having osteomalacia, bone metastases or Paget’s disease, and in characterising lesions at joints and/or entheses in SpAs, including PsA. Myeloma (p. 966) should be screened for with an FBC, measurement of CRP, and plasma and urinary protein electrophoresis. If these results are positive, a radiological skeletal survey should be obtained. Routine biochemistry, vitamin D and parathyroid hormone (PTH) should be measured if osteomalacia is suspected. In Paget’s disease, ALP may be elevated but can be normal in localised disease. Any persistently elevated ESR, CRP, angiotensin-converting enzyme (ACE), immunoglobulins, C3/C4 or platelets invariably indicates inflammatory disease. Laboratory investigations are normal in patients with FM alone and in hEDS. Management Management should be directed towards the underlying cause. Chronic pain of unknown cause and that associated with FM respond poorly to analgesics and NSAIDs, but may respond partially to antineuropathic agents, such as amitriptyline, duloxetine, gabapentin and pregabalin. Back pain Back pain is a common symptom that affects 60–80% of people at some time in their lives. Although the prevalence has not increased, reported disability from back pain has risen significantly in the last 30 years. In Western countries, back pain is the most common cause of sickness-related work absence. In the UK, 7% of adults consult their GP each year with back pain. Globally, low back pain is thought to affect about 9% of the population. The most important causes are summarised in Box 24.17. Clinical assessment The main purpose of clinical assessment is to differentiate the self-limiting disorder of acute mechanical back pain from serious spinal pathology, as summarised in Figure 24.11. Mechanical back pain is the most common cause of acute back pain in people aged 20–55. This accounts for more than 90% of episodes, and is usually acute and associated with lifting or bending. It is exacerbated by activity and is generally relieved by rest (Box 24.18). It is usually confined to the lumbar–sacral region, buttock or thigh, is asymmetrical and does not radiate beyond the knee (which would imply nerve root irritation). On examination, there may be asymmetric local paraspinal muscle spasm and tenderness, and painful restriction of some, but not all, movements. Low back pain is more common in manual workers, particularly those in occupations that involve heavy lifting and twisting. The prognosis 24.15 How to investigate a suspected fracture • Order X-rays in two projections at right angles to one another • Include the whole bone and the joints at either end (this may reveal an additional unsuspected fracture) • Check for evidence of displacement • Check for a break in the cortex • In suspected vertebral fracture, check for depression of the end plate • If clinical suspicion is high but no fracture is seen, request magnetic resonance imaging 24.14 Characteristics of different fracture types Fracture type Precipitation factor Disease Fragility fracture Fall from standing height or less Osteoporosis Osteopenia Vertebral fracture Bending, lifting, falling Osteoporosis Stress fracture Running, excessive training Normal High-energy fracture Major trauma Normal Pathological fracture Spontaneous, minimal trauma Malignancy Paget’s disease Osteomalacia obtained. Patients who are over the age of 50 and present with fragility fractures should be screened for osteoporosis by DXA. Management Management of fracture in the acute stage requires adequate pain relief, with opiates if necessary, reduction of the fracture to restore normal anatomy, and immobilisation of the affected limb to promote healing. This can be achieved either by the use of an external cast or splint, or by internal fixation. Femoral neck fractures present a special management problem since non-union and avascular necrosis are common. This is especially true with intracapsular hip fractures, which should be treated by joint replacement surgery. Following the fracture, rehabilitation is required with physiotherapy and a supervised exercise programme. If the DXA scan shows evidence of osteoporosis or other metabolic bone disease, this should be treated appropriately (p. 1046). Options for management of painful vertebral fracture are discussed on page 1002. Generalised musculoskeletal pain Clinical assessment Clinical history and examination need to be wide-ranging (Box 24.16). Relentlessly progressive pain occurring in association with weight loss suggests malignant disease with bone metastases. Generalised bone pain may also arise in severe osteomalacia, primary hyperparathyroidism and polyostotic Paget’s disease. Widespread pain can occur in PsA if there is enthesial as well as, or instead of, joint involvement; fatigue is also often present. Polyarticular RA or OA pains tend to be localised to sites of involvement, such as the lumbar spine, hips, knees and hands. Fibromyalgia (FM) syndrome (p. 1018) presents with generalised pain that particularly affects the trunk, back and neck. Accompanying features include fatigue, poor concentration and focal areas of hyperalgesia. Widespread pain may also occur 24.16 Some common causes of generalised pain • Myopathies • Psoriatic arthritis (enthesopathic) • Fibromyalgia • Parvovirus arthromyalgia • Rheumatic fever/post-streptococcal infection • Metastatic cancer • Severe osteomalacia

996 • RHEUMATOLOGY AND BONE DISEASE uphill. Patients may adopt a characteristic simian posture, with a forward stoop and slight flexion at hips and knees. The most common cause is the gradual development of coexisting contributing lesions such as facet joint arthritis, ligament flavum thickening or degenerative spondylolisthesis. Degenerative disc disease is a common cause of chronic low back pain in middle-aged adults. Prolapse of an intervertebral disc presents when discs are still well hydrated (in young and early middle age) with nerve root pain, which can be accompanied by a sensory deficit, motor weakness and asymmetrical reflexes. Examination may reveal a positive sciatic or femoral stretch test. About 70% of patients improve by 4 weeks. Inflammatory back pain (IBP) due to axial spondyloarthritis (axSpA) or PsA has a gradual onset and almost always occurs before the age of 40. It is associated with morning stiffness and improves with movement. Spondylolisthesis (p. 1059) may cause back pain that is generally good. After 2 days, 30% are better and 90% have recovered by 6 weeks. Recurrences of pain may occur and about 10–15% of patients go on to develop chronic back pain that may be difficult to treat. Psychological elements, such as job dissatisfaction, depression and anxiety, are important risk factors for the transition to chronic pain and disability. Back pain secondary to serious spinal pathology has different characteristics (Box 24.19). If there is clinical evidence of spinal cord or nerve root compression, sepsis including tuberculosis, or a cauda equina lesion (Box 24.20), urgent investigation is needed. Spinal stenosis presents insidiously with leg discomfort on walking that is relieved by rest, bending forwards or walking Fig. 24.11 Initial triage assessment of back pain. Back pain Mechanical Common, Acute onset Self-limiting Other Prolapsed disc Spinal stenosis Paget’s disease Fracture Inflammatory Axial spondyloarthritis Psoriatic spondyloarthritis Clinical assessment (Box 24.20) Destructive Malignancy Infection Persistent pain Fever/weight loss Inflammatory features Cauda equina syndrome Nerve root pain persisting > 4 weeks Further investigation and imaging Urgent investigation ± neurosurgical referral 24.19 Red flags for possible spinal pathology History • Age: presentation < 20 years or > 55 years • Character: constant, progressive pain unrelieved by rest • Location: thoracic pain • Past medical history: carcinoma, tuberculosis, HIV, systemic glucocorticoid use, osteoporosis • Constitutional: systemic upset, sweats, weight loss • Major trauma Examination • Painful spinal deformity • Severe/symmetrical spinal deformity • Saddle anaesthesia • Progressive neurological signs/muscle-wasting • Multiple levels of root signs 24.18 Features of mechanical low back pain • Pain varies with physical activity (improved with rest) • Onset often sudden and precipitated by lifting or bending • Recurrent episodes • Pain limited to back or upper leg • No clear-cut nerve root distribution • No systemic features • Prognosis good (90% recovery at 6 weeks) 24.17 Causes of low back pain • Mechanical (soft-tissue lesion) back pain • Intervertebral disc lesions (e.g. prolapse, disc degeneration) • Facet joint disease (osteoarthritis, psoriatic arthritis) • Vertebral fracture (p. 994) • Paget’s disease • Axial spondyloarthritis • Spondylodiscitis • Bone metastases • Spondylolisthesis (p. 1059) • Scheuermann’s disease (p. 1055)

Presenting problems in musculoskeletal disease • 997

Shoulder pain Shoulder pain is a common complaint over the age of 40 (Box 24.22). Varying pain patterns associated with common lesions are shown in Figure 24.12. For most shoulder lesions, general management is with analgesics, NSAIDs, local glucocorticoid injections and physiotherapy aimed at restoring normal movement and function. Surgery may be required in patients who have debilitating or persistent symptoms in association with rotator cuff lesions or severe acromioclavicular joint arthritis. If there is subacromial impingement, without evidence of a rotator cuff tear on MRI, subacromial glucocorticoid injection and physiotherapy constitute a reasonable first step. Calcific supraspinatus tendonitis unresponsive to glucocorticoid injection can be treated with barbotage (needle disruption of deposit under ultrasound guidance). Complete rotator cuff tears in people under 40 years of age may respond well to full surgical repair but results are is typically aggravated by standing and walking. Occasionally, diffuse idiopathic skeletal hyperostosis (DISH; p. 1058) can cause back pain but it is usually asymptomatic. Arachnoiditis is a rare cause of chronic severe low back pain. It is caused by chronic inflammation of the nerve root sheaths in the spinal canal and can complicate meningitis, spinal surgery or myelography with oil-based contrast agents. Investigations Investigations are not required in patients with acute mechanical back pain. Those with persistent pain (> 6 weeks) or red flags (see Box 24.19) should undergo further investigation. MRI is the investigation of choice because it can demonstrate spinal stenosis, cord compression or nerve root compression, as well as inflammatory changes in axSpA, malignancy and sepsis. Plain X-rays can be of value in patients suspected of having vertebral compression fractures, OA and degenerative disc disease. If metastatic disease is suspected, bone scintigraphy should be considered. Additional investigations that may be required include routine biochemistry and haematology, ESR and CRP (to screen for sepsis and inflammatory disease), protein and urinary electrophoresis (for myeloma), human leucocyte antigen (HLA)-B27 status in IBP and prostate-specific antigen (for prostate carcinoma). Management Education is important in patients with mechanical back pain. It should emphasise the self-limiting nature of the condition and the fact that exercise is helpful rather than damaging. Regular analgesia and/or NSAIDs may be required to improve mobility and facilitate exercise. Return to work and normal activity should take place as soon as possible. Bed rest is not helpful and may increase the risk of chronic disability. Referral for physical therapy should be considered if a return to normal activities has not been achieved by 6 weeks. Low-dose tricyclic antidepressant drugs may help pain, sleep and mood. Other treatment modalities that are occasionally used include epidural and facet joint injection, traction and lumbar supports, though there is limited randomised controlled trial evidence to support their use. Malignant disease, osteoporosis, Paget’s disease and SpAs require specific treatment of the underlying condition. Surgery is required in less than 1% of patients with low back pain but may be needed in progressive spinal stenosis, 24.20 Clinical features of radicular pain Nerve root pain • Unilateral leg pain worse than low back pain • Pain radiates beyond knee • Paraesthesia in same distribution • Nerve irritation signs (reduced straight leg raising that reproduces leg pain) • Motor, sensory or reflex signs (limited to one or adjacent nerve roots) • Prognosis reasonable (50% recovery at 6 weeks) Cauda equina syndrome • Difficulty with micturition • Loss of anal sphincter tone or faecal incontinence • Saddle anaesthesia • Gait disturbance • Pain, numbness or weakness affecting one or both legs 24.21 Typical causes of neck pain Mechanical • Postural • Whiplash injury • Facet joint • Cervical spondylosis Inflammatory • Infections • Axial spondyloarthritis • Psoriatic arthritis • Rheumatoid arthritis • Polymyalgia rheumatica • Discitis Metabolic • Axial calcium pyrophosphate dihydrate disease • Fibrous dysplasia • Paget’s disease Neoplastic • Metastases • Myeloma • Lymphoma • Intrathecal tumours Other • Fibromyalgia • Torticollis Referred • Pharynx • Cervical lymph nodes • Teeth • Angina pectoris • Aortic aneurysm • Pancoast tumour • Diaphragm in spinal cord compression and in some patients with nerve root compression. Regional musculoskeletal pain Regional musculoskeletal pain is a common presenting complaint, usually occurring as the result of age-related degenerative disease of tendons and ligaments, OA and trauma. Neck pain Neck pain is a common symptom that can occur following an injury or falling asleep in an awkward position, as a result of stress or in association with OA of the spine. The causes are shown in Box 24.21. Most cases resolve spontaneously or with a short course of NSAIDs or analgesics and some exercise therapy. Patients with persistent pain that follows a nerve root distribution and those with upper or lower limb neurological signs should be investigated by MRI and, if necessary, referred for a neurosurgical opinion.

998 • RHEUMATOLOGY AND BONE DISEASE • Tenosynovitis: affects flexor or extensor digital tendons. Pain and tenderness are well localised to the tendon lesions. There is often early-morning ‘claw-like’ digit stiffness. De Quervain’s tenosynovitis involves the tendon sheaths of abductor pollicis longus and extensor pollicis brevis. It produces pain maximal over the radial aspect of the distal forearm and wrist and marked pain on forced ulnar deviation of the wrist with the thumb held across the patient’s palm (Finkelstein’s sign). This test is not specific for this lesion alone. • Raynaud’s phenomenon: digital vasospasm triggered mostly by cold (p. 1035). • C6, C7 or C8 radiculopathy. • Carpal tunnel syndrome: hand position-dependent and/or nocturnal pain, numbness and paraesthesia of thumb and second to fourth digits. Hip pain Pain from the hip joint is usually felt deep in the groin, with variable radiation to the buttock, anterolateral thigh or knee (Fig. 24.13). Patients who report ‘hip pain’ sometimes point to greater trochanter or buttock areas. Greater trochanter pain syndrome is usually due to either gluteus medius insertional tendonitis/ enthesitis, trochanteric bursitis or referred pain (Box 24.24). Pain at this site may also be referred from the lumbosacral spine. A differential diagnosis of hip joint conditions (groin pain) is symphysitis (SpAs, including psoriasis disease, need ruling out). Other less common causes of pain in the hip/groin area include inguinal hernia, adductor tendonitis and enthesitis of anterior superior/inferior iliac spines. Knee pain In middle and older age, the most common cause of knee pain is OA, the features of which are described on page 1008. Pain that is associated with locking of the knee (sudden painful inability to extend fully) is usually due to a meniscal tear or osteochondritis dissecans. Referred pain from the hip may present at the knee and is reproduced by hip, not knee, movement. Pain from periarticular lesions is well localised to the involved structure (Box 24.25). Anterior knee pain may be due to patellar ligament or retinacular lesions (enthesitis, tendonitis, fat-pad syndrome) occurring typically Fig. 24.12 Pain patterns around the shoulder. The dark shading indicates sites of maximum pain. Rotator cuff and glenohumeral arthritis Acromioclavicular joint disease Bicipital tendinitis 24.23 Typical local causes of elbow pain Lesion Pain Examination findings Lateral humeral epicondylitis (e.g. traumatic ‘tennis elbow’ or SpA-related enthesitis) Lateral epicondyle Tenderness over epicondyle Radiation to extensor forearm Pain reproduced by resisted active wrist extension Medial humeral epicondylitis (e.g. traumatic ‘golfer’s elbow’ or SpA-related enthesitis) Medial epicondyle Tenderness over epicondyle Radiation to flexor forearm Pain reproduced by resisted active wrist flexion Olecranon bursitis (e.g. gout, rheumatoid arthritis or infective, as in tuberculosis) Olecranon Tender swelling (SpA = spondyloarthritis) 24.22 Clinical findings in shoulder pain Rotator cuff and subacromial lesions • Pain reproduced by resisted active movement: Abduction: supraspinatus External rotation: infraspinatus, teres minor Internal rotation: subscapularis Acromioclavicular joint • Pain on full abduction and adduction (at 90° of forward elevation) Bicipital (long head) tendinitis • Tenderness over bicipital groove • Pain reproduced by resisted active wrist supination or elbow flexion less good in older people. Adhesive capsulitis (frozen shoulder) presents with pain associated with marked restriction of elevation and external rotation. Adhesive capsulitis is commonly associated with diabetes mellitus and neck/radicular lesions. Treatment in the early stage is with analgesia, intra- and extracapsular glucocorticoid injection, and regular ‘pendulum’ exercises of the arm to mobilise. Complete recovery sometimes takes up to 2 years. For severe or persistent symptoms, joint distension and manipulation under anaesthesia are surgical options. Elbow pain The most common causes are repetitive trauma causing lateral epicondylitis (tennis elbow) and medial epicondylitis (golfer’s elbow) (Box 24.23). SpAs, including psoriatic disease, can present with the same symptoms (tendon insertion enthesitis). Management is by rest, analgesics and topical or systemic NSAIDs. Local glucocorticoid injections may be required in resistant cases. Olecranon bursitis can also follow local repetitive trauma but other causes include infections and gout. Hand and wrist pain Pain from hand or wrist joints is well localised to the affected joint, except for pain from the first carpometacarpal (CMC) joint, commonly targeted by OA or PsA; although maximal at the thumb base, the pain often radiates down the thumb and to the radial aspect of the wrist. Non-articular causes of hand pain include:

Presenting problems in musculoskeletal disease • 999

a manifestation of enthesitis. Pain affecting the back of the heel may be due to Achilles tendinitis or enthesitis. The MTP joints of the feet are commonly involved symmetrically in RA. The presentation is with pain on walking felt below the metatarsal heads, often described as ‘walking on marbles’. Patients with active inflammation of the MTP joints have pain when the forefoot is squeezed (p. 982). Involvement of the first MTP joint is common in OA or PsA and is associated, respectively, with hallux valgus and dactylitis. The hallux also a classical target in acute gout. Morton’s neuroma is a neuropathy of an interdigital nerve and is usually located between the third and fourth metatarsal heads. Women are most commonly affected (tight shoes can be to blame). Local sensory loss and a palpable tender swelling between the metatarsal heads may be detected. Footwear adjustment, with or without a local glucocorticoid injection, often helps but surgical decompression may be required if symptoms persist. from overuse and/or an SpA condition. Anterior knee pain is relatively common in adolescents and may be the result of patellar articular cartilage or ligament insertion osteochondritis. Ankle and foot pain Pain from the ankle (tibiotalar) joint due to OA or osteochondral defect is felt between the malleoli and is worse on weight-bearing. Pain from the subtalar joint (from the same lesions) is also worse on weight-bearing. Inflammatory arthritis of either of these joints (RA, PsA, CPPD arthritis or gout) often worsens and swells with rest. These diagnoses can be associated with hindfoot tenosynovitis (peroneal or posterior tibial). Pain under the heel is typically due to plantar fasciitis. This can occur as the result of overuse, which case it may respond to rest, padded footwear and local glucocorticoid injections, but can also arise in SpA as Fig. 24.13 Pain patterns of hip disease and trochanteric pain syndrome. The dark shading indicates sites of maximum pain. Trochanteric bursitis Hip disease 24.24 Local causes of hip pain Lesion Pain Examination findings Gluteus medius enthesitis Upper lateral thigh, worse on lying on that side at night Tenderness over greater trochanter Trochanteric bursitis As above As above Adductor tendinitis (usually an SpA-enthesitis or sports-related trauma lesion) Upper inner thigh Tenderness over adductor origin/tendon/muscle Pain reproduced by resisted active hip adduction Ischiogluteal enthesitis/bursitis Buttock, worse on sitting Tenderness over ischial prominence Pubic symphysitis (can mimic intra-articular hip lesions) Medial groin pain, can radiate to inner or even outer upper thighs Tenderness over symphysis joint If pain is worse on trunk curl/rectus activation under symphysisresting hand, it may be insertional rectus enthesitis (SpAs) (SpA = spondyloarthritis) 24.25 Local causes of knee pain Lesion Pain Examination findings Pre-patellar bursitis Over patella Tender fluctuant swelling in front of patella Superficial and deep infrapatellar bursitis and fat-pad syndrome Anterior knee, inferior to patella Tenderness in front of (superficial) or behind (deep) patellar tendon Pain on full flexion Anserine bursitis/ enthesitis Upper medial tibia Tenderness (± swelling) over upper medial tibia Medial collateral ligament lesions (e.g. enthesitis) Upper medial tibia Localised tenderness of upper medial tibia Pain reproduced by valgus stress on partly flexed knee Popliteal cyst (Baker’s cyst) Popliteal fossa Tender swelling of popliteal fossa Patellar ligament enthesopathy Anterior upper tibia Tenderness over tibial tubercle Osteochondritis of patellar ligament (Osgood–Schlatter disease) Anterior upper tibia Adolescents are affected Pain on resisted active knee extension

1000 • RHEUMATOLOGY AND BONE DISEASE serum and urine protein electrophoresis, serum ACE, ANAs/ ENAs, RF, complement and myositis-specific autoantibodies such as Jo-1. Open muscle biopsy (site guided by MRI detection of abnormal muscle) and electromyography (EMG) are usually required to make the diagnosis. The initial imaging screening for malignancy is usually a CT scan of the chest, abdomen and pelvis; upper gastrointestinal endoscopy and colonoscopy may also be considered. Management Management is determined by the cause but all patients with muscle disease should benefit from physiotherapy and graded exercises to maximise muscle function after the initial inflammation is controlled. Principles of management The management of rheumatological disorders should be tailored to the underlying diagnosis. Certain aspects are common to many disorders, however, and the general principles are discussed here. The therapeutic aims are: • to educate patients about their disease • to control pain, if it is present • to optimise function • to modify the disease process where this is possible • to identify and treat comorbidity. These aims are interrelated and success in one area often benefits others. Successful management requires careful assessment of the person as a whole. The management plan should be individualised and patient-centred, should involve relevant members of the multidisciplinary team, and should be agreed and understood by both the patient and all the practitioners that are involved. It must also take into account: • the patient’s activity requirements and occupational and recreational aspirations • risk factors that may influence the disease • the patient’s perceptions and knowledge of the condition • medications and coping strategies that have already been tried • comorbid disease and its therapy • the availability, costs and logistics of appropriate evidencebased interventions. The simplest and safest interventions should be tried first. Symptoms and signs may change with time, so the management plan for most patients will require regular review and re-adjustment. Core interventions that should be considered for everyone with a painful musculoskeletal condition are listed in Box 24.27. There are also other non-pharmacological and drug options, the choice of which depends on the nature and severity of the diagnosis. Education and lifestyle interventions Education Patients must always be informed about the nature of their condition and its investigation, treatment and prognosis, since education can improve outcome. Information and therapist contact can reduce pain and disability, improve self-efficacy and reduce the health-care costs of many musculoskeletal conditions, including OA and RA. The mechanisms are unclear but in part may result from improved adherence. Benefits are modest but potentially long-lasting, safe and cost-effective. Education can be provided through one-to-one discussion, written literature, Muscle pain and weakness Muscle pain and weakness can arise from a variety of causes. It is important to distinguish between a subjective feeling of generalised weakness occurring with fatigue, and an objective weakness with loss of muscle power and function. The former is a non-specific manifestation of many systemic conditions. Clinical assessment Proximal muscle weakness suggests the presence of a myopathy or myositis, which typically causes difficulty with standing from a seated position, walking up steps, squatting and lifting overhead. The causes are shown in Box 24.26. Worsening of symptoms on exercise and post-exertional cramps suggest a metabolic myopathy, such as glycogen storage disease (p. 370). A strong family history and onset in childhood or early adulthood suggest muscular dystrophy (p. 1143). Alcohol excess can cause an inflammatory myositis and atrophy of type 2 muscle fibres. Proximal myopathy may be a complication of glucocorticoid therapy, prolonged/severe hypercalcaemia and osteomalacia. Myopathy and myositis can also occur in association with many drugs (see ‘Further information’, p. 1060) and viral infections, including HIV; in the latter case, it may be due to HIV itself or to treatment with zidovudine. Polymyositis and dermatomyositis (p. 1039) are associated with coexisting/ co-presenting malignancy, especially gonadal tumours. Clinical examination should document the presence, pattern and severity of muscle weakness (p. 1081), assessed using the Medical Research Council (MRC) scale (no power (0) to full power (5)). Investigations Investigations should include routine biochemistry and haematology, ESR, CRP, creatine kinase, serum 25(OH)-vitamin D, PTH, parvovirus, hepatitis B/C, HIV and streptococcus serology, 24.26 Causes of proximal muscle pain or weakness Inflammatory • Polymyositis • Dermatomyositis • Other autoimmune connective tissue disease • Inclusion body myositis • Sarcoid • Myasthenia gravis Endocrine (Ch. 18) • Hypothyroidism • Hyperthyroidism • Cushing’s syndrome • Addison’s disease Metabolic (Ch. 14) • Myophosphorylase deficiency • Phosphofructokinase deficiency • Hypokalaemia • Carnitine deficiency • Osteomalacia (p. 1049) • Hypercalcaemia Genetic • Muscular dystrophy (various; p. 1143) Drugs/toxins • Alcohol • Cocaine • Glucocorticoids • Statins and fibrates • Tumour necrosis factor inhibitors • Zidovudine Infections (Ch. 11) • Viral (HIV, cytomegalovirus, rubella, Epstein–Barr, echo) • Parasitic (schistosomiasis, cysticercosis, toxoplasmosis) • Bacterial (Clostridium perfringens, staphylococci, tuberculosis, Mycoplasma)

Principles of management • 1001

Hydrotherapy induces muscle relaxation and facilitates enhanced movement in a warm, pain-relieving environment without the restraints of gravity and normal load-bearing. Various manipulative techniques may also help improve restricted movement. The combination of these with education and therapist contact enhances their benefits. Splints can give temporary rest and support for painful joints and periarticular tissues, and can prevent harmful involuntary postures during sleep. Prolonged rest must be avoided, however. Orthoses are more permanent appliances used to reduce instability and excessive abnormal movement. They include working wrist splints, knee orthoses, and iron and T-straps to control ankle instability. Orthoses are particularly suited to severely disabled patients in whom a surgical option is inappropriate and often need to be custom-made for the individual. Aids and appliances can provide dignity and independence for patients with respect to activities of daily living. Common examples are a raised toilet seat, raised chair height, extended handles on taps, a shower instead of a bath, thick-handled cutlery, and extended ‘hands’ to pull on tights and socks. Full assessment and advice from an occupational therapist maximise the benefits of these (Box 24.27). Self-help and coping strategies These help patients to cope better with, and adjust to, chronic pain and disability. They may be useful at any stage but are particularly so for patients with incurable problems, who have tried all available treatment options. The aim is to increase self-management through self-assessment and problem-solving, so that patients can recognise negative but potentially remediable aspects of their mood (stress, frustration, anger or low self-esteem) and their situation (physical, social, financial). These may then be addressed by changes in attitude and behaviour, as shown in Box 24.28. Involvement of the spouse or partner in mutual goal-setting can improve partnership adjustment. Such approaches are often an element of group education classes and pain clinics but may require more formal clinical psychological input. Tailored multidisciplinary approaches are required for patients with JIA and other chronic childhood diseases, dependent on age and maturity. Adolescents and young adults have specific demands, different to those of young children and adults, which are influenced by many issues in their lives impinging on the disease process, its impact and their ability to cope with it. Weight control Obesity aggravates pain at most sites through increased mechanical strain and is a risk factor for progression of joint damage in patients with OA and other types of arthritis. This should be explained to obese patients and strategies offered patient-led group education classes and interactive computer programs. Inclusion of the patient’s partner or carer is often appropriate; this is essential for childhood conditions but also helps in many chronic adult conditions, such as RA and FM. For children and adolescents with chronic diseases such as JIA, education and support of the whole family, schooling and psychological support is essential and best delivered through a multidisciplinary team. Exercise Several types of exercise can be prescribed: • Aerobic fitness training can produce long-term reduction in pain and disability. It improves well-being, encourages restorative sleep and benefits common comorbidity, such as obesity, diabetes, chronic heart failure and hypertension. • Local strengthening exercise for muscles that act over compromised joints also reduces pain and disability, with improvements in the reduced muscle strength, proprioception, coordination and balance that associate with chronic arthritis. ‘Small amounts often’ of strengthening exercise are better than protracted sessions performed infrequently. • Weight-bearing exercise is of value in osteoporosis, where it can result in modest increases in bone density and slow bone loss. Joint protection Excessive impact-loading and adverse repetitive use of a compromised joint or periarticular tissue can worsen symptoms in patients with arthritis. This can be mitigated by cessation of contact sports and by pacing of activities by dividing physical tasks into shorter segments with brief breaks in between. Other strategies include adaptations to machinery or tools at the workplace; the use of shock-absorbing footwear with thick soft soles, which can reduce impact-loading through feet, knees, hips and back; and the use of a walking stick on the contralateral side to a painful hip, knee or foot. Non-pharmacological interventions Physical and occupational therapy Local heat, ice packs, wax baths and other local external applications can induce muscle relaxation and provide temporary relief of symptoms in a range of rheumatic diseases. 24.27 Interventions for patients with rheumatic diseases Core interventions • Education • Aerobic conditioning • Muscle strengthening • Simple analgesics • Disease-modifying therapy • Reduction of adverse mechanical factors • Pacing of activities • Appropriate footwear • Weight reduction if obese Other options • Other analgesic drugs: Oral non-steroidal anti-inflammatory drugs Topical agents Opioid analgesics Amitriptyline Gabapentin/pregabalin • Local glucocorticoid injections • Physical treatments: Heat, cold, aids, appliances • Surgery • Coping strategies (see Box 24.28) 24.28 Self-help and coping strategies • Yoga and relaxation techniques to reduce stress • Avoidance of negative situations or activities that produce stress and increase in pleasant activities that give satisfaction • Information and discussion to alter beliefs about and perspectives on disease • Reduction or avoidance of catastrophising and maladaptive pain behaviour • Imagery and distraction techniques for pain • Expansion of social contact and better use of social services

1002 • RHEUMATOLOGY AND BONE DISEASE therapy and intra-articular injections have provided insufficient relief. The main approaches for damaged joints are osteotomy (cutting bone to alter joint mechanics and load transmission), excision arthroplasty (removing part or all of the joint), joint replacement (insertion of prosthesis in place of the excised joint) and arthrodesis (joint fusion). Surgical fixation of fractures is frequently required in patients with osteoporosis and other bone diseases. The main aims of surgery are to provide pain relief and improve function and quality of life. If surgery is to be successful, the aims and consequences of each operation should be considered as part of an integrated programme of management and rehabilitation by multidisciplinary teams of surgeons, allied health professionals and physicians, and carefully explained to the patient. Assessment of motivation, social support and environment is no less important than careful consideration of patients’ general health, their risks for major surgery, the extent of disease in other joints, and their ability to mobilise following surgery. For some severely compromised people, pain relief and functional independence are better served by provision of a suitable wheelchair, home adjustments and social services than by surgery that is technically successful but following which the patient cannot mobilise. Pharmacological treatment Analgesics Paracetamol (1 g up to 4 times daily) is the oral analgesic of first choice for mild to moderate pain. It is thought to work by inhibiting prostaglandin synthesis in the brain while having little effect on peripheral prostaglandin production. It is well tolerated and has few adverse effects and drug interactions. An increased risk of gastrointestinal events and cardiovascular disease has been reported with chronic usage in observational studies, but this may be due to channelling of patients at higher risk of these events for treatment with paracetamol rather than NSAID. Paracetamol can be combined with codeine (co-codamol) or dihydrocodeine (co-dydramol). These compound analgesics are more effective than paracetamol but have more side-effects, including constipation, headache and delirium, especially in the elderly. The centrally acting opioid analgesics tramadol and meptazinol may be useful for temporary control of severe pain unresponsive to other measures but can cause nausea, bowel upset, dizziness and somnolence, and withdrawal symptoms after chronic use. The non-opioid analgesic nefopam (30–90 mg 3 times daily) can help moderate pain, though side-effects (nausea, anxiety, dry mouth) often limit its use. Patients with severe or intractable pain may require strong opioid analgesics, such as oxycodone and morphine. Non-steroidal anti-inflammatory drugs NSAIDs are among the most widely prescribed drugs but their use has declined over recent years because long-term prescription is associated with an increased risk of cardiovascular disease. Oral NSAIDs are useful in the treatment of a range of rheumatic diseases with an inflammatory component. There is variability in response and patients who do not gain benefit from one NSAID may well do so with another. They inhibit the cyclo-oxygenase (COX) and prostaglandin H synthase enzymes, which convert arachidonic acid, derived from membrane phospholipids, to prostaglandins and leukotrienes by the COX and 5-lipoxygenase pathways, respectively (Fig. 24.14). There are two COX isoforms, on how to lose and maintain an appropriate weight (p. 700). Excessive weight loss can be counterproductive and adults with a BMI of < 20 kg/m2 are at increased risk of fractures. Patients should therefore be advised to maintain BMI within the 20–25 g/m2 range. Surgery A variety of surgical interventions can relieve pain and conserve or restore function in patients with bone, joint and periarticular disease (Box 24.29). Soft tissue release and tenosynovectomy can reduce inflammatory symptoms, improve function and prevent or retard tendon damage for variable periods, sometimes indefinitely. Synovectomy does not prevent disease progression but may be indicated for pain relief when drugs, physical 24.29 Surgical procedures in rheumatology and bone disease Procedure Indication Soft tissue release Carpal tunnel Median nerve compression Tarsal tunnel Posterior tibial nerve entrapment Flexor tenosynovectomy Relief of ‘trigger’ fingers Ulnar nerve transposition Ulnar nerve entrapment at elbow Fasciotomy Severe Dupuytren’s contracture Tendon repairs and transfers Hand extensor tendons Extensor tendon rupture Thumb and finger flexor tendons Flexor tendon rupture Synovectomy Wrist and extensor tendon sheath (+ excision of radial head) Pain relief and prevention of extensor tendon rupture in RA, resistant inflammatory synovitis Knee synovectomy Resistant inflammatory synovitis Osteotomy Femoral osteotomy Early OA of hip Tibial osteotomy Unicompartmental knee OA Deformed tibia in OA or Paget’s disease Excision arthroplasty First metatarsophalangeal joint (Keller’s procedure) Painful hallux valgus Radial head Painful distal radio-ulnar joint Lateral end of clavicle Painful acromioclavicular joint Metatarsal head Painful subluxed metatarsophalangeal joints Joint replacement arthroplasty Knee, hip, shoulder, elbow Painful damaged joints in OA and RA Arthrodesis Wrist Damaged joint: pain relief, improvement of grip Ankle/subtalar joints Damaged joint: pain relief, stabilisation of hindfoot Fracture repair Hip arthroplasty Fractured neck of femur External fixation Multiple fractures, open fractures Intramedullary nailing Tibial and femur fractures Screw, plating and wiring Wrist and other fractures Other procedures Nerve root decompression Spinal stenosis, nerve entrapment Kyphoplasty Painful vertebral fracture (evidence base poor) Vertebroplasty Painful vertebral fracture (evidence base poor)

Principles of management • 1003

non-ulcer-associated dyspepsia, abdominal pain and altered bowel habit, and rashes. Interstitial nephritis, asthma and anaphylaxis can also occur but are rare. Recommendations for NSAID prescribing are summarised in Box 24.32. Because of the risk of adverse effects, NSAIDs should be used with great care in the elderly (Box 24.33). Topical agents Topical NSAID creams and gels and capsaicin cream (chilli extract; 0.025%) can help in the treatment of OA and superficial periarticular lesions affecting hands, elbows and knees. They may be used as monotherapy or as an adjunct to oral analgesics. Topical NSAIDs can penetrate superficial tissues and even encoded by different genes. The COX-1 enzyme is constitutively expressed in gastric mucosa, platelets and kidneys, and production of prostaglandins at these sites protects against mucosal damage and regulates platelet aggregation and renal blood flow. The COX-2 enzyme is induced at sites of inflammation, producing prostaglandins that cause local pain and swelling. Inflammation also up-regulates COX-2 in the spinal cord, where it modulates pain perception. Ibuprofen, diclofenac and naproxen are non-selective drugs that inhibit both COX enzymes, whereas celecoxib and etoricoxib are selective inhibitors of COX-2. While NSAIDs have anti-inflammatory activity, they are not thought to have a disease-modifying effect in either OA or inflammatory rheumatic diseases. Non-selective NSAIDs can damage the gastric and duodenal mucosal barrier and are associated with an increased risk of upper gastrointestinal ulceration, bleeding and perforation. The adjusted increased risk (odds ratio) of bleeding or perforation from non-selective NSAIDs is 4–5, though differences exist between NSAIDs (Box 24.30). Dyspepsia is a poor guide to the presence of NSAID-associated ulceration and bleeding, and the principal risk factors are shown in Box 24.31. Co-prescription of a proton pump inhibitor (PPI) or misoprostol (200 μg twice or 3 times daily) reduces the risk of NSAID-induced ulceration and bleeding but H2-antagonists in standard doses are ineffective. The COX-2 selective NSAIDs are much less likely to cause gastrointestinal toxicity but benefit is attenuated in patients on low-dose aspirin. The National Institute for Health and Care Excellence (NICE) guidelines advise that a PPI should be co-prescribed with all NSAIDs, including COX-2-selective NSAIDs, even though the risk of gastrointestinal events with these is low. Since chronic PPI therapy is associated with an increased risk of hip fracture, the merits of giving PPI therapy with a COX-2-selective drug need to be weighed up carefully. Other side-effects of NSAIDs include fluid retention and renal impairment due to inhibition of renal prostaglandin production, Fig. 24.14 Mechanism of action of non-steroidal anti-inflammatory drugs. Membrane phospholipid Arachidonic acid Phospholipase A2 COX-2 (induced by cytokines) Prostaglandins Non-selective NSAID COX-1 (constitutive expression) Prostaglandins Pain Inflammation Mucosal integrity Platelet aggregation Renal blood flow COX-2 selective NSAID The most important risk factors. 24.31 Risk factors for NSAID-induced ulcers • Age > 60 years • Past history of peptic ulcer* • Past history of adverse event with NSAID • Concomitant glucocorticoid use • High-dose or multiple NSAIDs • High-risk NSAID (see Box 24.30) 24.32 Recommendations for the use of NSAIDs • Use the lowest dose for the shortest time possible to control symptoms • Avoid NSAIDs in patients on warfarin • Allow 2–3 weeks to assess efficacy. If response is inadequate, consider a trial of another NSAID • Never prescribe more than one NSAID at a time • Co-prescribe a proton pump inhibitor for patients with risk factors for gastrointestinal adverse effects (see Box 24.31) • Avoid in patients with vascular disease Drug Daily adult dose Doses/ day Idiosyncratic side-effects, comments Low risk Celecoxib 100–200 mg 1–2 Selective COX-2 inhibitor Etoricoxib 60–120 mg

Selective COX-2 inhibitor Medium risk Ibuprofen 1600–2400 mg Gastrointestinal adverse effects more likely than with COX-2 inhibitors, even with PPI therapy Naproxen 500–1000 mg Diclofenac 75–150 mg 3–4 1–2 2–3 High risk Indometacin 50–200 mg 3–4 High incidence of dyspepsia and CNS side-effects Ketoprofen 100–200 mg 2–4 Piroxicam 20–30 mg 1–2 Restricted use in those

60 years } } 24.30 Commonly used NSAIDs and their risk of gastrointestinal bleeding and perforation (CNS = central nervous system; COX = cyclo-oxygenase; PPI = proton pump inhibitor)

1004 • RHEUMATOLOGY AND BONE DISEASE Methotrexate Methotrexate (MTX) is the core DMARD in RA, JIA and PsA. It inhibits folic acid reductase, preventing formation of tetrahydrofolate, which is necessary for DNA synthesis in leucocytes and other cells. It is given orally in a starting dose of 10–15 mg weekly and escalated in 2.5 mg increments every 2–4 weeks to a maximum of 25 mg weekly until benefit or toxicity occurs. Folic acid (5 mg/week) should be co-prescribed to be taken the day after MTX since it reduces adverse effects without impairing efficacy. Benefit is usually observed after 4–8 weeks but treatment should continue for 3 weeks before the conclusion is reached that MTX has been ineffective. The most common adverse effects are nausea, vomiting and malaise, which usually occur one 1–2 days after the weekly dose. Individuals who experience these effects can sometimes be successfully treated with subcutaneous MTX. Patients should be warned of drug interaction with sulphonamides and the importance of avoiding excess alcohol, which enhances MTX hepatotoxicity. Acute pulmonary toxicity (pneumonitis) is rare but can occur at any time during treatment, and patients should be warned to stop therapy and seek advice if they develop any new respiratory symptoms. If pneumonitis occurs, treatment should be withdrawn and high-dose glucocorticoids given. MTX must be co-prescribed with robust contraception in women of child-bearing potential and treatment must be stopped for 3 months in advance of planning a pregnancy. Sulfasalazine Sulfasalazine (SSZ) can be used alone and or combination with MTX and another DMARD. Its mechanism of action is incompletely understood. Nausea and gastrointestinal intolerance are the main adverse effects but leucopenia, abnormal LFTs and rashes may also occur. The usual starting dose is 500 mg daily, escalating in 500 mg increments every 2 weeks to a maintenance dose of 2–4 g daily until benefit or toxicity occurs. Benefit may be reach the joint capsule, though intrasynovial levels mainly reflect blood-borne drug delivery. Capsaicin selectively binds to the protein transient receptor potential vanilloid type 1 (TRPV1), which is a heat-activated calcium channel on the surface of peripheral type C nociceptor fibres. Initial application causes a burning sensation but continued use depletes presynaptic substance P, with subsequent pain reduction that is optimal after a period of 1–2 weeks. Disease-modifying antirheumatic drugs Disease-modifying antirheumatic drugs (DMARDs) are a group of small-molecule inhibitors of the immune response. They are employed in a range of inflammatory rheumatic diseases, as well as in other chronic inflammatory conditions. The most common indications are summarised in Box 24.34. Most of these drugs have the potential to cause bone marrow suppression or liver dysfunction and they require regular blood monitoring. Monitoring requirements for commonly used DMARDs are also summarised in Box 24.34. If toxicity occurs, treatment may need to be stopped temporarily and resumed at a lower dose. If toxicity is severe, therapy may have to be withdrawn completely and another drug substituted. 24.33 Use of oral NSAIDs in old age • Gastrointestinal complications: age is a strong risk factor for bleeding and perforation, and for peptic ulceration. Elderly patients are more likely to die if they suffer NSAID-associated bleeding or perforation. • Cardiovascular disease: use NSAIDs with caution in patients with cardiovascular disease. Therapy with NSAIDs may exacerbate hypertension and heart failure. • Renal disease: use of NSAIDs may cause renal impairment. 24.34 Disease-modifying antirheumatic drugs Drug Maintenance dose Monitoring* Indications FBC LFTs Other Methotrexate 10–25 mg weekly orally ᅚ ᅚ RA, PsA, AxSpA, JIA Sulfasalazine 2–4 g daily orally ᅚ ᅚ RA, PsA, AxSpA, JIA Hydroxychloroquine 200–400 mg daily orally – – Visual function RA, SLE Leflunomide 10–20 mg daily orally ᅚ ᅚ BP RA, JIA, PsA Azathioprine 1–2.5 mg/kg daily orally ᅚ ᅚ SLE, SV Apremilast 30 mg twice daily orally – – – PsA Tofacitinib 5 mg twice daily orally ᅚ ᅚ Infection RA Baricitinib 2–4 mg daily orally ᅚ ᅚ Infection RA Cyclophosphamide 2 mg/kg daily orally 15 mg/kg IV ᅚ ᅚ eGFR SLE, SV Mycophenolate mofetil (MMF) 2–4 g daily orally ᅚ ᅚ – SLE, SV Gold (myocrisin) 50 mg 4-weekly IM ᅚ – Urinalysis RA Penicillamine 500–1500 mg daily orally ᅚ ᅚ Urinalysis RA Ciclosporin A 3–5 mg/kg daily orally – – BP, eGFR RA, PsA *Monitoring tests are usually done every 2 weeks on initiation of treatment for 6 weeks, then monthly for 3 months, then 3-monthly. (AxSpA = axial spondyloarthritis; BP = blood pressure; eGFR = estimated glomerular filtration rate; FBC = full blood count; IM = intramuscular; IV = intravenous; JIA = juvenile idiopathic arthritis; LFTs = liver function tests; PsA = psoriatic arthritis; RA = rheumatoid arthritis; SLE = systemic lupus erythematosus; SV = systemic vasculitis)

Principles of management • 1005

vasculitis and SLE. It can be given orally in a dose of 2 mg/kg/ day for 3–6 months or intravenously in a dose of 15 mg/kg every 3–4 weeks on 6–8 occasions. Adverse effects include nausea, anorexia, vomiting, bone marrow suppression, cardiac toxicity, alopecia and haemorrhagic cystitis. The risk of cystitis can be mitigated by co-administration of mesna (2-mercaptoethane sulfonate, which binds its urotoxic metabolites) and a high fluid intake. Mycophenolate mofetil Mycophenolate mofetil (MMF) works by inhibiting inosine monophosphate dehydrogenase, a rate-limiting enzyme in the synthesis of guanosine nucleotides in lymphocytes. MMF is frequently used in SLE and vasculitis in doses of 2–4 g daily orally. Haematological toxicity is the main adverse effect. Other DMARDs Gold, penicillamine and ciclosporin A have been superseded by more effective alternatives but are still occasionally used. Gold (sodium aurothiomalate, myocrisin) is indicated for RA. Its mechanism of action is unknown. It is given by intramuscular injection of 50 mg weekly after an initial test dose of 10 mg. Treatment is continued for up to 6 months until there is clinical benefit or adverse effects occur. If there is benefit, the frequency of injections is reduced to two-weekly and then monthly, providing that the response is maintained. Penicillamine is indicated for RA but is poorly tolerated. It is given in a starting dose of 125–250 mg daily on an empty stomach, and increased in 125 mg increments every 6 weeks to a maximum dose of 1500 mg daily until there is clinical benefit or adverse effects occur. Ciclosporin A is a calcineurin inhibitor that inhibits lymphocyte activation. It is occasionally used in RA at a dose of 2.5–4 mg/kg/day orally. Glucocorticoids Glucocorticoids have powerful anti-inflammatory and immunosuppressive effects. They promote apoptosis of many immune cells and activation of a wide range of pro-inflammatory signalling pathways. They are used orally, intravenously, intramuscularly and by intra-articular injection in the treatment of a wide range of inflammatory rheumatic diseases, as well as by local injection in patients with soft tissue rheumatism (p. 1026). Systemic glucocorticoids Systemic glucocorticoids are widely used in moderate to high doses to induce remission in early RA and in systemic and polyarticular JIA. They are also used at lower doses for maintenance therapy and in the treatment of flares in RA, PsA and axSpA with peripheral joint involvement. Glucocorticoids should be used with caution in PsA because of a rebound increase in activity of psoriasis when the effects wear off. Glucocorticoids are also used to induce remission and to maintain disease control in giant cell arteritis, polymyalgia rheumatica, vasculitis and SLE. Intra-articular and intramuscular glucocorticoids Intra-articular glucocorticoids are employed in the treatment of a wide range of inflammatory arthritides and are primarily indicated when there are one or two problem joints with persistent synovitis despite good general control of the disease. Methylprednisolone is one of the most widely used, typically in doses of 40–80 mg. Intramuscular methylprednisolone (80–120 mg) is a useful way of controlling inflammatory arthritis while waiting for the effects of a newly introduced DMARD to take effect, and is also helpful observed after 4–8 weeks but treatment should be continued for 3 months before the conclusion is reached that it has been ineffective. Orange staining of urine and contact lenses may occur. Hydroxychloroquine Hydroxychloroquine (HCQ) is used in the treatment of RA and SLE in a dose of 200–400 mg daily. Its mechanism of action is incompletely understood. A wide range of side-effects can potentially occur but HCQ is usually well tolerated in practice. With long-term use, there is a risk of ocular toxicity due to accumulation in the retina, although this is uncommon. It is usual to check visual function before starting treatment and to repeat this periodically while treatment is continued. HCQ is generally considered to be safe during pregnancy Leflunomide Leflunomide can be used alone or in combination with other drugs in a dose of 10–20 mg/day. It works by inhibiting dihydro-orotate dehydrogenase, an enzyme used by activated lymphocytes to synthesise pyrimidines necessary for DNA synthesis. It has low marrow toxicity but may cause liver dysfunction, hypertension and hirsutism. It must be co-prescribed with robust contraception in women of child-bearing potential. Treatment must be stopped for a period of 2 years in advance of planning a pregnancy. Azathioprine Azathioprine is most commonly used in vasculitis and SLE. It is metabolised to 6-mercaptopurine (6-MP), which blocks lymphocyte proliferation by inhibiting DNA synthesis. The typical starting dose is 1 mg/kg body weight per day, increasing to 2.5 mg/kg until a response is observed or toxicity occurs. Bone marrow suppression is the most important side-effect but nausea may also occur. Genetic polymorphisms in the enzyme thiopurine S-methyltransferase (TPMT) influence catabolism of 6-MP and sometimes genetic testing for TPMT variants is done to guide dosages. Allopurinol inhibits catabolism of azathioprine, necessitating a 75% reduction in azathioprine dose. Apremilast Apremilast is used in the treatment of PsA. It works by inhibiting phosphodiesterase D4 in leucocytes, which in turn suppresses production of pro-inflammatory cytokines, thereby reducing inflammation. Apremilast is given orally in a dose of 30 mg twice daily. The main adverse effects are gastrointestinal upset, weight loss and an increased risk of depression. Janus-activated kinase inhibitors Janus-activated kinase (JAK) inhibitors work by inhibiting JAK enzymes, which are a family of intracellular signalling molecules that play a key role in transducing the effects of several proinflammatory cytokines. They are indicated for patients with RA who have responded inadequately to standard DMARDs and provide an alternative to biologic treatments. Two JAK inhibitors are currently available: tofacitinib, which is given orally in a dose of 5 mg twice daily, and baricitinib, which is given orally in a dose of 2–4 mg once daily. The main adverse effects are an increased risk of opportunistic infections, hepatotoxicity and haematological toxicity. Cyclophosphamide Cyclophosphamide is a cytotoxic alkylating agent that cross-links DNA and halts cell division, causing immunosuppression. It is mainly used to induce remission in life-threatening systemic

1006 • RHEUMATOLOGY AND BONE DISEASE in AxSpA unless there is peripheral joint involvement. Anti-TNF therapy is contraindicated in patients with active infections such as untreated tuberculosis and those with indwelling catheters, due to the high risk of infection. Other contraindications are severe heart failure and multiple sclerosis, both of which may be worsened by treatment. Rituximab Rituximab is an antibody directed against the CD20 receptor, which is expressed on B lymphocytes and immature plasma cells. It causes profound B-cell lymphopenia for several months due to complement-mediated lysis of cells that express CD20. Rituximab is indicated in patients with RA who have not responded adequately to first-line therapy but is typically employed as a third-line treatment when TNF inhibitors have been ineffective. It is also used in place of cyclophosphamide to induce remission in patients with ANCA-positive vasculitis. In RA, the treatment can be repeated when signs of improvement are wearing off (anything from 6 months to 1 year or longer). In ANCA-positive vasculitis, a single cycle of treatment may last for up to 18 months. Rituximab is sometimes used off-label in SLE, even though clinical trials did not show efficacy. Adverse effects include hypogammaglobulinaemia, infusion reactions, an increased risk of infections and, rarely, progressive multifocal leucoencephalopathy (PML; p. 1123), a serious and potentially fatal infection of the CNS caused by reactivation of JC virus. Belimumab Belimumab is indicated in SLE. It is a monoclonal antibody that blocks the effects of the cytokine B-cell-activating factor of the TNF family (BAFF), which is required for B-cell survival and function. It is usually given when patients have had an inadequate response to glucocorticoids and hydroxychloroquine. The main in patients with stable disease who have a disease flare where a major change in DMARD strategy is not thought to be necessary. Biologics The term ‘biologic’ refers to a group of medications that includes monoclonal antibodies, fusion proteins and decoy receptors, which are used in the treatment of several inflammatory rheumatic diseases. They are targeted towards specific cytokines, receptors and other cell-surface molecules regulating the immune response (Fig. 24.15). The main adverse effect of the biologics used in inflammatory diseases is an increased risk of infections. Biologics are not carcinogenic, but patients who develop cancer while on treatment may exhibit accelerated progression of the tumour due to suppression of the immune response. Treatment costs are much higher than with DMARDs and many countries have set guidelines restricting their use to patients who have active disease despite having had an adequate trial of standard therapies. Their mechanisms of action, dosages and indications are summarised in Box 24.35. Anti-TNF therapy A variety of inhibitors of the pro-inflammatory cytokine TNF have been developed. Most are monoclonal antibodies that bind to and neutralise TNF, but etanercept is a decoy receptor that prevents TNF binding to its receptor. Anti-TNF therapy has traditionally been used as the first-line biological drug in RA when DMARD therapy has been incompletely effective. It has also traditionally been used as the first-line biologic in PsA and AxSpA, but anti IL-17A therapy (see below) has emerged as an equally effective alternative. Anti-TNF therapy is usually co-prescribed with MTX in RA and PsA as this increases efficacy, but TNF inhibitors are also effective as monotherapy. They are usually given as monotherapy Fig. 24.15 Targets for biologic therapies in inflammatory rheumatic diseases. Biologic treatments for inflammatory rheumatic diseases work by targeting key cytokines and other molecules involved in regulating the immune response. See page 64 for more details. (BAFF = B-cell-activating factor of the TNF family; CD = cluster of differentiation; IL = interleukin; TNF-α = tumour necrosis factor alpha; TNFi = inhibitor of tumour necrosis factor) T cell B cell Autoantibodies Plasma cell TNF-α IL-6 IL-1 Synovial fibroblast Dendritic cell CD80 IL-12 IL-23 IL-17 CD28 CD20 Activation Proliferation Proliferation BAFF Belimumab Rituximab Tocilizumab Anakinra Canakinumab TNFi Secukinumab Abatacept Ustekinumab Th17 cell Macrophage

Osteoarthritis • 1007

} Drug Maintenance dose Mechanism of action Indications Etanercept 50 mg weekly SC Decoy receptor for TNF-α RA, PsA, AxSpA, JIA Infliximab 3–5 mg/kg 8-weekly IV Antibody to TNF-α RA, PsA, AxSpA, JIA Adalimumab 40 mg 2-weekly SC Certolizumab 200 mg 2-weekly SC Golimumab 50 mg 4-weekly SC Rituximab 2 × 1 g 2 weeks apart IV Antibody to CD20; destroys B cells RA, vasculitis Belimumab 10 mg/kg 4-weekly IV Antibody to BAFF; inhibits B-cell activation SLE Abatacept 125 mg weekly SC or 10 mg/kg 4-weekly IV Inhibits T-cell activation RA Tocilizumab 162 mg weekly SC or 8 mg/kg 8-weekly IV Blocks IL-6 receptor RA, JIA Ustekinumab 45 mg 12-weekly SC Antibody to IL-12 and IL-23 PsA Secukinumab 150 mg 4-weekly SC Antibody to IL-17A PsA, AxSpA Anakinra 100 mg daily SC Decoy receptor for IL-1 RA, CAPS, AOSD Canakinumab 150 mg or 2 mg/kg 8-weekly SC Antibody to IL-1β CAPS, sJIA, AOSD, gout 24.35 Biological drugs for inflammatory rheumatic disease (AOSD = adult-onset Still’s disease; AxSpA = axial spondyloarthritis; BAFF = B-cell-activating factor of the TNF family; CAPS = cryopyrin-associated periodic syndromes; CD = cluster of differentiation; IL = interleukin; IV = intravenous; JIA = juvenile idiopathic arthritis; PsA = psoriatic arthritis; RA = rheumatoid arthritis; SC = subcutaneous; sJIA = systemic juvenile inflammatory arthritis; SLE = systemic lupus erythematosus; TNF-α = tumour necrosis factor alpha) An exception is when patients are MTX-intolerant, in which case it is often used as a first-line therapy, based on a randomised trial in which it showed greater efficacy than the TNF inhibitor adalimumab. Adverse effects include leucopenia, abnormal LFTs, hypercholesterolaemia, hypersensitivity reactions and an increase risk of diverticulitis. Ustekinumab Ustekinumab is an antibody to the p40 protein, which is a subunit of IL-23 and IL-12. It is indicated in patients with PsA who have not responded adequately to first-line therapy with other biologics. Adverse effects include an increased risk of infections, hypersensitivity reactions and an exfoliative dermatitis. Secukinumab Secukinumab is a monoclonal antibody to IL-17A. It is indicated in patients with PsA and axSpA, including ankylosing spondylitis, and who have not responded adequately to first-line therapy. Adverse effects include an increased risk of infections, nasopharyngitis and headache. Anakinra Anakinra is a decoy receptor for IL-1. It is occasionally used in RA but is less effective than other biological drugs. A more frequent indication is for the treatment of adult-onset Still’s disease (p. 1040) and in cryopirin-associated periodic syndromes (p. 81). Adverse effects include an increased risk of infections, hypersensitivity reactions and neutropenia. Canakinumab Canakinumab is indicated for the treatment of systemic JIA (Still’s disease), adult-onset Still’s disease, familial fever syndromes and acute flares of gout resistant to other treatments. It is a monoclonal antibody directed against the pro-inflammatory cytokine IL-1β. The usual maintenance dose in adults is 150–300 mg SC every 8 weeks. Adverse effects include an increased risk of infections, hypersensitivity reactions and neutropenia. Osteoarthritis Osteoarthritis (OA) is by far the most common form of arthritis and is a major cause of pain and disability in older people. It is characterised by focal loss of articular cartilage, subchondral osteosclerosis, osteophyte formation at the joint margin, and remodelling of joint contour with enlargement of affected joints. Epidemiology The prevalence rises progressively with age and it has been estimated that 45% of all people develop knee OA and 25% hip OA at some point during life. Although some are asymptomatic, the lifetime risk of having a total hip or knee replacement for OA in someone aged 50 is about 11% for women and 8% for men in the UK. There are major ethnic differences in susceptibility: the prevalence of hip OA is lower in Africa, China, Japan and the Indian subcontinent than in European countries, and that of knee OA is higher. Pathophysiology OA is a complex disorder with both genetic and environmental components (Box 24.36). Genetic factors are recognised as playing a key role in the pathogenesis of OA. Family-based studies have estimated that the heritability of OA ranges from about 43% at the knee to between 60% and 65% at the hip and adverse effects are an increased risk of infection, leucopenia and infusion reactions. Abatacept Abatacept is a fusion protein in which the Fc domain of IgG has been combined with the extracellular domain of CTLA4, which blocks T-cell activation by acting as a decoy for CD28, a co-stimulatory molecule necessary for T-cell activation (p. 69). It is indicated in patients with RA who have not responded adequately to first-line therapy but is typically employed as a third-line treatment when TNF inhibitors have been ineffective. The main adverse effect is an increased risk of infections. Tocilizumab Tocilizumab is a monoclonal antibody to the IL-6 receptor. It is indicated in patients with RA who have not responded adequately to first-line therapy or to TNF inhibitors. It is sometimes employed as a third-line treatment when TNF inhibitors have been ineffective.

1008 • RHEUMATOLOGY AND BONE DISEASE remodelling and cartilage thinning slowly alter the shape of the OA joint, increasing its surface area. It is almost as though there is a homeostatic mechanism operative in OA that causes enlargement of the failing joint to spread the mechanical load over a greater surface area. Patients with OA also have higher BMD values at sites distant from the joint and this is particularly associated with osteophyte formation. This is in keeping with observations made in epidemiological studies that show that patients with OA are partially protected from developing osteoporosis and vice versa. This is likely to be due to the fact that the genetic factors that predispose to osteoporosis might be protective for OA. The synovium in OA is often hyperplastic and may be the site of inflammatory change, but to a much lesser extent than in RA and other inflammatory arthropathies. Osteochondral bodies commonly occur within the synovium, reflecting chondroid metaplasia or secondary uptake and growth of damaged cartilage fragments. The outer capsule also thickens and contracts, usually retaining the stability of the remodelling joint. The muscles surrounding affected joints commonly show evidence of wasting and non-specific type II fibre atrophy. Clinical features OA has a characteristic distribution, mainly targeting the hips, knees, PIP and DIP joints of the hands, neck and lumbar spine (see Fig. 24.10). The main presenting symptoms are pain and functional restriction. The causes of pain in OA are not completely understood but may relate to increased pressure in subchondral bone (mainly causing night pain), trabecular microfractures, capsular distension and low-grade synovitis. Pain may also result from bursitis and enthesopathy secondary to altered joint mechanics. Typical OA pain has the characteristics listed in Box 24.37. For many people, functional restriction of the hands, knees or hips is an equal, if not greater, problem than pain. The clinical findings vary according to severity but are principally those of joint damage. hand, respectively. In most cases, the inheritance is polygenic and mediated by several genetic variants of small effect. OA can, however, be a component of multiple epiphyseal dysplasias, which are caused by mutations in the genes that encode components of cartilage matrix. Structural abnormalities, such as slipped femoral epiphysis and developmental dysplasia of the hip, are also associated with a high risk of OA, presumably due to abnormal load distribution across the joint. Similar mechanisms probably explain the increased risk of OA in patients with limb deformity secondary to Paget’s disease of bone. Biomechanical factors play an important role in OA related to certain occupations, such as farmers (hip OA), miners (knee OA) and elite or professional athletes (knee and ankle OA). It has been speculated that the higher prevalence of knee OA in the Indian subcontinent and East Asia might be accounted for by squatting. There is also a high risk of OA in people who have had destabilising injuries, such as cruciate ligament rupture, and those who have had meniscetomy. For most individuals, however, participation in recreational sport does not appear to increase the risk significantly. There is a strong association between obesity and OA, particularly of the hip. This is thought to be due partly to biomechanical factors but it has also been speculated that cytokines released from adipose tissue may play a role. Oestrogen appears to play a role; lower rates of OA have been observed in women who use hormone replacement therapy (HRT), and women who receive aromatase inhibitor therapy for breast cancer often experience a flare in symptoms of OA. Degeneration of articular cartilage is the defining feature of OA. Under normal circumstances, chondrocytes are terminally differentiated cells but in OA they start dividing to produce nests of metabolically active cells (Fig. 24.16A). Initially, matrix components are produced by these cells at an increased rate, but at the same time there is accelerated degradation of the major structural components of cartilage matrix, including aggrecan and type II collagen (see Fig. 24.5, p. 987). Eventually, the concentration of aggrecan in cartilage matrix falls and makes the cartilage vulnerable to load-bearing injury. Fissuring of the cartilage surface (‘fibrillation’) then occurs, leading to the development of deep vertical clefts (Fig. 24.16B), localised chondrocyte death and decreased cartilage thickness. This is initially focal, mainly targeting the maximum load-bearing part of the joint, but eventually large parts of the cartilage surface are damaged. Calcium pyrophosphate and basic calcium phosphate crystals often become deposited in the abnormal cartilage. OA is also accompanied by abnormalities in subchondral bone, which becomes sclerotic and the site of subchondral cysts (Fig. 24.16C). Fibrocartilage is produced at the joint margin, which undergoes endochondral ossification to form osteophytes. Bone 24.36 Risk factors for osteoarthritis Genetics • Skeletal dysplasias • Polygenic inheritance Developmental abnormalities • Developmental dysplasia of the hip • Slipped femoral epiphysis Repetitive loading • Farmers • Miners • Elite athletes Adverse biomechanics • Meniscectomy • Ligament rupture • Paget’s disease Obesity Trauma Hormonal • Oestrogen deficiency • Aromatase inhibitors Fig. 24.16 Pathological changes in osteoarthritis. A Abnormal nests of proliferating chondrocytes (arrows) interspersed with matrix devoid of normal chondrocytes. B Fibrillation of cartilage in OA. C X-ray of knee joint affected by OA, showing osteophytes at joint margin (white arrows), subchondral sclerosis (black arrows) and a subchondral cyst (open arrow). A C B

Osteoarthritis • 1009

impairment. Clinically, it may be detected by the presence of crepitus on joint movement, and squaring of the thumb base. Generalised nodal OA has a very strong genetic component: the daughter of an affected mother has a 1 in 3 chance of developing nodal OA herself. People with nodal OA are also at increased risk of OA at other sites, especially the knee. Knee OA At the knee, OA principally targets the patello-femoral and medial tibio-femoral compartments but eventually spreads to affect the whole of the joint (Fig. 24.19). It may be isolated or occur as part of generalised nodal OA. Most patients have bilateral and symmetrical involvement. In men, trauma is often a more important risk factor and may result in unilateral OA. The pain is usually localised to the anterior or medial aspect of the knee and upper tibia. Patello-femoral pain is usually worse going up and down stairs or inclines. Posterior knee pain suggests the presence of a complicating popliteal cyst (Baker’s cyst). Prolonged walking, rising from a chair, getting in or out of 24.38 Characteristics of generalised nodal osteoarthritis • Polyarticular finger interphalangeal joint osteoarthritis • Heberden’s (± Bouchard’s) nodes • Marked female preponderance • Peak onset in middle age • Good functional outcome for hands • Predisposition to osteoarthritis at other joints, especially knees • Strong genetic predisposition 24.37 Symptoms and signs of osteoarthritis Pain • Insidious onset over months or years • Variable or intermittent nature over time (‘good days, bad days’) • Mainly related to movement and weight-bearing, relieved by rest • Only brief (< 15 mins) morning stiffness and brief (< 5 mins) ‘gelling’ after rest • Usually only one or a few joints painful Clinical signs • Restricted movement due to capsular thickening or blocking by osteophyte • Palpable, sometimes audible, coarse crepitus due to rough articular surfaces • Bony swelling around joint margins • Deformity, usually without instability • Joint-line or periarticular tenderness • Muscle weakness and wasting • Mild or absent synovitis The correlation between the presence of structural change, as assessed by imaging, and symptoms such as pain and disability varies markedly according to site. It is stronger at the hip than at the knee, and poor at most small joints. This suggests that the risk factors for pain and disability may differ from those for structural change. At the knee, for example, reduced quadriceps muscle strength and adverse psychosocial factors (anxiety, depression) correlate more strongly with pain and disability than the degree of radiographic change. Radiological evidence of OA is very common in middle-aged and older people, and the disease may coexist with other conditions, so it is important to remember that pain in a patient with OA may be due to another cause. Generalised nodal OA Characteristics of this common form of OA are shown in Box 24.38. Some patients are asymptomatic whereas others develop pain, stiffness and swelling of one or more PIP and DIP joints of the hands from the age of about 40 years onwards. Gradually, these develop posterolateral swellings on each side of the extensor tendon, which slowly enlarge and harden to become Heberden’s (DIP) and Bouchard’s (PIP) nodes (Fig. 24.17). Typically, each joint goes through a phase of episodic symptoms (1–5 years) while the node evolves and OA develops. Once OA is fully established, symptoms may subside and hand function often remains good. Affected joints are enlarged as a result of osteophyte formation and often show characteristic lateral deviation, reflecting the asymmetric focal cartilage loss of OA (Fig. 24.18). Involvement of the first CMC joint is also common, leading to pain on trying to open bottles and jars, and functional Fig. 24.17 Nodal osteoarthritis. Heberden’s nodes and lateral (radial/ ulnar) deviation of distal interphalangeal joints, with mild Bouchard’s nodes at the proximal interphalangeal joints. Fig. 24.18 X-ray appearances in hand osteoarthritis. There is joint space narrowing affecting the proximal interphalangeal (PIP) and distal interphalangeal (DIP) joints in both hands. There are typical articular subchondral and ‘gullwing’ appearances to some osteoarthritis-affected joints, as well as osteophyte formation that is most marked at the second DIP joints bilaterally and the first PIP joint on the right hand (arrows).

1010 • RHEUMATOLOGY AND BONE DISEASE • restricted flexion and extension with coarse crepitus • bony swelling around the joint line. CPPD crystal deposition in association with OA is common at the knee. This may result in a more overt inflammatory component (stiffness, effusions) and super-added acute attacks of synovitis (‘pseudogout’; p. 1016), which may be associated with more rapid radiographic and clinical progression. Hip OA Hip OA most commonly targets the superior aspect of the joint (Fig. 24.21). It is often unilateral at presentation, frequently progresses with superolateral migration of the femoral head, and has a poor prognosis. The less common central (medial) OA shows more central cartilage loss and is largely confined to women. It is often bilateral at presentation and can be associated with generalised nodal OA. It has a better prognosis than superior hip OA and progression to axial migration of the femoral head is uncommon. The hip shows the best correlation between symptoms and radiographic change. Hip pain is usually maximal deep in the anterior groin, with variable radiation to the buttock, anterolateral thigh, knee or shin. Lateral hip pain, worse on lying on that side with tenderness over the greater trochanter, suggests secondary trochanteric bursitis. Common functional difficulties are the same as for knee OA; in addition, restricted hip abduction in women may cause pain during sexual intercourse. Examination may reveal: • an antalgic gait • weakness and wasting of quadriceps and gluteal muscles • pain and restriction of internal rotation with the hip flexed – the earliest and most sensitive sign of hip OA; other movements may subsequently be restricted and painful • anterior groin tenderness just lateral to the femoral pulse • fixed flexion, external rotation deformity of the hip • ipsilateral leg shortening with severe joint attrition and superior femoral migration. Obesity is associated with more rapid progression of hip OA. a car, or bending to put on shoes and socks may be difficult. Local examination findings may include: • a jerky, asymmetric (antalgic) gait with less time weightbearing on the painful side • a varus (Fig. 24.20) or, less commonly, valgus and/or a fixed flexion deformity • joint-line and/or periarticular tenderness (secondary anserine bursitis and medial ligament enthesopathy (see Box 24.25), causing tenderness of the upper medial tibia) • weakness and wasting of the quadriceps muscle Fig. 24.19 X-ray appearances in knee osteoarthritis. A Advanced osteoarthritis showing almost complete loss of joint space affecting both compartments and sclerosis of subchondral bone. B Skyline view of the patella femoral joint in a patient with severe patello-femoral osteoarthritis. There is almost complete loss of joint space and lateral displacement of the patella. A B Fig. 24.20 Typical varus knee deformity resulting from marked medial tibio-femoral osteoarthritis. Fig. 24.21 X-ray of hip showing changes of osteoarthritis. Note the superior joint space narrowing (N), subchondral sclerosis (S), marginal osteophytes (O) and cysts (C). O C N S O

Osteoarthritis • 1011

Erosive OA This term is used to describe an unusual group of patients with hand OA who have a more prolonged symptom phase, more overt inflammation, more disability and worse outcome than those with nodal OA. Distinguishing features include preferential targeting of PIP joints, subchondral erosions on X-rays, occasional ankylosis of affected joints and lack of association with OA elsewhere. It is unclear whether erosive OA is part of the spectrum of hand OA or a discrete subset. Investigations A plain X-ray of the affected joint should be performed and often this will show one or more of the typical features of OA (see Figs 24.18–24.22). In addition to providing diagnostic information, X-rays are of value in assessing the severity of structural change, which is helpful if joint replacement surgery is being considered. Non-weight-bearing postero-anterior views of the pelvis are adequate for assessing hip OA. Patients with suspected knee OA should have standing anteroposterior X-rays taken to assess tibio-femoral cartilage loss, and a flexed skyline view to assess patello-femoral involvement. Spine OA can often be diagnosed on a plain X-ray, which typically shows evidence of disc space narrowing and osteophytes. If nerve root compression or spinal stenosis is suspected, MRI should be performed. Routine biochemistry, haematology and autoantibody tests are usually normal, though OA is associated with a moderate acute phase response. Synovial fluid aspirated from an affected joint is viscous with a low cell count. Unexplained early-onset OA requires additional investigation, guided by the suspected underlying condition. X-rays may show typical features of dysplasia or avascular necrosis, widening of joint spaces in acromegaly, multiple cysts, chondrocalcinosis and MCP joint involvement in haemochromatosis (p. 895), or disorganised architecture in neuropathic joints. Management Treatment follows the principles outlined on pages 1000–1007. Measures that are pertinent in older people are summarised in Box 24.40. Education It is important to explain the nature of the condition fully, outlining the role of relevant risk factors such as obesity, heredity and Spine OA The cervical and lumbar spine are the sites most often targeted by OA, where it is referred to as cervical spondylosis and lumbar spondylosis, respectively (Fig. 24.22). Spine OA may occur in isolation or as part of generalised OA. The typical presentation is with pain localised to the low back region or the neck, although radiation of pain to the arms, buttocks and legs may also occur due to nerve root compression. The pain is typically relieved by rest and worse on movement. On physical examination, the range of movement may be limited and loss of lumbar lordosis is typical. The straight leg-raising test or femoral stretch test may be positive and neurological signs may be seen in the legs where there is complicating spinal stenosis or nerve root compression. Early-onset OA Unusually, typical symptoms and signs of OA may present before the age of 45. In most cases, a single joint is affected and there is a clear history of previous trauma. However, specific causes of OA need to be considered in people with early-onset disease affecting several joints, especially those not normally targeted by OA, in which case rare causes need to be considered (Box 24.39). Kashin–Beck disease is a rare form of OA that occurs in children, typically between the ages of 7 and 13, in some regions of China. The cause is unknown but suggested predisposing factors are selenium deficiency and contamination of cereals with mycotoxin-producing fungi. Fig. 24.22 X-ray of spine showing typical changes of osteoarthritis. Cervical spondylosis showing disc space narrowing between C6 and C7, osteophytes at the anterior vertebral body margins (thin arrows) and osteosclerosis at the apophyseal joints (thick arrow). 24.39 Causes of early-onset osteoarthritis Monoarticular • Previous trauma, localised instability Pauciarticular or polyarticular • Juvenile idiopathic arthritis (p. 1026) • Metabolic or endocrine disease: Haemochromatosis (p. 895) Ochronosis Acromegaly (p. 685) • Spondylo-epiphyseal dysplasia • Late avascular necrosis • Neuropathic joint • Kashin–Beck disease 24.40 Osteoarthritis in old age • Pain and disability: osteoarthritis is the principal cause in old age. • Calcium phosphate deposition disease: may cause acute attacks of synovitis (pseudogout) on a background of chronic osteoarthritis. • Falls: reduced muscle strength and pain associated with lower limb osteoarthritis increase the risk. • Muscle-strengthening exercises: safely reduce the pain and disability of knee osteoarthritis with accompanying improvements in balance and reduced tendency to fall. • Oral paracetamol and topical non-steroidal anti-inflammatory drugs: safe in older people, with no important drug interactions or contraindications. • Intra-articular injection of glucocorticoid: a very safe and often effective treatment, particularly useful for tiding a patient over a special event. • Total joint replacement: an excellent cost-effective treatment for severe disabling knee or hip osteoarthritis in older people. There is no age limit for joint replacement surgery.

1012 • RHEUMATOLOGY AND BONE DISEASE indicated when there is significant structural damage on X-ray. Although surgery should not be undertaken at an early stage during the development of OA, it is important to consider it before functional limitation has become advanced since this may compromise outcome. Patient-specific factors, such as age, gender, smoking and presence of obesity, should not be barriers to referral for joint replacement. Only a small proportion of patients with OA progress to the extent that total joint replacement is required but OA is by far the most frequent indication for this. Over 95% of joint replacements continue to function well into the second decade after surgery and most provide life-long, pain-free function. Up to 20% of patients are not satisfied with the outcome, however, and a few experience little or no improvement in pain. Other surgical procedures are performed much less frequently. Osteotomy is occasionally carried out to prolong the life of malaligned joints and to relieve pain by reducing intraosseous pressure. Cartilage repair is sometimes performed to treat focal cartilage defects resulting from joint injury. Crystal-induced arthritis A variety of crystals can deposit in and around joints and cause an acute inflammatory arthritis, as well as a more chronic arthritis associated with progressive joint damage (Box 24.41). Crystals can be the primary pathogenic agent, as in gout, or an accessory factor, as in calcium pyrophosphate deposition disease, in which crystals are deposited in joints that are already abnormal. Several factors influence crystal formation (Fig. 24.23). There must be sufficient concentration of the chemical components (ionic product), but whether a crystal then forms depends on the balance of tissue factors that promote and inhibit crystal nucleation and growth. The inflammatory potential of crystals resides in their physical irregularity and high negative surface charge, which can induce inflammation and damage cell membranes. Crystals may also cause mechanical damage to tissues and act as wear particles at the joint surface. They can reside in cartilage or tendon for years without causing inflammation or symptoms, and it is only when they are released that they trigger inflammation. This may occur spontaneously but can also result from local trauma, rapid changes in the concentration of the components that form crystals, or in association with an acute phase response triggered by intercurrent illness or surgery. In the longer term, a reduction in concentrations of the solutes that form crystals causes dissolution of crystals and remission of the arthritis. Gout Gout is the most common inflammatory arthritis in men and in older women. It is caused by deposition of monosodium urate monohydrate crystals in and around synovial joints. Epidemiology The prevalence of gout is approximately 1–2%, with a greater than 5 : 1 male preponderance. Gout has become progressively more common over recent years in affluent societies due to the increased prevalence of obesity and metabolic syndrome (p. 730), of which hyperuricaemia is an integral component. The risk of developing gout increases with age and with serum uric acid (SUA) levels. These are normally distributed in the general population and hyperuricaemia is defined as an SUA of more than 2 standard deviations above the mean for the trauma. The patent should be informed that established structural changes are permanent and that, although a cure is not possible at present, pain and function can often be improved. The prognosis should also be discussed, mentioning that it is generally good for nodal hand OA and better for knee than hip OA. Lifestyle advice Weight loss has a substantial beneficial effect on symptoms if the patient is obese and is probably one of the most effective treatments available for OA of the lower limbs. Strengthening and aerobic exercises also have beneficial effects in OA and should be advised, preferably with reinforcement by a physiotherapist (see Box 24.27). Quadriceps strengthening exercises are particularly beneficial in knee OA. Shock-absorbing footwear, pacing of activities, use of a walking stick for painful knee or hip OA, and provision of built-up shoes to equalise leg lengths can all improve symptoms. Non-pharmacological therapy Acupuncture and transcutaneous electrical nerve stimulation (TENS) have been shown to be effective in knee OA. Local physical therapies, such as heat or cold, can sometimes give temporary relief. Pharmacological therapy If symptoms do not respond to non-pharmacological measures, paracetamol should be tried. Addition of a topical NSAID, and then capsaicin, for knee and hand OA can also be helpful. Oral NSAIDs should be considered in patients who remain symptomatic. These drugs are significantly more effective than paracetamol and can be successfully combined with paracetamol or compound analgesics if the pain is severe. Strong opiates may occasionally be required. Antineuropathic drugs, such as amitriptyline, gabapentin and pregabalin, are sometimes used in patients with symptoms that are difficult to control but the evidence base for their use is poor. Neutralising antibodies to nerve growth factor have been developed and are a highly effective treatment for pain in OA but they are not yet licensed for routine clinical use. Intra-articular injections Intra-articular glucocorticoid injections are effective in the treatment of knee OA and are also used for symptomatic relief in the treatment of OA at the first CMC joint. The duration of effect is usually short but trials of serial glucocorticoid injections every 3 months in knee OA have shown efficacy for up to 1 year. Intra-articular injections of hyaluronic acid are effective in knee OA but the treatment is expensive and the effect short-lived. In the UK they have not been considered to be cost-effective by NICE. Neutraceuticals Chondroitin sulphate and glucosamine sulphate have been used alone and in combination for the treatment of knee OA. There is evidence from randomised controlled trials that these agents can improve knee pain to a small extent (3–5%) compared with placebo. Surgery Surgery should be considered for patients with OA whose symptoms and functional impairment impact significantly on their quality of life despite optimal medical therapy and lifestyle advice. Total joint replacement surgery is by far the most common surgical procedure for patients with OA. It can transform the quality of life for people with severe knee or hip OA and is

Crystal-induced arthritis • 1013

the balance between endogenous synthesis, and elimination by the kidneys (two-thirds) and gut (one-third). Purine nucleotide synthesis and degradation are regulated by a network of enzyme pathways, but xanthine oxidase plays a pivotal role in catalysing the conversion of hypoxanthine to xanthine and xanthine to uric acid. The causes of hyperuricaemia are shown in Box 24.42. In over 90% of patients, the main abnormality is reduced uric acid Fig. 24.23 Mechanisms of crystal formation. Solute excess pH Temperature Pressure [Na+] + [Urate] [Ca2+] + [PO4] Nucleating factors Growth-promoting factors Crystals Inflammation Trauma Rapidly reduced solute levels Reduced solute levels Inhibitors of crystal growth Shedding Dissolution Bone Cartilage 24.41 Crystal-associated arthritis and deposition in connective tissue Crystal Associations Common Monosodium urate monohydrate Acute gout Chronic tophaceous gout Calcium pyrophosphate dihydrate Acute ‘pseudogout’ Chronic (pyrophosphate) arthropathy Chondrocalcinosis Basic calcium phosphates Calcific periarthritis Calcinosis Uncommon Cholesterol Chronic effusions in rheumatoid arthritis Calcium oxalate Acute arthritis in dialysis patients Extrinsic crystals/ semi-crystalline particles: Synthetic crystals Acute synovitis Plant thorns/sea urchin spines Chronic monoarthritis, tenosynovitis population. SUA levels are higher in men, increase with age and are positively associated with body weight. Levels are higher in some ethnic groups (such as Maoris and Pacific islanders). Although hyperuricaemia is strong risk factor for gout, only a minority of hyperuricaemic individuals actually develop gout. Pathophysiology About one-third of the body uric acid pool is derived from dietary sources and two-thirds from endogenous purine metabolism (Fig. 24.24). The concentration of uric acid in body fluids depends on Fig. 24.24 Uric acid metabolism. The main pathways for uric acid production and elimination are shown, along with the site of action for urate-lowering therapies. Endogenous purines (~800mg/24 hrs) Renal excretion acid (~800mg/24 hrs) Intestinal excretion acid (~400mg/24 hrs) Purine salvage pathway Game, seafood, oily fish, offal De novo synthesis Inosine Inhibition of pathway Stimulation of pathway Hypoxanthine Xanthine oxidase Xanthine Allantoin Uricosuric drugs Pegloticase Allopurinol Febuxostat Xanthine oxidase Uric acid (~1200mg) Dietary purines (~400mg/24 hrs) 24.42 Causes of hyperuricaemia and gout Diminished renal excretion • Increased renal tubular reabsorption* • Renal failure • Lead toxicity • Lactic acidosis • Alcohol • Drugs: Thiazide and loop diuretics Low-dose aspirin Ciclosporin Pyrazinamide Increased intake • Game • Seafood • Offal • Red meat Increased production • Myeloproliferative and lymphoproliferative disease • Psoriasis • High fructose intake • Glycogen storage disease (p. 370) • Inherited disorders: Lesch–Nyhan syndrome (HPRT mutations) Phosphoribosyl pyrophosphate synthetase 1 mutations *Usually genetically determined (see text). (HPRT = hypoxanthine guanine phosphoribosyl transferase)

1014 • RHEUMATOLOGY AND BONE DISEASE • marked swelling with overlying red, shiny skin • self-limiting over 5–14 days, with complete resolution. During the attack, the joint shows signs of marked synovitis, swelling and erythema. There may be accompanying fever, malaise and even delirium, especially if a large joint such as the knee is involved. As the attack subsides, pruritus and desquamation of overlying skin are common. The main differential diagnosis is septic arthritis, infective cellulitis or reactive arthritis. Acute attacks may also manifest as bursitis, tenosynovitis or cellulitis, which have the same clinical characteristics. Many patients describe milder episodes lasting just a few days. Some have attacks in more than one joint. Others have further attacks in other joints a few days later (cluster attacks), the first possibly acting as a trigger. Simultaneous polyarticular attacks are unusual. Some people never have a second episode and in others several years may elapse before the next one. In many, however, a second attack occurs within 1 year and may progress to chronic gout, with chronic pain and joint damage, and occasionally severe deformity and functional impairment. Patients with uncontrolled hyperuricaemia who suffer multiple attacks of acute gout may also progress to chronic gout. The presentation of gout in the elderly may be atypical with chronic symptoms rather than acute attacks (Box 24.43). Crystals may be deposited in the joints and soft tissues to produce irregular firm nodules called tophi. These have a predilection for the extensor surfaces of fingers, hands, forearm, elbows, Achilles tendons and sometimes the helix of the ear. Tophi have a white colour (Fig. 24.26), differentiating them from rheumatoid nodules. Tophi can ulcerate, discharging white gritty material, become infected or induce a local inflammatory response, with erythema and pus in the absence of secondary infection. They are usually a feature of long-standing gout but can sometimes develop within 12 months in patients with chronic renal failure. Occasionally, tophi may develop in the absence of previous acute attacks, especially in patients on thiazide therapy who have coexisting OA. In addition to causing musculoskeletal disease, chronic hyperuricaemia may be complicated by renal stone formation (p. 431) and, if severe, renal impairment due to the development of interstitial nephritis as a result of urate deposition in the kidney. This is particularly common in patients with chronic tophaceous gout who are on diuretic therapy. Investigations The diagnosis of gout can be confirmed by the identification of urate crystals in the aspirate from a joint, bursa or tophus (see Fig. 24.6A, p. 988). In acute gout, the synovial fluid may be excretion by the kidney, which is genetically determined. Impaired renal excretion of urate also accounts for the occurrence of hyperuricaemia in chronic renal failure, and for hyperuricaemia associated with thiazide diuretic therapy. Other risk factors for gout include metabolic syndrome, high alcohol intake (predominantly beer, which contains guanosine), generalised OA, and a diet relatively high in game, offal, seafood, red meat and fructose, or low in vitamin C. Lead poisoning may cause gout (saturnine gout). The association between OA and gout is thought to be due to a reduction in levels of proteoglycan and other inhibitors of crystal formation in osteoarthritic cartilage, predisposing to crystal formation. Some patients develop gout because they over-produce uric acid. The mechanisms are poorly understood, except in the case of a few single gene disorders where there are mutations in genes that regulate purine metabolism (Box 24.42). Lesch–Nyhan syndrome is an X-linked recessive form of gout that is also associated with mental retardation, selfmutilation and choreoathetosis. An inherited cause should be suspected if other clinical features are present or there is an early age at onset with a positive family history. Severe hyperuricaemia can also occur in patients with haematological and other cancers who are undergoing chemotherapy due to increased purine turnover (tumour lysis syndrome). This is seldom connected with gout but can be associated with acute kidney injury (p. 411). Clinical features The classical presentation is with an acute monoarthritis, which affects the first MTP joint in over 50% of cases (Fig. 24.25). Other common sites are the ankle, midfoot, knee, small joints of hands, wrist and elbow. The axial skeleton and large proximal joints are rarely involved. Typical features include: • rapid onset, reaching maximum severity in 2–6 hours, and often waking the patient in the early morning • severe pain, often described as the ‘worst pain ever’ • extreme tenderness, such that the patient is unable to wear a sock or to let bedding rest on the joint Fig. 24.25 Podagra. Acute gout causing swelling, erythema and extreme pain and tenderness of the first metatarsophalangeal joint. 24.43 Gout in old age • Aetiology: a higher proportion of older patients have gout secondary to diuretic use and chronic kidney disease. Gout is often associated with osteoarthritis. • Presentation: may be atypical, with painful tophi and chronic symptoms, rather than acute attacks. Joints of the upper limbs are more frequently affected. • Management: acute attacks are best treated by aspiration and intra-articular injection of glucocorticoids, followed by early mobilisation. Non-steroidal anti-inflammatory drugs and colchicine should be used with caution because of increased risk of toxicity. Low doses of allopurinol (50 mg/day) should be given and increased gradually to avoid toxicity.

Crystal-induced arthritis • 1015

that are similar to those in other forms of advanced inflammatory arthritis. Management Management should focus on first dealing with the acute attack and then giving prophylaxis to lower SUA and prevent further attacks. Acute gout Oral colchicine given in doses of 0.5 mg twice or 3 times daily is the treatment of first choice in acute gout. It works by inhibiting microtubule assembly in neutrophils. The most common adverse effects are nausea, vomiting and diarrhoea. Oral NSAIDs are also effective but are used less commonly since many patients affected by acute gout have coexisting cardiovascular, cerebrovascular or chronic kidney disease. Oral prednisolone (15–20 mg daily) or intramuscular methylprednisolone (80–120 mg daily) for 2–3 days are highly effective and are a good choice in elderly patients where there is an increased risk of toxicity with colchicine and NSAID (Box 24.43). The IL-1β inhibitor canakinumab (see Box 24.35) is effective but extremely expensive and so seldom given. Local ice packs can also be used for symptomatic relief. Patients with recurrent episodes can keep a supply of an NSAID, colchicine or prednisolone and take it as soon as the first symptoms occur, continuing until the attack resolves. Joint aspiration can give pain relief, particularly if a large joint is affected, and may be combined with an intra-articular glucocorticoid injection if the diagnosis is clear and infection can be excluded. Prophylaxis Patients who have had a single attack of gout do not necessarily need to be given urate-lowering therapy, but individuals who have more than one acute attack within 12 months and those with complications such as tophi or erosions should be offered it (Box 24.44). The long-term therapeutic aim is to prevent attacks occurring by bringing uric acid levels below the level at which monosodium urate monohydrate crystals form. A therapeutic target of 360 μmol/L (6 mg/dL) is recommended in the British Society of Rheumatology guidelines, whereas the European League Against Rheumatism guidelines recommend a threshold of 300 μmol/L (5 mg/dL). Allopurinol is the drug of first choice. It inhibits xanthine oxidase, which reduces the conversion of hypoxanthine and xanthine to uric acid. The recommended starting dose is 100 mg daily, or 50 mg in older patients and in renal impairment. The dose of allopurinol should be increased by 100 mg every 4 weeks (50 mg in the elderly and those with renal impairment) until the target uric acid level is achieved, side-effects occur or the maximum recommended dose is reached (900 mg/day). Acute flares of gout often follow initiation of urate-lowering therapy. The patient should be warned about this and told to continue therapy, even if an attack occurs. The risk of flares can be reduced by prophylaxis with oral colchicine (0.5 mg twice daily) or an NSAID for the first few months. Alternatively, patients can be given a supply of colchicine, an NSAID or prednisolone to be taken at the first turbid due to an elevated neutrophil count. In chronic gout, the appearance is more variable but occasionally the fluid appears white due to the presence of urate crystals. Between attacks, aspiration of an asymptomatic first MTP joint or knee may still reveal crystals. A biochemical screen, including renal function, uric acid, glucose and lipid profile, should be performed because of the association with metabolic syndrome. Hyperuricaemia is usually present in gout but levels may be normal during an attack because serum urate falls during inflammation. Acute gout is characterised by an elevated ESR and CRP and with a neutrophilia, all of which return to normal as the attack subsides. Tophaceous gout may be accompanied by a modest but chronic elevation in ESR and CRP. X-rays are usually normal in acute gout but well-demarcated erosions may be seen in patients with chronic or tophaceous gout (Fig. 24.27). Tophi may also be visible on X-rays as soft tissue swellings. In late disease, destructive changes may occur Fig. 24.26 Tophus with white monosodium urate monohydrate crystals visible beneath the skin. Diuretic-induced gout in a patient with pre-existing nodal osteoarthritis. Fig. 24.27 Erosive arthritis in chronic gout. Punched-out (‘Lulworth Cove’) erosions (arrows) in association with a destructive arthritis affecting the first metatarsophalangeal joint. 24.44 Indications for urate-lowering drugs • Recurrent attacks of acute gout • Evidence of bone or joint damage • Tophi • Renal impairment • Nephrolithiasis

1016 • RHEUMATOLOGY AND BONE DISEASE levels are raised in patients with CPPD crystal deposition disease, possibly due to over-production, but why this happens is unclear. In hypophosphatasia (see Box 24.75, p. 1050), the predisposing factor is thought to be impaired degradation of pyrophosphate due to deficiency of ALP. In OA, it is thought that a reduction in the amounts of proteoglycan and other natural inhibitors of crystal formation in the abnormal cartilage also predispose to crystal deposition (see Fig. 24.23). Clinical features The typical presentation is with a swollen tender joint that is warm and erythematous with a large effusion. Fever is common and the patient may appear confused and ill. The knee is most commonly affected, followed by the wrist, shoulder, ankle and elbow. Trigger factors include trauma, intercurrent illness, dehydration and surgery. Septic arthritis and gout are the main differential diagnoses. Chronic arthropathy may also occur in association with CPPD crystal deposition disease, affecting the same joints that are involved in acute pseudogout. The presentation is with chronic pain, early morning stiffness, inactivity gelling and functional impairment. Acute attacks of pseudogout may be superimposed. Affected joints usually show features of OA, with varying degrees of synovitis. Effusion and synovial thickening are usually most apparent at knees and wrists. Wrist involvement may result in carpal tunnel syndrome and second and third MCP joints can be sign of an acute attack. In the longer term, annual monitoring of uric acid levels is recommended. In most patients, urate-lowering therapy needs to be continued indefinitely. Febuxostat also inhibits xanthine oxidase. It is typically used in patients with an inadequate response to allopurinol, and when allopurinol is contraindicated or causes adverse effects. Febuxostat undergoes hepatic metabolism and no dose adjustment is required for renal impairment. It is more effective than allopurinol but commonly provokes acute attacks when therapy is initiated. The usual starting dose is 80 mg daily, increasing to 120 mg daily in patients with an inadequate response. Prophylaxis against acute attacks should be given on initiating therapy, as described for allopurinol. Uricosuric drugs, such as probenecid, sulfinpyrazone and benzbromarone, lower urate levels but are seldom used in routine clinical practice. They are contraindicated in over-producers and those with renal impairment or urolithiasis and require patients to maintain a high fluid intake to avoid uric acid crystallisation in the renal tubules. Pegloticase is a biological treatment in which the enzyme uricase (oxidises uric acid to 5-hydroxyisourate, which is then converted to allantoin) has been conjugated to monomethoxypolyethylene glycol. It is indicated for the treatment of tophaceous gout resistant to standard therapy and is administered as an intravenous infusion every 2 weeks for up to 6 months. It is highly effective at controlling hyperuricaemia and can cause regression of tophi. The main adverse effects are infusion reactions (which can be treated with antihistamines or glucocorticoids) and flares of gout during the first 3 months of therapy. A limiting factor for longer-term treatment is the development of antibodies to pegloticase, which occur in a high proportion of cases and are associated with an impaired therapeutic response. Lifestyle measures are equally important as drug therapy in the treatment of gout. Patients should be advised to lose weight where appropriate and to reduce excessive alcohol intake, especially beer. Several antihypertensive drugs, including thiazides, β-blockers and ACE inhibitors, increase uric acid levels, whereas losartan has a uricosuric effect and should be substituted for other drugs if possible. Patients should be advised to avoid large amounts of seafood and offal, which have a high purine content, but a highly restrictive diet is not necessary. Calcium pyrophosphate dihydrate crystal deposition disease This condition is associated with deposition of calcium pyrophosphate dihydrate (CPPD) crystals within articular and hyaline cartilage and is often referred to as ‘pseudogout’. It is rare under the age of 55 years but occurs in 10–15% of people between 65 and 75 and 30–60% of those over 85. The knee (hyaline cartilage and menisci) is by far the most common site, followed by the wrist (triangular fibrocartilage) and pelvis (symphysis pubis). Risk factors are shown in Box 24.45. In many patients, chondrocalcinosis is asymptomatic and an incidental finding on X-ray. A proportion of patients present with an acute inflammatory arthritis (pseudogout) or a chronic inflammatory arthropathy superimposed on a background of OA, especially at the knee (Fig. 24.28), associated with joint damage and functional limitation. Pathophysiology The underlying mechanisms of crystal deposition are poorly understood. Clinical studies have shown that pyrophosphate Fig. 24.28 Chondrocalcinosis of the knee. The X-ray shows calcification of the fibrocartilaginous menisci (M) and articular hyaline cartilage (H). There is also narrowing (N) of the medial tibio-femoral compartment and osteophyte (O) formation. H M N O Common • Age • Osteoarthritis* Rare • Familial factors* • Haemochromatosis* • Hypophosphatasia *May be associated with structural damage to affected joints. • Hypomagnesaemia • Wilson’s disease • Primary hyperparathyroidism 24.45 Risk factors for chondrocalcinosis

Crystal-induced arthritis • 1017

and fever are common. Tendon calcification may be seen on X-ray. If the affected joint or bursa is aspirated, inflammatory fluid containing many calcium-staining (alizarin red S) aggregates may be obtained. During an acute attack, there may be a neutrophilia with an elevation in ESR and CRP. Routine biochemistry is normal. Treatment is with analgesics and NSAIDs. Attacks may also respond to a local injection of glucocorticoid. The condition usually resolves spontaneously over 1–3 weeks and this is often accompanied by dispersal and disappearance of calcific deposits on X-ray. Large deposits sometimes accumulate, causing limitation of joint movement, and may require surgical removal. Acute inflammatory arthritis Deposition of BCP occurs commonly in OA, both alone and in combination with CPPD crystals, in which case it is referred to as mixed crystal deposition disease. It may present with pseudogout or be an incidental finding. Milwaukee shoulder syndrome This is a rare syndrome, in which extensive deposition of BCP crystals in large joints is associated with progressive joint destruction. It is more common in women than in men. The onset is gradual with joint pain, sometimes precipitated by injury affected. Inflammatory features may be sufficiently pronounced to suggest RA. Inflammatory changes can occur at entheses and may involve tendons and the ligamentum flavum. Inflammation around the odontoid may occur secondary to CPPD deposition, leading to crowned dens syndrome; this presents clinically with neck pain. Severe damage and instability of knees or shoulders can mimic a neuropathic joint but no neurological abnormalities will be found. Investigations The pivotal investigation is joint aspiration, followed by examination of synovial fluid using compensated polarised microscopy to demonstrate CPPD crystals (see Fig. 24.6B, p. 988) and to permit distinction from gout. The aspirated fluid is often turbid and may be uniformly blood-stained, reflecting the severity of inflammation. Since sepsis and pseudogout can coexist, Gram stain and culture of the fluid should be performed to exclude sepsis, even if CPPD crystals are identified in synovial fluid. X-rays of the affected joint may show evidence of calcification in hyaline cartilage and/or fibrocartilage, although absence of calcification does not exclude the diagnosis. Signs of OA are frequently present. Screening for secondary causes (Box 24.45) should be undertaken, especially in patients who present under the age of 25 and those with polyarticular disease. Management Joint aspiration can sometimes provide symptomatic relief in pseudogout and in a few patients no further treatment is required. People with persistent symptoms can be treated with intra-articular glucocorticoids, colchicine or an NSAID. Since most patients with pseudogout are elderly, NSAIDs and colchicine must be used with caution. Early active mobilisation is also important. Chronic pyrophosphate-induced arthropathy should be managed as for OA (p. 1011). Basic calcium phosphate deposition disease Basic calcium phosphate (BCP) deposition disease is caused by the deposition of hydroxyapatite or apatite crystals and other basic calcium phosphate salts (octacalcium phosphate, tricalcium phosphate) in soft tissues. The main affected sites are tendons, ligaments and hyaline cartilage in patients with degenerative disease, and skeletal muscle and subcutaneous tissues in connective tissue diseases. Pathophysiology Under normal circumstances, inhibitors of mineralisation, such as pyrophosphate and proteoglycans, prevent calcification of soft tissues. When these protective mechanisms break down, abnormal calcification occurs. There are many causes (Box 24.46). In most situations calcification is of no consequence, but when the crystals are released an inflammatory reaction may be initiated, causing local pain and inflammation. Calcific periarthritis This occurs as the result of deposition of BCP in tendons, which provokes an acute inflammatory response. The most commonly affected site is the supraspinatus tendon (Fig. 24.29) but other sites may also be involved, including the tendons around the hip, feet and hands. The presentation is with acute pain, swelling and local tenderness that develops rapidly over 4–6 hours. The overlying skin may be hot and red, raising the possibility of infection. Attacks sometimes occur spontaneously but can also be triggered by trauma. Modest systemic upset Fig. 24.29 Shoulder X-ray showing supraspinatus tendon calcification (arrow). 24.46 Rheumatic diseases associated with basic calcium phosphate deposition Disease Site of calcification Calcific periarthritis Tendons and ligaments Dermatomyositis and polymyositis Subcutaneous tissue Systemic sclerosis (lcSScl) Subcutaneous tissue Mixed connective tissue disease Subcutaneous tissue Paget’s disease of bone Blood vessels Ankylosing spondylitis Ligaments Fibrodysplasia ossificans progressiva Subcutaneous tissues and muscle Milwaukee shoulder syndrome Tendons and ligaments Albright’s hereditary osteodystrophy (p. 664) Muscle (lcSScl = localised cutaneous systemic sclerosis)

1018 • RHEUMATOLOGY AND BONE DISEASE for all or some of the patient’s symptoms (Box 24.48). Extensive imaging is not recommended but bone scintigraphy can identify many conditions that can contribute to widespread pain and is a useful ‘negative’ test. The aims of management are to educate the patient about the condition, address unresolved psychological issues, achieve pain control and improve sleep. Wherever possible, education should include the spouse, family or carer. It should be acknowledged that the cause of FM is not fully understood but the widespread pain does not reflect inflammation, tissue damage or disease. The model of a self-perpetuating cycle of poor sleep and pain (see Fig. 24.30) is a useful framework for problem-based management. Understanding the diagnosis can often help the patient come to terms with the symptoms. Repeat or drawn-out investigation may reinforce beliefs in occult serious pathology and should be avoided. Low-dose amitriptyline (10–75 mg at night), with or without fluoxetine, may help by encouraging delta sleep and reducing or overuse. The disease progresses over a few months to cause severe pain and disability, associated with joint destruction. X-rays show joint space narrowing, osteophytes and calcification. Aspiration yields large volumes of relatively non-inflammatory fluid containing abundant BCP aggregates and often cartilage fragments. The differential diagnosis is end-stage avascular necrosis, chronic sepsis or neuropathic joint. There is no acute phase response and synovial fluid cultures are negative. Treatment is with analgesics, intra-articular injection of glucocorticoids, local physical treatments and physiotherapy. The clinical outcome is poor, however, and most patients require joint replacement. The cause is incompletely understood but it has been speculated that deposition of BCP crystals activates collagenase and other proteases in articular cells, which are responsible for the tissue damage. Autoimmune connective tissue disease Deposition of BCP may occur in the subcutaneous tissues and muscle of patients with systemic sclerosis and other autoimmune connective tissue diseases. Usually, the deposits are asymptomatic but they may be associated with pain and local ulceration. The mechanism by which this occurs is unclear and there is no specific treatment. Fibromyalgia Fibromyalgia (FM) is a condition of generalised pain and consequent disability. It is frequently associated with medically unexplained symptoms in other systems (p. 1187). The prevalence in the UK and US is about 2–3%. Although FM can occur at any age, including adolescence, it increases in prevalence with age, to reach a peak of 7% in women aged over 70. There is a strong female predominance of around 10 : 1. Risk factors include life events that cause (unresolved) psychosocial distress relating to previous abuse, marital disharmony, alcoholism or illness in the family, poor sleep health, previous injury or assault, and low income. FM arises in a variety of races and cultures. Pathophysiology The cause of FM is poorly understood but two abnormalities that may be interrelated (Fig. 24.30) and have been consistently reported in affected patients are disturbed, non-restorative sleep and pain sensitisation, probably caused by abnormal central pain processing. Clinical features The main presenting feature is widespread pain, which is often worst in the neck and back (Box 24.47). It is characteristically diffuse and unresponsive to analgesics and NSAIDs. Physiotherapy often makes FM pain worse. Fatiguability, most prominent in the morning, is another major problem and disability is often marked. Although people can usually dress, feed and groom themselves, they may be unable to perform tasks such as shopping or housework. They may have experienced major difficulties at work or may even retire because of pain and fatigue. Examination is unremarkable, apart from the presence of hyperalgesia on moderate digital pressure (enough just to whiten the nail) over multiple sites (Fig. 24.31). Investigations and management There are no abnormalities on routine blood tests or imaging but it is important to screen for other conditions that could account Fig. 24.30 Possible causative mechanisms in fibromyalgia. Disease Illness Regional pain syndrome Anxiety Life crisis Sleep disturbance Non-restorative sleep Reduced activity Poor aerobic fitness Pain Fatigue Functional disturbance 24.47 The spectrum of symptoms in fibromyalgia Usual symptoms • Widespread pain • Fatiguability • Disability • Broken, non-restorative sleep • Low affect, irritability, poor concentration Variable locomotor symptoms • Early-morning stiffness • Feeling of swelling in hands • Distal finger tingling Additional, variable, non-locomotor symptoms • Non-throbbing bifrontal headache (tension headache) • Colicky abdominal pain, bloating, variable bowel habit (irritable bowel syndrome) • Bladder fullness, nocturnal frequency (irritable bladder) • Hyperacusis, dyspareunia, discomfort when touched (allodynia) • Frequent side-effects with drugs (chemical sensitivity)

Bone and joint infections • 1019

support. Although treatment may improve quality of life and ability to cope, most people remain symptomatic for many years. Bone and joint infections Septic arthritis Septic arthritis is the most rapid and destructive joint disease. The incidence is 2–10 per 100 000 in the general population and 30–70 per 100 000 in those with pre-existing joint disease or joint replacement. Septic arthritis is associated with significant morbidity and still has a mortality of about 10% despite advances in antimicrobial therapy. The most important risk factor for mortality is increasing age. Pathogenesis Septic arthritis usually occurs as a result of haematogenous spread from infections of the skin or upper respiratory tract; infection from direct puncture wounds or secondary to joint aspiration is uncommon. Risk factors include increasing age, pre-existing joint disease (principally RA), diabetes mellitus, immunosuppression (by drugs or disease) and intravenous drug misuse. In RA, the skin is a frequent portal of entry because of maceration of skin between the toes due to joint deformity and difficulties with foot hygiene caused by hand deformity. Box 24.49 describes the particular considerations in old age. Clinical features The usual presentation is with acute or subacute monoarthritis and fever. The joint is usually swollen, hot and red, with pain at rest and on movement. Although any joint can be affected, lower limb joints, such as the knee and hip, are most commonly spinal cord wind-up. Many people with FM, however, are intolerant of even small doses of amitriptyline. There is limited evidence for the use of tramadol, serotonin–noradrenaline (norepinephrine) re-uptake inhibitors (SNRIs) such as duloxetine, and the anticonvulsants pregabalin and gabapentin. A graded increase in aerobic exercise can improve well-being and sleep quality. The use of self-help strategies and a cognitive behavioural approach with relaxation techniques should be encouraged. Sublimated anxiety relating to distressing life events should be specifically explored with appropriate counselling. There are patient organisations that provide additional information and Fig. 24.31 Typical tender points in fibromyalgia. Interspinous ligaments C5–7 Mid-supraspinatus Interspinous ligaments L4/5 Mid-gluteal Second/third costochondral junctions 1 cm distal to lateral epicondyle Medial fat pad (upper medial tibia) Skin-fold rolling of mid-trapezius 24.48 Laboratory investigations recommended before finalising a diagnosis of fibromyalgia Test Condition screened for Full blood count, liver and renal function tests General disease indicators Erythrocyte sedimentation rate, C-reactive protein, serum amyloid A, immunoglobulins Inflammatory disease Thyroid function Hypo-/hyperthyroidism Calcium, albumin, phosphate, alkaline phosphatase, parathyroid hormone, 25-hydroxyvitamin-D, serum angiotensin-converting enzyme Hyperparathyroidism, osteomalacia, sarcoid Antinuclear antibodies, extractable nuclear antigens, rheumatoid factor, anti-cyclic citrullinated peptide antibodies, complement C3 and C4, lupus anticoagulant, anti-cardiolipin antibodies, streptococcal antibodies Autoinflammatory and autoimmune diseases

1020 • RHEUMATOLOGY AND BONE DISEASE depending on the organism that is isolated. Microbiology advice should always be sought in complicated situations, such as when treating intravenous drug users, patients in intensive care and those who might be colonised by resistant organisms. It is traditional to continue intravenous antibiotics for 2 weeks and to follow this with oral treatment for another 4 weeks, but there is no evidence to support the optimal duration of treatment. Joint aspiration should be performed using a large-bore needle once or twice daily. If this is not possible, arthroscopic or open surgical drainage may be needed performed. Regular passive movement should be undertaken from the outset, and active movements encouraged once the condition has stabilised. Infected prosthetic joints require management by the orthopaedic team, but prolonged antibiotic treatment on its own is often ineffective and removal of the prosthesis is required for eradication of the infection. Arthritis may be a feature of Lyme disease caused by members of the Borrelia species of microorganisms (p. 255). It is generally a late manifestation, which usually affects large joints. Brucellosis presents with an acute febrile illness, followed in some cases by the development of localised infection, which can result in arthritis, bursitis, osteomyelitis, sacroiliitis and paravertebral or psoas abscesses. These conditions are discussed on pages 254 and 255. Viral arthritis The usual presentation is with acute polyarthritis following a febrile illness, which may be accompanied by a rash. Most cases of targeted. Patients with pre-existing arthritis may present with multiple joint involvement. In adults, the most likely organism is Staphylococcus aureus, particularly in patients with RA and diabetes. In young, sexually active adults, gonococcus may be responsible. Disseminated gonococcal infection occurs in up to 3% of patients with untreated gonorrhoea. This usually presents with migratory arthralgia, low-grade fever and tenosynovitis, which may precede the development of an oligo- or monoarthritis. Painful pustular skin lesions may also be present. Gram-negative bacilli or group B, C and G streptococci are important causes among the elderly and intravenous drug users. Less commonly, septic arthritis may be caused by group A streptococci, pneumococci, meningococci and Haemophilus influenzae. Investigations The pivotal investigation is joint aspiration but blood cultures should also be taken. The synovial fluid is usually turbid or bloodstained but may appear normal. If the joint is not readily accessible, aspiration should be performed under imaging guidance or in theatre. Prosthetic joints should only be aspirated in theatre. Synovial fluid should be sent for Gram stain and culture; cultures are positive in around 90% of cases but the Gram stain is positive in only 50%. In contrast, synovial fluid culture is positive in only 30% of gonococcal infections, making it important to obtain concurrent cultures from the genital tract (positive in 70–90% of cases). There is a leucocytosis with raised ESR and CRP in most patients, but these features may be absent in elderly or immunocompromised patients, or early in the disease course. Serial measurements of CRP and ESR are useful in following the response to treatment. Management The principles of management are summarised in Box 24.50. The patient should be admitted to hospital for pain relief and administration of parenteral antibiotics. Flucloxacillin (2 g IV 4 times daily) is the antibiotic of first choice pending the results of cultures, since it will cover most staphylococcal and streptococcal infections. If there is reason to suspect meticillin-resistant Staphylococcus aureus (such as a known carrier), vancomycin should be used instead while awaiting cultures. If a Gram-negative infection is suspected, gentamicin or vancomycin should be considered as first-line treatments. Cephalosporins are a potential alternative for Gram-negative infections but carry a high risk of Clostridium difficile infection in those aged over 65. Whatever antibiotic is chosen, the regimen may need to be changed, 24.49 Joint and bone infection in old age • Vertebral infection: more common. Recognition may be delayed, as symptoms may be attributed to compression fractures caused by osteoporosis. • Peripheral vascular disease: leads to more frequent involvement of the bones of the feet, and diabetic foot ulcers are also commonly complicated by osteomyelitis. • Prosthetic joint infections: now more common because of the increased frequency of prosthetic joint insertion in older people. • Gram-negative bacilli: more frequent pathogens than in younger people. • Cephalosporins: contraindicated due to the high risk of Clostridium difficile. • Septic arthritis: mortality is high in elderly patients. The evidence base for choice of antibiotic selection is poor. Local guidelines should be followed where available. 24.50 Emergency management of suspected septic arthritis Admit patient to hospital Perform urgent investigations • Aspirate joint: Send synovial fluid for Gram stain and culture Use imaging guidance if required • Send blood for culture, routine biochemistry and haematology, including erythrocyte sedimentation rate and C-reactive protein • Consider sending other samples (sputum, urine, wound swab) for culture, depending on patient history, to determine primary source of infection Commence intravenous antibiotic • Flucloxacillin (2 g 4 times daily) • If penicillin-allergic: Clindamycin (450–600 mg 4 times daily in younger patients) Intravenous vancomycin (1 g twice daily if age > 65 years) • If high risk of Gram-negative sepsis (recurrent urinary tract infection): Intravenous gentamicin (5 mg/kg once daily) or vancomycin (750–1000 mg twice daily) Relieve pain • Oral and/or intravenous analgesics • Consider local ice-packs Aspirate joint • Perform serial needle aspiration to dryness (1–3 times daily or as required) • Consider arthroscopic drainage if needle aspiration difficult Arrange physiotherapy • Early regular passive movement, progressing to active movements once pain controlled and effusion not re-accumulating

Rheumatoid arthritis • 1021

Investigations Patients suspected of having osteomyelitis should have an MRI, which is more sensitive than X-ray for detecting early changes. Where possible, cultures should be obtained by open or imagingguided biopsy of the lesion. Evidence of osteopenia, localised osteolysis and osteonecrosis may be seen on X-ray. Blood cultures should be taken, which may also reveal the causative organism. Routine bloods typically show evidence of an acute phase response with a neutrophilia and raised ESR and CRP. Management Early recognition is critical as once osteomyelitis becomes established and chronic, it may prove very hard to eradicate with antibiotics alone. The principles are those followed for septic arthritis, with parenteral antibiotics for 2 weeks, followed by oral antibiotics for at least 4 weeks. An exception is in localised osteomyelitis of the toes and fingers, which can often be treated successfully with a prolonged course of oral antibiotics. Resection of the infected bone and subsequent reconstruction may be required. Complications of chronic osteomyelitis include secondary amyloidosis (p. 81) and skin malignancy at the margin of a discharging sinus (Marjolin’s ulcer). Discitis Discitis is an unusual condition in which there is infection of the intervertebral disc, often extending into the epidural space or paravertebral soft tissues. Staph. aureus is the most common pathogen. Risk factors include diabetes mellitus, immunodeficiency or immunosuppressive therapy, and intravenous drug use. The presentation is with back pain accompanied by fever, and an acute phase response with high ESR and CRP and a neutrophilia. If the diagnosis is suspected, an MRI should be performed and blood cultures taken. If blood cultures are negative, open or imaging-guided biopsy of the lesion should be performed to try to identify the organism responsible. Management is with supportive care and parenteral antibiotics followed by oral antibiotics, as described for osteomyelitis. Tuberculosis Tuberculosis can affect the musculoskeletal system, usually targeting the spine (Pott’s disease) or large joints such as the hip, knee or ankle. The presentation is with pain, swelling and fever. The X-ray changes are non-specific and mycobacteria are seldom identified in the synovial fluid, so tissue biopsy is required for a definitive diagnosis. Medical management is described on page 592. In some cases, surgical débridement may be required for extensive joint disease, and spinal involvement may require surgical stabilisation and decompression. Rheumatoid arthritis Rheumatoid arthritis (RA) is a common form of inflammatory arthritis, occurring throughout the world and in all ethnic groups. The prevalence of RA is approximately 0.8–1.0% in Europe and the Indian subcontinent, with a female-to-male ratio of 3 : 1. The prevalence is lower in South-east Asia (0.4%). The highest prevalence in the world is in Pima Indians (5%). It is a chronic disease characterised by a clinical course of exacerbations and remissions. viral arthritis are self-limiting and settle down within 4–6 weeks. Human parvovirus arthropathy (mainly B19; p. 237) is the most common in Europe; adults may not have the characteristic ‘slapped cheek’ facial rash seen in children. The diagnosis can be confirmed by a rise in specific IgM. Polyarthritis may also occur rarely with hepatitis B and C, rubella (including rubella vaccination) and HIV infection. A variety of mosquito-borne viruses may cause epidemics of acute polyarthritis, including Ross River (Australia, Pacific), Chikungunya and O’nyong-nyong (Asia, Africa), and Mayaro viruses (South America). A wide variety of articular symptoms have been associated with HIV, mainly in the later stages of infection (Box 24.51). Management is symptomatic, with NSAIDs and analgesics. Osteomyelitis In osteomyelitis, the primary sites of infection are bone and bone marrow. Any part of a bone may be involved but there is preferential targeting of the juxta-epiphyseal regions of long bones adjacent to joints. The risk of osteomyelitis increases with age; the incidence is about 8.8 cases per 100 000 person-years in those under 18, rising to 40.8 cases in those aged 60–69 and 88.3 cases in those above the age of 80. Pathogenesis Haematogenous spread is the most common cause in children but contiguous spread of infection from adjacent soft tissues or as the result of surgery is more important in adults. Diabetes is a particularly important risk factor, accounting for about 30% of cases in recent series. Other risk factors include immunosuppressive therapy, HIV infection and sickle-cell disease, which particularly increases the risk of Salmonella infection. The organisms most frequently implicated are Staph. aureus, Staph. epidermidis and streptococci. The infection often results in a florid inflammatory response, with a greatly increased intraosseous pressure. If untreated, the condition may cause localised areas of osteonecrosis, leading to the development of a fragment of necrotic bone that is called a sequestrum. Eventual perforation of the cortex by pus stimulates local new bone formation (involucrum) in the periosteum, often leading to the development of sinuses that discharge through the skin. Clinical features The presentation is with localised bone pain and tenderness, often accompanied by malaise, night sweats and pyrexia. The adjacent joint may be painful to move and may develop a sterile effusion or secondary septic arthritis. 24.51 Musculoskeletal manifestations of HIV Condition Comment Non-specific arthralgia Most common; intermittent and polyarticular Reactive arthritis Psoriatic arthritis Idiopathic lower limb inflammatory arthritis Especially in men who have sex with men Osteonecrosis Myositis Vasculitis Sjögren’s-like disease Unclear if related to HIV, its treatment or intercurrent disease

1022 • RHEUMATOLOGY AND BONE DISEASE The disease is characterised by infiltration of the synovial membrane with lymphocytes, plasma cells, dendritic cells and macrophages. There is evidence that CD4+ T lymphocytes and B cells play important roles in the pathogenesis of RA by interacting with other cells in the synovium, as illustrated in Figure 24.32. Lymphoid follicles form within the synovial membrane in which T- and B-cell interactions occur, causing activation of T cells to produce cytokines and activation of B cells to produce autoantibodies, including RF and ACPA. Synovial macrophages are activated by TNF and interferon gamma (IFN-γ), produced by T cells. The macrophages produce several pro-inflammatory cytokines, including TNF, IL-1 and IL-6, which act on synovial fibroblasts to produce further cytokines, setting up a positive feedback loop. The synovial fibroblasts proliferate, causing synovial hypertrophy and producing matrix metalloproteinases and the proteinase ADAMTS-5, which degrade soft tissues and cartilage. Prostaglandins and nitric oxide produced within the inflamed synovium cause vasodilatation, resulting in swelling and pain. Systemic release of IL-6 triggers production of acute phase proteins by the liver. At the joint margin, the inflamed synovium (pannus) directly invades bone and cartilage to cause joint erosions. A key pathogenic factor in bone erosions and periarticular osteoporosis is osteoclast activation, stimulated by the production of M-CSF by synovial cells and RANKL by activated T cells (Fig. 24.32). New blood-vessel formation (angiogenesis) occurs, causing the inflamed synovium to become highly vascular. Pathophysiology RA is a complex disease with both genetic and environmental components. The importance of genetic factors is demonstrated by higher concordance of RA in monozygotic (12–15%) compared with dizygotic twins (3%), and an increased frequency of disease in first-degree relatives of patients. Genome-wide association studies have detected nearly 100 loci that are associated with the risk of developing RA. The strongest association is with variants in the HLA region. Recent studies have shown that the association with HLA is determined by variations in three amino acids in the HLA-DRβ1 molecule (positions 11, 71 and 74) and single variants HLA-B (at position 9) and HLA-DPβ1 (at position 9). The non-HLA loci generally lie within or close to genes involved in regulating the immune response. It is currently believed that RA occurs when an environmental stimulus, such as infection, triggers autoimmunity in a genetically susceptible host by modifying host proteins through processes like citrullination so that they become immunogenic. However, no single specific pathogen has been identified as a cause. An important environmental risk factor is cigarette smoking, which is also associated with more severe disease and reduced responsiveness to treatment. Remission may occur during pregnancy and sometimes RA first presents post-partum. This is likely to be due to suppression of the immune response during pregnancy but hormonal changes may also play a role. Fig. 24.32 Pathophysiology of rheumatoid arthritis. Some of the cytokines and cellular interactions believed to be important in rheumatoid arthritis are shown. (ADAMTS5 = aggrecanase; IL = interleukin; M-CSF = macrophage colony-stimulating factor; MMP = matrix metalloproteinase; RANKL = receptor activator of nuclear factor kappa B ligand; TNF = tumour necrosis factor) Autoantibodies B cell T cell TNF-α RANKL M-CSF MMP ADAMTS-5 TNF-α IL-1 IL-6 TNF-α IFN-γ TNF-α IL-1 IL-6 Activated B cells Immune complexes Osteoclast precursors Activated T cells Synovial fibroblasts Prostaglandins Nitric oxide Pain Vasodilatation Cartilage breakdown Acute phase proteins Bone erosions Vasculitis Plasma cells Host protein Protein becomes immunogenic Protein modified Immunogenic protein processed and presented to T cells by dendritic cells and B cells Peptide presented to T cell with HLA T cell activates B cell Dendritic cell Environmental trigger • Smoking • Infection Genetic predisposition • HLA-DR • Other immune response genes Macrophage

Rheumatoid arthritis • 1023

sheaths. Subluxation of the MTP joints of the feet may result in ‘cock-up’ toe deformities, causing pain on weight-bearing on the exposed MTP heads and the development of secondary adventitious bursae and callosities. In the hindfoot, a valgus deformity of the calcaneus may be observed as the result of damage to the ankle and subtalar joints. This is often associated with loss of the longitudinal arch (flat foot) due to rupture of the tibialis posterior tendon. Popliteal (Baker’s) cysts may occur in patients with knee synovitis, in which synovial fluid communicates with the cyst but is prevented from returning to the joint by a valve-like mechanism; this is not specific to RA. Rupture may be induced by knee flexion, leading to calf pain and swelling that may mimic a deep venous thrombosis (DVT). These joint deformities tend to be observed in older patients with long-standing disease but are becoming much less common with more aggressive treatment of RA in its early stages. Systemic features Anorexia, weight loss and fatigue may occur throughout the disease course. Osteoporosis is a common complication (p. 1044) and muscle-wasting may occur as the result of systemic inflammation and reduced activity. Extra-articular features are most common in patients with long-standing seropositive erosive disease but may occasionally occur at presentation, especially in men. Most are due to serositis, granuloma and nodule formation or vasculitis (Box 24.53). Nodules Rheumatoid nodules occur almost exclusively in RF- or ACPApositive patients, usually in extensor tendons (Fig. 24.34). They 24.52 Criteria for diagnosis of rheumatoid arthritis* Criterion Score Joints affected 1 large joint

2–10 large joints

1–3 small joints

4–10 small joints

10 joints (at least 1 small joint)

Serology Negative RF and ACPA

Low positive RF or ACPA

High positive RF or ACPA

Duration of symptoms < 6 weeks

6 weeks

Acute phase reactants Normal CRP and ESR

Abnormal CRP or ESR

Patients with a score ≥ 6 are considered to have definite RA. (ACPA = anti-citrullinated peptide antibody; CRP = C-reactive protein; ESR = erythrocyte sedimentation rate; RF = rheumatoid factor) *European League Against Rheumatism/American College of Rheumatology 2010 criteria. Within these blood vessels, pro-inflammatory cytokines activate endothelial cells, which support recruitment of yet more leucocytes to perpetuate the inflammatory process. Later, fibrous or bony ankylosis may occur. Muscles adjacent to inflamed joints atrophy and may be infiltrated with lymphocytes. This leads to progressive biomechanical dysfunction and may further amplify destruction. Rheumatoid nodules occur in patients who are RF- or ACPApositive and primarily affect extensor tendons. They consist of a central area of fibrinoid material surrounded by a palisade of proliferating mononuclear cells. Granulomatous lesions may occur in the pleura, lung, pericardium and sclera. Clinical features The typical presentation is with pain, joint swelling and stiffness affecting the small joints of the hands, feet and wrists in a symmetrical fashion. Large joint involvement, systemic symptoms and extra-articular features may also occur. Clinical criteria for the diagnosis of RA are shown in Box 24.52. Sometimes RA has an acute onset, with severe early morning stiffness, polyarthritis and pitting oedema. This occurs more commonly in old age. Another presentation is with proximal muscle stiffness mimicking polymyalgia rheumatica (p. 1042). Occasionally, the onset is palindromic, with relapsing and remitting episodes of pain, stiffness and swelling that last for only a few hours or days. Examination typically reveals swelling and tenderness of the affected joints. Erythema is unusual and its presence suggests coexistent sepsis. Characteristic deformities may develop with long-standing uncontrolled disease, although these have become less common over recent years with more aggressive management. They include ulnar deviation of the fingers, ‘swan neck’ deformity, the boutonnière or ‘button hole’ deformity, and a Z deformity of the thumb (Fig. 24.33). Dorsal subluxation of the ulna at the distal radio-ulnar joint may occur and contribute to rupture of the fourth and fifth extensor tendons. Triggering of fingers may occur because of nodules in the flexor tendon Fig. 24.33 The hand in rheumatoid arthritis. A Ulnar deviation of the fingers with wasting of the small muscles of the hands and synovial swelling at the wrists, the extensor tendon sheaths, the metacarpophalangeal and proximal interphalangeal joints. B ‘Swan neck’ deformity of the fingers. B A

1024 • RHEUMATOLOGY AND BONE DISEASE Ocular involvement The most common symptom is dry eyes (keratoconjunctivitis sicca) due to secondary Sjögren’s syndrome (p. 1038). Scleritis and peripheral ulcerative keratitis are uncommon but more serious and potentially sight-threatening complications that usually present with pain and redness. Clinical features and management are discussed in more detail on page 1172. Serositis Serositis is usually asymptomatic but may present with pleural or pericardial pain and breathlessness. Pericardial effusion and constrictive pericarditis may rarely occur. Cardiac involvement Heart block, cardiomyopathy, coronary artery occlusion and aortic regurgitation have all been reported but are rare. The risk of cardiovascular disease is increased due to a combination of conventional risk factors, such as high cholesterol, smoking, hypertension, reduced physical activity, NSAIDs, glucocorticoids and the effects of inflammatory cytokines on vascular endothelium. Pulmonary involvement Pulmonary fibrosis may occur but is often asymptomatic. There is some evidence that the risk of pulmonary fibrosis is increased by anti-TNF therapy, although its uncertain whether this is causal or a marker of more severe disease in patients who require anti-TNF treatment. Peripheral neuropathy Entrapment neuropathies may result from compression by hypertrophied synovium or by joint subluxation. Median nerve compression is the most common and bilateral carpal tunnel syndrome can occur as a presenting feature of RA. Other syndromes include ulnar nerve compression at the elbow or wrist, compression of the lateral popliteal nerve at the head of the fibula, and tarsal tunnel syndrome (entrapment of the posterior tibial nerve in the flexor retinaculum), which causes burning, tingling and numbness in the distal sole and toes. Diffuse symmetrical peripheral neuropathy and mononeuritis multiplex may occur in patients with rheumatoid vasculitis. Spinal cord compression This rare complication is caused by compression of the spinal cord from subluxation of the cervical spine at the atlanto-axial joint or at a subaxial level (Fig. 24.35). Atlanto-axial subluxation is due to erosion of the transverse ligament posterior to the odontoid peg. It can lead to cord compression or sudden death following minor trauma or manipulation. It should be suspected in any RA patient who describes new onset of occipital headache, particularly if symptoms of paraesthesia or electric shock are present in the arms. The onset is often insidious, with subtle loss of function that may initially be attributed to active disease. Reflexes and power can be difficult to assess in patients with extensive joint disease and therefore sensory or upper motor signs are most important. Patients with evidence of spinal cord compression require urgent neurosurgical referral for stabilisation and fixation. Other complications Amyloidosis is a rare complication of long-standing disease that usually presents with nephrotic syndrome. Microcytic anaemia can occur due to iron deficiency resulting from NSAIDinduced gastrointestinal blood loss, whereas normochromic, normocytic anaemia with thrombocytosis occurs in patients Fig. 24.34 Rheumatoid nodules and olecranon bursitis. Nodules were palpable within, as well as outside, the bursa. 24.53 Extra-articular manifestations of rheumatoid disease Systemic • Fever • Weight loss • Fatigue • Susceptibility to infection Musculoskeletal • Muscle-wasting • Tenosynovitis • Bursitis • Osteoporosis Haematological • Anaemia • Thrombocytosis • Eosinophilia Lymphatic • Felty’s syndrome (see Box 24.54) • Splenomegaly Nodules • Sinuses • Fistulae Ocular • Episcleritis • Scleritis • Scleromalacia • Keratoconjunctivitis sicca Vasculitis • Digital arteritis • Ulcers • Pyoderma gangrenosum • Mononeuritis multiplex • Visceral arteritis Cardiac • Pericarditis • Myocarditis • Endocarditis • Conduction defects • Coronary vasculitis • Granulomatous aortitis Pulmonary • Nodules • Pleural effusions • Fibrosing alveolitis • Bronchiolitis • Caplan’s syndrome (p. 611) Neurological • Cervical cord compression • Compression neuropathies • Peripheral neuropathy • Mononeuritis multiplex Amyloidosis (p. 81) are frequently asymptomatic but some may be complicated by ulceration and secondary infection. Vasculitis This is uncommon but may occur in seropositive patients. The presentation is with systemic symptoms, such as fatigue and fever and nail-fold infarcts. Rarely, cutaneous ulceration, skin necrosis and mesenteric, renal or coronary artery occlusion may occur.

Rheumatoid arthritis • 1025

there is clinical uncertainty about the presence of synovitis. Plain X-rays of the hands, wrist and feet are usually normal in early RA but periarticular osteoporosis and marginal joint erosions may be observed with more advanced disease. The main indication for an X-ray is in the assessment of patients with painful joints to determine whether significant structural damage has occurred. Patients who are suspected of having atlanto-axial disease should have lateral X-rays taken in flexion and extension, and an MRI. In those with suspected Baker’s cyst, ultrasound may be required to establish the diagnosis. DAS28 is widely used to assess disease activity, response to treatment and need for biological therapy. It involves counting the number of swollen and tender joints in the upper limbs and knees, and combining this with the ESR and the patient’s assessment of the activity of their arthritis on a visual analogue scale, where 0 indicates no symptoms and 100 the worst symptoms possible. This data are entered into a calculator to generate a numerical score. The higher the value, the more active the disease (Fig. 24.36). Management The treatment goal is to suppress inflammation, control symptoms and prevent joint damage. This involves a combination of pharmacological and non-pharmacological therapies. When RA occurs in women of child-bearing age, additional considerations need to be taken into account and these are summarised in Box 24.56. Pharmacological therapy DMARD therapy should be introduced in all patients as this improves outcome. A typical algorithm is shown in Figure 24.37. On first diagnosis, prednisolone should be started in a dose of 30 mg daily gradually reducing in 5 mg increments every 2 weeks until therapy is withdrawn after about 12 weeks. At the same time, methotrexate should be started in an initial dose of 15 mg weekly, along with folic acid 5 mg weekly, and escalated up to a maximum of 25 mg weekly, depending on the response. If the patient fails to respond adequately or dose-limiting toxicity occurs, then an additional DMARD should be commenced in combination with MTX. The most common combination is triple therapy, in which with active disease. Felty’s syndrome is a rare complication of seropositive RA in which splenomegaly occurs in combination with neutropenia and thrombocytopenia (Box 24.54). Localised or generalised lymphadenopathy can occur in patients with active disease but persistent lymphadenopathy may indicate the development of lymphoma, which is more common in patients with long-standing RA. Investigations The diagnosis of RA is essentially clinical but investigations are useful in confirming the diagnosis and assessing disease activity (Box 24.55). The ESR and CRP are usually raised but normal results do not exclude the diagnosis, especially if only a few joints are involved. Tests for ACPA are positive in about 70% of cases and are highly specific for RA, occurring in many patients before clinical onset of the disease. Similarly, RF is also positive in about 70% of cases, most of whom also test positive for ACPA. RF is less specific than ACPA, however, and positive tests can occur in other diseases (p. 991). Ultrasound examination and MRI are not routinely required but can be value in patients with symptoms suggestive of RA where Fig. 24.35 Subluxation of cervical spine. A Flexion, showing widening of the space (arrow) between the odontoid peg of the axis (behind) and the anterior arch of the atlas (in front). B Extension, showing reduction in this space. A B 24.54 Felty’s syndrome Risk factors • Age of onset 50–70 years • Female > male • Caucasians > blacks • Long-standing rheumatoid arthritis • Deforming but inactive disease • Seropositive for rheumatoid factor Common clinical features • Splenomegaly • Lymphadenopathy • Weight loss • Skin pigmentation • Keratoconjunctivitis sicca • Vasculitis, leg ulcers • Recurrent infections • Nodules Laboratory findings • Normochromic, normocytic anaemia • Neutropenia • Abnormal liver function • Thrombocytopenia • Impaired T- and B-cell immunity 24.55 Investigations and monitoring of rheumatoid arthritis To establish diagnosis • Clinical criteria • Erythrocyte sedimentation rate and C-reactive protein • Ultrasound or magnetic resonance imaging • Rheumatoid factor and anti-citrullinated peptide antibodies To monitor disease activity and drug efficacy • Pain (visual analogue scale) • Early morning stiffness (minutes) • Joint tenderness • Joint swelling • DAS28 score (see Fig. 24.36) • Erythrocyte sedimentation rate and C-reactive protein To monitor disease damage • X-rays • Functional assessment To monitor drug safety • Urinalysis • Full blood count • Chest X-ray • Urea and creatinine • Liver function tests

1026 • RHEUMATOLOGY AND BONE DISEASE flares can be dealt with by intra-articular glucocorticoid injections or a short course of oral glucocorticoids, but if a sustained flare occurs, a change in systemic DMARD and/or biologic therapy may need to be considered. Non-pharmacological therapy Physical and occupational therapy play important roles and it is vital for all patients to be assessed by an occupational therapist and physiotherapist and the appropriate advice and treatment provided. Surgery Synovectomy can be helpful in joints that have failed to respond adequately to systemic therapy and intra-articular injections. Joint replacement surgery may be required but the need for this has diminished over recent years, presumably as the result of more aggressive medical management. Other surgical procedures that can be helpful are excision of the metatarsal heads in patients with subluxation of the MTP joints; neurosurgery in patients with atlanto-axial subluxation; and fusion or the wrist or ankle in patients with joint damage (see Box 24.29, p. 1002). Juvenile idiopathic arthritis Juvenile idiopathic arthritis (JIA) is the term, accepted by the international community, for several forms of arthritis defined by the International League of Associations for Rheumatology 2001 criteria (Box 24.57). This includes juvenile forms of psoriatic arthritis (JPsA), rheumatoid arthritis (JRA) and more undifferentiated forms of inflammatory arthritis. The majority of patients with JIA have a phenotype that is distinct from adult inflammatory arthritis Fig. 24.36 Calculation of the Disease Activity Score 28 (DAS28). Erythrocyte sedimentation rate or C-reactive protein can be used for the calculation. Calculation • Count swollen joints • Count tender joints • Measure erythrocyte sedimentation rate • Note patient global health assessment (1–100) • Enter data into calculator: www.4s-dawn.com/das28 Interpretation • >5.1 High activity • 2.6–5.1 Moderate activity • <2.6 Remission

24.56 Rheumatoid arthritis in pregnancy • Immunological changes in pregnancy: many patients with rheumatoid arthritis go into remission during pregnancy. • Conception: methotrexate should be discontinued for at least 3 months and leflunomide discontinued for at least 24 months before trying to conceive. • Paracetamol: the oral analgesic of choice during pregnancy. • Oral non-steroidal anti-inflammatory drugs and selective cyclo-oxygenase 2 (COX-2) inhibitors: can be used from implantation to 20 weeks’ gestation. • Glucocorticoids: may be used to control disease flares; the main maternal risks are hypertension, glucose intolerance and osteoporosis. • Disease-modifying antirheumatic drugs (DMARDs) that may be used: sulfasalazine, hydroxychloroquine and azathioprine if required to control inflammation. • DMARDs that must be avoided: methotrexate, leflunomide, cyclophosphamide, mycophenolate and gold. • Biologic therapies: experience is limited but they may be relatively safe during pregnancy. The main theoretical risk is immunosuppression in the neonate, except for certolizumab, which does cross the placenta in negligible amounts. • Breastfeeding: methotrexate, leflunomide and cyclophosphamide are contraindicated. methotrexate, sulfasalazine and hydroxychloroquine are combined (Fig. 24.37). Other DMARDs can be substituted or added, along with a low-dose glucocorticoid such as prednisolone (5–10 mg daily) if the patient fails to respond fully. If disease activity remains high (DAS28 > 5.1) despite triple therapy, however, it is usual to progress to biologic therapy. The most commonly used first-line biologics in RA are TNF inhibitors, although several other options are available (p. 1006). When the patient has been stabilised on biologic treatment for 12 months or more, a reduction in dose should be considered, since it is possible to reduce the dose in up to 50% of patients without loss of therapeutic effect. The JAK inhibitors tofacitinib and baricitinib have efficacy in patients who fail to respond adequately to other DMARDs and provide an alternative to biologic therapies. RA is a chronic disease and flares can occur even in patients who are established on DMARD and biologic therapy. Transient Fig. 24.37 Algorithm for the management of rheumatoid arthritis. (DAS28 = Disease Activity Score 28; DMARD = disease-modifying antirheumatic drug; HCQ = hydroxychloroquine; MTX = methotrexate; SSZ = sulfasalazine) Decrease dose over 12 weeks Increase dose over 12 weeks Prednisolone MTX + New diagnosis of rheumatoid arthritis Continue triple therapy DAS28

2.6 Add SSZ

5.1 DAS28 2.6–5.1 Add biologic Change DMARD or add low-dose prednisolone DAS28 <2.6

Spondyloarthropathies • 1027

uveitis alone. Drug combinations are not well studied in JIA. Biologic therapies, including anti-TNF, are effective in JIA and are now a standard treatment in the presence of refractory disease or intolerance of methotrexate or other non-biologic immunotherapies. Tocilizumab is also effective in sJIA, and has been approved by NICE for use in the UK. Prognosis Suboptimal outcomes are associated with delayed diagnosis and referral to the specialist multidisciplinary team, inadequate disease control, presentation with uveitis, sJIA in males and poor engagement with services. Psychological support of affected children and their families is associated with improved outcome. Oligo-JIA often resolves at puberty. Polyarticular disease and sJIA remain active into adulthood in about 50% of cases. Common issues around the transition of adolescent patients into adulthood are shown in Box 24.58. Spondyloarthropathies Spondyloarthropathies (SpAs) comprise a group of related inflammatory musculoskeletal diseases that show overlap in their clinical features and have a shared immunogenetic association with HLA-B27 (Box 24.59). They include: • axial spondyloarthritis • ankylosing spondylitis • reactive arthritis • psoriatic arthritis and includes a strong association with uveitis. JIA affects about 1 : 1000 children and young people up to 16 years of age – similar to the prevalence of diabetes (1 : 700). The annual incidence is approximately 1 per 10 000 children and young people. Whereas joint restriction is attributed to damage in adults, in children it indicates inflammatory activity. Arthritis in children affects limb growth and has a negative effect on height and weight attainment. In young children, effective disease control can repair joint damage before puberty. Oligoarthritis is the most common form of JIA, accounting for about 60% of cases. It is more common in females and tends to affect large joints in an asymmetrical pattern. There is an association with uveitis and many patients are ANA-positive. Polyarticular JIA is heterogeneous: some patients are RF- and/ or ACPA-positive, while others are negative for autoantibodies. Systemic juvenile idiopathic arthritis (sJIA, formerly known as Still’s disease) is characterised by fever, rash, arthritis, hepatosplenomegaly and serositis in association with anaemia and a raised ESR and CRP. Autoantibody tests are negative. This form of JIA is associated with haemophagocytic syndrome. Many cases of enthesitis-related arthritis (ERA) are likely to be self-limiting forms of spondyloarthritis. ERA can progress over time into a more obviously defined spondyloarthropathy. Investigations ESR and CRP do not correlate well with the extent or severity of inflammation and may be normal. A very high ESR may indicate the presence of inflammatory bowel disease or (very rarely) leukaemia. Low haemoglobin is likely to be due to anaemia of chronic disease rather than iron deficiency. A positive ANA occurs in 40–75% of cases of JIA and indicates an increased risk of eye disease. Ultrasound is the radiological investigation of choice to confirm synovitis or tenosynovitis. The false-negative rate is higher in foot and ankle disease than in other joints. Arthroscopy should be avoided unless a biopsy is required. Synovial fluid aspiration, but not arthroscopy, is essential when considering sepsis and tuberculosis. Management The key approach is to gain early rapid control of inflammation, minimise the adverse effects of treatment and support the general physical and mental health of the patient, which requires full multidisciplinary team input. The standard immunotherapy is methotrexate (subcutaneous methotrexate is typically used in the young child). Alternative treatment includes leflunomide, sulfasalazine and hydroxychloroquine. Azathioprine and ciclosporin can be used to treat JIA with uveitis. Mycophenolate and tacrolimus are considered to have a specific role in treating 24.57 Clinical features of juvenile idiopathic arthritis Subtype Frequency Clinical features Immunology Systemic juvenile idiopathic arthritis 5% Fever, rash, arthralgia, hepatosplenomegaly Autoantibody-negative Oligoarthritis (≤ 4 joints) 60% Large-joint arthritis, uveitis ANA-positive Polyarthritis (≥ 5 joints) 20% Polyarthritis; may be extended form of oligoarthritis ANA-positive Enthesis-related 5% Sacroiliitis, enthesopathy HLA-B27-positive RF-positive 5% Polyarthritis, similar to RA RF-positive, ACPA-positive Psoriatic arthritis 5% Same as adult disease (p. 1032) Autoantibody-negative (ACPA = anti-citrullinated peptide antibody; ANA = antinuclear antibody; HLA = human leucocyte antigen; RA = rheumatoid arthritis; RF = rheumatoid factor) 24.58 Juvenile idiopathic arthritis in adolescence • Uveitis: may be clinically silent and persist into adulthood. All (not just those who are ANA-positive) need ophthalmic screening for eye involvement. • Persistence into adulthood: occurs in 50% of cases, especially in systemic disease. Specific supportive management through transition from adolescence to adulthood should be planned. • Reduced peak bone mass: common in polyarthritis and systemic juvenile idiopathic arthritis but there are few data on fracture risk and the evidence base for treatment is poor. • Therapy: methotrexate is standard treatment, used after NSAIDs alone are insufficient. Anti-TNF therapy is effective in all forms of juvenile idiopathic arthritis but long-term safety remains unclear. (ANA = antinuclear antibody; NSAIDs = non-steroidal anti-inflammatory drugs; TNF = tumour necrosis factor)

1028 • RHEUMATOLOGY AND BONE DISEASE Th17 axis (p. 65). In some situations, a triggering organism can be identified, as in reactive arthritis following bacterial dysentery or chlamydial urethritis, but in others the environmental trigger remains obscure. Familial clustering not only is common to the specific condition occurring in the proband, but also may extend to other diseases in the spondyloarthropathy group. Axial spondyloarthropathy Axial spondyloarthropathy includes classical ankylosing spondylitis (AS) as well as axial spondyloarthritis (axSpA). Inflammatory changes in the entire axial skeleton are characteristic of axSpA and can be visualised by MRI; structural alterations, such as new bone formation with syndesmophytes and ankylosis, develop later in the course of the disease. Accordingly, the criteria for diagnosing AS (Box 24.60), which require evidence of sacroiliitis on X-ray, are often only able to be applied many years after a patient’s symptoms started. Not all patients with axSpA will go on to develop AS. Pathophysiology Axial SpA and AS arise from an interaction between environmental pathogens and the host immune system in genetically susceptible individuals. Increased faecal carriage of Klebsiella aerogenes has been reported in patients with established AS and may relate to exacerbation of both joint and eye disease. There is increasing evidence that axSpA and AS are due to an abnormal host response to the intestinal microbiota with involvement of Th17 cells, which have a key role in mucosal immunity. This leads to production of various inflammatory cytokines, including IL-12, IL-23, IL-17 and TNF-α, which play vital roles in the pathogenesis of enthesitis and other inflammatory lesions (Fig. 24.38). There a strong association between axial spondyloarthropathy and carriage of the major histocompatibility complex (MHC) • arthritis with inflammatory bowel disease (enteropathic spondyloarthritis). In axial spondylitis and ankylosing spondylitis, the axial skeleton (i.e. the central core skeleton) is predominantly affected. In contrast to RA, in the SpAs there are frequent and notable non-synovial musculoskeletal lesions – mainly inflammatory in nature – of ligaments, tendons, periosteum and other bone lesions. A hallmark lesion of all SpAs is enthesitis, which is inflammation at the site of a ligament or tendon insertion into bone. Dactylitis, inflammation of a whole finger or toe, may also occur (see Fig. 24.43). It has been estimated that about 1% of the adult population in the USA may have an SpA (about 2.7 million). There is a striking association with HLA-B27, particularly for ankylosing spondylitis (> 95%). Additionally, SpAs are thought to arise as the result of an aberrant host response to infection and abnormal mucosal immunity mediated through changes in the IL-12, IL-23 and 24.59 Features common to spondyloarthropathies • Asymmetrical inflammatory oligoarthritis (lower > upper limb) • History of inflammatory back pain • Sacroiliitis and spinal osteitis • Enthesitis (e.g. gluteus medius insertion, plantar fascia origin) • Tendency for familial aggregation • HLA-B27 association • Psoriasis (of skin and/or nails) • Uveitis • Sterile urethritis and/or prostatitis • Inflammatory bowel disease • Aortic root lesions (aortic incompetence, conduction defects) (HLA = human leucocyte antigen) 24.60 Comparison of diagnostic criteria for axial spondyloarthritis (ASAS) and ankylosing spondylitis (modified New York) Axial spondyloarthritis Ankylosing spondylitis Imaging Sacroiliitis on MRI only Bilateral sacroiliitis on X-ray, even if changes are mild Unilateral sacroiliitis on X-ray if changes are definite History Back pain > 3 months that has four of the following characteristics:

  1. improved by exercise
  2. not relieved by rest
  3. insidious onset
  4. night pain
  5. age at onset < 45 Good response of back pain to NSAID Family history of spondyloarthritis History of inflammatory bowel disease Low back pain > 3 months improved by exercise and not relieved by rest Clinical examination Arthritis Enthesitis Uveitis Dactylitis Psoriasis Limitation of lumbar spine movement in sagittal and frontal planes Chest expansion reduced Investigations HLA-B27-positive Elevated CRP Axial spondyloarthritis is diagnosed from: sacroiliitis on MRI + one other feature on history, clinical examination or investigation. The diagnosis can also be made in HLA-B27-positive patients with >1 clinical feature in the absence of sacroiliitis Ankylosing spondylitis can be diagnosed on X-ray evidence of sacroiliitis with one other feature on history or examination (ASAS = Assessment of Spondylitis International Society; CRP = C-reactive protein; HLA = human leucocyte antigen; MRI = magnetic resonance imaging; NSAID = non-steroidal anti-inflammatory drug)

Spondyloarthropathies • 1029

attachments at humeral epicondyles. A number of validated clinical questionnaires, such as the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), Bath Ankylosing Spondylitis Functional Index (BASFI) and Ankylosing Spondylitis Disease Activity Score (ASDAS-CRP), can be used to assess disease activity and functional status in AS, though newer assessment tools are being developed that are more specific to a diagnosis of axSpA, such as the Assessment of Spondyloarthritis International Society Health Index (ASAS-H). Investigations The diagnosis is aided by ultrasound or MRI of entheses, or by MRI of the sacroiliac joints and spine (Fig. 24.39). Other findings class I molecule HLA-B27. This is particularly striking in patients defined as having AS, more than 95% of whom are positive for HLA-B27. Other susceptibility genes also implicated in susceptibility to AS include ERAP-1 (an endoplasmic reticulum protein with a role facilitating intracellular antigen processing and binding with its presenting MHC molecule HLA-B27), the IL-23 receptor and downstream signalling molecules involved in directing Th17 cell responses, such as STAT3 (see Fig. 4.3, p. 65). The HLA-B27 molecule itself is implicated through its antigen-presenting function or because of its propensity to form homodimers that activate leucocytes. HLA-B27 molecules may also misfold, causing increased endoplasmic reticulum stress. This could lead to inflammatory cytokine release by macrophages and dendritic cells, thus triggering inflammatory disease. Axial spondyloarthritis Clinical features The cardinal feature of axSpA is inflammatory back pain and early morning stiffness, with low back pain radiating to the buttocks or posterior thighs if the sacroiliac joints are involved. Symptoms are exacerbated by inactivity and relieved by movement. Musculoskeletal symptoms may be prominent at entheses, may be episodic and, if persistent, can present as widespread pain and be mistaken for fibromyalgia. Fatigue is common. A history of psoriasis (current, previous or in a first-degree relative) and inflammatory bowel symptoms (current or previous) are important clues. Physical signs include a reduced range of lumbar spine movements in all directions, pain on sacroiliac stressing and a high enthesitis index. Entheses that are typically affected include Achilles’ insertion, plantar fascia origin, patellar ligament entheses, gluteus medius insertion at the greater trochanter and tendon Fig. 24.38 Pathophysiology of axial spondyloarthropathy. In genetically susceptible individuals, it is thought that bacterial components penetrate the mucosal barrier to activate macrophages and dendritic cells in the intestinal submucosa. These cells produce increased amounts of interleukin 23 (IL-23), which acts on T cells, neutrophils and mast cells to make IL-17; IL-17 in turn has a pivotal role in driving inflammation, causing sacroiliitis and enthesitis. Presentation of antigen by dendritic cells also plays a pathogenic part in activating T cells, and tumour necrosis factor (TNF), produced by macrophages and activated T cells, contributes to the pathogenesis of inflammation. Production of IL-22 by T cells is thought to be involved in causing the new bone formation that is typical of axial spondyloarthropathy. T cell IL-17 TNF-α IL-17 IL-22 New bone formation IL-17 IL-23 Antigen IL-23 IL-23 Dendritic cell Macrophage Activation of immune cells in submucosa Gut epithelium Gut flora Microbial products Tissue immune cells Neutrophil Mast cell TNF-α Environmental trigger Genetic predisposition • HLA-B27 • ERAP-1 • STAT3, IL23R Inflammation Fig. 24.39 Magnetic resonance imaging appearances in sacroiliitis. Coronal MRI short T1 inversion recovery (STIR) sequence showing bilateral sacroiliitis in axial spondyloarthritis. Bone marrow oedema (circles) is present around both sacroiliac joints, which show irregularities due to erosions (arrows).

1030 • RHEUMATOLOGY AND BONE DISEASE develops in many patients over a period of many years. Secondary osteoporosis of the vertebral bodies frequently occurs, leading to an increased risk of vertebral fracture. In AS, spinal fusion varies in its extent and in most cases does not cause a gross flexion deformity, but a few patients develop marked kyphosis of the dorsal and cervical spine that may interfere with forward vision. This may prove incapacitating, especially when associated with fixed flexion contractures of hips or knees. Up to 40% of patients also have peripheral musculoskeletal lesions (asymmetrical, affecting entheses of large joints, such as the hips, knees, ankles and shoulders). Fatigue is a major complaint and is common to all SpAs, but its cause is unknown. Acute anterior uveitis is the most common extra-articular feature, which occasionally precedes joint disease. Other extra-articular features are occasionally observed but are rare (Box 24.61). Investigations In AS, X-rays of the sacroiliac joint show irregularity and loss of cortical margins, widening of the joint space and subsequently sclerosis, joint space narrowing and fusion. Lateral thoracolumbar spine X-rays may show anterior ‘squaring’ of vertebrae due to erosion and sclerosis of the anterior corners and periostitis of the waist. Bridging syndesmophytes may also be seen. These are areas of calcification that follow the outermost fibres of the annulus (Fig. 24.40). In advanced disease, ossification of the anterior longitudinal ligament and facet joint fusion may also be visible. The combination of these features may result in the may include raised ESR and CRP (although these can be normal), anaemia and positive HLA-B27. Faecal calprotectin is a useful screening test for associated inflammatory bowel disease. Management Patient education, NSAID use (optimally, once daily or slow release taken at bedtime) and physical therapy are key interventions at the outset. For severe and/or persistent peripheral musculoskeletal features of SpA, both sulfasalazine and methotrexate are reasonable therapy choices. These medications have no impact on spinal symptoms or disease progression. In patients who fail to respond adequately or who cannot tolerate NSAIDs, progression to biologic therapy with either TNF inhibitors or the IL-7A inhibitor secukinumab should be considered (see Box 24.35, p. 1007). Anti-TNF therapy is effective for both the axial and peripheral lesions of axSpA, but it is as yet unclear whether anti-TNF therapy modifies the natural history of the disease. Prognosis With such a recent definition of disease, the markers of prognosis in patients diagnosed with axSpA are not fully understood. It is clear that axSpA can remain mild and/or episodic in many patients for many years. HLA-B27 positivity, high persistent CRP and high functional incapacity are likely to be markers of poor prognosis, if not markers of extension ultimately to AS. Ankylosing spondylitis Ankylosing spondylitis (AS) is defined by the presence of sacroiliitis on X-ray and other structural changes on spine X-rays, which may eventually progress to bony fusion of the spine. There is a male-to-female ratio of about 3 : 1. In Europe, more than 90% of those affected are HLA-B27-positive (Caucasian HLA-B27 population prevalence is 9%). The overall prevalence of AS is below 0.5% in most populations. Over 75% of patients are able to remain in employment and enjoy a good quality of life. Even if severe ankylosis develops, functional limitation may not be marked, as long as the spine is fused in an erect posture. Clinical features Clinical features are the same as in axSpA. AS typically evolves slowly, with fluctuating symptoms of spinal inflammation; ankylosis 24.61 Extra-articular features of axial spondyloarthritis and ankylosing spondylitis • Fatigue, anaemia • Anterior uveitis (25%) • Prostatitis (80% of men) and sterile urethritis • Inflammatory bowel disease (up to 50% have IBD lesions) • Osteoporosis • Cardiovascular disease (aortic valve disease 20%) • Amyloidosis (rare) • Atypical upper lobe pulmonary fibrosis (very rare) Fig. 24.40 Radiographic changes in spondyloarthritis. A Fine symmetrical marginal syndesmophytes typical of ankylosing spondylitis (arrow). B Coarse, asymmetrical non-marginal syndesmophytes typical of psoriatic spondylitis (arrow). A B

Spondyloarthropathies • 1031

Reactive arthritis Reactive (spondylo)arthritis (ReA) is a ‘reaction’ to a number of bacterial triggers with clinical features in keeping with all SpA conditions. The known triggers are Chlamydia, Campylobacter, Salmonella, Shigella and Yersinia. Notably, non-SpA-related reactive arthritis can occur following infection with many viruses, Mycoplasma, Borrelia, streptococci and mycobacteria, including M. leprae, which causes leprosy (Hansen’s disease); however, the ‘reaction’ in these instances consists typically of myoarthralgias, is not associated with HLA-B27 and is generally not chronic. The arthritis associated with rheumatic fever (p. 515) is also an example of a reactive arthritis that is not associated with HLA-B27. Sexually acquired reactive arthritis (SARA) is predominantly a disease of young men, with a male preponderance of 15 : 1. This may reflect a difficulty in diagnosing the condition in young women, in whom Chlamydia infection is often asymptomatic and is hard to detect in practical terms. Between 1% and 2% of patients with non-specific urethritis seen at genitourinary medicine clinics have SARA (p. 1031). The syndrome of chlamydial urethritis, conjunctivitis and reactive arthritis was formerly known as Reiter’s disease. With enteric triggering infections (enteropathic ReA), HLA-B27 may predict the reactive arthritis and its severity, though the condition occurs in HLA-B27-negative people. The incidence of specific triggering infections causing reactive arthritis around the world varies, depending on the epidemiology of the infection and prevalence of HLA-B27 in the local population. Clinical features The onset is typically acute, with an inflammatory enthesitis, oligoarthritis and/or spinal inflammation. Lower limb joints and entheses are predominantly affected. In all types of ReA, there may be considerable systemic disturbance, with fever and weight loss. Achilles insertional enthesitis/tendonitis or plantar fasciitis may also be present. The first attack of arthritis is usually self-limiting, but recurrent or chronic arthritis can develop and about 10% still have active disease 20 years after the initial presentation. Low back pain and stiffness due to enthesitis and osteitis are common and 15–20% of patients develop sacroiliitis. Many extra-articular features in ReA involve the skin, especially in SARA: • circinate balanitis, which starts as vesicles on the coronal margin of the prepuce and glans penis, later rupturing to form superficial erosions with minimal surrounding erythema, some coalescing to give a circular pattern • keratoderma blennorrhagica, which begins as discrete waxy, yellow–brown vesico-papules with desquamating margins, occasionally coalescing to form large crusty plaques on the palms and soles of the feet • pustular psoriasis • nail dystrophy with subungual hyperkeratosis • mouth ulcers • conjunctivitis • uveitis, which is rare with the first attack but arises in 30% of patients with recurring or chronic arthritis. Other complications in ReA are very rare but include aortic incompetence, conduction defects, pleuro-pericarditis, peripheral neuropathy, seizures and meningoencephalitis. Investigations The diagnosis is usually made clinically but joint aspiration may be required to exclude crystal arthritis and articular infection. typical ‘bamboo’ spine (Fig. 24.41). Erosive changes may be seen in the symphysis pubis, ischial tuberosities and peripheral joints. Osteoporosis is common and vertebral fractures may occur. Atlanto-axial dislocation can arise as a late feature. MRI is more sensitive for detection of early sacroiliitis than X-rays (see Fig. 24.39) and can also detect inflammatory changes in the lumbar spine. DXA scanning is important as part of a fragility fracture assessment. As in axSpA, ESR and CRP are usually raised in active disease but may be normal; anaemia is often present. Autoantibodies, such as RF, ACPA and ANA, are negative. Management The aims of management are the same as in axSpA: to relieve pain and stiffness, maintain a maximal range of skeletal mobility and avoid the development of deformities. Mobilising exercises are important and are shown on many online resource sites (e.g. National Ankylosing Spondylitis Society, UK). A long-acting NSAID at night is helpful for alleviation of morning stiffness. Anti-TNF or anti-IL-17A therapy should be considered in patients who are inadequately controlled on standard therapy, as described for axSpA. Biologic therapies are often highly effective at improving symptoms but it is not clear whether they prevent ankylosis or alter the natural history of the disease. Local glucocorticoid injections can be useful for persistent plantar fasciitis, other enthesopathies and peripheral arthritis. Oral glucocorticoids may be required for acute uveitis but do not help spinal disease. Severe hip, knee or shoulder arthritis with secondary OA may require arthroplasty. Spinal osteotomy, to correct stoop and make eyeline/posture ‘more normal’, can make a significant difference to patients with severe ankylosed kyphotic spines. Fig. 24.41 ‘Bamboo’ spine of advanced ankylosing spondylitis. Note the symmetrical marginal syndesmophytes (arrows), sacroiliac joint fusion and generalised osteopenia.

1032 • RHEUMATOLOGY AND BONE DISEASE Pathophysiology Genetic factors have an important role in PsA and family studies have suggested that heritability may exceed 80%. Variants in the HLA-B and HLA-C genes are the strongest genetic risk factors but more than 30 other variants also play a part. Many of these variants overlap with those implicated in psoriasis (p. 1247), where there are more than 40 susceptibility loci. These lie within or close to genes in the IL-12, IL-23 and nuclear factor kappa B (NFκB) signalling pathways. It is thought that an environmental trigger, probably infectious in nature, triggers the disease in genetically susceptible individuals, leading to immune activation involving dendritic cells and T cells. CD8+ T cells (which recognise antigen presented in the context of HLA class I) are more abundant than CD4+ T cells within the joint, which is in keeping with the genetic association between PsA and HLA-C and B variants. There is increasing evidence that the IL-23/ IL-17 pathway plays a pivotal role in PsA. It is thought that the triggering stimulus causes over-production of IL-23 by dendritic cells, which in turn promotes differentiation and activation of Th17 cells, which produce the pro-inflammatory cytokine IL-17A. This, along with Th1 cytokines like IFN-γ and TNF-α, acts on macrophages and tissue-resident stromal cells at entheses, in bone and within the joint to produce additional pro-inflammatory cytokines and other mediators, which contribute to inflammation and tissue damage, as shown in Figure 24.42. Clinical features The presentation is with pain and stiffness affecting joints, tendons, spine and entheses. Joints are typically not swollen; however, several patterns of joint involvement are recognised (see below), including an oligoarticular form. These patterns are not mutually exclusive. Marked variation in disease patterns exists, including a disease course of intermittent exacerbation and remission. Destructive arthritis and disability are uncommon, except in the case of arthritis mutilans. Asymmetrical inflammatory mono-/oligoarthritis This often presents abruptly with a combination of synovitis and adjacent periarticular inflammation. It occurs most characteristically in the hands and feet, when synovitis of a finger or toe is coupled with tenosynovitis, enthesitis and inflammation of intervening tissue to give a ‘sausage digit’ or dactylitis (Fig. 24.43A). Large joints, such as the knee and ankle, may also be involved, sometimes with very large effusions. Symmetrical polyarthritis This accounts for about 25% of cases. It predominates in women and may resemble RA, with symmetrical involvement of small and large joints in both upper and lower limbs. Nodules and other extra-articular features of RA are absent and arthritis is generally less extensive and more benign. Distal interphalangeal joint arthritis This is quite a common pattern and can be difficult to distinguish from inflammatory generalised OA. PsA DIP joint disease is associated with psoriatic nail disease (Fig. 24.43B). Psoriatic spondylitis This type presents with inflammatory back or neck pain and prominent stiffness symptoms. Any structure in the spine can be involved, including intervertebral disc entheses and facet joints. It may occur alone or with any of the other clinical patterns described above and is typically unilateral or asymmetric in severity. ESR and CRP are raised, urethritis may be confirmed in the ‘two-glass test’ by demonstration of mucoid threads in the first-void specimen that clear in the second. High vaginal swabs may reveal Chlamydia on culture. Except for post-Salmonella arthritis, stool cultures are usually negative by the time the arthritis presents but serology may help confirm previous dysentery. RF, ACPA and ANA are negative. In chronic or recurrent disease, X-rays show periarticular osteoporosis; proliferative erosions, notably at entheses; periostitis, especially of metatarsals, phalanges and pelvis; and large, ‘fluffy’ calcaneal spurs. In contrast to AS, radiographic sacroiliitis is often asymmetrical and sometimes unilateral, and syndesmophytes are predominantly coarse and asymmetrical, often extending beyond the contours of the annulus (‘non-marginal’) (see Fig. 24.40B). Radiographic changes in the peripheral joints and spine are identical to those seen in psoriasis. Management Acute ReA should be treated with rest, NSAIDs and analgesics. Intra-articular or systemic glucocorticoids may be required in patients with severe monarticular synovitis or polyarticular disease, respectively. There is no convincing evidence for the use of antibiotics unless a triggering infection is identified. If chlamydial urethritis is diagnosed, it should be treated empirically with a short course of doxycycline or a single dose of azithromycin. Treatment with DMARDs (usually sulfasalazine or methotrexate) should be considered for patients with persistent marked symptoms, recurrent arthritis or severe keratoderma blennorrhagica. Anterior uveitis is a medical emergency requiring topical, subconjunctival or systemic glucocorticoids. For DMARD-recalcitrant cases, anti-TNF therapy should be considered. Psoriatic arthritis In the UK and Denmark the estimated population prevalence of psoriatic arthritis (PsA) from registry and coding data is approximately 0.2%. It is likely the true prevalence is considerably higher but this has not been extensively studied. The prevalence of PsA in psoriasis patients, based on clinical assessment, is variable but may be up to 40%. Early PsA may present as axSpA. The onset is usually between 25 and 40 years of age but juvenile forms exist. Occasionally, the arthritis and psoriasis develop synchronously but the onset of musculoskeletal and skin disease is frequently separated by many years. Classification of PsA requires key assessments of family history and screening for enthesitis (Box 24.62). 24.62 The CASPAR criteria for psoriatic arthritis Inflammatory articular disease (joint, spine or enthesis) with ≥ 3 points from the following (1 point each unless stated): • Current psoriasis (scores 2 points) • History of psoriasis in first- or second-degree relative • Psoriatic nail dystrophy • Negative IgM rheumatoid factor1 • Current dactylitis • History of dactylitis • Juxta-articular new bone2 (CASPAR = ClASsification for Psoriatic ARthritis) 2Ill-defined ossification near joint 1Established by any method except latex. margins (excluding osteophytes) on X-rays of hands or feet.

Spondyloarthropathies • 1033

Investigations The diagnosis is made on clinical grounds. Autoantibodies are generally negative and acute phase reactants, such as ESR and CRP, are raised in only a proportion of patients with active disease. X-rays may be normal or show erosive change with joint space narrowing. Features that favour PsA over RA include the characteristic distribution (see Fig. 24.10, p. 994) of proliferative erosions with marked new bone formation, absence of periarticular osteoporosis and osteosclerosis. Imaging of the axial skeleton often reveals features similar to those in chronic ReA, with coarse, asymmetrical, non-marginal syndesmophytes and asymmetrical sacroiliitis. MRI and ultrasound with power Doppler are increasingly employed to detect synovial inflammation and inflammation at the entheses. Management Therapy with NSAIDs and analgesics may be sufficient to manage symptoms in mild disease. Intra-articular glucocorticoid injections can control isolated synovitis or enthesitis. Splints and prolonged rest should be avoided because of the tendency to fibrous and bony ankylosis. Patients with spondylitis should be prescribed the same exercise and posture regime as in axSpA/AS. Therapy with DMARDs should be considered for persistent synovitis unresponsive to conservative treatment. Methotrexate is the drug of first choice and is also effective Arthritis mutilans This is a deforming erosive arthritis targeting the fingers and toes; it occurs in 5% of cases of PsA. Prominent cartilage and bone destruction results in marked instability. The encasing skin appears invaginated and ‘telescoped’ (‘main en lorgnette’) and the finger can be pulled back to its original length. Enthesitis-predominant This form of disease presents with pain and stiffness at the insertion sites of tendons and ligaments into bone (enthesitis). Symptoms can be extensive or localised. Typically affected entheses include Achilles tendon insertions, plantar fascia origins, patellar ligament attachments, hip abductor complex insertion at lateral femoral condyle, gluteus medius insertion at greater trochanter, humeral epicondyle tendon attachments, deltoid origin at acromial edge, intercostal muscle attachments at ribs, and pelvic ligament attachments. Nail changes include pitting, onycholysis, subungual hyperkeratosis and horizontal ridging, which are found in 85% of patients with PsA and can occur in the absence of skin disease. The characteristic rash of psoriasis (p. 1247) may be widespread, or confined to the scalp, natal cleft, umbilicus and genitals, where it is easily overlooked. Obtaining a history of psoriasis in a first-degree relative can be tricky but is important, given that a positive response contributes to making a diagnosis. Fig. 24.42 Pathogenesis of psoriatic arthritis. Some of the cytokines and cellular interactions believed to be important in psoriatic arthritis are shown. (ADAMTS-5 = aggrecanase; IL = interleukin; M-CSF = macrophage colony-stimulating factor; MMP = matrix metalloproteinase; TNF = tumour necrosis factor; RANKL = RANK ligand) IL-12 Th1 Th17 Th1 Th17 IL-23 IL-17 IL-17 IL-17 RANKL M-CSF Osteoclast precursors MMP ADAMTS-5 TNF-α IL-1 IL-6 TNF-α IFN-γ TNF-α IL-1 IL-6 Dysregulation of immune response in mucosa or skin Synovial fibroblasts Prostaglandins Nitric oxide Pain Vasodilatation Cartilage breakdown Enthesitis at tendon insertions Acute phase proteins Bone erosions Dendritic cell Environmental trigger • Infection • Trauma Genetic predisposition • HLA-C, HLA-B • Other immune response genes Macrophage IL-6

1034 • RHEUMATOLOGY AND BONE DISEASE In Crohn’s disease, more than in colitis, the arthritis usually coincides with exacerbations of the underlying bowel disease and the arthritis improves with effective treatment of the bowel disease. There is some suggestion that the severity and onset of inflammatory musculoskeletal symptoms can vary in association with changes in the integrity of the ileocaecal valve, raising the possibility that changes in gut flora may act as triggers for the associated SpA. NSAIDs are best avoided, since they can exacerbate IBD. Instead, judicious use of glucocorticoids, sulfasalazine and methotrexate may be considered. Liaison is necessary between gastroenterologist and rheumatologist with regard to choice of therapy. Anti-TNF therapy is effective in enteropathic arthritis but etanercept should be avoided, as it has no efficacy in IBD. When musculoskeletal symptoms worsen despite anti-TNF therapy, it is wise to exclude bacterial overgrowth as a triggering cause (blind-loop syndrome). Autoimmune connective tissue diseases Autoimmune connective tissue diseases (AICTDs) share many clinical features and are characterised by dysregulation of immune responses, autoantibody production that is often directed at components of the cell nucleus, and tissue damage. Systemic lupus erythematosus Systemic lupus erythematosus (SLE, ‘lupus’) is a rare disease with a prevalence that ranges from about 0.03% in Caucasians to 0.2% in Afro-Caribbeans. Some 90% of affected patients are female and the peak age at onset is between 20 and 30 years. SLE is associated with considerable morbidity and a fivefold increase in mortality compared to age- and gender-matched controls, mainly because of an increased risk of premature cardiovascular disease. Pathophysiology The cause of SLE is incompletely understood but genetic factors play an important role. There is a higher concordance in monozygotic twins and the disease is strongly associated with polymorphic variants at the HLA locus. In a few instances, SLE is associated with inherited mutations in complement components C1q, C2 and C4, in the immunoglobulin receptor FcγRIIIb or in the DNA exonuclease TREX1. Genome-wide association studies have identified common polymorphisms near several other genes that predispose to SLE, most of which are involved in regulating immune cell function. From an immunological standpoint, the characteristic feature of SLE is autoantibody production. These autoantibodies have specificity for a wide range of targets but many are directed against antigens present within the cell or within the nucleus. This has led to the hypothesis that SLE may occur because of defects in apoptosis or in the clearance of apoptotic cells, which causes inappropriate exposure of intracellular antigens on the cell surface, leading to polyclonal B- and T-cell activation and autoantibody production. This is supported by the fact that environmental factors that cause flares of lupus, such as ultraviolet light and infections, increase oxidative stress and cause cell damage. Whatever the underlying cause, autoantibody production and immune complex formation are thought to be important mechanisms of tissue damage in active SLE, leading to vasculitis and organ damage. for skin disease (see EULAR guidelines, ‘Further information’, p. 1060). Other DMARDs may also be helpful, including sulfasalazine, ciclosporin and leflunomide. Particular attention should be paid to monitoring liver function in patients treated with DMARDs, since abnormalities are common in PsA. Hydroxychloroquine is generally avoided, as it can cause exfoliative skin reactions; it may, however, be tried in the small subset of patients who have mild PsA but no psoriasis and are ANA-positive. Anti-TNF treatment should be considered for individuals with active synovitis who respond inadequately to standard DMARDs, and treatment is effective for both PsA and psoriasis. Ustekinumab, a monoclonal antibody that binds to and neutralises the p40 subunit of IL-12 and IL-23, improves joint, dactylitis and enthesitis lesions in PsA. Secukinumab, a monoclonal antibody that targets IL-17A, has similar efficacy to TNF inhibitors in PsA. Apremilast is an oral small-molecule inhibitor of phosphodiesterase 4 (PDE4), which is effective in PsA when DMARD therapy fails, although it appears to be less efficacious than biologic treatment. Adverse effects include weight loss, depression and suicidal ideation. Enteropathic (spondylo)arthritis The overall prevalence of inflammatory musculoskeletal disease in inflammatory bowel diseases (IBDs: Crohn’s disease and ulcerative colitis) is not well known, as studies have not adequately assessed enthesitis and osteitis lesions, but the musculoskeletal manifestations are in keeping with an SpA phenotype. Involvement of the peripheral joints is seen in about 20% of IBD patients. Oligoarticular disease predominantly affects the large lower limb joints (knees, ankles and hips). Radiographic evidence of sacroiliitis is present in about 20–25% of IBD patients. Fig. 24.43 Psoriatic arthropathy. A Dactylitis. B Distal interphalangeal joint pattern with accompanying nail dystrophy (pitting and onycholysis). A B

Autoimmune connective tissue diseases • 1035

due to the adverse effects of inflammation on the endothelium, chronic glucocorticoid therapy and the procoagulant effects of antiphospholipid antibodies. Lung Lung involvement is common and most frequently manifests as pleuritic pain (serositis) or pleural effusion. Other features include pneumonitis, atelectasis, reduced lung volume and pulmonary fibrosis that leads to breathlessness. The risk of thromboembolism is increased, especially in patients with antiphospholipid antibodies. Neurological Fatigue, headache and poor concentration are common and often occur in the absence of laboratory evidence of active disease. More specific features of cerebral lupus include visual hallucinations, chorea, organic psychosis, transverse myelitis and lymphocytic meningitis. Haematological Neutropenia, lymphopenia, thrombocytopenia and haemolytic anaemia may occur, due to antibody-mediated destruction of Clinical features Symptoms such as fever, weight loss and mild lymphadenopathy may occur during flares of disease activity, whereas others such as fatigue and low-grade joint pains can be constant and not particularly associated with active inflammatory disease. Arthritis Arthralgia is a common symptom, occurring in 90% of patients, and is often associated with early morning stiffness. Tenosynovitis may also occur but clinically apparent synovitis with joint swelling is rare. Joint deformities may arise (Jaccoud’s arthropathy) as the result of tendon damage but joint erosions are not a feature. Raynaud’s phenomenon Raynaud’s phenomenon (p. 504) is common and may antedate other symptoms by months or years. SLE can present with Raynaud’s phenomenon, along with arthralgia or arthritis. Secondary Raynaud’s phenomenon associated with SLE and other AICTDs needs to be differentiated from primary Raynaud’s phenomenon, which is common in the general population (up to 5%). Features in favour of secondary Raynaud’s phenomenon include age at onset of over 25 years, absence of a family history of Raynaud’s phenomenon, and occurrence in a male. Examination of capillary nail-fold loops using an ophthalmoscope (and oil placed on the skin) can show loss of the normal loop pattern, with capillary ‘fallout’ and dilatation and branching of loops; these features support either a diagnosis of systemic sclerosis or severe primary Raynaud’s phenomenon. If Raynaud’s phenomenon is severe, digital ulceration can occur (Fig. 24.44). Skin The skin is commonly involved in SLE, and many SLE skin eruptions are precipitated by exposure to ultraviolet light. The main types of skin involvement are: • The classic facial rash (up to 20% of patients). This is erythematous, raised and painful or itchy, and occurs over the cheeks with sparing of the nasolabial folds (Fig. 24.45). Rosacea is a mimic of this rash. • A discoid rash characterised by hyperkeratosis and follicular plugging, with scarring alopecia if it occurs on the scalp. • Diffuse, usually non-scarring alopecia, which may also occur with active disease. • Urticarial eruptions. • Livedo reticularis (Fig. 24.46), which is also a feature of antiphospholipid syndrome (p. 977) and can become frankly vasculitic, if severe. Kidney Renal involvement is one of the main determinants of prognosis and regular monitoring of urinalysis and blood pressure is essential. The typical renal lesion is a proliferative glomerulonephritis (p. 397), characterised by heavy haematuria, proteinuria and casts on urine microscopy. Cardiovascular The most common manifestation is pericarditis. Myocarditis and Libman–Sacks endocarditis can also occur. The endocarditis is due to accumulation on the heart valves of sterile fibrincontaining vegetations, which is thought to be a manifestation of hypercoagulability associated with antiphospholipid antibodies. The risk of atherosclerosis is greatly increased, as is the risk of stroke and myocardial infarction. This is thought to be multifactorial Fig. 24.44 Severe secondary Raynaud’s phenomenon leading to digital ulceration. Fig. 24.45 Malar rash of systemic lupus erythematosus, sparing the nasolabial folds. The rash is notably similar to rosacea, which may itself be associated with inflammatory joint diseases such as psoriatic arthritis.

1036 • RHEUMATOLOGY AND BONE DISEASE damage and maintain normal function. Patients should be advised to avoid sun and ultraviolet light exposure and to employ sun blocks (sun protection factor 25–50). Mild to moderate disease Patients with mild disease restricted to skin and joints can sometimes be managed with analgesics, NSAIDs and hydroxychloroquine. Frequently, however, glucocorticoids are also necessary (prednisolone 5–20 mg/day), often in combination with immunosuppressants such as methotrexate, azathioprine or mycophenolate mofetil (MMF). Increased doses of glucocorticoids may be required for flares in activity or complications such as pleurisy or pericarditis. The monoclonal antibody belimumab, which targets the β-cell growth factor BLyS, has recently been shown to be effective in patients with active SLE who have responded inadequately to standard therapy. Severe and life-threatening disease High-dose glucocorticoids and immunosuppressants are required for the treatment of renal, CNS and cardiac involvement. A commonly used regimen is pulsed methylprednisolone (10 mg/kg IV) plus cyclophosphamide (15 mg/kg IV), repeated at 2–3-weekly intervals for six cycles. Cyclophosphamide may cause haemorrhagic cystitis but the risk can be minimised by good hydration and co-prescription of mesna (2-mercaptoethane sulfonate), which binds its urotoxic metabolites. Because of the risk of azoospermia and premature menopause, sperm or oöcyte collection and storage need to be considered prior to treatment with cyclophosphamide. peripheral blood cells. The degree of lymphopenia is a good guide to disease activity. Gastrointestinal Mouth ulcers may occur and may or may not be painful. Peritoneal serositis can cause acute pain. Mesenteric vasculitis is a serious complication, which can present with abdominal pain, bowel infarction or perforation. Hepatitis is a recognised, though rare, feature. Paediatric disease Renal disease and cutaneous manifestations are more frequent in juvenile-onset SLE compared to disease in adults. Similarly, there is subsequently a higher incidence of renal disease, malar rash, Raynaud’s phenomenon, cutaneous vasculitis and neuropsychiatric manifestations than in adults. Investigations The diagnosis is based on a combination of clinical features and laboratory abnormalities. To fulfil the classification criteria for SLE, at least 4 of the 11 factors shown in Box 24.63 must be present or have occurred in the past. Checking of ANAs, antibodies to ENAs and complement, routine haematology, biochemistry and urinalysis are mandatory. Patients with active SLE test positive for ANA. Some authorities believe that ANA-negative SLE occurs (e.g. in the presence of antibodies to Ro) but others regard SLE as necessarily ANA-positive; the issue may be more to do with sensitivity of the ANA assay at any given time in a disease course. Anti-dsDNA antibodies are positive in many, but not all, patients and are tested at the time of diagnosis by most laboratories using ELISA. ELISAs have low specificity, whereas testing for anti-dsDNA antibodies using Crithidia luciliae is highly specific. Patients with active disease tend to have low levels of C3 due to complement consumption, but in some people low C3 and C4 may be the result of inherited complement deficiency in C1, C2 or C4 that predisposes to SLE (p. 66). Studies of other family members can help to differentiate inherited deficiency from complement consumption. A raised ESR, leucopenia and lymphopenia are typical of active SLE, along with anaemia, haemolytic anaemia and thrombocytopenia. CRP is often normal in active SLE, except in the presence of serositis; thus an elevated CRP suggests infection. Management The therapeutic goals are to educate the patient about the nature of the illness, to control symptoms and to prevent organ Fig. 24.46 Livedo reticularis (systemic lupus erythematosus and anti-phospholipid syndrome). 24.63 Criteria for the classification of systemic lupus erythematosus Features Characteristics Malar rash Fixed erythema, flat or raised, sparing the nasolabial folds Discoid rash Erythematous raised patches with adherent keratotic scarring and follicular plugging Photosensitivity Rash due to unusual reaction to sunlight Oral ulcers Oral or nasopharyngeal ulceration, which may be painless Arthritis Non-erosive, involving two or more peripheral joints Serositis Pleuritis (history of pleuritic pain or rub, or pleural effusion) or pericarditis (rub, electrocardiogram evidence or effusion) Renal disorder Persistent proteinuria > 0.5 g/24 hrs or cellular casts (red cell, granular or tubular) Neurological disorder Seizures or psychosis, in the absence of provoking drugs or metabolic derangement Haematological disorder Haemolytic anaemia or leucopenia* (< 4 × 109/L) or lymphopenia* (< 1 × 109/L) or thrombocytopenia* (< 100 × 109/L) in the absence of offending drugs Immunological Anti-DNA antibodies in abnormal titre or presence of antibody to Sm antigen or positive antiphospholipid antibodies Antinuclear antibody (ANA) Abnormal titre of ANA by immunofluorescence An adult has SLE if any 4 of 11 features are present serially or simultaneously *On two separate occasions.

Autoimmune connective tissue diseases • 1037

Pathophysiology The cause of SScl is not completely understood. There is evidence for a genetic component and associations with alleles at the HLA locus have been found. The disease occurs in all ethnic groups and race may influence severity. Isolated cases have been reported in which an SScl-like disease has been triggered by exposure to silica dust, vinyl chloride, epoxy resins and trichloroethylene. There is clear evidence of immunological dysfunction: T lymphocytes, especially those of the Th17 subtype, infiltrate the skin and there is abnormal fibroblast activation, leading to increased production of extracellular matrix in the dermis, primarily type I collagen. This results in symmetrical thickening, tightening and induration of the skin (scleroderma). Arterial and arteriolar narrowing occurs due to intimal proliferation and vessel wall inflammation. Endothelial injury causes release of vasoconstrictors and platelet activation, resulting in further ischaemia, which is thought to exacerbate the fibrotic process. Clinical features Skin Initially, there is non-pitting oedema of fingers and flexor tendon sheaths. Subsequently, the skin becomes shiny and taut, and distal skin creases disappear. There can be capillary loss. The face and neck are often involved, with thinning of the lips and radial furrowing. In some patients, skin thickening stops at this stage. Skin involvement restricted to sites distal to the elbow or knee (apart from the face) is thus classified as lcSScl (Fig. 24.48). Involvement proximal to the knee and elbow and on the trunk is classified as ‘diffuse disease’ (dcSScl). Raynaud’s phenomenon This is a universal feature and can precede other features by many years. Involvement of small blood vessels in the extremities may cause critical tissue ischaemia, leading to localised distal skin infarction and necrosis. Musculoskeletal features Arthralgia and flexor tenosynovitis are common. Restricted hand function is due to skin rather than joint disease and erosive arthropathy is uncommon. Muscle weakness and wasting can result from myositis. Gastrointestinal involvement Smooth muscle atrophy and fibrosis in the lower two-thirds of the oesophagus lead to reflux with erosive oesophagitis. MMF has been used successfully with high-dose glucocorticoids for renal involvement with results similar to those of pulsed cyclophosphamide but fewer adverse effects. Belimumab in combination with standard therapy significantly decreases disease activity in SLE patients and is safe and well tolerated. Its role in patients with renal and neurological disease is still under investigation. Rituximab has been reported as being effective in selected cases, though randomised controlled trials have not shown significant overall efficacy. Maintenance therapy Following control of acute disease, a typical maintenance regimen is oral prednisolone in a dose of 40–60 mg daily, gradually reducing to 10–15 mg/day or less by 3 months. Azathioprine (2–2.5 mg/kg/day), methotrexate (10–25 mg/week) or MMF (2–3 g/day) should also be prescribed. The long-term aim is to continue the lowest dose of glucocorticoid and immunosuppressant to maintain remission. Cardiovascular risk factors, such as hypertension and hyperlipidaemia, should be controlled and patients should be advised to stop smoking. Patients with SLE and the antiphospholipid antibody syndrome, who have had previous thrombosis, require life-long warfarin therapy. SLE patients are at risk of osteoporosis and hypovitaminosis D, and should be screened with biochemistry and DXA scanning accordingly. Systemic sclerosis Systemic sclerosis (SScl) is an autoimmune disorder of connective tissue, which results in fibrosis affecting the skin, internal organs and vasculature. It is characterised typically by Raynaud’s phenomenon, digital ischaemia (Fig. 24.47), sclerodactyly, and cardiac, lung, gut and renal disease. The peak age of onset is in the fourth and fifth decades and overall prevalence is 10–20 per 100 000, with a 4 : 1 female-to-male. It is subdivided into diffuse cutaneous systemic sclerosis (dcSScl: 30% of cases) and limited cutaneous systemic sclerosis (lcSScl: 70% of cases). Some patients with lcSScl have calcinosis and telangiectasia. The prognosis in dcSScl is poor (5-year survival about 70%). Features that associate with a poor prognosis include older age, diffuse skin disease, proteinuria, high ESR, a low gas transfer factor for carbon monoxide (TLCO) and pulmonary hypertension. Fig. 24.47 Systemic sclerosis. Hands showing tight, shiny skin, sclerodactyly, flexion contractures of the fingers and thickening of the left middle finger extensor tendon sheath. Fig. 24.48 Typical facial appearance showing telangiectasias in localised cutaneous systemic sclerosis.

1038 • RHEUMATOLOGY AND BONE DISEASE may help patients with symptoms of dysmotility/ pseudo-obstruction. • Hypertension. Aggressive treatment with ACE inhibitors is needed, even if renal impairment is present. • Joint involvement. This may be treated with analgesics and/or NSAIDs. If synovitis is present and both RA (i.e. an ‘overlap’ condition, which needs treatment on its own merit) and OA have been ruled out, low-dose methotrexate can be of value. • Progressive pulmonary hypertension. Early treatment with bosentan is required. In severe or progressive disease, heart–lung transplant may be considered. • Interstitial lung disease. Glucocorticoids and (pulse intravenous) cyclophosphamide are the mainstays of treatment in patients who have progressive interstitial lung disease. Mixed connective tissue disease Mixed connective tissue disease (MCTD) is a condition in which some clinical features of SScl, myositis and SLE all occur in the same patient. It commonly presents with indolent puffiness of the fingers (the appearance is between that of SpA-type dactylitis and sclerodactyly) with Raynaud’s phenomenon and myalgias. Most patients have anti-RNP antibodies. Management focuses on treating the components of the disease (see other sections). Primary Sjögren’s syndrome Primary Sjögren’s syndrome (PSS) is characterised by lymphocytic infiltration of salivary and lacrimal glands, leading to glandular fibrosis and exocrine failure. The typical age of onset is between 40 and 50, with a 9 : 1 female-to-male ratio. The disease may occur with other autoimmune diseases (secondary Sjögren’s syndrome). Clinical features The eye symptoms, termed keratoconjunctivitis sicca, are due to a lack of lubricating tears, which reflects inflammatory infiltration of the lacrimal glands. Conjunctivitis and blepharitis are frequent, and may lead to filamentary keratitis due to binding of tenacious mucous filaments to the cornea and conjunctiva. Oral involvement manifests as a dry mouth (xerostomia). There is a high incidence of dental caries and high risk of dental failure. Other sites of extraglandular involvement are listed in Box 24.64. Often the most disabling symptom is fatigue. There may be an association with inflammatory small-joint OA (clinical suspicion, though formal studies have not been done). Sialadenitis, osteoarthritis and xerostomia (SOX) syndrome has been described; this may occur independently of PSS or, more likely, constitute a mild form. Both interstitial lung disease and interstitial nephritis (sometimes complicated by renal tubular acidosis) require proactive screening. PSS is associated with a 40-fold increased lifetime risk of lymphoma, though the complication is still very rare. Investigations The diagnosis can be established by the Schirmer tear test, which measures tear flow over 5 minutes using absorbent paper strips placed on the lower eyelid; a normal result is more than 6 mm of wetting. Staining with rose bengal may show punctate epithelial abnormalities over the area not covered by the open eyelid. If the diagnosis remains in doubt, it can be confirmed by demonstrating focal lymphocytic infiltrate in a minor salivary gland biopsy. Most patients have an elevated ESR and Dysphagia and odynophagia may also occur. Involvement of the stomach causes early satiety and occasionally outlet obstruction. Recurrent occult upper gastrointestinal bleeding may indicate a ‘watermelon’ stomach (antral vascular ectasia; up to 20% of patients). Small intestine involvement may lead to malabsorption due to bacterial overgrowth and intermittent bloating, pain or constipation. Dilatation of bowel due to autonomic neuropathy may cause pseudo-obstruction with nausea, vomiting, abdominal discomfort and distension, often worse after food (symptoms can mimic those of an acute abdomen and can lead to erroneous laparotomy). Pulmonary involvement Pulmonary hypertension complicates long-standing disease and is six times more prevalent in lcSScl than in dcSScl. It usually presents with insidiously evolving exertional dyspnoea and signs of right heart failure. Interstitial lung disease is common in patients with dcSScl who have topoisomerase 1 antibodies (Scl70). Dyspnoea can evolve slowly over time or rapidly in occasional cases. Renal involvement One of the main causes of death is hypertensive renal crisis, characterised by rapidly developing accelerated phase hypertension (p. 514) and renal failure. Hypertensive renal crisis is much more likely to occur in dcSScl than in lcSScl, and in patients with topoisomerase 1 and RNP antibodies. Investigations As SScl can affect multiple organs, routine haematology, renal, liver and bone function tests and urinalysis are essential. ANA is positive in about 70%. About 30% of patients with dcSScl have antibodies to topoisomerase 1 (Scl70). About 60% of patients with lcSScl syndrome have anticentromere antibodies (p. 991). Chest X-ray, transthoracic echocardiography and lung function tests are recommended to assess for interstitial lung disease and pulmonary hypertension (low corrected transfer factor may indicate early pulmonary hypertension). High-resolution lung CT is recommended if interstitial lung disease suspected. If pulmonary hypertension is suspected, right heart catheter measurements should be arranged at a specialist cardiac centre. A barium swallow can assess oesophageal involvement. A hydrogen breath test can indicate bacterial overgrowth (p. 808). Management No treatments are available that halt or reverse the fibrotic changes that underlie the disease. The focus of management, therefore, is to slow the effects of the disease on target organs. • Raynaud’s phenomenon and digital ulcers. Avoidance of cold exposure, use of thermal insulating gloves/socks and maintenance of a high core temperature all help. If symptoms are persistent, calcium channel blockers, losartan, fluoxetine and sildenafil have efficacy. Courses of intravenous prostacyclin are used for severe disease and critical ischemia (e.g. 6–8 hours daily for 5 days). The endothelin-1 antagonist bosentan is licensed for treating ischaemic digital ulcers, and digital tip tissue health can be maintained with regular use of fucidin–hydrocortisone cream. • Gastrointestinal complications. Oesophageal reflux should be treated with proton pump inhibitors and anti-reflux agents. Rotating courses of antibiotics may be required for bacterial overgrowth (e.g. rifaximin, a tetracycline and metronidazole), while metoclopramide or domperidone

Autoimmune connective tissue diseases • 1039

Polymyositis and dermatomyositis Polymyositis (PM) and dermatomyositis (DM) are characterised by proximal skeletal and (cardiac and gut) smooth muscle inflammation. In DM, characteristic skin changes also occur. Both diseases are rare, with an incidence of 2–10 cases per million/year. They can occur in isolation or in association with other autoimmune diseases, and both are notably connected with (either previously diagnosed or undisclosed) malignancy. Clinical features The typical presentation of PM and DM is with symmetrical proximal muscle weakness over a few weeks, usually affecting the lower limbs more than the upper, in adults between 40 and 60 years of age. Patients report difficulty rising from a chair, climbing stairs and lifting, often (though not always) with muscle pain. Systemic features of fever, weight loss and fatigue are common. Respiratory or pharyngeal muscle involvement can lead to ventilatory failure or aspiration that requires urgent treatment. Interstitial lung disease occurs in up to 30% of patients and is strongly associated with the presence of antisynthetase (Jo-1) antibodies. In DM, the skin lesions include Gottron’s papules, which are scaly, erythematous or violaceous, psoriasiform plaques occurring over the extensor surfaces of PIP and DIP joints, and a heliotrope rash that is a violaceous discoloration of the eyelid in combination with periorbital oedema (Fig. 24.49). Similar rashes occur on the upper back, chest and shoulders (‘shawl’ distribution). Periungual nail-fold capillaries are often enlarged and tortuous. Investigations Muscle biopsy is the pivotal investigation and shows the typical features of fibre necrosis, regeneration and inflammatory cell infiltrate (Fig. 24.50). Occasionally, however, a biopsy may be normal, particularly if myositis is patchy so, invariably, MRI should be used to identify areas of abnormal muscle for biopsy. Serum levels of creatine kinase are typically raised and are a useful measure of disease activity, although a normal creatine kinase does not exclude the diagnosis, particularly in juvenile myositis. Electromyography is very useful for highlighting non-autoimmune/ non-inflammatory myopathies. Screening for underlying malignancy should be undertaken routinely (full examination, chest X-ray, serum urine and protein electrophoresis, CT of chest/abdomen/ pelvis; prostate-specific antigen should be included in men, and mammography in women). hypergammaglobulinaemia, and one or more autoantibodies, including ANA and RF. ANA-negative disease exists. Anti-Ro and anti-La antibodies are commonly present (see Box 24.10, p. 992). Patients with joint pain, fatigue and RF (with or without ANA) need careful assessment because a number of possibilities exist: PSS and inflammatory OA; RA with incidental ANA; RA/ SLE overlap; or RA/PSS overlap. Knowing ACPA status can help (it is positive in RA). Interstitial lung disease complicates PSS in a sizable minority of patients (persistent dry cough, dyspnoea, coarse ‘Velcro’ crackles on lung auscultation). A chest X-ray and lung function tests should be performed. Management No treatments that have disease-modifying effects have yet been identified and management is symptomatic. Lacrimal substitutes, such as hypromellose, should be used during the day in combination with more viscous lubricating application at night. Soft contact lenses can be useful for corneal protection in patients with filamentary keratitis, and occlusion of the lacrimal ducts is occasionally needed. Artificial saliva sprays, saliva-stimulating tablets, and pastilles and oral gels can be tried for xerostomia but often chewing gum is most effective. Adequate postprandial oral hygiene and prompt treatment of oral candidiasis are essential. Vaginal dryness is treated with lubricants. A trial of systemic pilocarpine (5–30 mg daily in divided doses) is worthwhile in early disease to amplify glandular function. Hydroxychloroquine (200 mg twice daily) is often used to address skin and musculoskeletal features and may help fatigue. Immunosuppression does not improve sicca symptoms but is essential for progressive interstitial lung disease (e.g. glucocorticoids and cyclophosphamide) and for interstitial nephritis (if hydroxychloroquine is ineffective alone). If non-resolving lymphadenopathy or salivary gland enlargement develops, biopsy should be undertaken to exclude malignancy. 24.64 Features of primary Sjögren’s syndrome Risk factors • Age of onset 40–60 • Female > male • HLA-B8/DR3 Common clinical features • Keratoconjunctivitis sicca • Xerostomia • Salivary gland enlargement • Rashes/skin irritation • Non-erosive arthralgia • Generalised osteoarthritis • Raynaud’s phenomenon • Fatigue Less common features • Low-grade fever • Interstitial lung disease • Anaemia, leucopenia • Thrombocytopenia • Cryoglobulinaemia • Vasculitis • Peripheral neuropathy • Lymphadenopathy • Lymphoreticular lymphoma • Glomerulonephritis • Interstitial nephritis • Renal tubular acidosis Autoantibodies frequently detected • Rheumatoid factor • Antinuclear antibody • SS-A (anti-Ro) • SS-B (anti-La) • Gastric parietal cell • Thyroid Associated autoimmune disorders • Systemic lupus erythematosus • Systemic sclerosis • Coeliac disease • Primary biliary cholangitis • Chronic active hepatitis • Myasthenia gravis (HLA = human leucocyte antigen) Fig. 24.49 Typical eyelid appearance in dermatomyositis. Note the oedema and telangiectasia.

1040 • RHEUMATOLOGY AND BONE DISEASE and results of investigations do not allow a clear diagnosis to be made on the basis of conventional criteria. However, recognising that autoimmunity is present (‘autoimmune diathesis’) without making a specific diagnosis can help patients move forwards with chronic symptomology. Some of these individuals will progress to having a recognisable AICTD with time; others will continue to have an undifferentiated disease that remains the same for many years, and in others the symptoms will recede. Clinical monitoring and periodic autoimmune serological testing of all patients is sensible. Adult-onset Still’s disease Adult-onset Still’s disease is a rare systemic inflammatory disorder of unknown cause, possibly triggered by infection; it is similar to sJIA. It presents with intermittent fever, rash and arthralgia, and has been associated with pregnancy and the postpartum period and with high levels of IL-18. Splenomegaly, hepatomegaly and lymphadenopathy may be present. Investigations typically provide evidence of an acute phase response, with a markedly elevated serum ferritin. Tests for RF and ANA are negative and so adult-onset Still’s disease may be better classified as an autoinflammatory rather than an autoimmune disease. Most patients respond to glucocorticoids but immunosuppressants, such as azathioprine or MMF, can be added when response is inadequate. Canakinumab or anakinra can be used for patients with resistant disease. Vasculitis Vasculitis is characterised by inflammation and necrosis of blood-vessel walls, with associated damage to skin, kidney, lung, heart, brain and gastrointestinal tract. There is a wide spectrum of involvement and severity, ranging from mild and transient disease affecting only the skin, to life-threatening fulminant disease with multiple organ failure. Principal sites of involvement for the main types of vasculitis are summarised in Figure 24.51. The clinical features result from a combination of local tissue ischaemia (due to vessel inflammation and narrowing) and the systemic effects of widespread inflammation. Systemic vasculitis should be considered in any patient with fever, weight loss, fatigue, Management Oral glucocorticoids (prednisolone 1 mg/kg daily) are the mainstay of initial treatment of PM and DM but high-dose intravenous methylprednisolone (1 g/day for 3 days) may be required in patients with respiratory or pharyngeal weakness. If there is a good response, glucocorticoids should be reduced by approximately 25% per month to a maintenance dose of 5–7.5 mg. Although most patients respond well to glucocorticoids, many need additional immunosuppressive therapy. Methotrexate and MMF are the first choices of many but azathioprine and ciclosporin are also used as alternatives. Rituximab appears to show efficacy in a majority of patients, although the only controlled study (which was criticised for its suboptimal design) was negative. In clinical practice, rituximab is an option for use with glucocorticoids, to maintain an early glucocorticoid-induced remission. Intravenous immunoglobulin (IVIg) may be effective in refractory cases. Mepacrine or hydroxychloroquine has been used for skinpredominant disease to some good effect in certain cases. One risk of treatment is glucocorticoid-induced myopathy. If the initial response to treatment is poor, further biopsy then shows type II fibre atrophy in glucocorticoid myopathy (compared with fibre necrosis and regeneration in active myositis). Juvenile dermatomyositis Juvenile dermatomyositis (JDM) is by far the most common inflammatory myopathy in children and adolescents, and typically does not require a search for malignancy. The incidence is 2–4 per million (USA and UK) with a median age of onset of 7 years (25% are below 4 years at diagnosis). Many clinical features are similar to those in the adult disease. JDM can be monocyclic, lasting up to 3 years (25–40%), or polycyclic, with periods of remission and relapse (60–75%). In some cases, polycyclic JDM can be chronic and life-long. It is ulcerative in 10–20%. As in adults, calcinosis occurs in about 30%. Intravenous methylprednisolone, then oral glucocorticoids and methotrexate produce a rapid response in many cases. Cyclophosphamide is used for lesional ulceration. IVIg is given in resistant cases. Undifferentiated autoimmune connective tissue disease In some patients, clinical features of AICTD occur, either simultaneously or sequentially, but at any one time the features Fig. 24.50 Muscle biopsy from a patient with polymyositis. The sample shows an intense inflammatory cell infiltrate in an area of degenerating and regenerating muscle fibres. Fig. 24.51 Types of vasculitis. The anatomical targets of different forms of vasculitis are shown. Giant cell arteritis Kawasaki disease Takayasu arteritis Polyarteritis nodosa Behçet’s disease Behçet’s disease Henoch-Schönlein purpura Polyangiitis with granulomatosis

Eosinophilic granulomatosis with polyangiitis Cryoglobulinaemic vasculitis Microscopic polyangiitis

Vasculitis • 1041

with MRI can be useful in localising abnormalities but, where possible, the diagnosis should be confirmed by biopsy of the kidney or lesions in the sinuses and upper airways. Management for organ-threatening or acute–severe disease is with high-dose glucocorticoids (e.g. daily pulse intravenous methylprednisolone 0.5–1 g for 3 days, then oral prednisolone 0.5 mg/kg) and intravenous cyclophosphamide (e.g. 0.5–1 g every 2 weeks for 3 months), followed by maintenance therapy with lower-dose glucocorticoids and azathioprine, methotrexate or MMF. Plasmapheresis should be considered for fulminant lung disease. Rituximab in combination with high-dose glucocorticoids is equally effective as oral cyclophosphamide at inducing remission in AAV. Glucocorticoids and methotrexate are an effective combination for treating limited AAV where there is indolent sinus, lung or skin disease. AAV has a tendency to relapse and patients must be followed on a regular and long-term basis, monitoring urinalysis for blood and protein, plasma creatinine, ESR, CRP, lung function and PR3 or MPO antibody titres. Takayasu arteritis Takayasu arteritis affects the aorta, its major branches and occasionally the pulmonary arteries. The typical age at onset is 25–30 years, with an 8 : 1 female-to-male ratio. It has a worldwide distribution but is most common in Asia. Takayasu arteritis is characterised by granulomatous inflammation of the vessel wall, leading to occlusion or weakening of the vessel wall. It presents with claudication, fever, arthralgia and weight loss. Clinical examination may reveal loss of pulses, bruits, hypertension and aortic incompetence. Investigation will identify an acute phase response and normocytic, normochromic anaemia but the diagnosis is based on angiography, which reveals coarctation, occlusion and aneurysmal dilatation. Treatment is with high-dose glucocorticoids and immunosuppressants, as described for ANCA-associated vasculitis. With successful treatment, the 5-year survival is 83%. Kawasaki disease Kawasaki disease is a vasculitis that mostly involves the coronary vessels. It presents as an acute systemic disorder, usually affecting children under 5 years. It occurs mainly in Japan and other Asian countries, such as China and Korea, but other ethnic groups may also be affected. Presentation is with fever, generalised rash, including palms and soles, inflamed oral mucosa and conjunctival injection resembling a viral exanthem. The cause is unknown but evidence of multisystem involvement, rashes, raised inflammatory markers and abnormal urinalysis (Box 24.65). Antineutrophil cytoplasmic antibody-associated vasculitis Antineutrophil cytoplasmic antibody-associated vasculitis (AAV) is a life-threatening disorder characterised by inflammatory infiltration of small blood vessels, fibrinoid necrosis and the presence of circulating antibodies to antineutrophil cytoplasmic antibody (ANCA). The combined incidence is about 10–15/1 000 000. Two main subtypes are recognised. Microscopic polyangiitis is a necrotising small-vessel vasculitis found with rapidly progressive glomerulonephritis, often in association with alveolar haemorrhage. Cutaneous and gastrointestinal involvement is common and other features include neuropathy (15%) and pleural effusions (15%). Patients are usually myeloperoxidase (MPO) antibody-positive. Secondly, granulomatosis with polyangiitis (formerly known as Wegener’s granulomatosis) is characterised by granuloma formation, mainly affecting the nasal passages, airways and kidney. A minority of patients present with glomerulonephritis. The most common presentation of granulomatosis with polyangiitis is with epistaxis, nasal crusting and sinusitis, but haemoptysis and mucosal ulceration may also occur. Deafness may be a feature due to inner ear involvement, and proptosis may occur because of inflammation of the retro-orbital tissue (Fig. 24.52). This causes diplopia due to entrapment of the extra-ocular muscles, or loss of vision due to optic nerve compression. Disturbance of colour vision is an early feature of optic nerve compression. Untreated nasal disease ultimately leads to destruction of bone and cartilage. Migratory pulmonary infiltrates and nodules occur in 50% of patients (as seen on high-resolution CT of lungs). Patients with granulomatosis with polyangiitis are usually proteinase-3 (PR3) antibody-positive (ELISA). Patients with active disease usually have a leucocytosis with elevated CRP, ESR and PR3. Complement levels are usually normal or slightly elevated. Imaging of the upper airways or chest 24.65 Clinical features of systemic vasculitis Systemic • Malaise • Fever • Night sweats • Weight loss with arthralgia and myalgia Rashes • Palpable purpura • Pulp infarcts • Ulceration • Livedo reticularis Ear, nose and throat • Epistaxis • Recurrent sinusitis • Deafness Respiratory • Haemoptysis • Cough • Poorly controlled asthma Gastrointestinal • Abdominal pain (due to mucosal inflammation or enteric ischaemia) • Mouth ulcers • Diarrhoea Neurological • Sensory or motor neuropathy Fig. 24.52 Eye involvement in antineutrophil cytoplasmic antibodyassociated vasculitis.

1042 • RHEUMATOLOGY AND BONE DISEASE have symptoms of PMR, and many patients with PMR go on to develop GCA if untreated, many rheumatologists consider them to be different manifestations of the same underlying disorder. Both diseases are rare under the age of 60 years. The average age at onset is 70, with a female-to-male ratio of about 3 : 1. The overall prevalence is about 20 per 100 000 in those over the age of 50 years. Clinical features The cardinal symptom of GCA is headache, which is often localised to the temporal or occipital region and may be accompanied by scalp tenderness. Jaw pain develops in some patients, brought on by chewing or talking. Visual disturbance can occur (most specifically amaurosis) and a catastrophic presentation is with blindness in one eye due to occlusion of the posterior ciliary artery. On fundoscopy, the optic disc may appear pale and swollen with haemorrhages, but these changes may take 24–36 hours to develop and the fundi may initially appear normal. Rarely, neurological involvement may occur, with transient ischaemic attacks, brainstem infarcts and hemiparesis. In GCA, constitutional symptoms, such as weight loss, fatigue, malaise and night sweats, are common. With PMR, there may be stiffness and painful restriction of active shoulder movements on waking. Muscles are not otherwise tender, and weakness and muscle-wasting are absent. Other conditions that cause PMR-like symptoms are shown in Box 24.66. Investigations The typical laboratory abnormality is an elevated ESR, often with a normochromic, normocytic anaemia. CRP may also be elevated and abnormal liver function can occur. Rarely, PMR and GCA can present with a normal ESR. More objective evidence for GCA should be obtained whenever possible. There are three investigations to consider: temporal artery biopsy, ultrasound of the temporal arteries and 19fluorodeoxyglucose positron emission tomography (19FDG PET scan). Characteristic biopsy findings are fragmentation of the internal elastic lamina with necrosis of the media in combination with a mixed inflammatory cell infiltrate. Diagnostic yield is highest with multiple biopsies and multiple section analysis (to detect ‘skip’ lesions). A negative biopsy does not exclude the diagnosis. On ultrasound examination, affected temporal arteries show a ‘halo’ sign. A strongly positive 19FDG PET scan is highly specific but sensitivity is low. Caution is needed in interpreting weakly positive images. Low-grade vascular uptake may occur in atheromatous arterial disease. Management Prednisolone should be commenced urgently in suspected GCA because of the risk of visual loss (Box 24.67). Response is thought to be an abnormal immune response to an infectious trigger. Cardiovascular complications include coronary arteritis, leading to myocardial infarction, transient coronary dilatation, myocarditis, pericarditis, peripheral vascular insufficiency and gangrene. Treatment is with aspirin (5 mg/kg daily for 14 days) and IVIg (400 mg/kg daily for 4 days). Polyarteritis nodosa Polyarteritis nodosa has a peak incidence between the ages of 40 and 50, with a male-to-female ratio of 2 : 1. The annual incidence is about 2/1 000 000. Hepatitis B is an important risk factor and the incidence is 10 times higher in the Inuit of Alaska, in whom hepatitis B infection is endemic. Presentation is with fever, myalgia, arthralgia and weight loss, in combination with manifestations of multisystem disease. The most common skin lesions are palpable purpura (Fig. 24.53), ulceration, infarction and livedo reticularis (see Fig. 24.46). Pathological changes comprise necrotising inflammation and vessel occlusion, and in 70% of patients arteritis of the vasa nervorum leads to neuropathy, which is typically symmetrical and affects both sensory and motor function. Severe hypertension and/or renal impairment may occur due to multiple renal infarctions but glomerulonephritis is rare (in contrast to microscopic polyangiitis). The diagnosis is confirmed by conventional or magnetic resonance angiography, which shows multiple aneurysms and smooth narrowing of mesenteric, hepatic or renal systems, or by muscle or sural nerve biopsy, which reveals the histological changes described above. Treatment is with high-dose glucocorticoids and immunosuppressants, as described for ANCA-associated vasculitis. Giant cell arteritis and polymyalgia rheumatica Giant cell arteritis (GCA) is a granulomatous arteritis that affects any large (including aorta) and medium-sized arteries. It is commonly associated with polymyalgia rheumatica (PMR), which presents with symmetrical, immobility-associated neck and shoulder girdle pain and stiffness. Since many patients with GCA Fig. 24.53 Rash of systemic vasculitis (palpable purpura). 24.66 Conditions that can mimic polymyalgia rheumatica • Calcium pyrophosphate disease • Spondyloarthritis • Hyper-/hypothyroidism • Psoriatic arthritis (enthesopathic) • Systemic vasculitis • Myeloma • Inflammatory myopathy (particularly inclusion body myositis, p. 1059) • Lambert–Eaton syndrome (p. 1143) • Multiple separate lesions (cervical spondylosis, cervical radiculopathy, bilateral subacromial impingement, facet joint arthritis, osteoarthritis of the acromioclavicular joint)

Vasculitis • 1043

It is predominantly a disease of children and young adults. The usual presentation is with purpura over the buttocks and lower legs, accompanied by abdominal pain, gastrointestinal bleeding and arthralgia. Nephritis can also occur and may present up to 4 weeks after the onset of other symptoms. Biopsy of affected tissue shows a vasculitis with IgA deposits in the vessel wall. Henoch–Schönlein purpura is usually a self-limiting disorder that settles spontaneously without specific treatment. Glucocorticoids and immunosuppressive therapy may be required in patients with more severe disease, particularly in the presence of nephritis. Cryoglobulinaemic vasculitis This is a small-vessel vasculitis that occurs when immunoglobulins precipitate out in the cold. Cryoglobulins are classified into three types (see Box 4.21, p. 84). Types II and III are associated with vasculitis. The typical presentation is with a vasculitic rash over the lower limbs, arthralgia, Raynaud’s phenomenon and neuropathy. Some cases are secondary to hepatitis C infection and others are associated with other autoimmune diseases. Affected patients should be screened for evidence of hepatitis B and C infection, and if the results are positive, these should be treated appropriately (pp. 875 and 878). There is no consensus as to how best to treat cryoglobulinaemic vasculitis in the absence of an obvious trigger. Glucocorticoids and immunosuppressive therapy are often used empirically but their efficacy is uncertain. In severe cases, plasmapheresis can be considered. Behçet’s disease This is a vasculitis of unknown aetiology that characteristically targets small arteries and venules. It is rare in Western Europe but more common in ‘Silk Route’ countries, around the Mediterranean and in Japan, where there is a strong association with HLA-B51. Oral ulcers are universal (Fig. 24.54). Unlike aphthous ulcers, they are usually deep and multiple, and last for 10–30 days. Genital ulcers are also a common problem, occurring in 60–80% of cases. The usual skin lesions are erythema nodosum or acneiform lesions but migratory thrombophlebitis and vasculitis also occur. Ocular involvement is common and may include anterior or posterior uveitis or retinal vasculitis. Neurological involvement occurs in 5% and mainly involves the brainstem, is dramatic, such that symptoms will completely resolve within 48–72 hours of starting therapy in virtually all patients. It is customary to use higher doses in GCA (60–80 mg prednisolone) than in PMR (15–20 mg), although the evidence base for this is weak. In both conditions, the glucocorticoid dose should be progressively reduced, guided by symptoms and ESR, with the aim of reaching a dose of 10–15 mg by about 8 weeks. The rate of reduction should then be slowed by 1 mg per month. If symptoms recur, the dose should be increased to that which previously controlled the symptoms, and reduction attempted again in another few weeks. Most patients need glucocorticoids for an average of 12–24 months. For advice on prophylaxis against giant cell-induced osteoporosis, see page 1047. Eosinophilic granulomatosis with polyangiitis (Churg–Strauss syndrome) Eosinophilic granulomatosis with polyangiitis (formerly known as Churg–Strauss syndrome) is a small-vessel vasculitis with an incidence of about 1–3 per 1 000 000. It is associated with eosinophilia. Some patients have a prodromal period for many years, characterised by allergic rhinitis, nasal polyposis and late-onset asthma that is often difficult to control. The typical acute presentation is with a triad of skin lesions (purpura or nodules), asymmetric mononeuritis multiplex and eosinophilia. Pulmonary infiltrates and pleural or pericardial effusions due to serositis may be present. Up to 50% of patients have abdominal symptoms provoked by mesenteric vasculitis. Patients with active disease have raised levels of ESR and CRP and an eosinophilia. Although antibodies to MPO or PR3 can be detected in up to 60% of cases, eosinophilic granulomatosis with polyangiitis is considered to be a distinct disorder from the other ANCA-associated vasculitides. Biopsy of an affected site reveals a small-vessel vasculitis with eosinophilic infiltration of the vessel wall. Management is with high-dose glucocorticoids and cyclophosphamide, followed by maintenance therapy with low-dose glucocorticoids and azathioprine, methotrexate or MMF. Henoch–Schönlein purpura Henoch–Schönlein purpura is a small-vessel vasculitis caused by immune complex deposition following an infectious trigger. 24.67 Emergency management of giant cell arteritis • Take blood for CRP, ESR, FBC, bone/liver/renal function, serum protein electrophoresis, CPK, RF, ACPA, ANA, ANCA, complement C3 and C4, immunoglobulins, PTH, TSH, vitamin D and urine electrophoresis • Commence prednisolone (40–60 mg daily), and simultaneously, a weekly oral bisphosphonate and calcium with vitamin D supplements • Consider urgent ophthalmology examination and temporal artery biopsy in patients with visual symptoms • Consider obtaining temporal artery ultrasound or 19FDG-PET scan • Review within 1 week and adjust glucocorticoid doses according to clinical response and results of investigations (ACPA = anti-citrullinated peptide antibody; ANA = antinuclear antibody; ANCA = antineutrophil cytoplasmic antibody; CPK = creatine phosphokinase; CRP = C-reactive protein; ESR = erythrocyte sedimentation rate; FBC = full blood count; 19FDG-PET = 19fluorodeoxyglucose positron emission tomography; PTH = parathyroid hormone; RF = rheumatoid factor; TSH = thyroid-stimulating hormone) Fig. 24.54 Oral ulceration in Behçet’s disease.

1044 • RHEUMATOLOGY AND BONE DISEASE in rural areas, due to low provision of technologies like DXA, which are required to make the diagnosis. Fractures in patients with osteoporosis can affect any bone but common sites are the forearm (Colles’ fracture), spine (vertebral fractures), humerus and hip. All of these fractures become more common with increasing age (Fig. 24.55). Since only about one-third of vertebral fractures come to medical attention (clinical vertebral fractures), the true number of patients with vertebral fracture is much greater than that shown in Figure 24.55. Of these, hip fractures are the most serious and have an immediate mortality of about 12% and a continued increase in mortality of about 20% when compared with age-matched controls. Treatment of hip fracture accounts for the majority of the health-care costs associated with osteoporosis. Pathophysiology The defining feature of osteoporosis is reduced bone density, which causes micro-architectural deterioration of bone tissue and leads to an increased risk of fracture, in response to minor trauma. The risk of fracture increases markedly with age in both genders (Fig. 24.55). This is mostly attributable to an increased risk of falling with age (p. 1308) but is also due in part to an age-related decline in bone mass, especially in women (Fig. 24.56). Bone mass increases during growth to reach a peak between the ages of 20 and about 45 years, but falls thereafter in both genders with an accelerated phase of bone loss after the menopause in women due to oestrogen deficiency. The loss of bone with ageing is caused by an imbalance in the bone remodelling cycle, whereby the amount of new bone formed by osteoblasts cannot keep pace with the amount that is removed by osteoclasts (see Fig. 24.2, p. 985). The reduction in bone formation is thought to be partly due to differentiation of bone marrow stem cells to adipocytes, as opposed to osteoblasts. Osteoporosis sometimes occurs because of failure to attain adequate levels of peak bone mass but is more commonly due to age-related bone loss. Osteoporosis is a complex disease that can occur in association with a wide variety of risk factors, as summarised in Box 24.69. Genetic factors account for up to 80% of variation in bone density, and genome-wide association studies have shown that susceptibility is determined in part by a large number of common variants, some of which are involved in the RANK and Wnt signalling pathways (see Fig. 24.3, p. 986). Rarely, osteoporosis may be caused by mutations in single genes. Environmental factors, such as exercise and calcium intake during growth and adolescence, are important in maximising peak bone mass and in regulating rates of post-menopausal bone loss. Smoking has a detrimental effect on BMD and is associated with an increased fracture risk, partly because female smokers have an earlier menopause than non-smokers. Heavy alcohol intake is a recognised cause of osteoporosis and fractures but moderate intake does not substantially alter risk. Idiopathic osteoporosis The term idiopathic osteoporosis is frequently used to describe the occurrence of osteoporosis in patients with no specific underlying cause. It is slightly misleading, since most, if not all, patients in this category have age-related osteoporosis or osteoporosis associated with inheritance of genetic variants that regulate bone density. Secondary osteoporosis Osteoporosis can occur in association with a variety of diseases and drug treatments, and in many cases more than one disease although the meninges, hemispheres and cord can also be affected, causing pyramidal signs, cranial nerve lesions, brainstem symptoms or hemiparesis. Recurrent thromboses also occur. Renal involvement is extremely rare. The diagnosis is primarily made on clinical grounds (Box 24.68) but one characteristic feature that can be of diagnostic value is the pathergy test, which involves pricking the skin with a needle and looking for evidence of pustule development within 48 hours. Oral ulceration can be managed with topical glucocorticoid preparations (soluble prednisolone mouthwashes, glucocorticoid pastes). Colchicine can be effective for erythema nodosum and arthralgia. Thalidomide (100–300 mg per day for 28 days initially) is very effective for resistant oral and genital ulceration but is teratogenic and neurotoxic. Glucocorticoids and immunosuppressants are indicated for uveitis and neurological disease. Relapsing polychondritis Relapsing polychondritis is a rare inflammatory disease of cartilage that classically presents with acute pain and swelling of one or both ear pinnae, sparing the lower non-cartilaginous portion. Around 30% of patients have coexisting autoimmune or connective tissue disease. Involvement of tracheobronchial cartilage leads to a hoarse voice, cough, stridor or expiratory wheeze. Other manifestations include collapse of the bridge of the nose, scleritis, hearing loss and cardiac valve dysfunction. Cartilage biopsy shows an inflammatory infiltrate in the perichondrium. Both ESR and CRP are raised in active disease. Pulmonary function tests, including flow–volume loops, should be performed to assess the degree of laryngotracheal disease, since this is an important cause of mortality. Mild disease usually responds to low-dose glucocorticoids or NSAIDs, whereas major tracheobronchial involvement requires high-dose glucocorticoids and immunosuppressants, as described for SLE. Diseases of bone Osteoporosis Osteoporosis is the most common bone disease. It has been estimated that more than 8.9 million fractures occur annually worldwide and most of these occur in patients with osteopenia or osteoporosis. About one-third of all women and one-fifth of men aged 50 and above suffer fractures at some point in life. The burden of osteoporosis-related fractures is predicted to increase by two- to threefold by 2050 on a worldwide basis, due to ageing of the population. Osteoporosis is under-diagnosed and under-treated in Asia and the Indian subcontinent, particularly 24.68 Criteria for the diagnosis of Behçet’s disease Recurrent oral ulceration: minor aphthous, major aphthous or herpetiform ulceration at least three times in 12 months plus two of the following: • Recurrent genital ulceration • Eye lesions: anterior uveitis, posterior uveitis, cells in vitreous on slit-lamp examination, retinal vasculitis • Skin lesions: erythema nodosum, pseudofolliculitis, papulopustular lesions, acneiform nodules • Positive pathergy test

Diseases of bone • 1045

Other contributory mechanisms include inhibition of intestinal calcium absorption, increased renal excretion of calcium and secondary hyperparathyroidism, which stimulates osteoclastic bone resorption. Pregnancy-associated osteoporosis This is a rare form of osteoporosis that typically presents with back pain and multiple vertebral fractures during the second or third trimester. The cause is unknown but may relate to an exaggeration of the bone loss that normally occurs during pregnancy in patients with pre-existing low bone mass. Clinical features Osteoporosis does not cause symptoms until a fracture occurs. Non-vertebral fractures are almost always caused by a traumatic event, most usually a simple fall. The term ‘fragility fracture’ is used to describe a fracture that occurs as the result of a fall from standing height or less. These are typical of osteoporosis. It is important to remember that the majority of people who suffer a fragility fracture do not have osteoporosis; some have normal bone density but most have osteopenia (Fig. 24.57 and p. 988). The clinical signs of fracture are pain, local tenderness and deformity. In hip fracture, the patient is (with rare exceptions) unable to weight-bear and has a shortened and externally rotated limb on the affected side. The presentation of vertebral fractures is variable. Some patients present with acute severe back pain. This may radiate to the anterior chest or abdominal wall and be mistaken for a myocardial infarction, aortic dissection or intra-abdominal pathology (p. 176). In others the presentation is with height loss and kyphosis in the absence of pain or with chronic back pain. Sometimes the presentation of osteoporosis is with radiological osteopenia or as a vertebral deformity on an X-ray that has been performed for other reasons. or risk factor is operative. The most important causes are summarised in Box 24.69. Secondary causes of osteoporosis are particularly common in men, occurring in up to 50% of patients. Hypogonadism, glucocorticoid use (see below) and alcohol excess are the most important predisposing factors. Glucocorticoid-induced osteoporosis Glucocorticoid-induced osteoporosis is a common problem in patients with systemic inflammatory and chronic pulmonary diseases. The risk of osteoporosis is related to dose and duration of glucocorticoid therapy and increases substantially in patients who have taken more than 7.5 mg of prednisolone daily for more than 3 months (or an equivalent dose of another glucocorticoid). Inhaled glucocorticoids can reduce bone density but the risk of osteoporosis is much lower than with systemic therapy. Glucocorticoids mainly cause osteoporosis by inhibiting bone formation and causing apoptosis of osteoblasts and osteocytes. Fig. 24.55 Fractures associated with osteoporosis. A X-ray of wrist. B Vertebrae. C Humerus. D Hip. E and F The changing incidence of each of these fractures with age in women and men, respectively. From Curtis EM, van der Velde R, Moon RJ, et al. Epidemiology of fractures in the United Kingdom 1988–2012: variation with age, sex, geography, ethnicity and socioeconomic status. Bone 2016; 87:19–26. A B C D E

Fractures 10 000 person-years 45 50 55 60 Age Women 65 70 75 80 85

Fractures 10 000 person-years 45 50 55 60 Age Men 65 70 75 80 85 F Hip Wrist Humerus Clinical vertebral Hip Wrist Humerus Clinical vertebral Fig. 24.56 Changes in bone mass and microstructure with age. Changes in men (blue line) and women (red line). Normal +1.0

–1.0 –2.0 –3.0

Age (years)

Osteopenia Osteoporosis Bone density T-score

1046 • RHEUMATOLOGY AND BONE DISEASE Investigations The most important investigation is DXA at the lumbar spine and hip (see Fig. 24.9, p. 990). This should be considered in patients age over 50 who have already suffered a fragility fracture, and in those with clinical risk factors (Box 24.70) when a fracture risk assessment tool (p. 1060) has returned an elevated value. The risk at which DXA should be performed remains a subject of debate but a 10-year risk of over 10% has been suggested, since there is evidence of benefit from treatment at this level. Other indications for DXA are in patients under 50 years who have very strong risk factors, such as premature menopause or high-dose glucocorticoids. Figure 24.58 provides a suggested algorithm for the investigation of patients with suspected osteoporosis. A history should be taken to identify any predisposing causes, such as early menopause, excessive alcohol intake, smoking and glucocorticoid therapy. Signs of endocrine disease, neoplasia and inflammatory disease should be sought on clinical examination. A falls history should be taken and a ‘get up and go’ test performed, especially in older patients (p. 1303). Screening for secondary causes of osteoporosis should be performed, as summarised in Box 24.71. Management The aim of treatment is to reduce the risk of fracture and this can be achieved by a combination of approaches. 24.69 Risk factors for osteoporosis Genetics • Single-gene disorders: LRP5 mutations Oestrogen receptor mutations • Polygenic inheritance: Common variants in many pathways Endocrine disease • Hypogonadism • Hyperthyroidism • Hyperparathyroidism • Cushing’s syndrome Inflammatory disease • Inflammatory bowel disease • Ankylosing spondylitis • Rheumatoid arthritis Drugs • Glucocorticoids • Gonadotrophin-releasing hormone (GnRH) agonists • Levothyroxine over-replacement • Aromatase inhibitors • Thiazolidinediones • Anticonvulsants • Alcohol intake > 3 U/day • Heparin Gastrointestinal disease • Malabsorption • Chronic liver disease Lung disease • Chronic obstructive pulmonary disease • Cystic fibrosis Miscellaneous • Myeloma • Homocystinuria • Anorexia nervosa* • Highly trained athletes* • HIV infection • Gaucher’s disease • Systemic mastocytosis • Immobilisation • Body mass index < 18 • Heavy smoking • Autoantibodies to osteoprotegerin (OPG) *Hypogonadism also plays a role in osteoporosis associated with these conditions. Fig. 24.57 Relation between bone mineral density (BMD) and fractures. A The relative risk of fracture increases exponentially as BMD falls (blue line), and is 14-fold higher in people with a T-score of <−3.5 compared with those with normal BMD. In absolute terms, however, more fractures occur in people with normal BMD or osteopenia (red line). B The proportions of fractures that occur in people with normal BMD, osteopenia and osteoporosis. +1 to +0.5

+1 +0.5 to 0 0 to -0.5 -0.5 to -1.0 -1.0 to -1.5 -1.5 to -2.0 -2.0 to -2.5 -2.5 to -3.0 -3.0 to -3.5 < -3.5

Number of fractures

Bone density T-score 18% Normal BMD Osteopenia Osteoporosis 50% 32% Normal BMD Osteopenia Osteoporosis Relative risk of fracture A B 24.70 Indications for dual X-ray absorptiometry (DXA) • Low-trauma fracture, age > 50 years • Clinical risk factors and 10-year fracture risk > 10% • Glucocorticoid therapy (> 7.5 mg prednisolone daily for > 3 months) • Assessment of response of osteoporosis to treatment • Assessment of progression of osteopenia to osteoporosis • Age < 50 years and very strong risk factors for osteoporosis

Diseases of bone • 1047

(p. 1308). Hip protectors can reduce the risk of hip fracture in selected patients but adherence is often poor. Pharmacological interventions Several drug treatments are now available to reduce the risk of fracture in osteoporosis. The dosages, mode of administration and indications are summarised in Box 24.72. More detail on the individual drugs is provided below. Bisphosphonates Bisphosphonates are the first-line treatment for osteoporosis. These are a class of drugs with a central core of P-C-P atoms, to which various side-chains are attached. Following administration, they target bone surfaces and are ingested by osteoclasts during the process of bone resorption. The bisphosphonate is released within the osteoclasts and impairs bone resorption. This in turn causes an increase in bone density but this is principally due to increased mineralisation of bone, rather than an increase in bone mass (Fig. 24.59). Bisphosphonates reduce the risk of fracture in patients with osteoporosis but do not completely prevent fractures occurring. Oral bisphosphonates are typically given for a period of 5 years, at which point the need for continued therapy should be evaluated, with a repeat DXA if possible. If patients have remained free of fractures after 5 years and if BMD levels have increased and no longer remain in the osteoporotic range, it is usual to instigate a 5-year spell off therapy. Treatment may be continued for up to 10 years in patients whose BMD levels remain in the osteoporotic range after 5 years. A change in treatment should be considered in patients who have lost BMD despite oral bisphosphonates (more than 4%). Most commonly, this will be a switch to parenteral zoledronic acid but teriparatide (TPTD) can also be considered in those with severe spinal osteoporosis. With intravenous zoledronic acid, 3 years of therapy is equivalent to 6 years in terms of fracture risk reduction and many experts recommend periods of 3 years on and 3 years off treatment to reduce the risk of over-suppression of bone turnover. Oral bisphosphonates are poorly absorbed from the gastrointestinal tract and should be taken on an empty stomach Non-pharmacological interventions Advice on smoking cessation, moderation of alcohol intake, adequate dietary calcium intake and exercise should be given. Those with recurrent falls or unsteadiness on a ‘get up and go’ test should be referred to a multidisciplinary falls prevention team Fig. 24.58 Algorithm for the investigation of patients with suspected osteoporosis. Fracture risk is assessed using FRAX or QFracture (see ‘Further information’, p. 1060). Age >50 Fracture risk >10% Age > 50 Low-trauma fracture Age <50 Very strong risk factors DXA spine and hip Screen for secondary causes Correct modifiable risk factors

1048 • RHEUMATOLOGY AND BONE DISEASE have received long-term bisphosphonates and appear to be the result of over-suppression of normal bone remodelling. In the vast majority, the benefits of bisphosphonate therapy far outweigh the risks but it is important for treatment to be targeted to patients with low BMD who are most likely to benefit. Denosumab Denosumab is a monoclonal antibody that inhibits bone resorption by neutralising the effects of RANKL (see Fig. 24.2, p. 985). It is administered by subcutaneous injection of 60 mg every 6 months in the treatment of osteoporosis and has similar efficacy to zoledronic acid. One potential adverse effect is hypocalcaemia but this can be mitigated by calcium and vitamin D supplements. Denosumab may rarely cause osteonecrosis of the jaw and atypical subtrochanteric fractures. If it is stopped, there is a rebound increase in bone turnover that can be associated with a greater risk of fracture and even hypercalcaemia. Because of this, many experts advise giving a bisphosphonate following cessation of denosumab. Calcium and vitamin D Combined calcium and vitamin D supplements have limited efficacy in the prevention of osteoporotic fractures when given alone but are widely used as an adjunct to other treatments. A typical daily dosage is 1000 mg calcium and 800 IU vitamin D. Calcium and vitamin D supplements have efficacy in preventing fragility fractures in elderly or institutionalised patients who are at high risk of deficiency (Box 24.74). Vitamin D supplements alone do not prevent fractures in osteoporosis but there is evidence that the response to bisphosphonates is blunted in patients with vitamin D deficiency. If the patient’s dietary calcium is sufficient, stand-alone vitamin D supplements (800 IU daily) can be prescribed as an adjunct to anti-osteoporosis therapies. Teriparatide Teriparatide (TPTD) is the 1-34 fragment of human PTH. It is an effective treatment for osteoporosis, which works by stimulating new bone formation. Although TPTD also stimulates bone resorption, the increase in bone formation is greater, resulting in increased bone density, particularly at sites rich in trabecular bone such as the spine. It is given by a self-administered subcutaneous injection in a dose of 20 μg daily for 2 years. At the end of this period, bisphosphonate therapy or another 24.72 Drug treatments for osteoporosis Drug Regimen Postmenopausal osteoporosis Glucocorticoid osteoporosis Male osteoporosis Alendronic acid 70 mg/week orally ᅚ ᅚ ᅚ Risedronate 35 mg/week orally ᅚ ᅚ ᅚ Ibandronate 150 mg/monthly orally 3 mg/3-monthly IV ᅚ ᅚ ᅚ Zoledronic acid 5 mg annually IV ᅚ ᅚ ᅚ Denosumab 60 mg 6-monthly SC ᅚ – ᅚ Calcium/vitamin D Calcium 500–1000 mg daily Vitamin D 400–800 IU orally ᅚ ᅚ ᅚ Teriparatide 20 μg/day SC ᅚ ᅚ ᅚ Abaloparatide 80 μg/day SC ᅚ – – Hormone replacement therapy Various preparations ᅚ – – Raloxifene 60 mg/day orally ᅚ – – Tibolone 1.25 mg/day orally ᅚ – – (IV = intravenous; SC = subcutaneous) with plain water; no food should be eaten for 30–45 minutes after administration. They are contraindicated in patients with oesophageal stricture or achalasia, since tablets may stick in the oesophagus, causing ulceration and perforation. Upper gastrointestinal upset occurs in about 5% of cases. Oral bisphosphonates can be used in patients with gastro-oesophageal reflux disease but may cause worsening of symptoms. The most common adverse effect with intravenous bisphosphonates is a transient influenza-like illness typified by fever, malaise, anorexia and generalised aches, which occurs 24–48 hours after administration. This is self-limiting but can be treated with paracetamol or NSAIDs if necessary. It predominantly occurs after the first exposure and tolerance develops thereafter. Other adverse effects are shown in Box 24.73. Osteonecrosis of the jaw is characterised by the presence of necrotic bone in the mandible or maxilla, typically occurring after tooth extraction when the socket fails to heal. This complication is very rare in osteoporosis but patients receiving bisphosphonates should be advised to pay attention to good oral hygiene. There is no evidence that temporarily stopping bisphosphonates for tooth extraction alters the risk of osteonecrosis of the jaw. Atypical subtrochanteric fractures have been described in patients who 24.73 Adverse effects of bisphosphonates Common • Upper gastrointestinal intolerance (oral) • Acute phase response (intravenous) Less common • Atrial fibrillation (intravenous zoledronic acid) • Hypocalcaemia (intravenous bisphosphonates) • Atypical subtrochanteric fractures Rare • Uveitis • Osteonecrosis of the jaw • Oesophageal ulceration

Diseases of bone • 1049

prevent vertebral and non-vertebral fractures in post-menopausal osteoporosis. Treatment is associated with a slightly increased risk of stroke but a reduced risk of breast cancer. Other drugs Romosozumab is antibody directed against sclerostin, which is under development for the treatment of osteoporosis. It increases bone formation, inhibits bone resorption and increases BMD. When given subcutaneously in a dose of 210 mg monthly, it reduces the risk of vertebral fractures in patients with postmenopausal osteoporosis. Calcitriol (1,25(OH)2D3), the active metabolite of vitamin D, is licensed for treatment of osteoporosis but it is seldom used because the data on fracture prevention are less robust than for other agents. Surgery Orthopaedic surgery with internal fixation is frequently required to reduce and stabilise osteoporotic fractures. Patients with intracapsular fracture of the femoral neck generally need hemiarthroplasty or total hip replacement in view of the high risk of avascular necrosis. Vertebroplasty is sometimes used in the treatment of painful vertebral compression fractures. It involves injecting methyl methacrylate (MMA) into the affected vertebral body under sedation and local anaesthesia. While randomised trials have shown that vertebroplasty provides no better pain relief than a sham procedure, it is still widely used, particularly in North America. Kyphoplasty is used under similar circumstances, but in this case a needle is introduced into the affected vertebral body and a balloon is inflated, which is then filled with MMA. It has similar efficacy to vertebroplasty but adverse effects are more common. Adverse effects with both procedures include spinal cord compression due to leakage of MMA and fat embolism. Osteomalacia, rickets and vitamin D deficiency Osteomalacia and rickets are characterised by defective mineralisation of bone. The most common cause is vitamin D deficiency, but both conditions can also occur as the result of inherited defects in renal phosphate excretion, and inherited defects in the vitamin D receptor and in the pathways responsible for vitamin D activation. Other causes are summarised in Box 24.75 and are discussed in more detail below. The term osteomalacia refers to the syndrome when it occurs in adults and rickets is the equivalent syndrome in children. The disease remains prevalent in frail older people who have a poor diet and limited sunlight exposure, and in some Muslim women. Vitamin D deficiency Vitamin D deficiency is defined to exist when serum 25(OH)D concentrations are below 25 nmol/L (10 ng/mL). People with vitamin D levels in the range 25–50 nmol/L (10–20 ng/mL) are classified as having vitamin D insufficiency, whereas those with 25(OH)D levels above 50 nmol/L (20 ng/mL) are classified as having normal vitamin D status. In the elderly, a more appropriate normal threshold may be 75 nmol/L (30 ng/mL) or more, though there is some debate on the issue and evidence is not conclusive. The likelihood of developing vitamin D deficiency is strongly related to sunlight exposure. It is common in northern latitudes (or southern latitudes in the southern hemisphere) and shows seasonal variation. Vitamin D deficiency is also common in women who, for cultural reasons, cover their skin and face. Vitamin D 24.74 Osteoporosis in old age • Bone loss: due to increased bone turnover, with an age-related defect switch in differentiation of bone marrow stromal cells to form adipocytes as opposed to osteoblasts. • Fractures due to osteoporosis: common cause of morbidity and mortality, although fracture healing is not delayed by age. • Recurrent fractures: those who suffer a fragility fracture are at increased risk of further fracture, so should be investigated for osteoporosis and treated if this is confirmed. • Falls: risk factors for falls (such as visual and neuromuscular impairments) are independent risk factors for hip fracture in elderly individuals, so intervention to prevent falls is as important as treatment of osteoporosis (p. 1308). • Intravenous zoledronic acid: reduces mortality and subsequent fracture in selected elderly patients with hip fractures. • Calcium and vitamin D: reduce the risk of fractures in those who are housebound or living in care homes. inhibitor of bone resorption should be administered to maintain the increase in BMD. TPTD and oral bisphosphonates should not be given in combination, however, since the bisphosphonate blunts the anabolic effect. The efficacy of TPTD for prevention of non-vertebral fractures is similar to that of bisphosphonates but it is superior to oral bisphosphonates in preventing vertebral fractures. The most common adverse effects are headache, muscle cramps and dizziness. Mild hypercalcaemia may occur but it is usually asymptomatic and does not require discontinuation of treatment. Monitoring of serum calcium is not required during TPTD treatment. Abaloparatide Abaloparatide is the 1-34 fragment of PTH-related protein. It works in a similar way to TPTD to stimulate bone formation. It is given as a self-administered injection of 80 μg daily for 18 months. At the end of this period an inhibitor of bone resorption should be given to maintain the increase in bone mass. Efficacy has been demonstrated for the prevention of vertebral fractures with effects similar to those of TPTD. Adverse effects are similar to those of TPTD. Hormone replacement therapy Cyclical HRT with oestrogen and progestogen prevents post-menopausal bone loss and reduces the risk of vertebral and non-vertebral fractures in postmenopausal women. It is primarily indicated for the prevention of osteoporosis in women with an early menopause (p. 655) and for treatment of women with osteoporosis in their early fifties who have troublesome menopausal symptoms. It is not recommended above the age of 60 because the risk of an increased risk of breast cancer, cardiovascular disease and venous thromboembolic disease. Raloxifene Raloxifene is a selective oestrogen receptor modulator (SERM) that acts as a partial agonist at oestrogen receptors in bone and liver, but as an antagonist in breast and endometrium. It is effective in reducing the risk of vertebral fractures but does not influence the risk of non-vertebral fracture and is seldom used. Adverse effects include muscle cramps, worsening of hot flushes and an increased risk of venous thromboembolic disease. Bazedoxifene is a related SERM that has similar effects to raloxifene. Tibolone Tibolone has partial agonist activity at oestrogen, progestogen and androgen receptors. It has been shown to

1050 • RHEUMATOLOGY AND BONE DISEASE about 70% is made in the skin, where 7-dehydrocholesterol is converted to cholecalciferol under the influence of ultraviolet light, whereas the remaining 30% is derived from the diet. The main dietary sources are oily fish and meat, although bread and dairy products are fortified with vitamin D in some countries. On entering the circulation, vitamin D is hydroxylated in the liver to form 25(OH) vitamin D and this is further hydroxylated in the kidney to form 1,25(OH)2D, the biologically active metabolite. The 1,25(OH)2D primarily acts on the gut to increase intestinal calcium absorption but also acts on the skeleton to stimulate bone remodelling. Synthesis of 1,25(OH)2D is regulated by a negative feedback loop orchestrated by the parathyroid glands. When vitamin D levels fall – as the result of lower sunlight exposure or dietary lack – production of 1,25(OH)2D is reduced, causing a reduction in calcium absorption from the gut. This causes a transient fall in serum calcium, which is detected by calciumsensing receptors on the parathyroid chief cells; this increases PTH secretion, which restores calcium levels to normal. Vitamin D deficiency is, therefore, usually characterised by a low level of 25(OH)D and a raised level of PTH. Sometimes, low 25(OH) D levels may be observed in the presence of a normal PTH concentration. This is of uncertain clinical significance but might be due to variations in levels of vitamin D-binding protein. Serum concentrations of vitamin D are under genetic control and are associated with variants close to the GC gene, which encodes vitamin D-binding protein; the DHCR7 gene, which encodes 7-dehydrocholesterol reductase, responsible for catalysing conversion of 7-DHC to 25(OH)D; the CYP2R1 gene, which encodes vitamin D-25-hydroxylase, responsible for hydroxylation of vitamin D in the liver; and the CYP24A1 gene, which encodes vitamin D-24-hydroxylase, responsible for converting 25(OH)D to the inactive metabolite 24,25(OH)2D. deficiency is more common in the winter and spring, and less common in summer and autumn (Fig. 24.60). Pathogenesis The source of vitamin D and pathways involved in regulating its metabolism are shown in Figure 24.61. In normal individuals, vitamin D (also known as cholecalciferol) comes from two sources: 24.75 Causes of osteomalacia and rickets Cause Predisposing factor Mechanism Vitamin D deficiency Classical Lack of sunlight exposure and poor diet Reduced cholecalciferol synthesis in the skin/low levels of vitamin D in the diet Gastrointestinal disease Malabsorption Malabsorption of dietary vitamin D and calcium Failure of 1,25 vitamin D synthesis Chronic renal failure Hyperphosphataemia and kidney damage Impaired conversion of 25(OH)D3 to 1,25(OH)2D3 Vitamin D-resistant rickets type I (autosomal recessive) Loss-of-function mutations in renal 25(OH)D 1α-hydroxylase enzyme Impaired conversion of 25(OH)D3 to 1,25(OH)2D3 Vitamin D receptor defects Vitamin D-resistant rickets type II (autosomal recessive) Loss-of-function mutations in vitamin D receptor Impaired response to 1,25(OH)2D3 Defects in phosphate and pyrophosphate metabolism Hypophosphataemic rickets (X-linked dominant) Mutations in PHEX Increased FGF23 production (mechanism unclear) Autosomal dominant hypophosphataemic rickets Mutation in FGF23 Mutant FGF23 is resistant to degradation Autosomal recessive hypophosphataemic rickets Mutations in DMP1 Increased production of FGF23 Local deficiency of DMP1 inhibits mineralisation Tumour-induced hypophosphataemic osteomalacia Ectopic production of FGF23 by tumour Over-production of FGF23 Hypophosphatasia Mutations in ALPL, which encodes alkaline phosphatase Inhibition of bone mineralisation due to accumulation of pyrophosphate in bone Iatrogenic and other causes Bisphosphonate therapy High-dose etidronate/pamidronate Drug-induced impairment of mineralisation Aluminium Use of aluminium-containing phosphate binders or aluminium in dialysis fluid Aluminium-induced impairment of mineralisation Fluoride High fluoride in water Inhibition of mineralisation by fluoride (FGF23 = fibroblast growth factor 23) Fig. 24.60 Seasonal changes in vitamin D concentrations. To convert nmol/L to ng/mL, multiply by 2.5. Adapted from McDonald HM, Mavroeidi A, Fraser WD, et al. Sunlight and dietary contributions to the seasonal vitamin D status of cohorts of healthy postmenopausal women living at northerly latitudes: a major cause for concern? Osteoporosis Int 2011; 22:2461–2472.

25(OH)D (nmol/L) SW England NE Scotland Summer Autumn Winter Spring

Diseases of bone • 1051

vitamin D deficiency or vitamin D insufficiency is uncertain. There is some evidence that response to bisphosphonate treatment of osteoporosis is impaired in patients with vitamin D deficiency and this is another indication for supplements. In patients who are receiving intravenous bisphosphonates and denosumab for osteoporosis, vitamin D deficiency should be corrected by supplementation to reduce the risk of hypocalcaemia. In this case, it is customary to give higher doses of vitamin D, such as 20 000–25 000 IU once a week for 4 weeks or to give lower doses over a more prolonged period. Osteomalacia and rickets Severe and prolonged vitamin D deficiency can result in the occurrence of osteomalacia in adults and rickets in children. Improvements in nutrition mean that these are now relatively uncommon conditions in developed countries but they remain prevalent in elderly housebound individuals, some Muslim women who wear a veil (hijab) that covers a large amount of exposed skin, and people with malabsorption. Pathogenesis Osteomalacia and rickets occur as the result of chronic secondary hyperparathyroidism, which invariably accompanies severe and long-standing vitamin D deficiency. The sustained elevation in PTH levels maintains normal levels of serum calcium by increasing bone resorption, which eventually causes progressive demineralisation of the skeleton. Phosphate that is released during the process of bone resorption is lost through increased renal excretion, resulting in hypophosphataemia. The raised levels of PTH stimulate osteoblast activity and cause new bone formation Fig. 24.61 Vitamin D metabolism. Vitamin D is produced in the skin from 7-dehydrocholesterol (7-DHC) by ultraviolet B (UVB) light. The 7-dehydrocholesterol reductase enzyme, which is encoded by the DHCR7 gene, opposes the effect of UVB by converting 7-DHC to cholesterol. The vitamin D then undergoes hydroxylation steps in the liver and kidney to form the active metabolite 1,25(OH)2D, which regulates calcium homeostasis by stimulating calcium absorption from the diet and bone resorption. See text for details. Liver Kidney Parathyroids Gut Sunlight 7-DHC 1,25(OH2)D (active) Calcium absorption↑ Bone resorption↑ -ve feedback Renal tubules 24,25(OH2)D (inactive) Serum calcium↑ Serum phosphate↓ CYP2R1 Vitamin D Cholesterol UVB DCHR7 PTH Calcium-sensing receptor PTH secretory granules Parathyroid chief cell –ve Ca2+ Ca2+ Ca2+ Bone CYP27B1 CYP24A1 25(OH)D (inactive) PTH Clinical features Vitamin D deficiency does not cause symptoms and the diagnosis is made as the result of biochemical testing. Low circulating concentrations of vitamin D have been associated with a wide range of diseases, including most types of cancer, diabetes, multiple sclerosis and chronic inflammatory diseases. These associations are unlikely to be causal but most probably arise as the result of reduced sunlight exposure and poor diet in people who are ill. If vitamin D deficiency is prolonged and severe, then osteomalacia and rickets may occur, as discussed below. The consequences of biochemical vitamin D deficiency and insufficiency on bone health and general health are unclear. Investigations The diagnosis can be made by measurement of serum 25(OH)D. In patients with low 25(OH)D, measurements of PTH, serum calcium, phosphate and ALP should also be considered. Low levels of 25(OH)D in the absence of other abnormalities is unlikely to be of any clinical significance and may be due to low levels of vitamin D-binding protein. If low 25(OH)D levels are combined with raised levels of PTH, this is of more significance since it indicates secondary hyperparathyroidism. Serum ALP, calcium and phosphate levels are normal in uncomplicated vitamin D deficiency. Management The clinical benefit of treating biochemical vitamin D deficiency is uncertain. Vitamin D supplements should be considered in patients who have low 25(OH)D levels and raised levels of PTH. In most patients, cholecalciferol in a dose of 800 IU daily should be sufficient to correct the deficiency. The benefit of treating seasonal

1052 • RHEUMATOLOGY AND BONE DISEASE thickening and widening of the epiphyseal plate. A radionuclide bone scan may show multiple hot spots in the ribs and pelvis at the site of fractures and the appearance may be mistaken for metastases. Where there is doubt, the diagnosis can be confirmed by bone biopsy, which shows the pathognomonic features of increased thickness and extent of osteoid seams (Fig. 24.62B). Management Osteomalacia and rickets respond promptly to treatment with vitamin D. A wide variety of doses can be used. Treatment with between 10 000 and 25 000 IU daily for 2–4 weeks is associated with rapid clinical improvement, an elevation in serum 25(OH)D and a reduction in PTH. Serum ALP levels sometimes rise initially as mineralisation of bone increases but eventually fall to within the reference range as the bone disease heals. Subsequently, the dose of vitamin D can usually be reduced to a maintenance level of 800–1600 IU daily (10–20 μg), except in patients with malabsorption, who may require higher doses. Vitamin D-resistant rickets This is a genetically determined condition that presents in childhood with rickets that is resistant to therapy with vitamin D in standard dosages. Pathogenesis Type I vitamin D-resistant rickets (VDRR) is caused by inactivating mutations in the 25-hydroxyvitamin D 1α-hydroxylase (CYP27B1) enzyme, which converts 25(OH)D to the active metabolite 1,25(OH)2D3. Type II VDRR is caused by inactivating mutations in the vitamin D receptor, which impair its ability to activate gene transcription. Both are recessive disorders and consanguinity is common. Clinical features These are as described above for infantile rickets. The diagnosis is usually first suspected when the patient fails to respond to vitamin D supplementation. Investigations The biochemical features of type I VDRR are similar to those of ordinary vitamin D deficiency, except that levels of 25(OH)D are normal but 1,25(OH)2D is low. In type II VDRR, 25(OH)D is normal but PTH and 1,25(OH)2D3 values are raised. Management Type I VDRR responds fully to treatment with the active vitamin D metabolites 1α-hydroxyvitamin D (1–2 μg daily, orally) or 1,25-dihydroxyvitamin D (0.25–1.5 μg daily, orally). Calcium supplements are not necessary unless there is dietary deficiency. Type II VDRR sometimes responds partially to very high doses of active vitamin D metabolites, which can activate the mutant receptor, although additional calcium and phosphate supplements are also necessary. Hereditary hypophosphataemic rickets This group of disorders are caused by inherited defects in renal tubular phosphate reabsorption. The most common is X-linked hypophosphataemic rickets (XLH), but autosomal dominant and autosomal recessive forms also occur (Box 24.75). but the matrix is not mineralised properly because of deficiency of calcium and phosphate. The under-mineralised bone is soft, mechanically weak and subject to fractures, particularly stress fractures. Normal levels of serum calcium tend to be maintained until a very advanced stage, when hypocalcaemia may occur. Clinical features Vitamin D deficiency in children causes delayed development, muscle hypotonia, craniotabes (small unossified areas in membranous bones of the skull that yield to finger pressure with a cracking feeling), bossing of the frontal and parietal bones and delayed anterior fontanelle closure, enlargement of epiphyses at the lower end of the radius, and swelling of the rib costochondral junctions (‘rickety rosary’). Osteomalacia in adults can present with fractures and low BMD, mimicking osteoporosis. Other symptoms include bone pain and general malaise. Proximal muscle weakness is prominent and the patient may walk with a waddling gait and struggle to climb stairs or stand up from a chair. There may be bone and muscle tenderness on pressure, and focal bone pain can be due to fissure fractures of the ribs and pelvis. Investigations The diagnosis can usually be made by measurement of serum 25(OH)D, PTH, calcium, phosphate and ALP. Typically, serum ALP levels are raised, 25(OH)D levels are undetectable and PTH is markedly elevated. Serum phosphate levels tend to be low but serum calcium is usually normal, unless the disease is advanced. X-rays often show osteopenia or vertebral crush fractures and, with more advanced disease, focal radiolucent areas (pseudofractures or Looser’s zones) may be seen in ribs, pelvis and long bones (Fig. 24.62A). In children, there is Fig. 24.62 Osteomalacia. A X-ray of the pelvis showing pseudofractures affecting the inferior and superior pubic rami on the left side (arrows). Healing pseudofractures with callus formation are also visible at the inferior and superior pubic rami on the right side (arrows). B Photomicrograph of bone biopsy from an osteomalacic patient showing thick osteoid seams (stained light blue, arrows) that cover almost all of the bone surface. Calcified bone is stained dark blue. A B

Diseases of bone • 1053

be identified by whole-body MRI or CT. Medical management is with phosphate supplements and active vitamin D metabolites but the treatment of choice is surgical resection of the primary tumour, which is curative. Hypophosphatasia Hypophosphatasia is an autosomal recessive disorder caused by loss-of-function mutations in the TNALP gene, which result in accumulation of pyrophosphate and inhibition of bone mineralisation. Chondrocalcinosis may also occur. The typical presentation is with severe intractable rickets during infancy, sometimes in association with seizures. Investigations show low or undetectable levels of serum ALP but normal levels of calcium, phosphate, PTH and vitamin D metabolites. Urinary excretion of pyridoxal 5′ phosphate and phosphoethanolamine (substrates for ALP) is increased. Until recently, this condition was fatal during childhood but remarkable therapeutic responses have been obtained with recombinant ALP therapy (asfotase alfa), which is curative. Heterozygous carriers of mutation in TNALP may present in adulthood with osteoporosis, fractures and low ALP values. The best mode of treatment for these patients remains to be determined, except that bisphosphonates should be avoided since they may exacerbate the mineralisation defect. Other causes of osteomalacia These are summarised in Box 24.75. Osteomalacia may occur as a component of renal osteodystrophy in patients with chronic kidney disease. The mechanism is reduced conversion of 25(OH)D into the active metabolite 1,25(OH)2D by the failing kidney (p. 418). Aluminium intoxication is now rare due to reduced use of aluminium-containing phosphate binders and removal of aluminium from the water supplies used in dialysis. If aluminium intoxication is suspected, the diagnosis can be confirmed by demonstration of aluminium at the calcification front in a bone biopsy. Osteomalacia due to bisphosphonates has mostly been described in patients with Paget’s disease who are receiving etidronate and high-dose pamidronate. It is usually asymptomatic and healing occurs when treatment is stopped. Excessive fluoride intake causes osteomalacia due to direct inhibition of mineralisation and is common in parts of the world where there is a high fluoride content in drinking water. The condition reverses when fluoride intake is reduced. Paget’s disease of bone Paget’s disease of bone (PDB) is characterised by focal areas of increased and disorganised bone remodelling involving one or more skeletal sites. The disease is common in the UK, affecting about 1% of those aged above 55, and in other countries in Europe. It is rare in Scandinavia, the Indian subcontinent and the rest of Asia. The prevalence doubles each decade from the age of 50 onwards and affects up to 8% of the UK population by the age of 85. Pathophysiology The primary abnormality is increased osteoclastic bone resorption, accompanied by marrow fibrosis, increased vascularity of bone and increased, but disorganised, bone formation. Osteoclasts in PDB are greater in number and unusually large, containing characteristic nuclear inclusion bodies. Genetic factors are important and mutations in the SQSTM1 gene are a common Pathophysiology All forms of hereditary hypophosphataemic rickets are associated with raised circulating concentrations of the phosphate-regulating hormone fibroblast growth factor 23 (FGF23). This hormone is produced by osteocytes (see Fig 24.3, p. 986) and enters the circulation, where it is normally inactivated by proteolytic cleavage. Production of FGF23 by osteocytes is under tonic inhibition by DMP1 and PHEX. In XLH, the inhibitory effect on FGF23 production is lost due to mutations in PHEX and a similar situation occurs in autosomal recessive hypophosphataemic rickets (ARHR1) due to loss-of-function mutations in DMP1. Mutations in the ENPP1 gene, which encodes a phosphatase responsible for degradation of pyrophosphate, can also cause a recessive form of hypophosphataemic rickets (ARHR2). In autosomal dominant hypophosphataemic rickets (ADHR), the FGF23 protein carries mutations that prevent FGF23 being degraded, thereby causing accumulation of intact FGF23 hormone in the circulation. In all three diseases, the elevation in FGF23 results in osteomalacia and rickets by causing phosphaturia by up-regulation of sodium-dependent phosphate transporters in the renal tubules, and also by inhibiting conversion of 25(OH)D to 1,25(OH)2D by the kidney, which in turn causes reduced calcium and phosphate absorption from the gut. Clinical features The presentation is with symptoms and signs of rickets during childhood that do not respond to vitamin D supplementation. In adults, hypophosphataemic rickets may be accompanied by dental abscesses, and by bone and joint pain due to the development of an enthesopathy. Investigations The diagnosis can be confirmed by the finding of low serum phosphate levels and a reduction in tubular reabsorption of phosphate. Serum levels of vitamin D are normal and PTH is normal or slightly elevated. Serum concentrations of FGF23 are markedly elevated. The causal mutation can be defined by genetic testing. Management The aim of treatment is to ameliorate symptoms, restore normal growth and maintain serum phosphate levels within the reference range. Traditionally, treatment has been with phosphate supplements (1–4 g daily) and 1-α-hydroxyvitamin D (1–2 μg daily) or 1,25-dihydroxyvitamin D (0.5–1.5 μg daily) with the aim of promoting intestinal calcium and phosphate absorption. Levels of calcium and phosphate, as well as renal function, should be monitored regularly and the doses of phosphate and vitamin D metabolites carefully titrated to maintain serum phosphate within the normal range but avoid hypercalcaemia. Recently, a neutralising antibody to FGF23 has been developed that can reverse the biochemical abnormalities in hereditary hypophosphataemic rickets and it is likely that this will be a future treatment option. Tumour-induced osteomalacia This is a rare syndrome caused by over-production of FGF23 by mesenchymal tumours. The presentation is with severe osteomalacia and hypophosphataemia in an adult patient with no obvious predisposing risk factor for vitamin D deficiency. Biochemical findings are as described for hereditary hypophosphataemic rickets. The underlying tumour can sometimes

1054 • RHEUMATOLOGY AND BONE DISEASE in affected bones (Fig. 24.63A). If the bone scan is positive, X-rays should be taken to confirm the diagnosis. Bone biopsy is not usually required but may help to exclude osteosclerotic metastases in cases of diagnostic uncertainty. Management The main indication for treatment with inhibitors of bone resorption is bone pain, which is thought to be due to increased metabolic activity (Box 24.76). Patients should be carefully assessed to determine the cause of the pain since it can be difficult to differentiate the pain caused by increased metabolic activity of PDB from that caused by complications such as bone deformity, nerve compression symptoms and OA. The bisphosphonates pamidronate, risedronate and zoledronic acid are highly effective at suppressing the elevations in bone turnover that are characteristic of PDB and also improve bone pain that is caused by increased metabolic activity. If there is doubt about whether the pain is due to PDB, it can be worthwhile giving a therapeutic trial of bisphosphonate to determine whether the symptoms improve. A positive response indicates that the pain was due to increased metabolic activity. There is no evidence as yet to suggest that bisphosphonates prevent the development of complications in PDB. Repeated courses of bisphosphonates can be given if symptoms recur. cause of classical PDB. The presence of nuclear inclusion bodies in osteoclasts has fuelled speculation that PDB might be caused by a slow virus infection but this is unproven. Biomechanical factors may influence which bones are affected, as PDB often starts at sites of muscle insertions into bone and, in some cases, localises to bones or limbs that have been subjected to repetitive trauma or overuse. Involvement of subchondral bone can compromise the joint and predispose to OA. The prevalence of PDB has fallen in many countries over recent decades, suggesting that environmental factors play a role, but the identity of these triggers remains unclear. Clinical features The axial skeleton is predominantly affected and common sites of involvement are the pelvis, femur, tibia, lumbar spine, skull and scapula. The most common presentation is with bone pain localised to an affected site but bone deformity, deafness and pathological fractures may also be presenting features. Many patients are asymptomatic and the diagnosis is frequently made on the basis of an X-ray or blood test performed for another reason. Clinical signs include bone deformity and expansion, and increased warmth over an affected bone. Neurological problems, such as deafness, cranial nerve defects, nerve root pain, spinal cord compression and spinal stenosis, may occur due to enlargement of affected bones and encroachment on the spinal cord and nerve foramina. Surprisingly, deafness seldom results from compression of the auditory nerve but is conductive, due to osteosclerosis of the temporal bone. The increased vascularity of Pagetic bone can rarely precipitate high-output cardiac failure in elderly patients with limited cardiac reserve. Osteosarcoma is an unusual but serious complication that presents with increasing pain and swelling of an affected site. Investigations The characteristic features are an isolated elevation in ALP and bone expansion on X-rays, with alternating areas of radiolucency and osteosclerosis (Fig. 24.63B). Levels of ALP can be normal if only a single bone is affected. The best way of identifying affected sites is a radionuclide bone scan, which shows increased uptake 24.76 Medical management of Paget’s disease Drug Route of administration Dose Etidronate Oral 400 mg daily for 3–6 months Tiludronate Oral 400 mg daily for 3–6 months Risedronate Oral 30 mg daily for 2 months Pamidronate IV 1–3 × 60 mg infusions Zoledronic acid IV 1 × 5 mg infusion Calcitonin SC 100–200 IU 3 times weekly for 2–3 months Fig. 24.63 Paget’s disease. A 99mTc-labelled bisphosphonate scintigraphy from a patient with Paget’s disease, illustrating the intense tracer uptake and deformity of the affected femur. B The typical radiographic features with expansion of the femur, alternating areas of osteosclerosis and radiolucency of the trochanter, and pseudofractures breaching the bone cortex (arrows). A B

Diseases of bone • 1055

important predisposing factors include high-dose glucocorticoid treatment, alcohol excess, SLE, HIV and radiotherapy, but in many of these conditions the pathophysiology is poorly understood. The presentation is with pain localised to the affected site, which is exacerbated by weight-bearing. The diagnosis can be confirmed by MRI, which shows evidence of subchondral necrotic bone and bone marrow oedema. X-rays are normal in the early stages but later may show evidence of osteosclerosis and deformity of the affected bone. There is no specific treatment. Management should focus on controlling pain and encouraging mobilisation (p. 1000). Symptoms often improve spontaneously with time but joint replacement may be required in patients who have persisting pain in association with significant structural damage to the affected joint. Scheuermann’s osteochondritis This disorder predominantly affects adolescent boys, who develop a dorsal kyphosis in association with irregular radiographic ossification of the vertebral end plates. It has a strong genetic component and may be inherited in an autosomal dominant manner. Most patients are asymptomatic but back pain, aggravated by exercise and relieved by rest, may occur. Excessive exercise and heavy manual labour before epiphyseal fusion has occurred may aggravate symptoms. Management consists of advice to avoid excessive activity and provision of protective postural exercises. Rarely, corrective surgery may be required if there is severe deformity. Scheuermann’s disease can sometimes present for the first time in adulthood, when it can be confused with osteoporotic vertebral fractures. It can be differentiated from osteoporosis by the characteristic X-ray changes, which show mild wedge deformity of 3–4 adjacent vertebrae, irregularity of the vertebral end plates, and normal BMD on DXA examination. Polyostotic fibrous dysplasia This is an acquired systemic disorder that mainly affects the skeleton and is caused by somatic mutations in the GNAS1 gene. The characteristic presentation is with bone pain and pathological fractures. Associated features include endocrine dysfunction, especially precocious puberty, and café-au-lait skin pigmentation (McCune–Albright syndrome). The diagnosis can usually be made by imaging, which shows focal, predominantly osteolytic lesions with bone expansion on X-rays (Fig. 24.65), and focal increased uptake on bone scan. The condition can resemble Paget’s disease of bone but the earlier age of onset and pattern of involvement are usually distinctive. Very rarely, malignant change can occur and should be suspected if there is a sudden increase in pain and swelling. Management is symptomatic. Intravenous bisphosphonates are often used in an attempt to control pain but the evidence base for their use is weak. Orthopaedic surgery may be required for treatment of fracture and deformity. Endocrine manifestations, such as precocious puberty (p. 654), may require specific treatment. Osteogenesis imperfecta Osteogenesis imperfecta (OI) is the name given to a group of disorders characterised by severe osteoporosis and multiple fractures in infancy and childhood. Most cases are caused by mutations in the COL1A1 and COL1A2 genes, which encode the proteins that make type I collagen. These result in reduced collagen production (in mild OI) or in formation of abnormal collagen chains that are rapidly degraded (in severe OI). Mutations Other bone diseases Complex regional pain syndrome type 1 Complex regional pain syndrome (CRPS) type 1 is characterised by gradual onset of pain, swelling and local tenderness, usually affecting a limb extremity. It may be triggered by fracture but can also occur in association with soft tissue injury, pregnancy and intercurrent illness or can develop spontaneously. The cause is unknown but abnormalities of the sympathetic nervous system are thought to play a pathogenic role. The affected limb is swollen and tender, and there may be evidence of regional autonomic dysfunction, with abnormal sweating and changes in skin colour and temperature. The diagnosis is primarily clinical, based on the features shown in Box 34.12 (p. 1349). Support for the diagnosis can be obtained with MRI, which shows bone marrow oedema, or radionuclide bone scan, which shows a local increase in tracer uptake (Fig. 24.64). X-rays show localised osteoporosis. Haematology, biochemistry and immunology are normal. The aims of treatment are to control pain and encourage mobilisation. Analgesics, NSAIDs, antineuropathic agents, calcitonin, glucocorticoids, β-adrenoceptor antagonists (β-blockers), sympathectomy and bisphosphonates have all been tried but none is particularly effective. Although some cases resolve with time, many individuals have persistent symptoms and fail to regain normal function. Osteonecrosis Osteonecrosis describes death of bone due to impairment of its blood supply. The most commonly affected sites are the femoral head, humeral head and femoral condyles. In some cases, the condition occurs as the result of direct trauma that interrupts the blood supply to the affected bone. This is the reason for osteonecrosis of the femoral head in patients with subtrochanteric fractures of the femoral neck, and in patients with thrombophilia and haemoglobinopathies, such as sickle cell disease. Other Fig. 24.64 Complex regional pain syndrome (osteodystrophy). 99mTc-labelled bisphosphonate scintigraphy showing increased uptake in femoral condyle.

1056 • RHEUMATOLOGY AND BONE DISEASE disease) shows autosomal dominant inheritance and presents with bone pain, cranial nerve palsies, osteomyelitis, OA or fracture, or is sometimes detected as an incidental radiographic finding. The responsible mutations affect either the genes that regulate osteoclast differentiation (RANK, RANKL), causing ‘osteoclast-poor’ osteopetrosis, or the genes involved in bone resorption, causing ‘osteoclast-rich’ osteopetrosis. These include mutations in the TCIRG1 gene, which encodes a component of the osteoclast proton pump, and mutations in the CLCN7 gene, which encodes the osteoclast chloride pump. Management is difficult. IFN-γ treatment can improve blood counts and reduce frequency of infections, but in severe cases haematopoietic stem cell transplantation is required to provide a source of osteoclasts that resorb bone normally. Sclerosing bone dysplasias These are rare diseases characterised by osteosclerosis and increased bone formation. Van Buchem’s disease and sclerosteosis are recessive disorders caused by loss-of-function mutations in the SOST gene, which normally suppresses bone formation (see Fig. 24.3, p. 986). The resulting lack of sclerostin causes increased bone formation and bone overgrowth, leading to enlargement of the cranium and jaw, tall stature and cranial nerve palsies. There is no effective treatment. High bone mass syndrome is a benign disorder caused by mutations in the LRP4 or LRP5 gene, which is characterised by unusually high bone density. The mutations render the LRP receptors resistant to the inhibitory effects of SOST. Most patients are asymptomatic but bone overgrowth in the palate (torus palatinus) and enlargement of the mandible can occur in later life. Treatment is not usually required. Camurati–Engelmann disease is an autosomal dominant condition caused by gain of function in the TGFB1 gene. It presents with bone pain, muscle weakness and osteosclerosis mainly affecting the diaphysis of long bones. Glucocorticoids can help the bone pain, although usually analgesics are also required. Bone and joint tumours Primary tumours of bones and joints are rare, have a peak incidence in childhood and adolescence, and can be benign or malignant (Box 24.77). Paget’s disease of bone (p. 1053) accounts for most cases of osteosarcoma occurring above the age of 40. Osteosarcoma This is a rare tumour with an incidence of 0.6–0.85 per 100 000 population. It is the most common primary bone tumour. Most in several other genes have been described that can cause OI, some of which affect post-translational modification of collagen and others that affect bone formation. Many patients have no family history. Some of these have new mutations whereas others may have recessive forms of the disease. The Sillence classification is commonly used to grade severity. This varies from neonatal lethal OI (type II), through very severe OI with multiple fractures in infancy and childhood (types III and IV), to mild (type I), in which affected patients typically have blue sclerae. The diagnosis of OI is usually obvious clinically, based on the presentation with multiple low-trauma fractures during infancy. The disease can be mistaken for non-accidental injury in childhood and for osteoporosis in adulthood; in such cases, genetic testing can be of diagnostic value. Treatment is multidisciplinary, involving surgical reduction and fixation of fractures and correction of limb deformities, and physiotherapy and occupational therapy for rehabilitation of patients with bone deformity. Bisphosphonates are widely used in the treatment of OI, especially intravenous pamidronate in children, but there is limited evidence for efficacy in fracture prevention. Osteopetrosis Osteopetrosis is a rare group of inherited diseases caused by failure of osteoclast function. Presentation is highly variable, ranging from a lethal disorder that presents with bone marrow failure in infancy to a milder and sometimes asymptomatic form that presents in adulthood. Severe osteopetrosis is inherited in an autosomal recessive manner and presents with failure to thrive, delayed dentition, cranial nerve palsies (due to absent cranial foramina), blindness, anaemia and recurrent infections due to bone marrow failure. The adult-onset type (Albers–Schönberg Fig. 24.65 McCune–Albright syndrome. X-ray of tibia in a patient with McCune–Albright syndrome showing expansile osteolytic lesion. 24.77 Primary tumours of the musculoskeletal system Cell type Benign Malignant Osteoblast Osteoid osteoma Osteosarcoma Chondrocyte Chondroma Osteochondroma Chondrosarcoma Fibroblast Fibroma Fibrosarcoma Bone marrow cell Eosinophilic granuloma Ewing’s sarcoma Endothelial cell Haemangioma Angiosarcoma Osteoclast precursor Giant cell tumour Malignant giant cell tumour

Rheumatological involvement in other diseases • 1057

Endocrine disease Hypothyroidism (p. 639) may present with carpal tunnel syndrome or, rarely, with painful, symmetrical proximal myopathy and muscle hypertrophy. Both resolve with levothyroxine replacement. Primary hyperparathyroidism (p. 663) is associated with osteoporosis and also predisposes to calcium pyrophosphate dihydrate deposition disease and to calcific periarthritis, especially in patients with renal disease. Diabetes mellitus (Ch. 20) commonly causes diabetic cheiroarthropathy, characterised by tightening of skin and periarticular structures, causing flexion deformities of the fingers that may be painful. Diabetic osteopathy presents as forefoot pain with radiographic progression from osteopenia to complete osteolysis of the phalanges and metatarsals. Diabetes also predisposes to osteoporosis, fragility fractures, adhesive capsulitis, Dupuytren’s contracture, septic arthritis and Charcot’s joints. Acromegaly (p. 685) can be associated with mechanical back pain, with normal or excessive movement; carpal tunnel syndrome; and Raynaud’s syndrome and an arthropathy (50%). The arthropathy mainly affects the large joints and has clinical similarities to OA but with a normal or increased range of movement. X-rays may show widening of joint spaces, squaring of bone ends, generalised osteopenia and tufting of terminal phalanges. It does not improve with treatment of the acromegaly. patients present under the age of 30 but osteosarcoma also occurs in the elderly in association with Paget’s disease. The presentation is with local pain and swelling. X-rays show expansion of the bone with a surrounding soft tissue mass, often containing islands of calcification. If the diagnosis is being considered, MRI or CT should be performed to determine the extent of tumour. Patients suspected of having osteosarcoma should be referred to a specialist team for biopsy. Treatment depends on histological type but generally involves surgical removal of the tumour, followed by chemotherapy and radiotherapy. The prognosis is normally good in cases that present in childhood and adolescence, but poor in elderly patients with osteosarcoma related to Paget’s disease of bone. Chondrosarcoma This is the second most common primary bone tumour. Presentation is as described for osteosarcoma. The treatment of choice is surgical resection since chondrosarcomas are relatively resistant to chemotherapy and radiotherapy. The prognosis is good for low-grade tumours but poor for anaplastic tumours. Ewing’s sarcoma This is the third most common sarcoma, which presents almost exclusively under the age of 40. Presentation is as described for osteosarcoma. Treatment is by local excision and surgical resection. The prognosis is excellent for patients who present before metastasis has occurred. Metastatic bone disease Metastatic bone disease may present in a variety of ways: with localised or generalised progressive bone pain, generalised regional pain, symptoms of spinal cord compression, or acute pain due to pathological fracture. Systemic features, such as weight loss and anorexia, and symptoms referable to the primary tumour are often present. The tumours that most commonly metastasise to bone are myeloma and those of bronchus, breast, prostate, kidney and thyroid. Management is discussed in Chapter 33. Rheumatological involvement in other diseases Many systemic diseases can affect the locomotor system, and many drugs may cause adverse locomotor effects (Box 24.78). The most common examples are described here. Bone disease in sarcoidosis is described on page 608, haemophilia on page 972 and sickle-cell anaemia on page 952. Malignant disease Malignant disease can cause a variety of non-metastatic musculoskeletal problems (Box 24.79). One of the most striking is hypertrophic pulmonary osteoarthropathy (HPOA), characterised by clubbing and painful swelling of the limbs, periosteal new bone formation and arthralgia/arthritis. The most common causes are bronchial carcinoma and mesothelioma (pp. 598 and 618). Bone scans show increased periosteal uptake before new bone is apparent on X-ray. The course follows that of the underlying malignancy and HPOA resolves if this is cured. 24.78 Drug-induced effects on the musculoskeletal system Musculoskeletal problem Principal drug Secondary gout Thiazides, furosemide, alcohol Osteoporosis Glucocorticoids, heparin, glitazones, aromatase inhibitors, GnRH agonists Osteomalacia Anticonvulsants, etidronate and pamidronate (high-dose) Osteonecrosis Glucocorticoids, alcohol Drug-induced lupus syndrome Procainamide, hydralazine, isoniazid, chlorpromazine Arthralgias, arthritis Glucocorticoid withdrawal, glibenclamide, methyldopa, ciclosporin, isoniazid, barbiturates Myalgia Glucocorticoid withdrawal, L-tryptophan, fibrates, statins Myopathy Glucocorticoids, chloroquine Myositis, myasthenia Penicillamine, statins Cramps Glucocorticoids, ACTH, diuretics, carbenoxolone Vasculitis Amphetamines, thiazides (ACTH = adrenocorticotrophic hormone; GnRH = gonadotrophin-releasing hormone) 24.79 Rheumatological manifestations of malignancy • Polyarthritis • Dermatomyositis and polymyositis • Hypophosphataemic osteomalacia • Hypertrophic osteoarthropathy • Vasculitis, connective tissue disease • Raynaud’s syndrome • Polymyalgia rheumatica-like syndrome

1058 • RHEUMATOLOGY AND BONE DISEASE (hypertrophic) new bone formation. Management principally involves orthoses and occasionally arthrodesis. Miscellaneous conditions Anterior tibial compartment syndrome This is characterised by severe pain in the front of the lower leg, aggravated by exercise and relieved by rest. Symptoms result from fascial compression of the muscles in the anterior tibial compartment and may be associated with foot drop. Treatment is by surgical decompression. Carpal tunnel syndrome This is a common nerve entrapment syndrome caused by compression of the median nerve at the wrist. It presents with numbness, tingling and pain in a median nerve distribution (p. 1139). The most common causes are hypothyroidism, diabetes mellitus, RA, obesity and pregnancy, especially in the third trimester. In some patients, no underlying cause may be identified. Carpal tunnel syndrome often responds to treatment of the underlying condition but other options include local glucocorticoid injections and surgical decompression. Diffuse idiopathic skeletal hyperostosis Diffuse idiopathic skeletal hyperostosis (DISH) is a common disorder, affecting 10% of men and 8% of women over the age of 65, and is associated with obesity, hypertension and type 2 diabetes mellitus. It is characterised by florid new bone formation along the anterolateral aspect of at least four contiguous vertebral bodies (Fig. 24.67). DISH is distinguished from lumbar spondylosis by the absence of disc space narrowing and marginal vertebral body sclerosis, and from ankylosing spondylitis by the absence of sacroiliitis or apophyseal joint fusion. It is usually an Haematological disease Haemochromatosis (p. 895) is complicated by an arthropathy in about 50% of cases. It typically presents between the ages of 40 and 50, and may predate other features of the disease. The small joints of the hands and wrists are typically affected but the hips, shoulders and knees may also be involved. The X-ray changes resemble OA but cysts are often multiple and prominent, with little osteophyte formation. Involvement of the radiocarpal and MCP joints may occur, which is unusual in primary OA, and about 30% have calcium pyrophosphate dihydrate deposition disease and/ or pseudogout. Treatment of the haemochromatosis does not influence the arthropathy, and management is as described for OA. Haemophilia (p. 972) can be complicated by haemarthrosis, which, if recurrent, can result in the development of secondary OA. Sickle-cell disease (p. 952) may be associated with bone pain, osteonecrosis and osteomyelitis. Thalassaemia (p. 953) may be complicated by bone deformity, especially affecting the craniofacial bones, and by osteoporosis. Neurological disease Neurological disease may result in rapidly destructive arthritis of joints, first described by Charcot in association with syphilis. The cause is incompletely understood but may involve repetitive trauma as the result of sensory loss and altered blood flow secondary to impaired sympathetic nervous system control. The main predisposing diseases and sites of involvement are: • diabetic neuropathy (hindfoot) • syringomyelia (shoulder, elbow, wrist) • leprosy (hands, feet) • tabes dorsalis (knees, spine). The presentation is with subacute or chronic monoarthritis. Pain can occur, especially at the onset, but once the joint is severely deranged, pain is often minimal and signs become disproportionately greater than symptoms. The joint is often grossly swollen, with effusion, crepitus, marked instability and deformity, but usually no increased warmth. X-rays show disorganisation of normal joint architecture and often multiple loose bodies (Fig. 24.66), and either no (atrophic) or gross Fig. 24.66 Wrist X-ray showing a neuropathic (Charcot) joint in a patient with syringomyelia. Note the disorganised architecture with complete loss of the proximal carpal row, bony fragments and soft tissue swelling. Fig. 24.67 Diffuse idiopathic skeletal hyperostosis (DISH). Anteroposterior X-ray of the thoracic spine showing right-sided, flowing new bone joining more than four contiguous vertebrae. The disc spaces are preserved.

Miscellaneous conditions • 1059

muscle weakness and atrophy, with pathological changes of inflammation, degeneration and mitochondrial abnormality in affected muscle fibres. Inclusion body myositis typically presents with distal muscle weakness. In time, muscles atrophy. Investigation is the same as for polymyositis (p. 1039). There is typically a slightly elevated creatine kinase and myopathic changes on EMG. Muscle biopsy shows abnormal fibres containing rimmed vacuoles and filamentous inclusions in the nucleus and cytoplasm. Therapeutic response to glucocorticoids and immunosuppressants is notably poor. There is anecdotal report of efficacy with IVIg but trial evidence is lacking. Periodic fever syndromes These are a group of rare inherited disorders that present with intermittent attacks of fever, rash, arthralgia and myalgia. They are discussed in more detail on page 81. Pigmented villonodular synovitis Pigmented villonodular synovitis is an uncommon proliferative disorder of synovium, which typically affects young adults. It is caused by a somatic chromosomal translocation in synovial cells that places the CSF1 gene downstream of the COL6A3 gene promoter. The result is local over-production of M-CSF, which causes accumulation of macrophages in the joint. The presentation is with joint swelling, limitation of movement and local discomfort. The diagnosis can be confirmed by MRI or synovial biopsy. Treatment is by surgical or radiation synovectomy. Scoliosis Scoliosis is characterised by an abnormal lateral curvature of the spine of greater than 10°. It typically presents during childhood or adolescence but usually persists into adulthood, when it can be associated with back pain, deformity and secondary OA. In about 20% of cases, scoliosis is secondary to a neuromuscular disorder, such as muscular dystrophy, cerebral palsy or neurofibromatosis. It may also occur in association with connective tissue disorders, such as Marfan’s syndrome. The term idiopathic scoliosis is used to described the remaining cases where there is no obvious cause. In fact, there is strong evidence from twin studies that idiopathic scoliosis is genetically mediated. The diagnosis can usually be made clinically by physical examination, which shows the characteristic spinal deformity. Spinal X-rays can be used to confirm the diagnosis and assess severity. External bracing and/ or surgical intervention are often performed in adolescents with severe deformities to correct deformity or prevent progression but the evidence base is poor. In adulthood, treatment is symptomatic in nature with analgesics, NSAID or antineuropathic medications. Spondylolysis Spondylolysis describes a break in the integrity of the neural arch. The principal cause is an acquired defect in the pars interarticularis due to a fracture, mainly seen in gymnasts, dancers and runners, in whom it is an important cause of back pain. Spondylolisthesis describes the condition in which a defect causes slippage of a vertebra on the one below. This may be congenital, post-traumatic or degenerative. Rarely, it can result from metastatic destruction of the posterior elements. Uncomplicated spondylolysis does not cause symptoms but spondylolisthesis can lead to low back pain asymptomatic radiographic finding but can cause back pain or pain at peripheral sites, such as the heel, in association with calcaneal spur formation. Dupuytren’s contracture Dupuytren’s contracture results from fibrosis and contracture of the superficial palmar fascia of the hands. The patient is unable to extend the fingers fully and there is puckering of the skin with palpable nodules. The ring and little fingers are usually the first and worst affected. Dupuytren’s contracture is usually painless but causes problems due to limitation of hand function and snagging of the curled fingers in pockets. It is age-related, usually bilateral and more common in men. There is a strong genetic component and sometimes may be familial, with dominant inheritance. The condition can be associated with plantar fibromatosis, Peyronie’s disease, alcohol misuse and chronic vibration injury. It is very slowly progressive. Often no treatment is required but it can be treated medically by local injections of collagenase or surgically by fasciotomy if symptoms are troublesome. Hypermobility syndromes Hypermobility is characterised by increased joint laxity and joint pain. Causes include Marfan’s syndrome, resulting from mutations in the FBN1 gene (p. 508); osteogenesis imperfecta (p. 1055); and Ehlers–Danlos syndrome types I, II and IV, caused by mutations in the COL3A1, COL5A1 and COL5A2 genes (p. 970). The term hypermobile Ehlers–Danlos syndrome (hEDS), which is also known as EDS type III, is used to describe a polygenic form of hypermobility. Many patients with this condition have hypermobile joints but do not have symptoms, whereas in others a range of symptoms can occur, including chronic joint and ligamentous pain, fibromyalgia-like symptoms, recurrent dislocations, easy bruising, abdominal symptoms, mitral valve prolapse (p. 520) and postural tachycardia syndrome, in which there is dizziness, hypotension and an increased heart rate on standing. The diagnosis of EDS type III is clinical and can be made when the modified Beighton score is 4 or above in the presence of arthralgia in four or more joints (Box 24.80). There is no specific treatment, apart from the general principles listed on page 1000, but some patients become very disabled as the result of their symptoms and are difficult to manage. Inclusion body myositis Inclusion body myositis is the most frequent primary myopathy in middle age and after. It is characterised by slowly progressive 24.80 Modified Beighton score for joint hypermobility Clinical test Score Extend little finger > 90° 1 point each side Bring thumb back parallel to/touching forearm 1 point each side Extend elbow > 10° 1 point each side Extend knee > 10° 1 point each side Touch floor with flat of hands, legs straight 1 point Hypermobile = a score of 6 or more points out of a possible 9 for epidemiological studies, or 4 or more points (with arthralgia in four or more joints) for a clinical diagnosis of the benign joint hypermobility syndrome

1060 • RHEUMATOLOGY AND BONE DISEASE Further information Journal articles Campion EW. Calcium pyrophosphate deposition disease. N Engl J Med 2016; 374:2575–2578. Compston J. Osteoporosis: advances in risk assessment and management. Clin Med (Lond) 2016; 16(Suppl 6): s121–s124. Gossec L, Smolen JS, Ramiro S, et al. European League Against Rheumatism (EULAR) recommendations for the management of psoriatic arthritis with pharmacological therapies: 2015 update. Ann Rheum Dis 2016; 75:499–510. Mukhtyar C, Flossman O, Hellmich B, et al. Outcomes from studies of antineutrophil cytoplasm antibody associated vasculitis: a systematic review by the European League Against Rheumatism systemic vasculitis task force. Ann Rheum Dis 2008; 67:1004–1010. Ralston SH. Paget’s disease of bone. N Engl J Med 2013; 368:644–650. Scott DL, Woolf F, Huizinga TW. Rheumatoid arthritis. Lancet 2010; 376:1094–1108. Taurog JD, Avneesh C, Colbert RA. Ankylosing spondylitis and axial spondyloarthritis. N Engl J Med 2016; 374:2563–2567. Teng MWL, Bowman EP, McElwee JJ, et al. IL-12 and IL-23 cytokines: from discovery to targeted therapies for immunemediated inflammatory diseases. Nat Med 2015; 21:719–729. Zhang W, Doherty M, Bardin T, et al. EULAR recommendations for gout. Part II: Management. Ann Rheum Dis 2006; 65:1312–1324. Websites 4s-dawn.com/DAS28 Calculator for this measure of activity in rheumatoid arthritis. asas-group.org Repository of resources to aid assessment of spondyloarthritis. basdai.com/BASDAI.php BASDAI calculator for assessing ankylosing spondylitis. omim.org Online Mendelian Inheritance in Man (OMIM): genetic diseases. shef.ac.uk/FRAX/ and qfracture.org/ Fracture risk assessment tools. sign.ac.uk Scottish Intercollegiate Guidelines Network 142 – Management of osteoporosis and the prevention of fragility fractures. thefreelibrary.com Information on drug-induced myopathies. vasculitis.org/ Vasculitis resources from the European Vasculitis Society. aggravated by standing and walking. Occasionally, symptoms of nerve root or spinal compression may occur. The diagnosis can be made on lateral X-rays of the lumbar spine but MRI may be required if there is neurological involvement. Advice on posture and muscle-strengthening exercises is required in mild cases. Surgical fusion is indicated for severe and recurrent low back pain. Surgical decompression is mandatory prior to fusion in patients with significant lumbar stenosis or symptoms of cauda equina compression. Synovitis–acne–pustulosis–hyperostosis– osteitis syndrome The synovitis–acne–pustulosis–hyperostosis–osteitis (SAPHO) syndrome is a disorder characterised by bone pain and swelling due to a sterile osteomyelitis and hyperostosis predominantly targeting the clavicles and bones of the anterior chest wall. SAPHO syndrome is thought to be part of a spectrum of autoinflammatory bone diseases that includes chronic recurrent (sterile) multifocal osteomyelitis in children and adolescents. Other features include a pustulotic rash affecting the palms and soles of the feet, sacroiliitis and synovitis of peripheral joints. It most commonly presents in children and young or middle-aged adults. Various treatments have been used, including glucocorticoids, DMARDs, bisphosphonates, anakinra and TNF blockers, with most success arising from biologic use. The cause is unknown but has been suggested to be an autoimmune process triggered by a bacterial or viral pathogen. Trigger finger This occurs as the result of stenosing tenosynovitis in the flexor tendon sheath, with intermittent locking of the finger in flexion. It can arise spontaneously or in association with inflammatory diseases such as RA. Symptoms usually respond to local glucocorticoid injections but surgical decompression is occasionally required.

Ch04-3 Clinical Medicine

15-25 Neurology

25 Neurology

Neurology JP Leach RJ Davenport Clinical examination of the nervous system 1062 Functional anatomy and physiology 1064 Functional anatomy of the nervous system 1065 Localising lesions in the central nervous system 1071 Investigation of neurological disease 1072 Neuroimaging 1072 Neurophysiological testing 1074 Presenting problems in neurological disease 1078 Headache and facial pain 1080 Dizziness, blackouts and ‘funny turns’ 1080 Status epilepticus 1080 Coma 1080 Delirium 1080 Amnesia 1080 Weakness 1081 Sensory disturbance 1083 Abnormal movements 1084 Abnormal perception 1086 Altered balance and vertigo 1086 Abnormal gait 1086 Abnormal speech and language 1087 Disturbance of smell 1088 Visual disturbance and ocular abnormalities 1088 Hearing disturbance 1093 Bulbar symptoms – dysphagia and dysarthria 1093 Bladder, bowel and sexual disturbance 1093 Personality change 1094 Sleep disturbance 1094 Psychiatric disorders 1094 Functional symptoms 1094 Headache syndromes 1095 Epilepsy 1097 Vestibular disorders 1104 Disorders of sleep 1105 Excessive daytime sleepiness (hypersomnolence) 1105 Parasomnias 1105 Neuro-inflammatory diseases 1106 Paraneoplastic neurological disorders 1110 Neurodegenerative diseases 1111 Movement disorders 1112 Ataxias 1115 Tremor disorders 1115 Dystonia 1116 Hemifacial spasm 1116 Motor neuron disease 1116 Spinal muscular atrophy 1117 Infections of the nervous system 1117 Meningitis 1118 Parenchymal viral infections 1121 Parenchymal bacterial infections 1124 Diseases caused by bacterial toxins 1125 Prion diseases 1126 Intracranial mass lesions and raised intracranial pressure 1127 Raised intracranial pressure 1127 Brain tumours 1129 Paraneoplastic neurological disease 1132 Hydrocephalus 1132 Idiopathic intracranial hypertension 1133 Head injury 1133 Disorders of cerebellar function 1134 Disorders of the spine and spinal cord 1134 Cervical spondylosis 1134 Lumbar spondylosis 1135 Spinal cord compression 1136 Intrinsic diseases of the spinal cord 1137 Diseases of peripheral nerves 1138 Entrapment neuropathy 1139 Multifocal neuropathy 1140 Polyneuropathy 1140 Guillain–Barré syndrome 1140 Chronic polyneuropathy 1140 Brachial plexopathy 1141 Lumbosacral plexopathy 1141 Spinal root lesions 1141 Diseases of the neuromuscular junction 1141 Myasthenia gravis 1141 Lambert–Eaton myasthenic syndrome 1143 Diseases of muscle 1143 Muscular dystrophies 1143 Inherited metabolic myopathies 1144 Acquired myopathies 1144

1062 • NEUROLOGY Clinical examination of the nervous system Insets (winging of scapula, 12th nerve palsy, wasting of thenar eminence) Courtesy of Dr R.E. Cull, Western General Hospital, Edinburgh. Higher cerebral function Orientation Memory Speech and language Localised cortical functions Cranial nerves Optic fundi Papilloedema Optic atrophy Cupping of disc (glaucoma) Hypertensive changes Signs of diabetes Observation/general Back Scoliosis Operative scars Evidence of spina bifida occulta Winging of scapula Neck and skull Skull size and shape Neck stiffness and Kernig’s test Carotid bruit • General appearance • Mood (e.g. anxious, depressed) • Facial expression (or lack thereof) • Handedness • Nutritional status • Blood pressure Stance and gait Posture Romberg’s test Arm swing Pattern of gait Tandem (heel-toe) gait Sensory Pin-prick, temperature Joint position, vibration Two-point discrimination Motor Wasting, fasciculation Abnormal posture Abnormal movements Tone (including clonus) Strength Coordination Tendon reflexes Abdominal reflexes Plantar reflexes Winging of right scapula (muscular dystrophy) Right 12th nerve palsy: wasting of right side of tongue 7th nerve palsy: drooping mouth and flattening of nasolabial skin fold Wasting of right thenar eminence due to cervical rib Pes cavus Haemorrhagic papilloedema

3rd nerve palsy: one eye points ‘down and out’

Clinical examination of the nervous system • 1063

1 Examination of gait and posture Procedure Abnormality Disease Rising from chair Difficulty rising Proximal muscle weakness or joint disorders Gait initiation Difficulty starting to walk, frozen Cerebrovascular disease or parkinsonism Posture Stooped Parkinsonism Retropulsion/ anteropulsion Postural instability Parkinsonism Arms during walking Reduced arm swing Parkinsonism or upper motor neuron lesion Enhanced tremor Parkinsonism Dystonic posturing Dystonia Gait pattern Circumduction (stiff leg moves outwards in ‘circular’ manner) Hemiparesis, typically after stroke ‘Slapping’, high-stepping due to foot drop L5 radiculopathy or common peroneal nerve lesion Narrow-based, short strides, freezing in doorways Parkinsonism Stiff-legged, scissors gait Spastic paraparesis (multiple sclerosis, vascular disease, spinal cord lesions) Wide-based, unsteady, unable to perform tandem gait Cerebellar lesion Waddling gait Myopathies with proximal weakness 4 Examination of cranial nerves Nerve Name Tests I Olfactory Ask patient about sense of smell (examine only if change is reported) II Optic Visual acuity and colour vision Visual fields Pupillary responses Ophthalmoscopy III Oculomotor Eyelids (ptosis) Pupil size, symmetry, reactions Eye movements IV Trochlear Eye movements (superior oblique muscle) V Trigeminal Facial sensation Corneal reflex Muscles of mastication VI Abducens Eye movements (lateral rectus muscle) VII Facial Facial symmetry and movements VIII Vestibulocochlear Otoscopy Hearing Tuning fork tests (Rinne and Weber) IX Glossopharyngeal Swallowing X Vagus Palatal elevation (uvula deviates to side opposite lesion) Swallowing Cough (bovine) Speech XI Accessory Look for wasting of trapezius/sternocleidomastoid Elevation of shoulders Turning head to right and left XII Hypoglossal Look for wasting/fasciculation Tongue protrusion (deviates to side of lesion) 6 Root values of tendon reflexes Reflex Root value Arm Biceps jerk C5 Supinator jerk C6 Triceps jerk C7 Finger jerk C8 Leg Knee jerk L3/L4 Ankle jerk S1 Motor and sensory homunculi. The motor and sensory homunculi illustrate the cortical areas serving each anatomical area within the pre-central (motor) and post-central (sensory) gyri. Motor Sensory Toes Motor cortex (pre-central gyrus) Knee Trunk Arm Neck Face Tongue Teeth Somatic cortex (post-central gyrus) Leg Arm Face Tongue

1064 • NEUROLOGY 25.1 Neurological emergencies • Status epilepticus (p. 1080) • Stroke (if thrombolysis available) (p. 1158) • Guillain–Barré syndrome (p. 1140) • Myasthenia gravis (if bulbar and/or respiratory) (p. 1141) • Spinal cord compression (p. 1136) • Subarachnoid haemorrhage (p. 1160) • Neuroleptic malignant syndrome (p. 1197) The complexity of the brain differentiates us from other species, and its interactions with the spinal cord and peripheral nerves combine to allow us to perceive and react to the external world while maintaining a stable internal environment. The cerebral cortex provides a platform for processing information and forming a response, and in doing so, both forms and is affected by our personality and mental state. Neurology has for too long been misperceived as a specialty in which intricate clinical examination and numerous investigations are required to diagnose obscure and untreatable conditions. In fact, nervous system disorders are common, accounting for around 10% of the UK’s general practice consultations, 20% of acute medical admissions, and most chronic physical disability. The development of specific, effective treatments has made accurate diagnosis essential. Neurological management requires knowledge of a range of common conditions, which can then be applied to individual patients after careful history-taking, with lesser contributions arising from targeted examination and considered investigation. Pathological and anatomical localisation of symptoms and signs is important, but skill can be required to identify those not associated with neurological disease, differentiating patients requiring investigation and treatment from those who need reassurance. Initially, it is important to exclude conditions that constitute neurological emergencies (Box 25.1). If the presentation is not an emergency, time can be taken to reach a diagnosis. The history should provide a hypothesis for the site and nature of the potential pathology, which a focused examination may refine, and direct appropriate further investigations. An informed discussion with the patient and family regarding diagnosis, management and prognosis may then take place. As stroke has become a specific subspecialty in many centres, it is described in a separate chapter, although it is clearly a neurological condition. This chapter should be read with it, to help clarify how the presentation, diagnosis and management of stroke present their own challenges. Functional anatomy and physiology Cells of the nervous system The nervous system comprises billions of specialised cells, forming a spectacular network of connections, each human brain having almost as many connections as there are grains of sand in the whole world. In addition to neurons, there are three types of glial cells. Astrocytes form the structural framework for neurons Fig. 25.1 Cells of the nervous system. (CSF = cerebrospinal fluid) Astrocyte foot processes surround the brain capillary (site of blood–brain barrier) Capillary Red blood cell in capillary Tight junction Capillary endothelial cell Astrocyte Synapse Neuron Oligodendrocyte Axon CSF Ependymal cell Sensory cell body in dorsal root ganglion Motor neuron cell body in anterior horn Spinal cord grey matter Node of Ranvier Vas nervorum Sensory axon Motor axon Schwann cell

Functional anatomy and physiology • 1065

and control their biochemical environment, their foot processes adjoining small blood vessels and forming the blood–brain barrier (Fig. 25.1). Oligodendrocytes are responsible for the formation and maintenance of the myelin sheath, which surrounds axons and is essential for maintaining the speed and consistency of action potential propagation along axons. Peripheral nerves have axons invested in myelin made by oligodendrocytes (Schwann cells). Microglial cells derive from monocytes/macrophages and play a role in fighting infection and removing damaged cells. Ependymal cells line the cerebral ventricles. Generation and transmission of the nervous impulse The role of the central nervous system (CNS) is to generate outputs in response to external stimuli and changes in internal Fig. 25.2 Neurotransmission and neurotransmitters. (1) An action potential arriving at the nerve terminal depolarises the membrane and this opens voltage-gated calcium channels. (2) Entry of calcium causes the fusion of synaptic vesicles containing neurotransmitters with the pre-synaptic membrane and release of the neurotransmitter across the synaptic cleft. (3) The neurotransmitter binds to receptors on the post-synaptic membrane either (A) to open ligand-gated ion channels that, by allowing ion entry, depolarise the membrane and initiate an action potential (4), or (B) to bind to metabotropic receptors that activate an effector enzyme (e.g. adenylyl cyclase) and thus modulate gene transcription via the intracellular second messenger system, leading to changes in synthesis of ion channels or modulating enzymes. (5) Neurotransmitters are taken up at the pre-synaptic membrane and/or metabolised. (cAMP = cyclic adenosine monophosphate; DNA = deoxyribonucleic acid; mRNA = messenger ribonucleic acid) Transcription factor Microtubules in axon down which neurotransmitters and/or precursors are transported

Ca2+ Voltage-gated calcium channels Action potential

Ions Ions G-protein mRNA DNA Cell nucleus Translation New ion channel or modulating enzyme Second messengers e.g. cAMP A B Fig. 25.3 The major anatomical components of the nervous system. Posterior Anterior Cerebral hemispheres Sensation and perception Cerebellum Brainstem Spinal cord Autonomic Autonomic Behaviour and motor Gastrointestinal tract Sensory receptor Heart and circulation Muscle Neuromuscular junction Bladder Reproductive organs conditions. The CNS has to maintain a delicate balance between responsivity to external stimuli and remaining stoic enough to remain stable in a rapidly changing environment. Each neuron receives input by synaptic transmission from dendrites (branched projections of other neurons), which sum to produce output in the form of an action potential that is then conducted along the axon, resulting in synaptic transmission to other neurons or, in the motor system, to muscle cells. Summation of the inputs causes net changes in the target neuron’s electrochemical gradient, which, if large enough, will trigger an action potential. Communication between cells is by synaptic transmission that involves the release of neurotransmitters to interact with structures on the target cell’s surface, including ion channels and other cell surface receptors (Fig. 25.2). At least 20 different neurotransmitters are known to act at different sites in the nervous system, most of which are potentially amenable to pharmacological manipulation. Each neuronal cell body may receive synaptic input from thousands of other neurons. The synapsing neuron terminals are also subject to feedback regulation via receptor sites on the pre-synaptic membrane, modifying the release of transmitter across the synaptic cleft. In addition to such acute effects, some neurotransmitters produce long-term modulation of metabolic function or gene expression. This effect probably underlies more complex processes such as long-term memory. Functional anatomy of the nervous system Major components of the nervous system and their interrelationships are depicted in Figure 25.3.

1066 • NEUROLOGY are regions dealing with numerical function. The non-dominant parietal lobe is concerned with spatial awareness and orientation. The temporal lobes contain the primary auditory cortex and primary vestibular cortex. On the inner medial sides lie the olfactory and parahippocampal cortices, which are involved in memory function. The temporal lobes also link intimately to the limbic system, including the hippocampus and the amygdala, which are involved in memory and emotional processing. The dominant temporal lobe also participates in language functions, particularly verbal comprehension (Wernicke’s area). Musical processing occurs across both temporal lobes, rhythm on the dominant side and melody/pitch on the non-dominant. The occipital lobes are responsible for visual interpretation. The contralateral visual hemifield is represented in each primary visual cortex, with surrounding areas processing specific visual submodalities such as colour, movement or depth, and the analysis of more complex visual patterns such as faces. Deep to the grey matter in the cortices, and the white matter (composed of neuronal axons), are collections of cells known as the basal ganglia that are concerned with motor control; the thalamus, which is responsible for the level of attention to sensory perception; the limbic system, concerned with emotion and memory; and the hypothalamus, responsible for homeostasis, such as temperature Cerebral hemispheres The cerebral hemispheres coordinate the highest level of nervous function, the anterior half dealing with executive (‘doing’) functions and the posterior half constructing a perception of the environment. Each cerebral hemisphere has four functionally specialised lobes (Box 25.2 and Fig. 25.4), with some functions being distributed asymmetrically (‘lateralised’), to produce cerebral dominance for functions such as motor control, speech or memory. Cerebral dominance aligns limb dominance with language function: in right-handed individuals the left hemisphere is almost always dominant, while around half of left-handers have a dominant right hemisphere. Frontal lobes are concerned with executive function, movement, behaviour and planning. As well as the primary and supplementary motor cortex, there are specialised areas for control of eye movements, speech (Broca’s area) and micturition. The parietal lobes integrate sensory perception. The primary sensory cortex lies in the post-central gyrus of the parietal lobe. Much of the remainder is devoted to ‘association’ cortex, which processes and interprets input from the various sensory modalities. The supramarginal and angular gyri of the dominant parietal lobe form part of the language area (p. 1088). Close to these 25.2 Cortical lobar functions Lobe Function Effects of damage Cognitive/behavioural Associated physical signs Positive phenomena Frontal Personality Emotional control Social behaviour Contralateral motor control Language Micturition Disinhibition Lack of initiation Antisocial behaviour Impaired memory Expressive dysphasia Incontinence Impaired smell Contralateral hemiparesis Frontal release signs1 Seizures – often nocturnal with motor activity Versive head movements Parietal: dominant Language Calculation Dysphasia Acalculia Dyslexia Apraxia3 Agnosia5 Contralateral hemisensory loss Astereognosis2 Agraphaesthesia4 Contralateral homonymous lower quadrantanopia Asymmetry of optokinetic nystagmus (OKN) Focal sensory seizures Parietal: non-dominant Spatial orientation Constructional skills Neglect of contralateral side Spatial disorientation Constructional apraxia Dressing apraxia Contralateral hemisensory loss Astereognosis2 Agraphaesthesia4 Contralateral homonymous lower quadrantanopia Asymmetry of OKN Focal sensory seizures Temporal: dominant Auditory perception Language Verbal memory Smell Balance Receptive aphasia Dyslexia Impaired verbal memory Contralateral homonymous upper quadrantanopia Complex hallucinations (smell, sound, vision, memory) Temporal: non-dominant Auditory perception Melody/pitch perception Non-verbal memory Smell Balance Impaired non-verbal memory Impaired musical skills (tonal perception) Contralateral homonymous upper quadrantanopia Complex hallucinations (smell, sound, vision, memory) Occipital Visual processing Visual inattention Visual loss Visual agnosia Homonymous hemianopia (macular sparing) Simple visual hallucinations (e.g. phosphenes, zigzag lines) 1Grasp reflex, palmomental response, pout response. 2Inability to determine three-dimensional shape by touch. 3Inability to perform complex movements in the presence of normal motor, sensory and cerebellar function. 4Inability to ‘read’ numbers or letters drawn on hand, with the eyes shut. 5Inability to recognise familiar objects, e.g. faces.

Functional anatomy and physiology • 1067

and appetite control. The cerebral ventricles contain cerebrospinal fluid (CSF), which cushions the brain during cranial movement. CSF is formed in the lateral ventricles and protects and nourishes the CNS. CSF flows from third to fourth ventricles and through foramina in the brainstem to dissipate over the surface of the CNS, eventually being reabsorbed into the cerebral venous system (see Fig. 25.44, p. 1132). The brainstem In addition to containing all the sensory and motor pathways entering and leaving the hemispheres, the brainstem houses the nuclei and projections of most cranial nerves, as well as other important collections of neurons in the reticular formation (Fig. 25.5). Cranial nerve nuclei provide motor control to muscles of the head (including face and eyes) and coordinate sensory input from the special sense organs and the face, nose, mouth, larynx and pharynx. They also relay autonomic messages, including pupillary, salivary and lacrimal functions. The reticular formation is mainly involved in control of conjugate eye movements, the maintenance of balance and arousal, and cardiorespiratory control. The spinal cord The spinal cord is the route for virtually all communication between the extracranial structures and the CNS. Afferent and efferent fibres are grouped in discrete bundles but collections of cells in the grey matter are responsible for lower-order motor reflexes and the primary processing of sensory information. Fig. 25.4 Anatomy of the cerebral cortex. Face Parahippocampal cortex Corpus callosum Foot Supplementary motor area Superior temporal gyrus

Inferior frontal gyrus Primary motor cortex Leg Central sulcus Primary sensory cortex Supramarginal gyrus Angular gyrus Primary visual cortex 1 Frontal eye field 2 Broca’s area 3 Primary vestibular cortex 4 Primary auditory cortex 5 Wernicke’s area Frontal lobe Temporal lobe Parietal lobe Occipital lobe Key Fig. 25.5 Anatomy of the brainstem. Cranial nerves Cerebellum 10th 9th 8th 7th 6th 5th 3rd 4th Pontine nuclei Sensory tracts Motor tracts Pyramidal motor tract Reticular system 12th 11th

1068 • NEUROLOGY resulting in weakness and reduced muscle tone. Subsequently, denervated muscle fibres atrophy, causing muscle wasting, and depolarise spontaneously, causing ‘fibrillations’. Except in the tongue, these are usually perceptible only on electromyography (EMG; p. 1076). With the passage of time, neighbouring intact neurons sprout to provide re-innervation, but the neuromuscular junctions of the enlarged motor units are unstable and depolarise spontaneously, causing fasciculations (large enough to be visible). Fasciculations therefore imply chronic denervation with partial re-innervation. Upper motor neurons Upper motor neurons have both inhibitory and excitatory influence on the function of lower motor neurons in the anterior horn. Lesions affecting the upper motor neuron result in increased tone, most evident in the strongest muscle groups (i.e. the extensors of the lower limbs and the flexors of the upper limbs). The weakness of upper motor neuron lesions is conversely more pronounced in the opposing muscle groups. Loss of inhibition will also lead to brisk reflexes and enhanced reflex patterns of movement, such as flexion withdrawal to noxious stimuli and spasms of extension. The increased tone is more apparent during rapid stretching (‘spastic catch’) but may quickly give way with sustained tension (the ‘clasp-knife’ phenomenon). More primitive reflexes are also released, manifest as extensor plantar Sensory peripheral nervous system The sensory cell bodies of peripheral nerves are situated just outside the spinal cord, in the dorsal root ganglia in the spinal exit foramina, while the distal ends of their neurons utilise various specialised endings for the conversion of external stimuli into action potentials. Sensory nerves consist of a combination of large, fast, myelinated axons (which carry information about joint position sense and commands to muscles) and smaller, slower, unmyelinated axons (which carry information about pain and temperature, as well as autonomic function). Motor peripheral nervous system The anterior horns of the spinal cord comprise cell bodies of the lower motor neurons. To increase conduction speed, peripheral motor nerve axons are wrapped in myelin produced by Schwann cells. Motor neurons release acetylcholine across the neuromuscular junction, which changes the muscle end-plate potential and initiates muscle contraction. The autonomic system The autonomic system regulates the cardiovascular and respiratory systems, the smooth muscle of the gastrointestinal tract, and many exocrine and endocrine glands throughout the body. The autonomic system is controlled centrally by diffuse modulatory systems in the brainstem, limbic system, hypothalamus and frontal lobes, which are concerned with arousal and background behavioural responses to threat. Autonomic output divides functionally and pharmacologically into two divisions: the parasympathetic and sympathetic systems. The motor system A programme of movement formulated by the pre-motor cortex is converted into a series of excitatory and inhibitory signals in the motor cortex that are transmitted to the spinal cord in the pyramidal tract (Fig. 25.6). This passes through the internal capsule and the ventral brainstem before crossing (decussating) in the medulla to enter the lateral columns of the spinal cord. The pyramidal tract ‘upper motor neurons’ synapse with the anterior horn cells of the spinal cord grey matter, which form the lower motor neurons. Any movement necessitates changes in posture and muscle tone, sometimes in quite separate muscle groups to those involved in the actual movement. The motor system consists of a hierarchy of controls that maintain body posture and muscle tone, on which any movement is superimposed. In the grey matter of the spinal cord, the lowest order of the motor hierarchy controls reflex responses to stretch. Muscle spindles sense lengthening of the muscle; they provide the afferent side of the stretch reflex and initiate a monosynaptic reflex leading to protective or reactive muscle contraction. Inputs from the brainstem are largely inhibitory. Polysynaptic connections in the spinal cord grey matter control more complex reflex actions of flexion and extension of the limbs that form the basic building blocks of coordinated actions, but complete control requires input from the extrapyramidal system and the cerebellum. Lower motor neurons Lower motor neurons in the anterior horn of the spinal cord innervate a group of muscle fibres termed a ‘motor unit’. Loss of lower motor neurons causes loss of contraction within this unit, Fig. 25.6 The motor system. Neurons from the motor cortex descend as the pyramidal tract in the internal capsule and cerebral peduncle to the ventral brainstem, where most cross low in the medulla (A). In the spinal cord the upper motor neurons form the corticospinal tract in the lateral column before synapsing with the lower motor neurons in the anterior horns. The activity in the motor cortex is modulated by influences from the basal ganglia and cerebellum. Pathways descending from these structures control posture and balance (B). Neuromuscular junction A B Skeletal muscle Anterior horn cells Lateral corticospinal tract Spinal cord Foot Hand Mouth Cortical pyramidal cells Motor cortex Basal ganglia Cerebellum Descending control of posture and balance Pyramidal tract Internal capsule

Functional anatomy and physiology • 1069

Vision The neurological organisation of visual pathways is shown in Figure 25.7. Fibres from ganglion cells in the retina pass to the optic disc and then backwards through the lamina cribrosa to the optic nerve. Nasal optic nerve fibres (subserving the temporal visual field) cross at the chiasm but temporal fibres do not. Hence, fibres in each optic tract and further posteriorly carry representation of contralateral visual space. From the lateral geniculate nucleus, lower fibres pass through the temporal lobes on their way to the primary visual area in the occipital cortex, while the upper fibres pass through the parietal lobe. Normally, the eyes move conjugately (in the same direction at the same speed), though horizontal convergence allows fusion of images at different distances. The control of eye movements begins in the cerebral hemispheres, particularly within the frontal eye fields, and the pathway then descends to the brainstem with input from the visual cortex, superior colliculus and cerebellum. Horizontal and vertical gaze centres in the pons and mid-brain, respectively, coordinate output to the ocular motor nerve nuclei (3, 4 and 6), which are connected to each other by the medial longitudinal fasciculus (MLF) (Fig. 25.8). The MLF is particularly important in coordinating horizontal movements of the eyes. The resulting signals to extraocular muscles are supplied by the oculomotor (3rd), trochlear (4th) and abducens (6th) cranial nerves. The pupillary size is determined by a combination of parasympathetic and sympathetic activity. Parasympathetic fibres originate in the Edinger–Westphal subnucleus of the 3rd nerve, and pass with the 3rd nerve to synapse in the ciliary ganglion before supplying the constrictor pupillae of the iris. Sympathetic fibres originate in the hypothalamus, pass down the brainstem and cervical spinal cord to emerge at T1, return up to the eye in association with the internal carotid artery, and supply the dilator pupillae. responses. Spasticity may not be present until some weeks after the onset of an upper motor neuron lesion. The extrapyramidal system Circuits between the basal ganglia and the motor cortex constitute the extrapyramidal system, which controls muscle tone, body posture and the initiation of movement (see Fig. 25.6). Lesions of the extrapyramidal system produce an increase in tone that, unlike spasticity, is continuous throughout the range of movement at any speed of stretch (‘lead pipe’ rigidity). Involuntary movements are also a feature of extrapyramidal lesions (p. 1084), and tremor in combination with rigidity produces typical ‘cogwheel’ rigidity. Extrapyramidal lesions also cause slowed and clumsy movements (bradykinesia), which characteristically reduce in size with repetition, as well as postural instability, which can precipitate falls. The cerebellum The cerebellum fine-tunes and coordinates movement initiated by the motor cortex, including articulation of speech. It also participates in the planning and learning of skilled movements through reciprocal connections with the thalamus and cortex. A lesion in a cerebellar hemisphere causes lack of coordination on the same side of the body. Cerebellar dysfunction impairs the smoothness of eye movements, causing nystagmus, and renders speech dysarthric. In the limbs, the initial movement is normal, but as the target is approached, the accuracy of the movement deteriorates, producing an ‘intention tremor’. The distances of targets are misjudged (dysmetria), resulting in ‘past-pointing’. The ability to produce rapid, accurate, regularly alternating movements is also impaired (dysdiadochokinesis). The central vermis of the cerebellum is concerned with the coordination of gait and posture. Disorders of this area therefore produce a characteristic ataxic gait (see below). Fig. 25.7 Visual pathways and visual field defects. Schematic representation of eyes and brain in transverse section. Retina Optic nerve Optic chiasm Optic tract Lateral geniculate body Optic radiation Lower fibres in temporal lobe Upper fibres in anterior parietal lobe Occipital cortex Visual fields L R Visual field defects Monocular blindness Bitemporal hemianopia Right homonymous hemianopia Right superior homonymous quadrantanopia Right inferior homonymous quadrantanopia Right homonymous hemianopia with macular sparing R

L

1070 • NEUROLOGY sensation (including vibration) enter the spinal cord at the posterior horn and pass without synapsing into the ipsilateral posterior columns. In contrast, fibres conveying pain and temperature sensory information (nociceptive neurons) synapse with secondorder neurons that cross the midline in the spinal cord before ascending in the contralateral anterolateral spinothalamic tract to the brainstem. The second-order neurons of the dorsal column sensory system cross the midline in the upper medulla to ascend through the brainstem. Here they lie just medial to the (already crossed) spinothalamic pathway. Brainstem lesions can therefore cause sensory loss affecting all modalities on the contralateral side of the body. Distribution of facial sensory loss due to brainstem lesions arises from the anatomy of the trigeminal fibres within the brainstem. Fibres from the back of the face (near the ears) descend within the brainstem to the upper part of the spinal cord before synapsing, the second-order neurons crossing the midline and then ascending with the spinothalamic fibres. Fibres conveying sensation from more anterior areas of the face descend a shorter distance in the brainstem. Thus, sensory loss in the face from low brainstem lesions is in a ‘balaclava helmet’ distribution, as the longer descending trigeminal fibres are affected. Both dorsal column and spinothalamic tracts end in the thalamus, relaying from there to the parietal cortex. Pain Pain is a complex perception that is only partly related to activity in nociceptor neurons (p. 1338 and Fig. 34.2). Higher up, chronic and severe pain interacts extensively with mood and can exacerbate or be exacerbated by mood disorder, including depression and anxiety. Modification of psychological and psychiatric sequelae is a vital part of pain management (p. 1343). Sphincter control The sympathetic supply to the bladder arises from roots T11–L2 to synapse in the inferior hypogastric plexus, while the parasympathetic supply leaves from S2–4. In addition, a somatic supply to the external (voluntary) sphincter arises from S2–4, travelling via the pudendal nerves. Fig. 25.8 Control of conjugate eye movements. Downward projections pass from the cortex to the pontine lateral gaze centre (A). The pontine gaze centre projects to the 6th cranial nerve nucleus (B), which innervates the ipsilateral lateral rectus and projects to the contralateral 3rd nerve nucleus (and hence medial rectus) via the medial longitudinal fasciculus (MLF). Tonic inputs from the vestibular apparatus (C) project to the contralateral 6th nerve nucleus via the vestibular nuclei. B A C MLF 6th 8th 4th 3rd Pontine lateral gaze centre Lateral rectus Right Medial rectus Left Fig. 25.9 Areas of the cerebral cortex involved in the generation of spoken language. Arcuate fasciculus Posterior language comprehension area (Wernicke's) Broca's area Auditory cortex Bulbar muscles Corticobulbar tract Verbal memory Speech Much of the cerebral cortex is involved in the process of forming and interpreting communicating sounds, especially in the dominant hemisphere (see Box 25.2). Decoding of speech sounds (phonemes) is carried out in the upper part of the posterior temporal lobe. The attribution of meaning, as well as the formulation of the language required for the expression of ideas and concepts, occurs predominantly in the lower parts of the anterior parietal lobe (the angular and supramarginal gyri). The temporal speech comprehension region is called Wernicke’s area (Fig. 25.9). Other parts of the temporal lobe contribute to verbal memory, where lexicons of meaningful words are ‘stored’. Parts of the non-dominant parietal lobe appear to contribute to non-verbal aspects of language in recognising meaningful intonation patterns (prosody). The frontal language area is in the posterior end of the dominant inferior frontal gyrus known as Broca’s area. This receives input from the temporal and parietal lobes via the arcuate fasciculus. The motor commands generated in Broca’s area pass to the cranial nerve nuclei in the pons and medulla, as well as to the anterior horn cells in the spinal cord. Nerve impulses to the lips, tongue, palate, pharynx, larynx and respiratory muscles result in the series of ordered sounds comprising speech. The cerebellum also plays an important role in coordinating speech, and lesions of the cerebellum lead to dysarthria, where the problem lies in motor articulation of speech. The somatosensory system The body surface can be described by dermatomes, each dermatome being an area of skin in which sensory nerves derive from a single spinal nerve root (Fig. 25.10). Sensory information ascends in two anatomically discrete systems (Fig. 25.11). Fibres from proprioceptive organs and those mediating specific

Functional anatomy and physiology • 1071

disappears and activity becomes dominated by deepening slow-wave activity. As sleep deepens and dreaming begins, the limbs become flaccid, movements are ‘blocked’ and EEG signs of rapid eye movements (REM) are superimposed on the slow wave. REM sleep persists for a short spell before another slowwave spell starts, the cycle repeating several times throughout the night. REM phases lengthen as sleep progresses. REM sleep seems to be the most important part of the sleep cycle for refreshing cognitive processes, and REM sleep deprivation causes tiredness, irritability and impaired judgement. Localising lesions in the central nervous system After taking a history and examining the patient, the clinician should have an idea of the nature and site of any pathology (see Box 25.10). Given the intricate anatomy of the brainstem, this section will dwell on the possible localisation in more detail (see Fig. 25.5). Brainstem lesions typically present with symptoms due to cranial nerve, cerebellar and upper motor neuron dysfunction and are most commonly caused by vascular disease. Since the anatomy of the brainstem is very precisely organised, it is usually possible to localise the site of a lesion on the basis of careful history and examination in order to determine exactly Storage of urine is maintained by inhibiting parasympathetic activity and thus relaxing the detrusor muscle of the bladder wall. Continence is also helped by simultaneous sympathetic- and somatic-mediated tonic contraction of the urethral sphincters. Voiding in adults is usually carried out under conscious control, which triggers relaxation of tonic inhibition on the pontine micturition centre from higher centres, leading to relaxation of the pelvic floor muscles and external and internal urethral sphincters, along with parasympathetic-mediated detrusor contraction. Personality and mood The physiology and pathology of mood disorders are discussed elsewhere (Ch. 28) but it is important to remember that any process affecting brain function may influence mood and affect. Conversely, mood disorder may have a significant effect on perception and function. It can be difficult to disentangle whether psychological and psychiatric changes are the cause or the effect of any neurological symptoms. Sleep The function of sleep is unknown but it is required for health. Sleep is controlled by the reticular activating system in the upper brainstem and diencephalon. It is composed of different stages that can be visualised on electroencephalography (EEG). As drowsiness occurs, normal EEG background alpha rhythm Fig. 25.10 The areas supplied by specific levels of the spinal cord. These are approximations and in practice there is much overlap. The clinical utility of these dermatomes has diminished somewhat with the advent of good magnetic resonance imaging of the spinal cord but it remains important to ascertain the presence of a ‘spinal level’ of sensation, to remember the supply of saddle area, and to note the cervical descent of some facial spinothalamic pathways. A Anterior. B Posterior. C3 C2 C4 C5 T2 T1 C6 C7 C8 T3 T4 T5 T6 T7 T8 T9 T12 T11 T10 L1 L2 S2 S3 S4 S2 L3 L4 L5 S1 S 5 C3 C2 C4 C5 T1 T2 T3 T4 T5 T6 T7 T8 T9 T10 T11 T12 L1 L2 L3 C8 C7 C6 L4 L5 S1 S2, 3 B A

1072 • NEUROLOGY Neuroimaging Neurological imaging has traditionally allowed only assessment of structure but advances are allowing much more sophistication. Imaging modalities can use X-rays (plain X-rays, computed tomography (CT), CT angiography, myelography and angiography), magnetic resonance (MR imaging (MRI), MR angiography (MRA)), ultrasound (Doppler imaging of blood vessels) and nuclear medicine techniques (single photon emission computed tomography (SPECT) and positron emission tomography (PET)). The uses and limitations of each of these are shown in Box 25.4. Different sequences for analysing MRI signals can provide helpful information for characterising tissues and pathologies (Box 25.5). Specialist MR techniques, such as functional MRI (fMRI), MR spectroscopy or diffusion tensor imaging (DTI), can be used to assess brain metabolism and chemical compositions. This may be dynamic and can provide ‘maps’ of cortical function to help plan lesionectomy and epilepsy surgery. Similarly, MR spectroscopy can outline the chemical composition of specific regions, providing notions of whether lesions are ischaemic, neoplastic or inflammatory. Some degenerative neurological conditions cause functional rather than structural abnormalities that make metabolic and neurochemical assessment increasingly useful. PET scanning can display glucose metabolism in dementia and epilepsy. SPECT scanning uses the lipid-soluble properties of radioactive tracers to mark cerebral blood flow at the time of injection to help in investigating seizures. Dopaminergic pathway tracers can assess the integrity of the nigrostriatal pathway in patients with possible parkinsonism. which tracts/nuclei are affected, usually invoking the fewest number of lesions. For example, in a patient presenting with sudden onset of upper motor neuron features affecting the right face, arm and leg in association with a left 3rd nerve palsy, the lesion will be in the left cerebral peduncle in the brainstem and the pathology is likely to have been a discrete stroke, as the onset was sudden. This combination of symptoms and signs is known as Weber’s syndrome, and is one of several well-described brainstem syndromes, which are listed in Box 25.3. The effects of individual cranial nerve deficits are discussed in the sections on eye movements (p. 1088) and on facial weakness, sensory loss in brainstem lesions, dysphonia and dysarthria, and bulbar symptoms (pp. 1082, 1083, 1087 and 1093). Investigation of neurological disease Experienced clinicians make most neurological diagnoses on history alone, with a lesser contribution from examination and investigation. As investigations become more complex and more easily available, it is tempting to adopt a ‘scan first, think later’ approach to neurological symptoms. The frequency of ‘falsepositive’ results, the wide range of normality, and the negative implications for patients (unnecessary expense, inconvenience, discomfort and worry) necessitate a more thoughtful approach. Investigation may include assessment of structure (imaging) and function (neurophysiology). Neurophysiological testing has become so complex that in some countries it constitutes a separate specialty focusing on electroencephalography, evoked potentials, nerve conduction studies and electromyography. Fig. 25.11 The main somatic sensory pathways. Vestibulospinal tract Lateral spinothalamic tract Pain, temperature and poorly localised touch Joint position, vibration and accurate touch Dorsal column Gracile and cuneate nuclei Thalamus Parietal cortex 25.3 Major focal brainstem syndromes Name of syndrome Site of lesions Clinical features Weber Anterior cerebral peduncle (mid-brain) Ipsilateral 3rd palsy Contralateral upper motor neuron 7th palsy Contralateral hemiplegia Claude Cerebral peduncle Involving red nucleus Ipsilateral 3rd palsy Contralateral cerebellar signs Parinaud Dorsal mid-brain (tectum) Vertical gaze palsy Convergence disorders Convergence retraction nystagmus Pupillary and lid disorders Millard–Gubler Ponto-medullary junction Ipsilateral 6th palsy Ipsilateral lower motor neuron 7th palsy Contralateral hemiplegia Wallenberg Lateral medulla Ipsilateral 5th, 9th, 10th, 11th palsy Ipsilateral Horner’s syndrome Ipsilateral cerebellar signs Contralateral spinothalamic sensory loss Vestibular disturbance

Investigation of neurological disease • 1073

25.5 Different magnetic resonance imaging (MRI) sequences T1 T2 T2-FLAIR A ‘Anatomically correct’ B ‘Reverse T1’ C T2 with CSF signal dampened Grey matter (cortex) Grey White White White matter White Grey Grey Cerebrospinal fluid (CSF) Black White Black Insets courtesy of Dr Ravi Jampana, Consultant Neuroradiologist, Dept of Neuroradiology, Institute of Neuroscience, Queen Elizabeth University Hospital, Glasgow. of intravenous contrast and thinner slicing but CT is not optimal for lesions of meninges, cranial nerves or subtle parenchymal changes. MRI resolution is unaffected by bone and so is more useful in posterior fossa disease. Its sensitivity for cortical and white matter changes makes it the modality of choice in inflammatory conditions such as multiple sclerosis and in the investigation of epilepsy. Different MRI techniques can selectively suppress Head and orbit Plain skull X-rays now have a very limited role in neurological disease. CT or MRI is needed for intracranial imaging. CT is good for demonstrating bone and calcification well. It will also detect abnormalities of the brain and ventricles, such as atrophy, tumours, cysts, abscesses, vascular lesions and hydrocephalus. Diagnostic yield may be improved by the use 25.4 Imaging techniques for the nervous system Technique Applications Advantages Disadvantages Comments X-ray/CT Plain X-rays, CT, CTA Radiculography Myelography Intra-arterial angiography Widely available Relatively cheap Relatively quick Ionising radiation Contrast reactions Invasive (myelography and angiography) X-rays: used for fractures or foreign bodies CT: first line for stroke Intra-arterial angiography: gold standard for vascular lesions MRI Structural imaging MRA Functional MRI MR spectroscopy High-quality soft tissue images, useful for posterior fossa and temporal lobes No ionising radiation Non-invasive Expensive Less widely available MRA images blood flow, not vessel anatomy Claustrophobic Pacemakers are a contraindication Contrast (gadolinium) reactions Functional MR and spectroscopy: mainly research tools Ultrasound Doppler Duplex scans Cheap Quick Non-invasive Operator-dependent Poor anatomical definition Screening tool to assess need for carotid endarterectomy Radioisotope Isotope brain scan SPECT PET In vivo imaging of functional anatomy (ligand binding, blood flow) Poor spatial resolution Ionising radiation Expensive Not widely available Isotope scans: obsolete SPECT: useful in movement disorders, epilepsy and dementias PET: mainly research tool (CT = computed tomography; CTA = computed tomographic angiography; MRA = magnetic resonance angiography; MRI = magnetic resonance imaging; PET = positron emission tomography; SPECT = single photon emission computed tomography)

1074 • NEUROLOGY Neurophysiological testing Electroencephalography The electroencephalogram (EEG) detects electrical activity arising in the cerebral cortex via electrodes placed on the scalp to record the amplitude and frequency of the resulting waveforms. With closed eyes, the normal background activity is 8–13 Hz (known as alpha rhythm), most prominent occipitally and suppressed on eye opening. Other frequency bands seen over different parts of the brain in different circumstances are beta (faster than 13/ sec), theta (4–8/sec) and delta (slower than 4/sec). Normal EEG patterns evolve with age and alertness; lower frequencies predominate in the very young and during sleep. In recent years, digital technology has allowed longer, cleaner EEG recordings that can be analysed in a number of ways and recorded alongside contemporaneous video of any clinical ‘event’. Meanwhile, the development of intracranial recording allows more sensitive monitoring via surgically placed electrodes in and around lesions to help increase the efficacy and safety of epilepsy surgery. Abnormal EEGs result from a number of conditions. Examples include an increase in fast frequencies (beta) seen with sedating drugs such as benzodiazepines, or marked focal slowing noted over a structural lesion such as a tumour or an infarct. Improved quality and accessibility of imaging have made EEG redundant in lesion localisation, except in the specialist investigation of epilepsy (p. 1100). EEG remains useful in progressive and continuous disorders such as reduced consciousness (p. 194), encephalitis signal from fluid or fat, for example, and so increase sensitivity for more subtle pathologies. Examples of brain imaged by the various techniques are shown in Figure 25.12. Cervical, thoracic and lumbar spine X-rays are useful for imaging bony structures and can show destruction or damage to vertebrae, for example, but will provide no information about non-bony tissues, such as intervertebral discs, spinal cord and nerve roots. They have some usefulness in dynamic imaging, e.g. flexion/extension of the spine, in the assessment of instability. MRI has transformed spinal investigation, as it can give information not only about vertebrae and intervertebral discs but also about their effects on the spinal cord and nerve roots. Myelography (usually with CT) is an invasive technique requiring injection of contrast into the lumbar theca. While outlining the nerve roots and spinal cord provides some detail about abnormal structure, the accuracy and availability of MRI have reduced the need for it. Myelography may still be used where MRI is unavailable, contraindicated, or precluded by a patient’s claustrophobia. Examples of the cervical spine imaged by plain X-rays, myelography and MRI are shown in Figure 25.13. Blood vessels Imaging of the extra- and intracranial blood vessels and disturbance of arterial or venous blood flow is described on page 1161. Fig. 25.12 Different techniques of imaging the head and brain. A Computed tomogram showing complete middle cerebral artery infarct (arrows). B Magnetic resonance image showing widespread areas of high signal in multiple sclerosis (arrows). C Single photon emission computed tomography scan after caudate infarct showing relative hypoperfusion of overlying right cerebral cortex (arrows). D Normal positron emission tomogram (PET scan) of brain. A–C, Courtesy of Dr D. Collie. D, Courtesy of Dr Ravi Jampana, Consultant Neuroradiologist, Dept of Neuroradiology, Institute of Neuroscience, Queen Elizabeth University Hospital, Glasgow. C A B D

Investigation of neurological disease • 1075

but, conversely, the presence of epileptiform features does not of itself make a diagnosis. Up to 5% of some normal populations may demonstrate epileptiform discharges on EEG, preventing its use as a screening test for epilepsy, most notably in younger patients with a family history of epilepsy. In view of this, the EEG should not be used where epilepsy is merely ‘possible’. (p. 1121), and certain dementias such as Creutzfeldt–Jakob disease (p. 1127). Since sleep induces marked changes in cerebral activity, EEG can be useful in diagnosis of sleep disturbances. In paroxysmal disorders such as epilepsy, EEG is at its most useful when it captures activity during one of the events in question. Over 50% of patients with epilepsy have a normal ‘routine’ EEG Fig. 25.13 Different techniques of imaging the cervical spine. A Lateral X-ray showing bilateral C6/7 facet dislocation. B Myelogram showing widening of cervical cord due to astrocytoma (arrows). C Magnetic resonance image showing posterior epidural compression from adenocarcinomatous metastasis to the posterior arch of T1 (arrows). A–C, Courtesy of Dr D. Collie. A B C C6 C7 Fig. 25.14 Electroencephalograms in epilepsy. A Generalised epileptic discharge, as seen in epilepsy syndromes such as childhood absence or juvenile myoclonic epilepsy. B Focal sharp waves over the right parietal region (circled), with spread of discharge to cause a generalised tonic–clonic seizure.

A B

15 14 13 12

Secondary generalised seizure

1076 • NEUROLOGY 25.15). These are around 500 times larger than sensory nerve potentials, typically around 1–20 millivolts. Since a proportion of stimulated impulses in motor nerves will ‘reflect’ back from the anterior horn cell body (forming the ‘F’ wave), it is also possible to obtain some information about the condition of nerve roots. Repetitive nerve stimulation (RNS) at 3–15/sec provides consistent CMAPs in healthy muscle. In myasthenia gravis (p. 1141), however, where there is partial blockage of acetylcholine receptors, there is a diagnostic fall (decrement) in CMAP amplitude. In contrast, an increasing CMAP with high-frequency RNS is seen in Lambert–Eaton myasthenic syndrome (p. 1143). Electromyography Electromyography (EMG) is usually performed alongside NCS and involves needle recording of muscle electrical potential during rest and contraction. At rest, muscle is electrically silent but loss of nerve supply causes muscle membrane to become unstable, manifest as fibrillations, positive sharp waves (‘spontaneous activity’) or fasciculations. Motor unit action potentials are recorded during muscle contraction. Axonal loss or destruction will result in fewer motor units. Resultant sprouting of remaining units will lead to increasing size of each individual unit on EMG. Myopathy, in contrast, causes muscle fibre splitting, which results in a large number of smaller units on EMG. Other abnormal activity, such as myotonic discharges, may signify abnormal ion channel conduction, as in myotonic dystrophy or myotonia congenita. Specialised single-fibre electromyography (SFEMG) can be used to investigate neuromuscular junction transmission. Measuring ‘jitter’ and ‘blocking’ can identify the effect of antibodies in reducing the action of acetylcholine on the receptor. Evoked potentials The cortical response to visual, auditory or electrical stimulation can be measured on an EEG as an evoked potential (EP). If a stimulus is provided – e.g. to the eye, the tiny EEG response can be discerned when averaging 100–1000 repeated stimuli. Assessing the latency (the time delay) and amplitude can give Therefore the EEG in epilepsy is predominantly used for classification and prognostication, but in some patients can help localise the seat of epileptiform discharges when surgery is being considered. During a seizure, high-voltage disturbances of background activity (‘discharges’) are often noted. These may be generalised, as in the 3 Hz ‘spike and wave’ of childhood absence epilepsy, or more focal, as in localisation-related epilepsies (Fig. 25.14). Techniques such as hyperventilation or photic stimulation can be used to increase the yield of epileptiform changes, particularly in the generalised epilepsy syndromes. While some argue that it is possible to detect ‘spikes’ and ‘sharp waves’ to lend support to a clinical diagnosis, these are non-specific and therefore not diagnostic, and can lead an unwary clinician to err in ascribing other symptoms to epilepsy. Nerve conduction studies Electrical stimulation of a nerve causes an impulse to travel both efferently and afferently along the underlying axons. Nerve conduction studies (NCS) make use of this, recording action potentials as they pass along peripheral nerves and (with motor nerves) as they pass into the muscle belly. Digital recording has enhanced sensitivity and reproducibility of these tiny potentials. By measuring the time taken to traverse a known distance, it is possible to calculate nerve conduction velocities (NCVs). Healthy nerves at room temperature will conduct at a speed of 40–50 m/sec. If the recorded potential is smaller than expected, this provides evidence of a reduction in the overall number of functioning axons. Significant slowing of conduction velocity, in contrast, suggests impaired conduction due to peripheral nerve demyelination. Such changes in NCS may be diffuse (as in a hereditary demyelinating peripheral neuropathy, p. 1138), focal (as in pressure palsies, p. 1139) or multifocal (e.g. Guillain–Barré syndrome, p. 1140; mononeuritis multiplex, p. 1140). The information gained can allow the disease responsible for peripheral nerve dysfunction to be better deduced (see Box 25.84, p. 1139). Stimulation of motor nerves allows for the recording of compound muscle action potentials (CMAPs) over muscles (Fig. Fig. 25.15 Motor nerve conduction tests. Electrodes (R) on the muscle (abductor pollicis here) record the compound muscle action potential (CMAP) after stimulation at the median nerve at the wrist (S1) and from the elbow (S2). The velocity from elbow to wrist can be determined if the distance between the two stimulating electrodes (d) is known. A prolonged L1 (L = latency) would be caused by dysfunction distally in the median nerve (e.g. in carpal tunnel syndrome). A prolonged L2 is caused by slow nerve conduction (as in demyelinating neuropathy). The F wave is a small delayed response that appears when the electrical signal travels backwards to the anterior horn cell, sparking a second action potential in a minority of fibres (see text). (NCV = nerve conduction velocity)

Anterior horn cells Antidromic conduction: generates F wave Orthodromic conduction F wave CMAP Abductor pollicis brevis Median nerve NCV = d L2 – L1 S2 S1 L1 L2 R Amplitude d

Investigation of neurological disease • 1077

causative antibodies (see Boxes 25.52 and 25.53, p. 1111) and it is likely that further conditions will turn out to have an immune basis. Genetic testing This evolving field represents a huge untapped area for neurological exploration, particularly with the development of genome-wide association study (GWAS) and whole-genome sequencing. Relevant subsections will detail the increasing numbers of inherited neurological conditions that can now be diagnosed by DNA analysis (p. 56). These include diseases caused by increased numbers of trinucleotide repeats, such as Huntington’s disease (p. 1114); myotonic dystrophy (p. 1143); and some types of spinocerebellar ataxia (p. 1115). Mitochondrial DNA can also be sequenced to diagnose relevant disorders (p. 1144). Lumbar puncture Lumbar puncture (LP) is the technique used to obtain both a CSF sample and an indirect measure of intracranial pressure. After local anaesthetic injection, a needle is inserted between lumbar spinous processes (usually between L3 and L4) through the dura and into the spinal canal. Intracranial pressure can be deduced (if patients are lying on their side) and CSF removed for analysis. CSF pressure measurement is important in the diagnosis and monitoring of idiopathic intracranial hypertension (p. 1133). In this condition, the LP itself is therapeutic. CSF is normally clear and colourless, and the tests that are usually performed include a naked eye examination of the CSF and centrifugation to determine the colour of the supernatant (yellow, or xanthochromic, some hours after subarachnoid haemorrhage; p. 1160). Measurement of absorption of specific light wavelengths helps quantify the amount of haem metabolites in CSF. Routine analysis involves a cell count, as well as glucose and protein concentrations. CSF assessment is important in investigating infections (meningitis or encephalitis), subarachnoid haemorrhage and inflammatory conditions (multiple sclerosis, sarcoidosis and cerebral lupus). Normal values and abnormalities found in specific conditions are shown in Box 25.6. More sophisticated analysis allows measurement of antibody formation solely within the CNS (oligoclonal bands), genetic analysis (e.g. polymerase chain reaction (PCR) for herpes simplex or tuberculosis), immunological tests (paraneoplastic antibodies) and cytology (to detect malignant cells). If there is a cranial space-occupying lesion causing raised intracranial pressure, LP presents a theoretical risk of downward shift of intracerebral contents, a potentially fatal process known as coning (p. 1128). Consequently, LP is contraindicated if there is any clinical suggestion of raised intracranial pressure (papilloedema), depressed level of consciousness, or focal neurological signs suggesting a cerebral lesion, until imaging (by CT or MRI) has excluded a space-occupying lesion or hydrocephalus. When there is a risk of local haemorrhage (thrombocytopenia, disseminated intravascular coagulation or anticoagulant treatment), then caution should be exercised or specific measures should be taken. LP can be safely performed in patients on antiplatelet drugs or low-dose heparin, but may be unsafe in patients who are fully anticoagulated due to the increased risk of epidural haematoma. About 30% of LPs are followed by a postural headache, due to reduced CSF pressure. The frequency of headache information about the integrity of the relevant pathway. MRI now provides more information about CNS pathways, thus reducing reliance on EPs. In practice, visual evoked potentials (VEPs) are most commonly used to help differentiate CNS demyelination from small-vessel white-matter changes (Fig. 25.16). Magnetic stimulation Central conduction times can also be measured using electromagnetic induction of action potentials in the cortex or spinal cord by the local application of specialised coils. Again, MRI has made this technique largely redundant, other than for research. Routine blood tests Many systemic conditions that can affect the nervous system can be identified by simple blood tests. Nutritional deficiencies, metabolic disturbances, inflammatory conditions or infections may all present or be associated with neurological symptoms, and basic blood tests (full blood count, erythrocyte sedimentation rate, C-reactive protein, biochemical screening) may provide clues. Specific blood tests will be highlighted in the relevant subsections of this chapter. Human immunodeficiency virus (HIV) infection is increasingly recognised as a cause of neurological disease and the clinician should have a low threshold for checking this. Immunological tests Recent developments have seen a host of new immune-mediated conditions emerge in clinical neurology, with antibody targets ranging from muscle and neuromuscular junction disturbance (causing weakness and muscle pain) to specific neuronal ion channels (causing cognitive decline, epilepsy and psychiatric changes). The 21st century has seen the identification of many Fig. 25.16 Visual evoked potential (VEP) recording. The abnormality is in the left hemisphere, with delay in latency and a reduction in signal of the P100. 5 μV 5 μV 5 μV 5 μV 5 μV 5 μV 5 μV 5 μV 5 μV 5 μV

L R ms ms P100 P100

1078 • NEUROLOGY Presenting problems in neurological disease While history is important in all medical specialties, it is especially key in neurology, where many neurological diagnoses have no confirmatory test. History-taking allows doctor and patient to get to know one another; many neurological diseases follow chronic paths and this may be the first of many such consultations. It also allows the clinician to obtain information about the patient’s affect, cognition and psychiatric state. History-taking is a highly active process. While there are generic templates (Box 25.7), each individual story will follow its own course, and diagnostic considerations during the history will guide further questioning. It is important to be clear about what patients mean by certain words. They may find it difficult to describe symptoms: for instance, weakness may be called ‘numbness’, while there are many possible interpretations of ‘dizziness’. These must be clarified; even in emergency situations, a clear, accurate history is the foundation of any management plan. While the story should come primarily from the patient, input from eye-witnesses and family members is crucial if the patient is unable to provide details or if there has been loss of consciousness. This need for corroboration and clarification means the telephone is as important as any investigation. The aim of the history is to address two key issues: where is the lesion and what is the lesion (Box 25.8)? These should remain uppermost in the doctor’s mind while the history is being elicited. Some common combinations of symptoms may suggest particular locations for a lesion (Box 25.10). Enquiry about handedness is important; lateralisation of the dominant hand helps designate the dominant hemisphere, which in turn may help to localise any pathologies, or to plan rehabilitation or treatment strategies in asymmetrical disorders such as stroke or Parkinson’s disease. Epidemiology must be borne in mind. How likely is it that this particular patient has any specific condition under consideration? can be reduced by using smaller or atraumatic needles. Rarer complications involve transient radicular pain, and pain over the lumbar region during the procedure. Aseptic technique renders secondary infections such as meningitis extremely rare. Biopsy Biopsies of nervous tissue (peripheral nerve, muscle, meninges or brain) are occasionally required for diagnosis. Nerve biopsy can help in the investigation of peripheral neuropathy. Usually, a distal sensory nerve (sural or radial) is targeted. Histological examination can help identify underlying causes, such as vasculitides or infiltrative disorders like amyloid. Nerve biopsy should not be undertaken lightly since there is an appreciable morbidity; it should be reserved for cases where the diagnosis is in doubt after routine investigations and where it will influence management. Muscle biopsy is performed more frequently and is indicated for the differentiation of myositis and myopathies. These conditions can usually be distinguished by histological examination, and enzyme histochemistry can be useful when mitochondrial diseases and storage diseases are suspected. The quadriceps muscle is most commonly biopsied but other muscles may also be sampled if they are involved clinically. Although pain and infection can follow the procedure, these are less of a problem than after nerve biopsy. Brain biopsy is required when imaging fails to clarify the nature of intracerebral lesions, e.g. in unexplained degenerative diseases such as unusual cases of dementia and in patients with brain tumours. Most biopsies are performed stereotactically through a burr hole in the skull, which lowers complication rates. Nevertheless, haemorrhage, infection and death still occur and brain biopsy should be considered only if a diagnosis is otherwise elusive. Biopsy of other organs can be useful in the diagnosis of systemic disorders presenting as neurological problems, such as tonsillar biopsy (diagnosis of prion diseases), or rectal or fat biopsy (for assessment of amyloid). 25.6 How to interpret cerebrospinal fluid results Normal Subarachnoid haemorrhage Acute bacterial meningitis Viral meningitis Tuberculous meningitis Multiple sclerosis Pressure 50–250 mm of water Increased Normal/increased Normal Normal/increased Normal Colour Clear Blood-stained Xanthochromic Cloudy Clear Clear/cloudy Clear Red cell count (× 106/L) 0–4 Raised Normal Normal Normal Normal White cell count (× 106/L) 0–4 Normal/slightly raised 1000–5000 polymorphs 10–2000 lymphocytes 50–5000 lymphocytes 0–50 lymphocytes Glucose

50–60% of blood level Normal Decreased Normal Decreased Normal Protein < 0.45 g/L Increased Increased Normal/increased Increased Normal/increased Microbiology Sterile Sterile Organisms on Gram stain and/or culture Sterile/virus detected Ziehl–Neelsen/auramine stain or tuberculosis culture positive Sterile Oligoclonal bands Negative Negative Can be positive Can be positive Can be positive Often positive

Presenting problems in neurological disease • 1079

Evolution over several days, however, might make demyelination (multiple sclerosis) a possible diagnosis, or perhaps a subdural haematoma if the weakness was preceded by a head injury in an older person taking warfarin. Progression over weeks might bring an intracranial mass lesion or motor neuron disease into the differential. Slow progression over a year or so, with difficulty in using the hand, could suggest a degenerative process such For example, a 20-year-old with right-sided headache and tenderness will not have temporal arteritis, but this is an important possibility if such symptoms present in a 78-year-old female. Determining the evolution, speed of onset and progression of a disease is important (Box 25.11). For example, if right-hand weakness occurred overnight, it would suggest a stroke in an older person or an acute entrapment neuropathy in a younger one. 25.7 How to take a neurological history Introduction • Age and sex • Handedness Presenting complaint • Symptoms (clarify: see text) • Overall pattern: intermittent or persistent? • If intermittent, how often do symptoms occur and how long do they last? • Speed of onset: seconds, minutes, hours, days, weeks, months, years, decades? • Better, worse or the same over time? • Associated symptoms (including non-neurological) • Disability caused by symptoms • Change in walking • Difficulty with fine hand movements, e.g. writing, fastening buttons, using cutlery • Effect on work, family life and leisure Background • Previous neurological symptoms and whether similar to current symptoms • Previous medical history • Domestic situation • Driving licence status • Medications (current and at time of symptom onset) • Alcohol/smoking habits • Recreational drug and other toxin exposure • Family history and developmental history • What are patient’s thoughts/fears/concerns? 25.8 The key diagnostic questions Where is the lesion? • Is it neurological? • If so, to which part of the nervous system does it localise? Central versus peripheral Sensory versus motor versus both What is the lesion? • Hereditary or congenital • Acquired: Traumatic Infective Neoplastic Degenerative Inflammatory or immune-mediated Vascular Functional 25.10 How to ‘localise’ neurological disease Combination of symptoms/signs Probable site Possible pathology Other important information Painless loss of hemilateral function Cerebral cortex Usually vascular, inflammatory or neoplastic Associated systemic symptoms Tempo of evolution Pyramidal weakness of all four limbs or both legs, bladder signs, sensory loss Spinal cord Usually vascular, inflammatory or neoplastic Associated systemic symptoms Tempo of evolution Cranial nerve lesions, with limb pyramidal signs or sensory loss ± sphincter disturbance Brainstem Mid-brain Pons Medulla Usually vascular or inflammatory Rarely neoplastic Associated systemic symptoms Tempo of evolution Visual loss + pyramidal signs and/or cerebellar signs Widespread cerebral lesions Usually inflammatory Less commonly vasculitic Tempo of evolution Weakness and/or sensory loss in a combination of individual peripheral nerves Several peripheral nerves (‘mononeuritis multiplex’) Usually inflammatory or diabetic Associated systemic symptoms Widespread LMN and UMN signs Upper and lower motor neurons Motor neuron disease Cervical myeloradiculopathy Associated localised cervical symptoms Distal loss of sensation and/or weakness Generalised peripheral nerves See causes of neuropathy (p. 1138) Associated systemic symptoms (LMN/UMN = lower/upper motor neuron) 25.9 Neurological examination in old age • Pupils: tend to be smaller, making fundoscopy more difficult. • Limb tone: more difficult to assess because of poor relaxation and concomitant joint disease. • Ankle reflexes: may be absent. • Gait assessment: more difficult because of concurrent musculoskeletal disease and pre-existing neurological deficits. • Sensory testing: especially difficult when there is cognitive impairment. • Vibration sense: may be reduced distally in the legs.

1080 • NEUROLOGY frequently felt in the second and third divisions of the nerve and often triggered by talking or chewing. Facial shingles most commonly affects the first (ophthalmic) division of the trigeminal nerve, and pain usually precedes the rash. Post-herpetic neuralgia may follow, typically a continuous burning pain throughout the affected territory, with marked sensitivity to light touch (allodynia) and resistance to treatment. Destructive lesions of the trigeminal nerve usually cause numbness rather than pain. Persistent idiopathic facial pain is most frequently seen in middle-aged women, who report persistent pain, with no abnormal signs or investigations, and is similar to other forms of idiopathic chronic pain. Dizziness, blackouts and ‘funny turns’ Acute onset of dizziness or blackouts will present to the acute medical department. In neurological practice, it is common to deal with patients presenting with a history of multiple events. While detailed questioning will be dealt with in the relevant section (p. 181), the neurologist will have to tease out the pattern of each of the different attack types experienced by the patient to be able to form a treatment and investigation plan, one of the challenges of clinical neurology. Status epilepticus Status epilepticus is seizure activity not resolving spontaneously, or recurrent seizure with no recovery of consciousness in between. Persisting seizure activity has a recognised mortality and is a medical emergency. Diagnosis is usually clinical and can be made on the basis of the description of prolonged rigidity and/or clonic movements with loss of awareness. As seizure activity becomes prolonged, movements may become more subtle. Cyanosis, pyrexia, acidosis and sweating may occur, and complications include aspiration, hypotension, cardiac arrhythmias and renal or hepatic failure. In patients with pre-existing epilepsy, the most likely cause is a fall in antiepileptic drug levels. In de novo status epilepticus, it is essential to exclude precipitants such as infection (meningitis, encephalitis), neoplasia and metabolic derangement (hypoglycaemia, hyponatraemia or hypocalcaemia). Treatment and investigation are outlined in Box 25.12. Coma Coma and loss of consciousness usually present to the acute medical admissions department (p. 194). Clarification of cause and prognosis may require specialist neurological input. Delirium Delirium describes cortical dysfunction and replaces the older term ‘acute confusional state’. It has a range of primary causes, and given its role in precipitating acute admission, it is covered in detail on page 183. Amnesia Memory disturbance is a common symptom. In the absence of significant functional impairment (e.g. inability to work, dyspraxias, loss of daily function), many patients will prove to have benign memory dysfunction related to age, mood or psychiatric disorders. as Parkinson’s disease. The impact on day-to-day activities, such as walking, climbing stairs and carrying out fine hand movements, should also be established in order to gauge the level of associated disability. Estimates of the frequency and duration of specific events are essential when taking details of a paroxysmal disorder such as migraine and epilepsy. Vague terms such as ‘a lot’ or ‘sometimes’ are unhelpful, and it can assist the patient if choices are given to estimate numbers, such as once a day, week or month. Many neurological symptoms are not explained by disease. Describing these as ‘functional’ is less pejorative and more acceptable to patients than ‘psychogenic’ or ‘hysterical’. Functional symptoms require considerable experience in diagnosis and are frequently missed (p. 1094). Headache and facial pain Most headaches are chronic disorders but acute presentation of headaches is an important aspect of emergency medical care. Headache may be divided into primary (benign) or secondary, and most patients, whether presenting in clinic or as emergencies, have primary syndromes (see Box 10.10, p. 184). The emergency clinical assessment of headaches is dealt with on page 185. Ocular pain Assuming that ocular disease (such as acute glaucoma) has been excluded, ocular pain may be due to trigeminal autonomic cephalalgias (TACs) or, rarely, inflammatory or infiltrative lesions at the apex of the orbit or the cavernous sinus, when 3rd, 4th, 5th or 6th cranial nerve involvement is usually evident. Ocular pain and headache are also discussed on page 1170. Facial pain Pain in the face can be due to dental or temporomandibular joint problems. Acute sinusitis is usually apparent from other features of sinus congestion/infection and may cause localised pain over the affected sinus, but is almost never the explanation for persistent facial pain or headache. Facial pain is not uncommon in migraine but some syndromes can present solely with facial pain. The most common neurological causes of facial pain are trigeminal neuralgia, herpes zoster (shingles) and post-herpetic neuralgia, all characterised by their extreme severity. In trigeminal neuralgia, the patient describes bouts of brief (seconds), lancinating pain (‘electric shocks’), most 25.11 The evolution of symptoms Onset Evolution Possible causes Sudden (minutes to hours) Stable/improvement Vascular (stroke/transient ischaemic attack (TIA)) Nerve entrapment syndromes Functional Gradual Progressive over days Demyelination Infection Gradual Progressive over weeks to months Neoplastic/paraneoplastic Gradual Progressive over months to years Genetic Degenerative

Presenting problems in neurological disease • 1081

amnesia recurs in only around 10–20% of cases. A vascular aetiology is unlikely (TGA is not a risk factor for subsequent vascular disease) and amnesia may be due to a benign process similar to migraine, occurring in the hippocampus. TGA causes no physical signs and, provided there is a typical history (which requires a witness), no investigation is necessary and patients may be reassured. Persistent amnesia Serious neurological disease must be excluded in patients with persistent memory disturbance, although many will prove to have benign symptoms. Symptoms corroborated by relatives or colleagues are likely to be more significant than those noted by the patient only. Where poor concentration is at the heart of cognitive deterioration, it is more likely to be due to an underlying mood disorder. It is important to assess the timing of onset and to establish which aspects of memory are affected. Complaints of getting lost or of losing complex abilities are more pathological than wordfinding difficulties. Disturbance of episodic or working memory (previously called ‘short-term memory’) must be distinguished from semantic memory (memory for concept-based knowledge unrelated to specific experiences). Episodic memory is selectively impaired in Korsakoff’s syndrome (often secondary to alcohol) or bilateral temporal lobe damage. It can also be seen in conjunction with other types of dementia. Progressive deterioration over months suggests an underlying dementia, and a full medical assessment must be performed to detect any underlying medical problem. It is important to identify and treat depression (p. 1185) in patients with memory loss. Depression may present as a ‘pseudo-dementia’, with concentration and memory impairment as dominant features, and this is often reversible with antidepressant medication. Any patient with dementia (particularly of Alzheimer’s type) may develop depression in the early stages of their illness, however. Specific causes of progressive dementia, with their investigation and treatment, are described elsewhere (p. 1191). Weakness The assessment of weakness requires the application of basic anatomy, physiology and some pathology to the interpretation of the history and clinical findings. Points to consider are shown on Figure 25.17 and in Boxes 25.13 and 25.14. The pattern and evolution of weakness and the clinical signs provide clues to the site and nature of the lesion. It is important to establish whether the patient has loss of power rather than reduced sensation or generalised fatigue. Pain may restrict movement and thus mimic weakness. Paradoxically, sensory neglect (p. 1083) may leave patients unaware of severe weakness. Patients with parkinsonism may complain of weakness; extrapyramidal signs of rigidity (cogwheel or lead pipe) and bradykinesia should be evident, and a resting tremor (usually asymmetrical) may provide a further clue (p. 1112). Simple observation of the patient walking into the consulting room may be diagnostic, and is as important as formal strength testing. Movement restricted by pain should be apparent, and other features (contractures, wasting, fasciculations, abnormal movements/postures) all provide diagnostic clues. Weakness is a common symptom arising without an underlying degenerative or destructive cause (functional symptom). Functional 25.12 Management of status epilepticus Initial • Ensure airway is patent; give oxygen to prevent cerebral hypoxia • Check pulse, blood pressure, BM stix and respiratory rate • Secure intravenous access • Send blood for: Glucose, urea and electrolytes, calcium and magnesium, liver function, antiepileptic drug levels Full blood count and coagulation screen Storing a sample for future analysis (e.g. drug misuse) • If seizures continue for > 5 mins: give midazolam 10 mg bucally or nasally or lorazepam 4 mg IV if access available or diazepam 10 mg rectally or IV if necessary; repeat once only after 15 mins • Correct any metabolic trigger, e.g. hypoglycaemia Ongoing If seizures continue after 30 mins • IV infusion (with cardiac monitoring) with one of: Phenytoin: 15 mg/kg at 50 mg/min Sodium valproate: 20–30 mg/kg IV at 40 mg/min Phenobarbital: 10 mg/kg at 100 mg/min • Cardiac monitor and pulse oximetry: Monitor neurological condition, blood pressure, respiration; check blood gases If seizures still continue after 30–60 mins • Transfer to intensive care: Start treatment for refractory status with intubation, ventilation and general anaesthesia using propofol or thiopental EEG monitor Once status controlled • Commence longer-term antiepileptic medication with one of: Sodium valproate 10 mg/kg IV over 3–5 mins, then 800– 2000 mg/day Phenytoin: give loading dose (if not already used as above) of 15 mg/kg, infuse at < 50 mg/min, then 300 mg/day Carbamazepine 400 mg by nasogastric tube, then 400– 1200 mg/day • Investigate cause The increasing publicity given to dementia, combined with a natural fear of losing one’s mind, has led to an increase in patients presenting with memory loss but many will have benign symptoms. Investigation and treatment of the dementias are discussed elsewhere (p. 1191). Temporary loss of memory may be due to a transient delirium related to infection, the post-ictal period after seizure, or transient global amnesia. These are usually distinguished on the basis of the history. Transient amnesia resulting directly from a seizure (transient epileptic amnesia) is a rare result of temporal lobe epilepsy. Transient global amnesia Transient global amnesia (TGA) predominantly affects middle-aged people, with an abrupt, discrete loss of anterograde memory function lasting up to a few hours. During the episode, patients are unable to record new memories, resulting in repetitive questioning, the hallmark of this condition. Consciousness is preserved and patients may perform even complex motor acts normally. During the attack there is retrograde amnesia for the events of the past few days, weeks or years. After 4–6 hours, memory function and behaviour return to normal but the patient has persistent, complete amnesia for the duration of the attack itself. There are no seizure markers and, unlike epileptic amnesia, transient global

1082 • NEUROLOGY Facial weakness Facial nerve palsy (Bell’s palsy) One of the most common causes of facial weakness is Bell’s palsy, a lower motor neuron lesion of the 7th (facial) nerve, affecting all ages and both sexes. It is more common following upper respiratory tract infections, during pregnancy, and in patients with diabetes, immunosuppression and hypertension. weakness does not conform to typical organic patterns, and the signs in Box 25.13 are absent. Clinical examination is often variable (e.g. the patient can walk but appears to have no leg movement when assessed on the couch), and strength may appear to ‘give way’, with the patient able to achieve full power for brief bursts, which does not occur in disease. Hoover’s sign is useful to confirm functional weakness, and relies on eliciting the normal phenomenon of simultaneous hip extension when the contralateral hip flexes. In functional weakness, hip extension weakness may be seen; this then returns to full strength when contralateral hip flexion is tested. This sign may be demonstrated to the patient in a non-confrontational manner, to show that the potential limb power is intact. 25.14 How to assess weakness Clinical finding Likely level of lesion/diagnosis Pattern and distribution Isolated muscles Radiculopathy or mononeuropathy Both limbs on one side (hemiparesis) Cerebral hemisphere, less likely cord or brainstem One limb Neuronopathy, plexopathy, cord/brain Both lower limbs (paraparesis) Spinal cord; look for a sensory level Fatigability Myasthenia gravis Bizarre, fluctuating, not following anatomical rules Functional Signs Upper motor neuron Brain/spinal cord Lower motor neuron Peripheral nervous system Evolution of the weakness Sudden and improving Stroke/mononeuropathy Evolving over months or years Meningioma, cervical spondylotic myelopathy Gradually worsening over days or weeks Cerebral mass, demyelination Associated symptoms Absence of sensory involvement Motor neuron disease, myopathy, myasthenia 25.13 Distinguishing signs in upper versus lower motor neuron syndromes Upper motor neuron lesion Lower motor neuron lesion Inspection Normal (may be wasting in chronic lesions) Wasting, fasciculation Tone Increased with clonus Normal or decreased, no clonus Pattern of weakness Preferentially affects extensors in arms, flexors in leg Hemiparesis, paraparesis or tetraparesis Typically focal, in distribution of nerve root or peripheral nerve, with associated sensory changes Deep tendon reflexes Increased Decreased/absent Plantar response Extensor (Babinski sign) Flexor Fig. 25.17 Patterns of motor loss according to the anatomical site of the lesion. Anterior horn, motor root, plexus and peripheral nerve Upper limbs Contralateral hemiplegia Central lesion Peripheral lesion Tetraplegia Paraplegia Upper motor neuron lesion Spinal cord Lower motor neuron lesion Lower limbs

Presenting problems in neurological disease • 1083

Sensory neurological examination needs to be undertaken and interpreted with care because the findings depend, by definition, on subjective reports. The reported distribution of sensory loss can be useful, however, when combined with the coexisting deficits of motor and/or cranial nerve function (Fig. 25.18). Sensory loss in peripheral nerve lesions Here the symptoms are usually of sensory loss and paraesthesia. Single nerve lesions cause disturbance in the sensory distribution of the nerve, whereas in diffuse neuropathies the longest neurons are affected first, giving a characteristic ‘glove and stocking’ distribution. If smaller nerve fibres are preferentially affected (e.g. in diabetic neuropathy), temperature and pin-prick (pain) are reduced, whilst vibration sense and proprioception (modalities served by the larger, well-myelinated, sensory nerves) may be relatively spared. In contrast, vibration and proprioception are particularly affected if the neuropathy is demyelinating in character (p. 1138), producing symptoms of tightness and swelling with impairment of proprioception and vibration sensation. Sensory loss in nerve root lesions These typically present with pain as a prominent feature, either within the spine or in the limb plexuses. Pain is often felt in the myotome rather than the dermatome. The nerve root involved may be deduced from the dermatomal pattern of sensory loss (p. 1071), although overlap may lead to this being smaller than expected. Sensory loss in spinal cord lesions Transverse lesions of the spinal cord produce loss of all sensory modalities below that segmental level, although the clinical level may only be manifest 2–3 segments lower than the anatomical site of the lesion. Very often, there is a band of paraesthesia or hyperaesthesia at the top of the area of sensory loss. Clinical examination may reveal dissociated sensory loss, i.e. different patterns in the spinothalamic and dorsal columnar pathways. If the transverse lesion is vascular due to anterior spinal artery thrombosis, the spinothalamic pathways may be affected while the posterior one-third of the spinal cord (the dorsal column modalities) may be spared. Lesions damaging one side of the spinal cord will produce loss of spinothalamic modalities (pain and temperature) on the opposite side, and of dorsal column modalities (joint position and vibration sense) on the same side of the body – the Brown–Séquard syndrome (p. 1084). Lesions in the centre of the spinal cord (such as syringomyelia: see Box 25.83 and Fig. 25.51, pp. 1138 and 1139) spare the dorsal columns but involve the spinothalamic fibres crossing the cord from both sides over the length of the lesion. There is no sensory loss in segments above and below the lesion; this is described as ‘suspended’ sensory loss. There is sometimes reflex loss at the level of the lesion if afferent fibres of the reflex arc are affected. An isolated lesion of the dorsal columns is not uncommon in multiple sclerosis. This produces a characteristic unpleasant, tight feeling over the limb(s) involved and, while there is no loss of pin-prick or temperature sensation, the associated loss of proprioception may severely limit function of the affected limb(s). Sensory loss in brainstem lesions Lesions in the brainstem can be associated with sensory loss but the distribution depends on the site of the lesion. A lesion limited to the trigeminal nucleus or its sensory projections will cause The lesion is within the facial canal. Symptoms usually develop subacutely over a few hours, with pain around the ear preceding the unilateral facial weakness. Patients often describe the face as ‘numb’ but there is no objective sensory loss (except to taste, if the chorda tympani is involved). Hyperacusis may occur if the nerve to stapedius is involved and impairment of parasympathetic fibres may cause diminished salivation and tear secretion. Examination reveals an ipsilateral lower motor neuron facial nerve palsy (no sparing of forehead muscles). Vesicles in the ear or on the palate may indicate primary herpes zoster infection (p. 239). A clinical search for signs of other causes of lower motor neuron facial nerve weakness, such as parotid or scalp lesions, trauma or skull base lesions, is justified. Glucocorticoids improve recovery rates if started within 72 hours of onset but antiviral drugs are not effective. Artificial tears applied regularly prevent corneal drying, and taping the eye shut overnight helps prevent exposure keratitis and corneal abrasion. Patients unable to close the eye should be referred urgently to an ophthalmologist. About 80% of patients recover spontaneously within 12 weeks. Plastic surgery may be considered for the minority left with facial disfigurement after 12 months. Recurrence is unusual and should prompt further investigation. Aberrant re-innervation may occur during recovery, producing unwanted facial movements, such as eye closure when the mouth is moved (synkinesis) or ‘crocodile tears’ (tearing during salivation). Unlike Bell’s palsy, lesions with an upper motor neuron origin may spare the upper face. Cortical lesions may cause a facial weakness either in isolation or with associated hemiparesis and speech difficulties. Sensory disturbance Sensory symptoms are common and frequently benign. Patients often find sensory symptoms difficult to describe and sensory examination is difficult for both doctor and patient. While neurological disease can cause sensory symptoms, systemic disorders can also be responsible. Tingling in both hands and around the mouth can occur as the result of hyperventilation (p. 558) or hypocalcaemia (p. 662). When there is dysfunction of the relevant cerebral cortex, the patient’s perception of the wholeness or actual presence of the relevant part of the body may be distorted. Numbness and paraesthesia The history may give the best clues to localisation and pathology. Certain common patterns are recognised: in migraine, the aura may consist of spreading tingling or paraesthesia, followed by numbness evolving over 20–30 minutes over one half of the body, often splitting the tongue. Sensory loss caused by a stroke or transient ischaemic attack (TIA) occurs much more rapidly and is typically negative (numbness) rather than positive (tingling). Rarely, unpleasant paraesthesia of sensory epilepsy spreads within seconds. The sensory alteration of inflammatory spinal cord lesions often ascends from one or both lower limbs to a distinct level on the trunk over hours to days. Psychogenic sensory change can occur as a manifestation of anxiety or as part of a conversion disorder (p. 1202). In such cases, the distribution usually neither conforms to a known anatomical pattern nor fits with any organic disease. Care must be taken in diagnosing non-organic sensory problems; a careful history and examination will ensure there is no other objective neurological deficit.

1084 • NEUROLOGY nociceptive pain, which is secondary to pathological processes such as inflammation. Neuropathic pain has distinctive features and typically provokes a very unpleasant, persistent, burning sensation. There is often increased sensitivity to touch, so that light brushing of the affected area causes exquisite pain (allodynia). Painful stimuli are felt as though they arise from a larger area than that touched, and spontaneous bursts of pain may also occur. Pain may be elicited by other modalities (allodynia) and is considerably affected by emotional influences. The most common causes of neuropathic pain are diabetic neuropathies, trigeminal and post-herpetic neuralgias, and trauma to a peripheral nerve. Treatment of these syndromes can be difficult. Drugs that modulate various parts of the nociceptive system, such as gabapentin, carbamazepine or tricyclic antidepressants, may help. Localised treatment (topical treatment or nerve blocks) sometimes succeeds but may increase the sensory deficit and worsen the situation. Electrical stimulation has occasionally proved successful. For further information, see page 1347. Abnormal movements Disorders of movement lead to either extra, unwanted movement (hyperkinetic disorders) or too little movement (hypokinetic disorders) (Box 25.15). In either case, the lesion often localises to the basal ganglia, although some tremors are related to cerebellar or brainstem disturbance. Functional movement disorders are common and may mimic all of the organic syndromes below. The most important hypokinetic disorder is Parkinson’s disease (p. 1112). Parkinsonism is a clinical description of a collection of symptoms, including tremor, bradykinesia and rigidity. While the history is always important, observation is clearly vital; much ipsilateral facial sensory disturbance. For example, pain resembling trigeminal neuralgia can be seen in patients with multiple sclerosis. The anatomy of the trigeminal connections means that lesions in the medulla or spinal cord can give rise to ‘balaclava’ patterns of sensory loss (p. 1070). Sensory pathways running up from the spinal cord can also be damaged in the brainstem, resulting in simultaneous sensory loss in arm(s) and/or leg(s). Sensory loss in hemispheric lesions The temporal, parietal and occipital lobes receive sensory information regarding the various modalities of touch, vision, hearing and balance (see Box 25.2, p. 1066). The initial points of entry into the cortex are the respective primary cortical areas (see Fig. 25.4, p. 1067). Damage to any of these primary areas will result in reduction or loss of the ability to perceive that particular modality: ‘negative’ symptomatology. Abnormal excitation of these areas can result in a false perception (‘positive’ symptoms), the most common of which is migrainous visual aura (flashing lights or teichopsia). Cortical lesions are more likely to cause a mixed motor and sensory loss. Substantial lesions of the parietal cortex (as in large strokes) can cause severe loss of proprioception and may even abolish conscious awareness of the existence of the affected limb(s), known as neglect; this can be difficult to distinguish from paralysis. Pathways are so tightly packed in the thalamus that even small lacunar strokes can cause isolated contralateral hemisensory loss. Neuropathic pain Neuropathic pain is a positive neurological symptom caused by dysfunction of the pain perception apparatus, in contrast to Fig. 25.18 Patterns of sensory loss. A Generalised peripheral neuropathy. B Sensory roots: some common examples. C Single dorsal column lesion (proprioception and some touch loss). D Transverse thoracic spinal cord lesion. E Unilateral cord lesion (Brown–Séquard): ipsilateral dorsal column (and motor) deficit and contralateral spinothalamic deficit. F Central cord lesion: ‘cape’ distribution of spinothalamic loss. G Mid-brainstem lesion: ipsilateral facial sensory loss and contralateral loss on body below the vertex. H Hemisphere (thalamic) lesion: contralateral loss on one side of face and body. C5 C7 L5 A B C D E F G H Unilateral cord lesion (Brown–Séquard) Central cord lesion Mid-brainstem lesion Hemisphere (thalamic) lesion Transverse thoracic spinal cord lesion Single dorsal column lesion Sensory roots Generalised peripheral neuropathy

Presenting problems in neurological disease • 1085

part affected. In the assessment of tremor, the position, body part affected, frequency and amplitude should be considered, as these provide diagnostic clues (Box 25.16). Other hyperkinetic syndromes Non-rhythmic involuntary movements include chorea, athetosis, ballism, dystonia, myoclonus and tics. They are categorised by clinical appearance, and coexistence and overlap are common, such as in choreoathetosis. Chorea Chorea refers to jerky, brief, purposeless involuntary movements, appearing fidgety and affecting different areas. They suggest disease in the caudate nucleus (as in Huntington’s disease, p. 1114) and are a common complication of levodopa treatment for Parkinson’s disease. Other causes are shown in Box 25.17. 25.15 Movement disorders Description Features Examples Hypokinetic disorders Parkinsonism Akinesia Rigidity Tremor Loss of postural reflexes Other features depending on cause Idiopathic Parkinson’s disease Other degenerative syndromes Drug-induced (See Box 25.54) Catatonia Mutism Sustained posturing and waxy flexibility Usually psychiatric; if neurological, is most commonly of vascular origin Hyperkinetic disorders Tremor Rhythmical oscillation of body part (see Box 25.16) Essential tremor Parkinson’s disease Drug-induced Chorea Jerky, brief, involuntary movements Huntington’s disease Drug-induced Tics Stereotyped, repetitive movements, briefly suppressible Tourette’s syndrome Myoclonus Shock-like muscle jerks Epilepsy Hypnic jerks (p. 1086) Focal cortical disease Dystonia Sustained muscle contraction causing abnormal postures ± tremor Genetic Generalised dystonic syndromes Focal dystonias in adults (e.g. torticollis) Others Various Paroxysmal hyperkinetic dyskinesias Hemifacial spasm Tardive syndromes 25.16 Causes and characteristics of tremors Body part affected Position Frequency Amplitude Character Physiological Both arms > legs Posture, movement High Small (fine) Enhanced by anxiety, emotion, drugs, toxins Parkinsonism Unilateral or asymmetrical Arm > leg, chin, never head Rest Postural and re-emergent may occur Low (3–4 Hz) Moderate Typically pill-rolling, thumb and index finger, other features of parkinsonism Essential tremor Bilateral arms, head Movement High (8–10 Hz) Low to moderate Family history; 50% respond to alcohol Dystonic Head, arms, legs Posture Variable Variable Other features of dystonia, often jerky tremors Functional Any Any Variable Variable Distractible of the skill in diagnosing movement disorders lies in pattern recognition. Once it is established whether the problem is hypo- or hyperkinetic, the next task is to categorise the movements further, accepting that there is often overlap. Videoing the movements (with the patient’s consent), so that they can be shown to a movement disorder expert, may provide a quick diagnosis in cases of uncertainty. Tremor Tremor is caused by alternating agonist/antagonist muscle contractions and produces a rhythmical oscillation of the body 25.17 Causes of chorea Hereditary • Huntington’s disease (HD) and HD-like syndromes • Wilson’s disease • Neuroacanthocytosis • Dentato-rubro-pallidoluysian atrophy • Benign hereditary chorea • Paroxysmal dyskinesias Cerebral birth injury (including kernicterus) Cerebral trauma Drugs • Levodopa (long-term with Parkinson’s disease) • Antipsychotics • Antiepileptics • Oral contraceptive Metabolic • Disorders affecting thyroid, parathyroid, glucose, sodium, calcium and magnesium balance • Pregnancy Autoimmune • Post-streptococcal (Sydenham’s chorea) • Antiphospholipid antibody syndrome • Autoimmune encephalitis • Systemic lupus erythematosus Structural lesions of basal ganglia (usually caudate) • Vascular • Demyelination • Brain tumour

1086 • NEUROLOGY effects of gravity and alterations in body position and load (and hence centre of gravity) in order to prevent a person from falling. This requires input from a variety of sensory modalities (visual, vestibular and proprioceptive), processing by the cerebellum and brainstem, and output via a number of descending pathways (e.g. vestibulospinal, rubrospinal and reticulospinal tracts). Disorders of balance can therefore arise from any part of this process. Disordered input (loss of vision, vestibular disorders or lack of joint position sense), processing (damage to vestibular nuclei or cerebellum) or motor function (spinal cord lesions, leg weakness of any cause) can all impair balance. The patient may complain of different symptoms, depending on the location of the lesion. For example, loss of joint position sense or cerebellar function may result in a sensation of unsteadiness, while damage to the vestibular nuclei or labyrinth may result in an illusion of movement, such as vertigo (see below). A careful history is vital. Since vision can often compensate for lack of joint position sense, patients with peripheral neuropathies or dorsal column loss will often find their problem more noticeable in the dark. Examination of such patients may yield physical signs that again depend on the site of the lesion. Sensory abnormalities may be manifest as altered visual acuities or visual fields, possibly with abnormalities on fundoscopy, altered eye movements (including nystagmus, p. 1090), impaired vestibular function (p. 1104) or lack of joint position sense. Disturbance of cerebellar function may be manifest as nystagmus, dysarthria or ataxia, or difficulty with gait (unsteadiness or inability to perform tandem gait; see below). Leg weakness, if present, will be detectable on examination of the limbs. Vertigo Vertigo is defined as an abnormal perception of movement of the environment or self, and occurs because of conflicting visual, proprioceptive and vestibular information about a person’s position in space. Vertigo commonly arises from imbalance of vestibular input and is within the experience of most people, since this is the ‘dizziness’ that occurs after someone has spun round vigorously and then stops. Bilateral labyrinthine dysfunction often causes some unsteadiness. Labyrinthine vertigo usually lasts days at a time, though it may recur, while vertigo arising from central (brainstem) disorders is often persistent and accompanied by other brainstem signs. Benign paroxysmal positional vertigo (p. 1104) lasts a few seconds on head movement. A careful history will reveal the likely cause in most patients. Abnormal gait Many neurological disorders can affect gait. Observing patients as they walk into the consulting room can be very informative, although formal examination is also important. Neurogenic gait disorders need to be distinguished from those due to skeletal abnormalities, usually characterised by pain producing an antalgic gait, or limp. Gait alteration incompatible with any anatomical or physiological deficit may be due to functional disorders. Pyramidal gait Upper motor neuron lesions cause characteristic extension of the affected leg. The resultant tendency for the toes to strike the ground on walking requires the leg to swing outwards at the hip (circumduction). Nevertheless, a shoe on the affected side worn down at the toes may provide evidence of this type of Athetosis Slower, writhing movement of the limbs are often combined with chorea and have similar causes. Ballism This more dramatic form of chorea causes often violent flinging movements of one limb (monoballism) or one side of the body (hemiballism). The lesion localises to the contralateral subthalamic nucleus and the most common cause is stroke. Dystonia Sustained involuntary muscle contraction causes abnormal postures or movement. It may be generalised (usually in childhoodonset genetic syndromes) or, more commonly, focal/segmental (such as in torticollis, when the head is twisted repeatedly to one side). Some dystonias occur only with specific tasks, such as writer’s cramp or other occupational ‘cramps’. Dystonic tremor is associated, and is asymmetrical and of large amplitude. Myoclonus Myoclonus consists of brief, isolated, random jerks of muscle groups. This is physiological at the onset of sleep (hypnic jerks). Similarly, a myoclonic jerk is a component of the normal startle response, which may be exaggerated in some rare (mostly genetic) disorders. Myoclonus may occur in disorders of the cerebral cortex, such as some forms of epilepsy. Alternatively, myoclonus can arise from subcortical structures or, more rarely, from segments of the spinal cord. Tics Tics are stereotyped repetitive movements, such as blinking, winking, head shaking or shoulder shrugging. Unlike dyskinesias, the patient may be able to suppress them, although only for a short time. Isolated tics are common in childhood and usually disappear. Tourette’s syndrome is defined by the presence of multiple motor and vocal tics that may evolve over time; it is frequently associated with psychiatric disease, including obsessive compulsions, depression, self-harm or attention deficit disorder. Tics may also occur in Huntington’s and Wilson’s diseases, or after streptococcal infection. Abnormal perception The parietal lobes are involved in the higher processing and integration of primary sensory information. This takes place in areas referred to as ‘association’ cortex, damage to which gives rise to sensory (including visual) inattention, disorders of spatial perception, and disruption of spatially orientated behaviour, leading to apraxia. Apraxia is the inability to perform complex, organised activity in the presence of normal basic motor, sensory and cerebellar function (after weakness, numbness and ataxia have been excluded as causes). Examples of complex motor activities include dressing, using cutlery and geographical orientation. Other abnormalities that can result from damage to the association cortex involve difficulty reading (dyslexia) or writing (dysgraphia), or the inability to recognise familiar objects (agnosia). The results of damage to particular lobes of the brain are given in Box 25.2 (p. 1066). Altered balance and vertigo Balance is a complicated dynamic process that requires ongoing modification of both axial and limb muscles to compensate for the

Presenting problems in neurological disease • 1087

Marche à petits pas This gait is characterised by small, slow steps and marked instability. It differs from the festination found in Parkinson’s disease (see below), in that it lacks increasing pace and freezing. The usual cause is small-vessel cerebrovascular disease and there may be accompanying bilateral upper motor neuron signs. Extrapyramidal gait The rigidity and bradykinesia of basal ganglia dysfunction (p. 1112) lead to a stooped posture and characteristic gait difficulties, with problems initiating walking and controlling the pace of the gait. Patients may become stuck while trying to start walking or when walking through doorways (‘freezing’). The centre of gravity will be moved forwards to aid propulsion, which, with poor axial control, can lead to an accelerating pace of shuffling and difficulty stopping. This produces the festinant gait: initial stuttering steps that quickly increase in frequency while decreasing in length. Abnormal speech and language Speech disturbance may be isolated to disruption of sound output (dysarthria) or may involve language disturbance (dysphasia). Dysphonia (reduction in the sound/volume) is usually due to mechanical laryngeal disruption, whereas dysarthria is more typically neurological in origin. Dysphasia is always neurological and localises to the dominant cerebral hemisphere (usually left, regardless of handedness). Combinations of speech and swallowing problems are explained below (p. 1093). Dysphonia Dysphonia describes hoarse or whispered speech. The most common cause is laryngitis, but dysphonia can also result from a lesion of the 10th cranial nerve or disease of the vocal cords, including laryngeal dystonia. Parkinsonism may cause hypophonia with marked reduction in speech volume, often in association with dysarthria, making speech difficult to understand. Dysarthria Dysarthria is characterised by poorly articulated or slurred speech and can occur in association with lesions of the cerebellum, brainstem and lower cranial nerves, as well as in myasthenia or myopathic disease. Language function is not affected. The quality of the speech tends to differ, depending on the cause, but gait. In hemiplegia, the asymmetry between affected and normal sides is obvious on walking, but in paraparesis both lower limbs swing slowly from the hips in extension and are dragged stiffly over the ground – described as ‘walking in mud’. Foot drop In normal walking, the heel is the first part of the foot to hit the ground. A lower motor neuron lesion affecting the leg will cause weakness of ankle dorsiflexion, resulting in a less controlled descent of the foot, which makes a slapping noise as it hits the ground. In severe cases, the foot will have to be lifted higher at the knee to allow room for the inadequately dorsiflexed foot to swing through, resulting in a high-stepping gait. Myopathic gait During walking, alternating transfer of the body’s weight through each leg requires adequate hip abduction. In proximal muscle weakness, usually caused by muscle disease, the hips are not properly fixed by these muscles and trunk movements are exaggerated, producing a rolling or waddling gait. Ataxic gait An ataxic gait can result from lesions in the cerebellum, vestibular apparatus or peripheral nerves. Patients with lesions of the central portion of the cerebellum (the vermis) walk with a characteristic broad-based gait ‘as if drunk’ (cerebellar function is particularly sensitive to alcohol). Patients with acute vestibular disturbances walk similarly but the accompanying vertigo is characteristic. Inability to walk heel to toe may be the only sign of less severe cerebellar dysfunction. Proprioceptive defects can also cause an ataxic gait. The impairment of joint position sense makes walking unreliable, especially in poor light. The feet tend to be placed on the ground with greater emphasis, presumably to enhance proprioceptive input, resulting in a ‘stamping’ gait. Apraxic gait In an apraxic gait, power, cerebellar function and proprioception are normal on examination of the legs. The patient may be able to carry out complex motor tasks (e.g. bicycling motion) while recumbent and yet cannot formulate the motor act of walking. In this higher cerebral dysfunction, the feet appear stuck to the floor and the patient cannot walk. Gait apraxia is a sign of diffuse bilateral hemisphere disease (such as normal pressure hydrocephalus) or diffuse frontal lobe disease. 25.18 Causes of dysarthria Type Site Characteristics Associated features Myopathic Muscles of speech Indistinct, poor articulation Weakness of face, tongue and neck Myasthenic Motor end plate Indistinct with fatigue and dysphonia Fluctuating severity Ptosis, diplopia, facial and neck weakness Bulbar Brainstem Indistinct, slurred, often nasal Dysphagia, diplopia, ataxia ‘Scanning’ Cerebellum Slurred, impaired timing and cadence, ‘sing-song’ Ataxia of limbs and gait, tremor of head/limbs Nystagmus Spastic (‘pseudo-bulbar’) Pyramidal tracts Indistinct, nasal tone, mumbling Poor rapid tongue movements, increased reflexes and jaw jerk Parkinsonian Basal ganglia Indistinct, rapid, stammering, quiet Tremor, rigidity, slow shuffling gait Dystonic Basal ganglia Strained, slow, high-pitched Dystonia, athetosis

1088 • NEUROLOGY Disturbance of smell Symptomatic olfactory loss is most commonly due to local causes (nasal obstruction) but may follow head injury. Hyposmia may predate motor symptoms in Parkinson’s disease by many years, although it is rarely noticed by the patient. Frontal lobe lesions are a rare cause. Positive olfactory symptoms may arise in Alzheimer’s disease or epilepsy. Visual disturbance and ocular abnormalities Disturbances of vision may be due to primary ocular disease or to disorders of the central connections and visual cortex. Visual symptoms are usually negative (loss of vision) but sometimes positive, most commonly in migraine. Eye movements may be disturbed, giving rise to double vision (diplopia) or blurred vision. Loss of vision is also discussed on page 1170. Visual loss Visual loss can occur as the result of lesions in any areas between the retina and the visual cortex. Patterns of visual field loss are explained by the anatomy of the visual pathways (see Fig. 25.7, p. 1069). Associated clinical manifestations are described in Box 25.19. Visual symptoms affecting one eye only are due to lesions anterior to the optic chiasm. Transient visual loss is quite common and sudden-onset visual loss lasting less than 15 minutes is likely to have a vascular origin. It may be difficult to know whether the visual loss was monocular (carotid circulation) or binocular (vertebrobasilar circulation), and it is important to ask if the patient tried closing each eye in turn to see whether the symptom affected one eye or both. Visual field testing is an important part of the examination, either at the bedside or formally with perimetry. Field defects become more symmetrical (congruous), the closer the lesion comes to the visual cortex. Migrainous visual symptoms are very common and, when associated with typical headache and other migraine features, rarely pose a diagnostic challenge. They may occur in isolation, however, making distinction from TIA difficult, but TIAs typically cause negative (blindness) symptoms, whereas migraine causes positive phenomena (see below). TIAs often last for a shorter time (a few minutes), compared to the 10–60-minute duration of migraine aura, and have an abrupt onset and end, unlike the gradual evolution of a migraine aura. Positive visual phenomena The most common cause is migraine; patients may describe silvery zigzag lines (fortification spectra) or flashing coloured lights (teichopsia), usually preceding the headache. Simple flashes of light (phosphenes) may indicate damage to the retina (e.g. detachment) or to the primary visual cortex. Formed visual hallucinations may be caused by drugs or may be due to epilepsy or ‘release phenomena’ in a blind visual field (Charles Bonnet syndrome). Double vision Diplopia arises from misalignment of the eyes, meaning that the image is not projected to the same points on the two retinas. At its most subtle it may be reported as blurred rather than it can be very difficult to distinguish the different types clinically (Box 25.18). Dysarthria is discussed further in the section on bulbar symptoms (p. 1093). Dysphasia Dysphasia (or aphasia) is a disorder of the language content of speech. It can occur with lesions over a wide area of the dominant hemisphere (Fig. 25.19). Dysphasia may be categorised according to whether the speech output is fluent or non-fluent. Fluent aphasias, also called receptive aphasias, are impairments related mostly to the input or reception of language, with difficulties either in auditory verbal comprehension or in the repetition of words, phrases or sentences spoken by others. Speech is easy and fluent but there are difficulties related to the output of language as well, such as paraphasia (either substitution of similar-sounding non-words, or incorrect words) and neologisms (non-existent words). Examples include Wernicke’s aphasia (which localises to the superior posterior temporal lobe), transcortical sensory aphasia, conduction aphasia and anomic aphasia. Non-fluent aphasias, also called expressive aphasias, are difficulties in articulating, but in most cases there is relatively good auditory verbal comprehension. Examples include Broca’s aphasia (associated with pathologies in the inferior frontal region), transcortical motor aphasia and global aphasia. ‘Pure’ aphasias are selective impairments in reading, writing or the recognition of words. These disorders may be quite selective. For example, a person is able to read but not write, or is able to write but not read. Examples include pure alexia, agraphia and pure word deafness. Dysphasia (a focal symptom) is frequently misinterpreted as disorientation (which is non-focal) and it is important always to consider dysphasia as an alternative explanation for the apparently ‘confused’ patient. Dysphasia can be misheard/ misspelt as dysphagia, and for this reason some prefer to use ‘aphasia’ to avoid confusion. Fig. 25.19 Classification of cortical speech problems. (1) Wernicke’s aphasia: fluent dysphasia with poor comprehension and poor repetition. (2) Conduction aphasia: fluent aphasia with good comprehension and poor repetition. (3) Broca’s aphasia: non-fluent aphasia with good comprehension and poor repetition. (4) Transcortical sensory aphasia: fluent aphasia with poor comprehension and good repetition. (5) Transcortical motor aphasia: non-fluent aphasia with good comprehension and good repetition. Large lesions affecting all of regions 1–5 cause global aphasia.

Sylvian fissure Central sulcus

Presenting problems in neurological disease • 1089

gaze, whether the images are separated horizontally or vertically, and whether there are any associated symptoms or signs, such as ptosis or pupillary disturbance. Binocular diplopia may result from central disorders or from disturbance of the ocular motor nerves, muscles or the double vision. Monocular diplopia indicates ocular disease, while binocular diplopia suggests a neurological cause. Closing either eye in turn will abort binocular diplopia. Once the presence of binocular diplopia is confirmed, it should be established whether the diplopia is maximal in any particular direction of 25.19 Clinical manifestations of visual field loss Site of lesion Common causes Complaint Visual field loss Associated physical signs Retina/optic disc Vascular disease (including vasculitis) Glaucoma Inflammation Partial/complete visual loss depending on site, involving one or both eyes Altitudinal field defect Arcuate scotoma Reduced acuity Visual distortion (macula) Abnormal retinal appearance Optic nerve Optic neuritis Sarcoidosis Tumour Leber’s hereditary optic neuropathy Partial/complete loss of vision in one eye Often painful Central vision particularly affected Central or paracentral scotoma Monocular blindness Reduced acuity Reduced colour vision Relative afferent pupillary defect Optic atrophy (late) Optic chiasm Pituitary tumour Craniopharyngioma Sarcoidosis May be none Rarely, diplopia (‘hemifield slide’) Bitemporal hemianopia Pituitary function abnormalities Optic tract Tumour Inflammatory disease Disturbed vision to one side of midline Incongruous contralateral homonymous hemianopia Temporal lobe Stroke Tumour Inflammatory disease Disturbed vision to one side of midline Contralateral homonymous upper quadrantanopia Memory/language disorders Parietal lobe Stroke Tumour Inflammatory disease Disturbed vision to one side of midline Bumping into things Contralateral homonymous lower quadrantanopia Contralateral sensory disturbance Asymmetry of optokinetic nystagmus Occipital lobe Stroke Tumour Inflammatory disease Disturbed vision to one side of midline Difficulty reading Bumping into things Homonymous hemianopia (may be macula-sparing) Damage to other structures supplied by posterior cerebral circulation 25.20 Common causes of damage to cranial nerves 3, 4 and 6 Site Common pathology Nerve(s) involved Associated features Brainstem Infarction Haemorrhage Demyelination Intrinsic tumour 3 (mid-brain) 6 (ponto-medullary junction) Contralateral pyramidal signs Ipsilateral lower motor neuron facial palsy Other brainstem/cerebellar signs Intrameningeal Meningitis (infective/malignant) 3, 4 and/or 6 Meningism, features of primary disease course Raised intracranial pressure

Papilloedema 3 (uncal herniation) Features of space-occupying lesion Aneurysms 3 (posterior communicating artery) 6 (basilar artery) Pain Features of subarachnoid haemorrhage Cerebello-pontine angle tumour

8, 7, 5 nerve lesions (order of likelihood) Ipsilateral cerebellar signs Trauma 3, 4 and/or 6 Other features of trauma Cavernous sinus Infection/thrombosis Carotid artery aneurysm Caroticocavernous fistula 3, 4 and/or 6 May be 5th nerve involvement also Pupil may be fixed, mid-position (Sympathetic plexus on carotid may also be affected) Superior orbital fissure Tumour (e.g. sphenoid wing meningioma) Granuloma 3, 4 and/or 6 May be proptosis, chemosis Orbit Vascular (e.g. diabetes, vasculitis) Infections Tumour Granuloma Trauma 3, 4 and/or 6 Pain Pupil often spared in vascular 3rd nerve palsy

1090 • NEUROLOGY contralateral side to cause the eyes to drift towards the side of the lesion. This elicits recurrent compensatory fast movements away from the side of the lesion, manifest as unidirectional horizontal nystagmus. Vertical and torsional components can be seen with damage to other parts of the vestibular apparatus. The nystagmus of peripheral labyrinthine lesions is accompanied by vertigo and usually by nausea, vomiting and unsteadiness, but as the CNS habituates, the nystagmus disappears (fatigues) quite quickly. Central vestibular nystagmus is more persistent. Nystagmus also occurs as a consequence of drug toxicity and nutritional deficiency (e.g. thiamin). The severity is variable, and it may or may not result in visual degradation, though it may be associated with a sensation of movement of the visual world (oscillopsia). Nystagmus may occur as a congenital phenomenon, in which case both phases are equal and ‘pendular’, rather than having alternating fast and slow components. Ptosis Various disorders may cause drooping of the eyelids (ptosis) and these are listed in Box 25.21 and shown on Figure 25.21. Abnormal pupillary responses Abnormal pupillary responses may arise from lesions at several points between the retina and brainstem. Lesions of the oculomotor nerve, ciliary ganglion and sympathetic supply produce characteristic ipsilateral disorders of pupillary function. ‘Afferent’ defects result from damage to an optic nerve, impairing the direct response of a pupil to light, although leaving the consensual response from stimulation of the normal eye intact. Structural damage to the iris itself can also result in pupillary abnormalities. Causes are given in Box 25.22. An example is shown in Figure 25.22. Papilloedema There are several causes of swelling of the optic disc but the term ‘papilloedema’ is reserved for swelling secondary to raised intracranial pressure, when obstructed axoplasmic flow from retinal ganglion cells results in swollen nerve fibres, which in turn cause capillary and venous congestion, producing papilloedema. neuromuscular junction (see Fig. 25.8, p. 1070). The pattern of double vision, along with any associated features, usually allows the clinician to infer which nerves/muscles are affected, while the mode of onset and other features (e.g. fatigability in myasthenia) provide further clues to the cause. The causes of ocular motor nerve palsies are listed in Box 25.20. Examination findings are illustrated in Figure 25.20. Nystagmus Nystagmus describes a repetitive to-and-fro movement of the eyes. In central lesions, the slow drifts are the primary abnormal movement, each followed by fast (corrective) phases. Nystagmus occurs because the control systems of the eyes are defective, causing them to drift off target; corrections then become necessary to return fixation to the object of interest, causing nystagmus. The direction of the fast phase is usually designated as the direction of the nystagmus because it is easier to see. Nystagmus may be horizontal, vertical or torsional, and usually involves both eyes synchronously. It may be a physiological phenomenon in response to sustained vestibular stimulation or movement of the visual world (optokinetic nystagmus). There are many causes of pathological nystagmus, the most common sites of lesions being the vestibular system, brainstem and cerebellum. The brainstem and the cerebellum are involved in maintaining eccentric positions of gaze. Lesions will therefore allow the eyes to drift back in towards primary position, producing nystagmus with fast component beats in the direction of gaze (gaze-evoked nystagmus). This is the most common type of ‘central’ nystagmus; it is most commonly bidirectional and not usually accompanied by vertigo. Other signs of brainstem dysfunction may be evident. Brainstem disease may also cause vertical nystagmus. Unilateral cerebellar lesions may result in gaze-evoked nystagmus when looking in the direction of the lesion, where the fast phases are directed towards the side of the lesion. Cerebellar hemisphere lesions also cause ‘ocular dysmetria’, an overshoot of target-directed, fast eye movements (saccades) resembling ‘past-pointing’ in limbs. In vestibular lesions, damage to one of the horizontal canals or its connections will allow the tonic output from the healthy Fig. 25.20 Examination findings in 3rd, 4th and 6th nerve palsy. Diplopia tends to be more obvious on lateral gaze compared to primary position. Cranial nerve palsy Right 3rd nerve palsy Unable to adduct right eye Squint worse Right eye turns down and out N.B. Pupil dilated; ptosis Right 4th nerve palsy (more evident on downgaze) Right eye elevates more as it moves medially Right eye turns slightly up No obvious squint Right 6th nerve palsy Able to adduct right eye No obvious squint Right eye turns medially Unable to abduct right eye Squint worse Direction of gaze Primary position Direction of gaze

Presenting problems in neurological disease • 1091

The earliest sign is the cessation of venous pulsation seen at the disc, progression causing the disc margins to become red (hyperaemic). Disc margins become indistinct and haemorrhages may occur in the retina (Fig. 25.23). Lack of papilloedema never excludes raised intracranial pressure. Other causes of optic disc swelling are listed in Box 25.23. Some normal variations of disc appearance (e.g. optic nerve drusen, p. 1178) can mimic disc swelling. Optic disc swelling is also discussed on page 1171. Optic atrophy Loss of nerve fibres causes the optic disc to appear pale, as the choroid becomes visible (Fig. 25.24). A pale disc (optic 25.21 Common causes of ptosis Mechanism Causes Associated clinical features 3rd nerve palsy Isolated palsy (see Box 25.20) Central/supranuclear lesion Ptosis is usually complete Extraocular muscle palsy (eye ‘down and out’) Depending on site of lesion, other cranial nerve palsies (e.g. 4, 5 and 6) or contralateral upper motor neuron signs Sympathetic lesion (Horner’s syndrome: see Fig. 25.22) Central (hypothalamus/brainstem) Peripheral (lung apex, carotid artery pathology) Idiopathic Ptosis is partial Lack of sweating on affected side Depending on site of lesion, brainstem signs, signs of apical lung/brachial plexus disease, or ipsilateral carotid artery stroke Myopathic Myasthenia gravis Dystrophia myotonica Extraocular muscle palsies Usually bilateral More widespread muscle weakness, with fatigability in myasthenia Progressive external ophthalmoplegia Other characteristic features of individual causes Other Functional ptosis Pseudo-ptosis (e.g. blepharospasm) Local orbital/lid disease Age-related levator dehiscence Resistance to eye opening Eyebrows depressed rather than raised May be local orbital abnormality Fig. 25.21 Differential diagnosis of unilateral ptosis. (CPEO = chronic progressive external ophthalmoplegia) Neurological causes of unilateral ptosis Smaller pupil Larger pupil Diplopia worse on upgaze Diplopia Diplopia Increasing accommodation ?3rd nerve paralysis 3rd nerve paralysis Normal pupil Normal pupil Horner’s syndrome Check for dilated pupil and other signs of 3rd nerve paralysis Fatigable weakness Myasthenia excluded Consider myasthenia gravis Family history Consider mitochondrial disorder, e.g. CPEO Fig. 25.22 Right-sided Horner’s syndrome due to paravertebral metastasis at T1. There is ipsilateral partial ptosis and a small pupil.

1092 • NEUROLOGY 25.22 Pupillary disorders Disorder Cause Ophthalmological features Associated features 3rd nerve palsy See Box 25.21 Dilated pupil (especially with external compression) Extraocular muscle palsy (eye is typically ‘down and out’) Complete ptosis Other features of 3rd nerve palsy (see Box 25.21) Horner’s syndrome (see Fig. 25.22) Lesion to sympathetic supply Small pupil Partial ptosis Iris heterochromia (if congenital) Ipsilateral failure of sweating (anhidrosis) Holmes–Adie syndrome (tonic pupil) Lesion of ciliary ganglion (usually idiopathic) Dilated pupil Light-near dissociation (accommodate but do not react to light) Vermiform movement of iris during contraction Disturbance of accommodation Generalised areflexia Argyll Robertson pupil Dorsal mid-brain lesion (syphilis or diabetes) Small, irregular pupils Light-near dissociation Other features of tabes dorsalis (p. 1125) Local pupillary damage Trauma/inflammatory disease Irregular pupils, often with adhesions to lens (synechiae) Variable degree of reactivity Other features of trauma/underlying inflammatory disease (e.g. cataract, blindness etc.) Relative afferent pupillary defect (Marcus Gunn pupil) Damage to optic nerve Pupils symmetrical – swinging torch test reveals dilatation in abnormal eye Decreased visual acuity/colour vision Central scotoma Optic disc swelling or pallor Fig. 25.23 Mechanism of optic disc oedema (papilloedema). A Normal. B Disc oedema (e.g. due to cerebral tumour). C Fundus photograph of the left eye showing optic disc oedema with a small haemorrhage on the nasal side of the disc. (CSF = cerebrospinal fluid) C, Courtesy of Dr B. Cullen. Choroid Optic disc CSF Optic nerve Central retinal vein Meningeal sheath Retinal veins Choroid Increased CSF pressure Optic nerve Venous dilatation Swollen optic disc Axonal transport block Swollen axons A B C 25.23 Common causes of optic disc swelling Raised intracranial pressure (papilloedema) • Cerebral mass lesion (tumour, abscess) • Obstructive hydrocephalus • Idiopathic intracranial hypertension Obstruction of ocular venous drainage • Central retinal vein occlusion • Cavernous sinus thrombosis Systemic disorders affecting retinal vessels • Hypertension • Vasculitis • Hypercapnia Optic nerve damage • Demyelination (optic neuritis/ papillitis) • Leber’s hereditary optic neuropathy • Anterior ischaemic optic neuropathy • Toxins (e.g. methanol) • Infiltration of optic disc • Sarcoidosis • Glioma • Lymphoma Fig. 25.24 Fundus photograph of the left eye of a patient with familial optic atrophy. Note the marked pallor of the optic disc.

Presenting problems in neurological disease • 1093

will cause upper motor neuron bulbar paralysis, known as ‘pseudobulbar palsy’. Here the tongue is small and contracted, and moves slowly; the jaw jerk is brisk, and there may be associated emotional variability. Causes of these are shown in Box 25.24. Bladder, bowel and sexual disturbance While isolated disturbances of bladder, bowel and sexual function are rarely the sole presenting features of neurological disease, they are common complications of many chronic disorders such as multiple sclerosis, stroke and dementia, and are frequently found post head injury. Abnormalities in these functions considerably reduce quality of life for patients. Incontinence and its management are discussed elsewhere (pp. 397, 835 and 1309). Bladder dysfunction The anatomy and physiology involved in controlling bladder functions are discussed on page 386 but it is worth emphasising the role of the pontine micturition centre, which is itself under higher control via inputs from the pre-frontal cortex, mid-brain and hypothalamus. In the absence of conscious control (e.g. in coma or dementia), distension of the bladder to near capacity evokes reflex detrusor contraction (analogous to the muscle stretch reflex), and reciprocal changes in sympathetic activation and relaxation of the distal sphincter result in coordinated bladder emptying. Damage to the lower motor neuron pathways (the pelvic and pudendal nerves) produces a flaccid bladder and sphincter with overflow incontinence, often accompanied by loss of pudendal sensation. Such damage may be due to disease of the conus medullaris or sacral nerve roots, either within the dura (as in inflammatory or carcinomatous meningitis) or as they pass through the sacrum (trauma or malignancy), or due to damage to the nerves themselves in the pelvis (infection, haematoma, trauma or malignancy). Damage to the pons or spinal cord results in an ‘upper motor neuron’ pattern of bladder dysfunction due to uncontrolled over-activity of the parasympathetic supply. The bladder is small and highly sensitive to being stretched. This results in frequency, urgency and urge incontinence. Loss of the coordinating control of the pontine micturition centre will also result in the phenomenon of detrusor–sphincter dyssynergia, in which detrusor contraction and sphincter relaxation are not coordinated; the spastic bladder will often try to empty against a closed sphincter. This manifests as both urgency and an inability to pass urine, which is distressing and painful. The resultant incomplete bladder emptying predisposes to urinary infection, and the prolonged high intravesical pressure may result in obstructive uropathy and renal failure; post-micturition bladder ultrasound may confirm incomplete bladder emptying. More severe lesions of the spinal cord, as in spinal cord compression or trauma, can result in painless urinary retention as bladder sensation, normally carried in the lateral spinothalamic tracts, will be disrupted. Damage to the frontal lobes gives rise to loss of awareness of bladder fullness and consequent incontinence. Coexisting cognitive impairment may result in inappropriate micturition. These features may be seen in hydrocephalus, frontal tumours, dementia and bifrontal subdural haematomas. When a patient presents with bladder symptoms, it is important to localise the lesion on the basis of history and examination, remembering that most bladder problems are not neurological atrophy) follows optic nerve damage; causes include previous optic neuritis or ischaemic damage, long-standing papilloedema, optic nerve compression, trauma and degenerative conditions (e.g. Friedreich’s ataxia, p. 1116). Hearing disturbance Each cochlear organ has bilateral cortical representation, so unilateral hearing loss is a result of peripheral organ damage. Bilateral hearing dysfunction is usual and is most commonly due to age-related degeneration or noise damage, although infection and drugs (particularly diuretics and aminoglycoside antibiotics) can be a primary cause. Prominent deafness may suggest a mitochondrial disorder (see Box 25.93, p. 1144). Bulbar symptoms – dysphagia and dysarthria Swallowing is a complex activity involving the coordinated action of lips, tongue, soft palate, pharynx and larynx, which are innervated by cranial nerves 7, 9, 10, 11 and 12. Structural causes of dysphagia are considered on page 778. Neurological mechanisms are vulnerable to damage at different points, resulting in dysphagia that is usually accompanied by dysarthria. Tempo is again crucial: acute onset of dysphagia may occur as a result of brainstem stroke or a rapidly developing neuropathy, such as Guillain–Barré syndrome or diphtheria. Intermittent fatigable muscle weakness (including dysphagia) would suggest myasthenia gravis. Dysphagia developing over weeks or months may be seen in motor neuron disease, basal meningitis and inflammatory brainstem disease. More slowly developing dysphagia suggests a myopathy or possibly a brainstem or skull-base tumour. Pathologies affecting lower cranial nerves (9, 10, 11 and 12) frequently manifest bilaterally, producing dysphagia and dysarthria. The term ‘bulbar palsy’ is used to describe lower motor neuron lesions, either within the medulla or outside the brainstem. The tongue may be wasted and fasciculating, and palatal movement is reduced. Upper motor neuron innervation of swallowing is bilateral, so persistent dysphagia is unusual with a unilateral upper motor lesion (the exception being in the acute stages of, for example, a hemispheric stroke). Widespread lesions above the medulla 25.24 Causes of pseudobulbar and bulbar palsy Type Pseudobulbar Bulbar Genetic – Kennedy’s disease (X-linked bulbospinal neuronopathy) Vascular Bilateral hemisphere (lacunar) infarction Medullary infarction (see Box 25.3, p. 1072) Degenerative Motor neuron disease (p. 1116) Motor neuron disease Syringobulbia Inflammatory/ infective Multiple sclerosis (p. 1106) Cerebral vasculitis Myasthenia (p. 1140) Guillain–Barré syndrome (p. 1140) Poliomyelitis (p. 1123) Lyme disease (p. 255) Vasculitis Neoplastic High brainstem tumours Brainstem glioma Malignant meningitis

1094 • NEUROLOGY speech, motor planning and organisation. Those with orbitofrontal lesions of the frontal lobes, in contrast, become disinhibited, displaying grandiosity or irresponsible behaviour. Memory is substantially intact but frontal release signs may emerge, such as a grasp reflex, palmomental response or pout. Proximity to the olfactory bulb and tracts means that inferior frontal lobe tumours may be associated with anosmia. Disturbance to the cortical areas responsible for speech or memory can result in changes that may be interpreted as changes in personality. Sleep disturbance Disturbances of sleep are common and are not usually due to neurological disease. Patients may complain of insomnia (difficulty sleeping), excessive daytime sleepiness, disturbed behaviour during night-time sleep, parasomnia (sleep walking and talking, or night terrors) or disturbing subjective experiences during sleep and/or its onset (nightmares, hypnagogic hallucinations, sleep paralysis). A careful history (from bed partner as well as patient) usually allows specific causes of sleep disturbance to be identified and these are discussed in more detail on page 1105. Psychiatric disorders Psychiatric disorders are described in Chapter 28 but may cause or result from neurological problems. Care is needed in their identification, as effective management will help the underlying neurological illness. Functional symptoms Many patients presenting with neurological symptoms do not have a defined neurological disease and are best described as having functional symptoms (p. 1187). Some of these are psychogenic (or conversion) disorders. Such patients often have symptoms affecting multiple systems and an impressively long list of consultations and negative tests from other medical specialties when they present. Considering the possibility of a functional origin may save the patient some further anxiety and further investigation (which will be unnecessary, expensive, possibly invasive, and inconvenient). unless there are overt neurological signs. Clinical features and management are summarised in Box 25.25. Rectal dysfunction The rectum has an excitatory cholinergic input from the parasympathetic sacral outflow, and inhibitory sympathetic supply similar to the bladder. Continence depends largely on skeletal muscle contraction in the puborectalis and pelvic floor muscles supplied by the pudendal nerves, as well as the internal and external anal sphincters. Damage to the autonomic components usually causes constipation (a common early symptom in Parkinson’s disease) but diabetic neuropathy can be associated with diarrhoea. Lesions affecting the conus medullaris, the somatic S2–4 roots and the pudendal nerves may cause faecal incontinence. Erectile failure and ejaculatory failure These related functions are under autonomic control via the pelvic nerves (parasympathetic, S2–4) and hypogastric nerves (sympathetic, L1–2). Descending influences from the cerebrum are important for erection but it can occur as a reflex phenomenon in response to genital stimulation. Erection is largely parasympathetic and may be impaired by a number of drugs, including anticholinergic, antihypertensive and antidepressant agents. Sympathetic activity is important for ejaculation and may be inhibited by α-adrenoceptor antagonists (α-blockers). For further information on erectile dysfunction, see page 440. Personality change While this is often due to psychiatric illness, neurological conditions that alter the function of the frontal lobes can cause personality change and mood disorder (see Box 25.2, p. 1066). Personality change due to a frontal lobe disorder may occur as the result of structural damage due to stroke, trauma, tumour or hydrocephalus. The nature of any change may help localise the lesion. Patients with mesial frontal lesions become increasingly withdrawn, unresponsive and mute (abulic), often in association with urinary incontinence, gait apraxia and an increase in tone known as gegenhalten, in which the patient varies the resistance to movement in proportion to the force exerted by the examiner. Patients with lesions of the dorsolateral pre-frontal cortex develop a dysexecutive syndrome, which involves difficulties with 25.25 Neurogenic bladder: clinical features and treatment Type Site of lesion Result Treatment Atonic (lower motor neuron) Sacral segments of cord (conus medullaris) Sacral roots and nerves Loss of detrusor contraction Difficulty initiating micturition Bladder distension with overflow Intermittent self-catheterisation In-dwelling catheterisation Hypertonic (upper motor neuron) Pyramidal tract in spinal cord or brainstem Urgency with urge incontinence Bladder sphincter incoordination (dyssynergia) Incomplete bladder emptying Anticholinergics: Solifenacin Tolterodine Imipramine Intermittent self-catheterisation Cortical Post-central Pre-central Frontal Loss of awareness of bladder fullness Difficulty initiating micturition Inappropriate micturition Loss of social control Intermittent or in-dwelling catheterisation

Headache syndromes • 1095

round the head or pressure at the vertex. It is of constant character and generalised, but often radiates forwards from the occipital region. It may be episodic or persistent, although the severity may vary, and there is no associated vomiting or photophobia. Tension-type headache is rarely disabling and patients appear well. The pain often progresses throughout the day. Tenderness may be present over the skull vault or in the occiput but is easily distinguished from the triggered pains of trigeminal neuralgia and the exquisite tenderness of temporal arteritis. Analgesics may be taken with chronic regularity, despite little effect, and may perpetuate the symptoms (see ‘Medication overuse headache’ below). Management Most benefit is derived from a careful assessment, followed by discussion of likely precipitants and reassurance that the prognosis is good. The concept of medication overuse headache needs careful explanation. An important therapeutic step is to allow patients to realise that their problem has been taken seriously and rigorously assessed. Physiotherapy (with muscle relaxation and stress management) may help and low-dose amitriptyline can provide benefit. Investigation is rarely required. The reassurance value of brain imaging needs careful assessment: the pick-up rate of structural abnormalities is exceedingly low, and significantly outweighed by the likelihood of identifying an incidental and irrelevant finding (e.g. an arachnoid cyst, Chiari I malformation or vascular abnormality). The value of such ‘reassurance’ is usually over-estimated by doctors and patients alike. Migraine Migraine usually appears before middle age, or occasionally in later life; it affects about 20% of females and 6% of males at some point in life. Migraine is usually readily identifiable from the history, although unusual variants can cause uncertainty. Pathophysiology The cause of migraine is unknown but there is increasing evidence that the aura (see below) is due to dysfunction of ion channels causing a spreading front of cortical depolarisation (excitation) followed by hyperpolarisation (depression of activity). This process (the ‘spreading depression of Leão’) spreads over the cortex at a rate of about 3 mm/min, corresponding to the aura’s symptomatic spread. The headache phase is associated with vasodilatation of extracranial vessels and may be relayed by hypothalamic activity. Activation of the trigeminovascular system is probably important. A genetic contribution is implied by the frequently positive family history, and similar phenomena occurring in disorders such as CADASIL (p. 1052) or mitochondrial disease (p. 1144). The female preponderance and the frequency of migraine attacks at certain points in the menstrual cycle also suggest hormonal influences. Oestrogen-containing oral contraception sometimes exacerbates migraine and increases the very small risk of stroke in patients who suffer from migraine with aura. Doctors and patients often over-estimate the role of dietary precipitants such as cheese, chocolate or red wine. When psychological factors contribute, the migraine attack often occurs after a period of stress, being more likely on Friday evening at the end of the working week or at the beginning of a holiday. Clinical features Some patients report a prodrome of malaise, irritability or behavioural change for some hours or days. Around 20% of Weakness and sensory change predominate among patients with functional neurological disorders but pain or loss of consciousness can also occur. Associated symptoms, such as tiredness, lethargy, poor concentration, bowel upset (irritable bowel syndrome) and gynaecological complaints, are common. A functional cause should always be considered, as it can allow for more rapid diagnosis and minimise investigation. Some clinical features may hint at a functional origin for symptoms (Box 25.26). It is the clinician’s (rewarding, albeit sometimes challenging) job to elicit the context of the patient’s symptoms in a sensitive and non-judgemental manner. Whatever the cause of the illness, it is important to acknowledge that mood and sleep disturbance will exacerbate neurological symptoms, thus increasing disability. The best practitioners have the skill to carry the patient with them when describing the patterns of behaviour contributing to worsening symptoms. Assessment to detect an underlying or exacerbating mood disorder is vital in all patients, ensuring that depression and anxiety are managed to minimise their secondary effects on neurological symptoms. Headache syndromes Acute management of headache is dealt with on page 184 but management of chronic, complex, or refractory headaches may require specialist input. Headaches may be classified as primary or secondary, depending on the underlying cause (see Box 10.10, p. 184). Secondary headache may be due to structural, infective, inflammatory or vascular conditions, discussed later in this chapter. Primary headache syndromes are described here. Tension-type headache This is the most common type of headache and is experienced to some degree by the majority of the population. Pathophysiology Tension-type headache is incompletely understood, and some consider that it is simply a milder version of migraine; certainly, the original notion that it is due primarily to muscle tension (hence the unsatisfactory name) has long since been dismissed. Anxiety about the headache itself may lead to continuation of symptoms, and patients may become convinced of a serious underlying condition. Clinical features The pain of tension headache is characterised as ‘dull’, ‘tight’ or like a ‘pressure’, and there may be a sensation of a band 25.26 Clinical features suggestive of functional disorder • Inconsistent examination findings (e.g. Hoover’s sign, p. 1082) • Situational provocation of events (e.g. in medical settings) • Associated mental health disorders: Anxiety Depression • Lack of anatomical coherence to neurological symptoms • Florid or bizarre descriptions of individual symptoms • History of multiple other systemic symptoms inadequately explained by disease (asthma/breathlessness, fatigue, pain, gastrointestinal symptoms)

1096 • NEUROLOGY Cluster headache Cluster headaches (also known as migrainous neuralgia) are much less common than migraine. Unusually for headache syndromes, there is a significant male predominance and onset is usually in the third decade. Pathophysiology The cause is unknown but this type of headache differs from migraine in many ways, suggesting a different pathophysiological basis. Although uncommon, it is the most common of the trigeminal autonomic cephalalgia syndromes. Functional imaging studies have suggested abnormal hypothalamic activity. Patients are more often smokers with a higher than average alcohol consumption. Clinical features Cluster headache is strikingly periodic, featuring runs of identical headaches beginning at the same time for weeks at a stretch (the ‘cluster’). Patients may experience either one or several attacks within a 24-hour period, and typically are awoken from sleep by symptoms (‘alarm clock headache’). Cluster headache causes severe, unilateral periorbital pain with autonomic features, such as ipsilateral tearing, nasal congestion and conjunctival injection (occasionally with the other features of a Horner’s syndrome). The pain, though severe, is characteristically brief (30–90 minutes). In contrast to the behaviour of those with migraine, patients are highly agitated during the headache phase. The cluster period is typically a few weeks, followed by remission for months to years, but a small proportion do not experience remission. Management Acute attacks can usually be halted by subcutaneous injections of sumatriptan or inhalation of 100% oxygen. The brevity of the attack probably prevents other migraine therapies from being effective. Migraine prophylaxis is often ineffective too but attacks can be prevented in some patients by verapamil, sodium valproate, or short courses of oral glucocorticoids. Patients with severe debilitating clusters can be helped with lithium therapy, although this requires monitoring (p. 1200). Trigeminal neuralgia This is characterised by unilateral lancinating facial pain, most commonly involving the second and/or third divisions of the trigeminal nerve territory, usually in patients over the age of 50 years. Pathophysiology For most, trigeminal neuralgia remains an idiopathic condition but there is a suggestion that it may be due to an irritative lesion involving the trigeminal root zone, in some cases an aberrant loop of artery. Other compressive lesions, usually benign, are occasionally found. Trigeminal neuralgia associated with multiple sclerosis may result from a plaque of demyelination in the brainstem. Clinical features The pain is repetitive, severe and very brief (seconds or less). It may be triggered by touch, a cold wind or eating. Physical signs are usually absent, although the spasms may make the patient wince and sit silently (tic douloureux). There is a tendency for the condition to remit and relapse over many years. Rarely, there patients experience an aura and are said to have migraine with aura (previously known as classical migraine). The aura may manifest as almost any neurological symptom but is most often visual, consisting of fortification spectra, which are usually positive phenomena such as shimmering, silvery zigzag lines marching across the visual fields for up to 40 minutes, sometimes leaving a trail of temporary visual field loss (scotoma). Sensory symptoms characteristically spreading over 20–30 minutes, from one part of the body to another, are more common than motor ones, and language function can be affected, leading to similarities with TIA/stroke. Isolated aura may occur (i.e. the neurological symptoms are not followed by headache). The 80% of patients with characteristic headache but no ‘aura’ are said to have migraine without aura (previously called ‘common’ migraine). Migraine headache is usually severe and throbbing, with photophobia, phonophobia and vomiting lasting from 4 to 72 hours. Movement makes the pain worse and patients prefer to lie in a quiet, dark room. In a small number of patients the aura may persist, leaving more permanent neurological disturbance. This persistent migrainous aura may occur with or without evidence of brain infarction. Management Avoidance of identified triggers or exacerbating factors (such as the combined contraceptive pill) may prevent attacks. Treatment of an acute attack consists of simple analgesia with aspirin, paracetamol or non-steroidal anti-inflammatory agents. Nausea may require an antiemetic such as metoclopramide or domperidone. Severe attacks can be aborted by one of the ‘triptans’ (e.g. sumatriptan), which are potent 5-hydroxytryptamine (5-HT, serotonin) agonists. These can be administered via the oral, subcutaneous or nasal route. Caution is needed with ergotamine preparations because they may lead to dependence. Overuse of any analgesia, including triptans, may contribute to medication overuse headache. If attacks are frequent (more than two per month), prophylaxis should be considered. Many drugs can be chosen but the most frequently used are vasoactive drugs (β-blockers), antidepressants (amitriptyline, dosulepin) and antiepileptic drugs (valproate, topiramate). Women with aura should avoid oestrogen treatment for either oral contraception or hormone replacement, although the increased risk of ischaemic stroke is minimal. Medication overuse headache With increasing availability of over-the-counter medication, headache syndromes perpetuated by analgesia intake are becoming much more common. Medication overuse headache (MOH) can complicate any headache syndrome but is especially common with migraine and chronic tension-type headache. The most frequent culprits are compound analgesics (particularly codeine and other opiate-containing preparations) and triptans, and MOH is usually associated with use on more than 10–15 days per month. Management is by withdrawal of the responsible analgesics. Patients should be warned that the initial effect will be to exacerbate the headache, and migraine prophylactics may be helpful in reducing the rebound headaches. Relapse rates are high, and patients often need help and support in withdrawing from analgesia; a careful explanation of this paradoxical concept is vital.

Epilepsy • 1097

Epilepsy A seizure can be defined as the occurrence of signs and/or symptoms due to abnormal, excessive or synchronous neuronal activity in the brain. The lifetime risk of an isolated seizure is about 5%, although incidence is highest at the extremes of age. Epilepsy is the tendency to have unprovoked seizures. While the prevalence of active epilepsy in European countries is about 0.5%, the figure in developing countries may be higher because of parasitic illnesses such as cysticercosis (p. 298). A recent change in definition allows the diagnosis of epilepsy to be made after a single seizure with a high risk of recurrence (e.g. a single seizure in the presence of a cortical lesion). Such changes may lead to an observed increase in epilepsy incidence. Historical terms such as ‘grand mal’ (implying tonic–clonic seizures) and ‘petit mal’ (intended originally to mean ‘absence seizures’ but commonly misused to describe ‘anything other than grand mal’) have been superseded. Subsequent revisions, including terms such as ‘complex partial’ and ‘simple partial’, have been imprecise and carry little information about underlying pathology, treatment or prognosis. The modern equivalents for these terms will be given below, but it is preferable to adhere to the 2010 iteration of the International League Against Epilepsy’s classification (Box 25.28). Pathophysiology To function normally, the brain must maintain a continual balance between excitation and inhibition, remaining responsive to the environment while avoiding continued unrestrained spontaneous activity. The inhibitory transmitter gamma-aminobutyric acid (GABA) is particularly important, acting on ion channels to enhance chloride inflow and reducing the chances of action potential formation. Excitatory amino acids (glutamate and aspartate) allow influx of sodium and calcium, producing the opposite effect. It is likely that many seizures result from an imbalance may be combined features of trigeminal neuralgia and cluster headache (‘cluster–tic’). Management The pain often responds to carbamazepine. It is wise to start with a low dose and increase gradually, according to effect. In patients who cannot tolerate carbamazepine, oxcarbazepine, gabapentin, pregabalin, amitriptyline or glucocorticoids may be effective alternatives, but if medication is ineffective or poorly tolerated, surgical treatment should be considered. Decompression of the vascular loop encroaching on the trigeminal root is said to have a 90% success rate. Otherwise, localised injection of alcohol or phenol into a peripheral branch of the nerve may be effective. Headaches associated with specific activities These usually affect men in their thirties and forties. Patients develop a sudden, severe headache with exertion, including sexual activity. There is usually no vomiting or neck stiffness, and the headache lasts less than 10–15 minutes, though a less severe dullness may persist for some hours. Subarachnoid haemorrhage needs to be excluded by CT and/or CSF examination (see Fig. 26.14, p. 1162) after a first event. The pathogenesis of these headaches is unknown. Although frightening, attacks are usually brief and patients may need only reassurance and simple analgesia for the residual headache. The syndrome may recur, and prevention may be necessary with propranolol or indometacin. Other headache syndromes A number of rare headache syndromes produce pains about the eye similar to cluster headaches (Box 25.27). These include chronic paroxysmal hemicrania and SUNCT (short-lasting unilateral neuralgiform headaches with conjunctival injection and tearing). The recognition of these syndromes is useful because they often respond to specific treatments such as indometacin. 25.27 Benign paroxysmal headaches Type Character of pain Duration Location Comment Ice pick Stabbing Very brief (split-second) Variable, usually temporoparietal Benign, more common in migraine Ice cream Sharp, severe 30–120 secs Bitemporal/occipital Obvious trigger by cold stimuli Exertional/sexual activity Bursting, thunderclap Severe for mins, then less severe for hours Generalised Subarachnoid haemorrhage needs to be excluded Cough Bursting Secs to mins Occipital or generalised Intracranial pathology needs to be excluded (especially craniocervical junction) Cluster headache (migrainous neuralgia) Severe unilateral, with ptosis, tearing, conjunctival injection, unilateral nasal congestion 30–90 mins 1–3 times per day Periorbital Usually in men, occurring in clusters over weeks/months Chronic paroxysmal hemicrania Severe unilateral with cluster headache-like autonomic features (see above) 5–20 mins, frequently through day Periorbital/temporal Usually in women, responds to indometacin SUNCT* Severe, sharp, triggered by touch or neck movements 15–120 secs, repetitive through day Periorbital May respond to carbamazepine *Short-lasting, unilateral, neuralgiform headache with conjunctival injection, tearing, rhinorrhoea and forehead sweating.

1098 • NEUROLOGY Clinical features Seizure type and epilepsy type Patients can experience more than one type of seizure attack, and it is important to document each attack type and the patient’s age at its onset, along with its frequency, duration and typical features. Any triggers should be identified (Box 25.29). The type of seizure, other clinical features and investigations can then be used to determine the epilepsy syndrome, as discussed below. Where there is doubt about the type, this is best stated and a full classification should be deferred until the evolution of the clinical features clarifies the picture. To classify seizure type, the clinician should ask firstly whether there is a focal onset, and secondly whether the seizures conform to one of the recognised patterns (see Box 25.28). Epilepsy that starts in patients beyond their mid-thirties will almost invariably reflect a focal cerebral event. Where activity remains focal, the classification will be obvious. With generalised tonic–clonic seizures, a focal onset will be heralded by positive neurological symptoms and signs corresponding to the normal function of that area. Occipital onset causes visual changes (lights and blobs of colour), temporal lobe onset causes false recognition (déjà vu), sensory strip involvement causes sensory alteration (burning, tingling), and motor strip involvement causes jerking. Alternatively, patients report a previous local cortical insult, and it may be reasonably (but not invariably) inferred that this is the seat of epileptogenesis. 25.28 Classification of seizures (2010 International League Against Epilepsy classification) Generalised seizures • Tonic–clonic (in any combination) • Absence: Typical Atypical Absence with special features • Myoclonic absence • Eyelid myoclonia • Myoclonic: Myoclonic Myoclonic–atonic Myoclonic–tonic • Clonic • Tonic • Atonic Focal seizures • Without impairment of consciousness or awareness (was ‘simple partial’): Focal motor Focal sensory • With impairment of consciousness or awareness (was ‘complex partial’) • Evolving to a bilateral, convulsive seizure (was ‘secondarily generalised seizure’): Tonic Clonic Tonic–clonic Unknown • Epileptic spasms Fig. 25.25 The pathophysiological classification of seizures. A A focal seizure originates from a paroxysmal discharge in a focal area of the cerebral cortex (often the temporal lobe); the seizure may subsequently spread to the rest of the brain (secondary generalisation) via diencephalic activating pathways. B In genetic generalised epilepsies (GGEs) the abnormal electrical discharges originate from the diencephalic activating system and spread simultaneously to all areas of the cortex. A B Focal seizure ± secondary generalisation Primary generalised seizure 25.29 Trigger factors for seizures • Sleep deprivation • Missed doses of antiepileptic drugs in treated patients • Alcohol (particularly withdrawal) • Recreational drug misuse • Physical and mental exhaustion • Flickering lights, including TV and computer screens (generalised epilepsy syndromes only) • Intercurrent infections and metabolic disturbances • Uncommon: loud noises, music, reading, hot baths between this excitation and inhibition. Intracellular recordings during seizures demonstrate a paroxysmal depolarisation shift in neuronal membrane potential, an upshift in internal potential predisposing to recurrent action potentials. In vivo, epileptic cortex shows repetitive discharges involving large groups of neurons. Focal epilepsy Seizures may be related to a localised disturbance in the cortex, becoming manifest in the first instance as focal seizures. Any disturbance of cortical architecture and function can precipitate this, whether focal infection, tumour, hamartoma or trauma-related scarring. If focal seizures remain localised, the symptoms experienced depend on which cortical area is affected. If areas in the temporal lobes become involved, then awareness of the environment becomes impaired but without associated tonic–clonic movements. When both hemispheres become involved, the seizure becomes generalised (Fig. 25.25). Generalised epilepsies The new terminology is genetic generalised epilepsies (GGEs) (previously idiopathic generalised epilepsies) to reflect their likely cause. These seizures are generalised at onset, abnormal activity probably originating in the central mechanisms controlling cortical activation (Fig. 25.25) and spreading rapidly. This group constitutes around 30% of all epilepsy and is likely to reflect widespread disturbance of structure or function. GGEs almost always become apparent before the age of 35. Seizure activity is usually apparent on EEG as spike and wave discharges (see Fig. 25.14, p. 1075). Other generalised seizures may involve merely brief loss of awareness (absence seizures), single jerks (myoclonus) or loss of tone (atonic seizures), as detailed in Box 25.28.

Epilepsy • 1099

originates (as above). The patient then becomes rigid (tonic) and unconscious, falling heavily if standing (‘like a log’) and risking facial injury. During this phase, breathing stops and central cyanosis may occur. As cortical discharges reduce in frequency, jerking (clonic) movements emerge for 2 minutes at most. Afterwards, there is a flaccid state of deep coma, which can persist for some minutes, and on regaining awareness the patient may be confused, disorientated and/or amnesic. During the attack, urinary incontinence and tongue-biting may occur. A severely bitten, bleeding tongue after an attack of loss of consciousness is pathognomonic of a generalised seizure but less marked lingual injury can occur in syncope. Subsequently, the patient usually feels unwell and sleepy, with headache and myalgia. Witnesses are usually frightened by the event, often believe the person to be dying, and may struggle to give a clear account of the episode. Some may not describe the tonic or clonic phase and may not mention cyanosis or tongue-biting. In less typical episodes, post-ictal delirium, or sequelae such as headache or myalgia, may be the main pointers to the diagnosis. Causes of generalised tonic–clonic seizures are listed in Box 25.31. Absence seizures Absence seizures (previously ‘petit mal’) always start in childhood. The attacks are rarely mistaken for focal seizures because of their brevity. They can occur so frequently (20–30 times a day) that they are mistaken for daydreaming or poor concentration in school. Myoclonic seizures These are typically brief, jerking movements, predominating in the arms. In epilepsy, they are more marked Focal seizures The classification of focal seizures is shown in Box 25.28. They are caused by localised cortical activity with retained awareness. The localisation of such symptoms is described above. A spreading pattern of seizure may occur, the abnormal sensation spreading much faster (in seconds) than a migrainous focal sensory attack. Awareness may become impaired if spread occurs to the temporal lobes (previously ‘complex partial seizure’). Patients stop and stare blankly, often blinking repetitively, making smacking movements of their lips or displaying other automatisms, such as picking at their clothes. After a few minutes consciousness returns but the patient may be muddled and feel drowsy for a period of up to an hour. The age of onset, preceding aura, longer duration and post-ictal symptoms usually make these easy to differentiate from childhood absence seizures (see below). Seizures arising from the anterior parts of the frontal lobe may produce bizarre behaviour patterns, including limb posturing, sleep walking or even frenetic, ill-directed motor activity with incoherent screaming. Video EEG may be necessary to differentiate these from psychogenic attacks (which are more common) but abruptness of onset, stereotyped nature, relative brevity and nocturnal preponderance may indicate a frontal origin. Causes of focal seizures are given in Box 25.30. Generalised seizures Tonic–clonic seizures An initial ‘aura’ may be experienced by the patient, depending on the cortical area from which the seizure 25.30 Causes of focal seizures Idiopathic • Benign Rolandic epilepsy of childhood • Benign occipital epilepsy of childhood Focal structural lesions Genetic • Tuberous sclerosis (p. 1264) • Autosomal dominant nocturnal frontal lobe epilepsy • Autosomal dominant partial epilepsy with auditory features (ADPEAF) • von Hippel–Lindau disease (p. 1132) • Neurofibromatosis (p. 1131) • Cerebral migration abnormalities Infantile hemiplegia Dysembryonic • Cortical dysgenesis • Sturge–Weber syndrome Mesial temporal sclerosis (associated with febrile convulsions) Cerebrovascular disease (Ch. 26) • Intracerebral haemorrhage • Cerebral infarction • Arteriovenous malformation • Cavernous haemangioma Tumours (primary and secondary) (p. 1129) Trauma (including neurosurgery) Infective (p. 1117) • Cerebral abscess (pyogenic) • Toxoplasmosis • Cysticercosis • Tuberculoma • Subdural empyema • Encephalitis • Human immunodeficiency virus (HIV) Inflammatory • Autoimmune encephalopathies (e.g. anti-voltage-gated potassium channel antibodies, anti-NMDA receptor antibodies, anti-glycine receptor antibodies) • Sarcoidosis • Vasculitis 25.31 Causes of generalised tonic–clonic seizures Generalisation from focal seizures • See Box 25.30 Genetic • Inborn errors of metabolism (p. 1144) • Storage diseases • Phakomatoses (e.g. tuberous sclerosis, p. 1264) Cerebral birth injury Hydrocephalus Cerebral anoxia Drugs • Antibiotics: penicillin, isoniazid, metronidazole • Antimalarials: chloroquine, mefloquine • Ciclosporin • Amphetamines (withdrawal) • Cardiac anti-arrhythmics: lidocaine, disopyramide • Psychotropic agents: phenothiazines, tricyclic antidepressants, lithium Alcohol (especially withdrawal) Toxins • Organophosphates (sarin) • Heavy metals (lead, tin) Metabolic disease • Hypocalcaemia • Hyponatraemia • Hypomagnesaemia • Hypoglycaemia • Renal failure • Liver failure Infective • Post-infectious encephalopathy • Meningitis (p. 1118) Inflammatory • Multiple sclerosis (uncommon; (p. 1106) • Systemic lupus erythematosus (p. 1034) Diffuse degenerative diseases • Alzheimer’s disease (uncommonly; p. 1992) • Creutzfeldt–Jakob disease (rarely; p. 1127)

1100 • NEUROLOGY to assess prognosis once a firm diagnosis has been made. The recurrence rate after a first seizure is approximately 40% and most recurrent attacks occur within a month or two of the first. Further seizures are less likely if an identified trigger can be avoided (see Box 25.29). Other investigations for infective, toxic and metabolic causes (Box 25.34) may be appropriate. An EEG performed immediately after a seizure may be more helpful in showing focal features than if performed after a delay. in the morning or on awakening from sleep, and tend to be provoked by fatigue, alcohol, or sleep deprivation. Atonic seizures These are seizures involving brief loss of muscle tone, usually resulting in heavy falls with or without loss of consciousness. They occur only in the context of epilepsy syndromes that involve other forms of seizure. Tonic seizures These are associated with a generalised increase in tone and an associated loss of awareness. They are usually seen as part of an epilepsy syndrome and are unlikely to be isolated. Clonic seizures Clonic seizures are similar to tonic–clonic seizures. The clinical manifestations are similar but there is no preceding tonic phase. Seizures of uncertain generalised or focal nature Epileptic spasms While these are highlighted in the classification system, they are unusual in adult practice and occur mainly in infancy. They signify widespread cortical disturbance and take the form of marked contractions of the axial musculature, lasting a fraction of a second but recurring in clusters of 5–50, often on awakening. Epilepsy syndromes Many patients with epilepsy fall into specific patterns, depending on seizure type(s), age of onset and treatment responsiveness: the so-called electroclinical syndromes (Box 25.32). It is anticipated that genetic testing will ultimately demonstrate similarities in molecular pathophysiology. Box 25.33 highlights the more common epilepsy syndromes, which are largely of early onset and are sensitive to sleep deprivation, hyperventilation, alcohol and photic stimulation. Epilepsies that do not fit into any of these diagnostic categories can be delineated firstly on the basis of the presence or absence of a known structural or metabolic condition (presumed cause), and then on the basis of the primary mode of seizure onset (generalised versus focal). Investigations Single seizure All patients with transient loss of consciousness should have a 12-lead ECG. Where seizure is suspected or definite, patients should have cranial imaging with either MRI or CT, although the yield is low unless focal signs are present. EEG may help 25.32 Electroclinical epilepsy syndromes Adolescence to adulthood • Juvenile absence epilepsy (JAE) • Juvenile myoclonic epilepsy (JME) • Epilepsy with generalised tonic–clonic seizures alone • Progressive myoclonus epilepsies (PMEs) • Autosomal dominant epilepsy with auditory features (ADEAF) • Other familial temporal lobe epilepsies Less specific age relationship • Familial focal epilepsy with variable foci (childhood to adult) • Reflex epilepsies Distinctive constellations • Mesial temporal lobe epilepsy with hippocampal sclerosis (MTLE with HS) • Rasmussen’s syndrome • Gelastic (from the Greek word for laughter) seizures with hypothalamic hamartoma • Hemiconvulsion–hemiplegia–epilepsy Epilepsies with structural–metabolic causes • Malformations of cortical development (hemimegalencephaly, heterotopias etc.) • Neurocutaneous syndromes (tuberous sclerosis complex, Sturge–Weber etc.) • Tumour • Infection • Trauma • Angioma • Perinatal insults • Stroke etc. Epilepsies of unknown cause Conditions with epileptic seizures not needing long-term treatment • Benign neonatal seizures (BNS) • Febrile seizures (FS) 25.33 Common generalised epilepsy syndromes Syndrome Age of onset Type of seizure EEG features Treatment Prognosis Childhood absence epilepsy 4–8 years Frequent brief absences 3/sec spike and wave Ethosuximide Sodium valproate Levetiracetam 40% develop GTCS, 80% remit in adulthood Juvenile absence epilepsy 10–15 years Less frequent absences than childhood absence Poly-spike and wave Sodium valproate Levetiracetam 80% develop GTCS, 80% seizure-free in adulthood Juvenile myoclonic epilepsy 15–20 years GTCS, absences, morning myoclonus Poly-spike and wave, photosensitivity Sodium valproate Levetiracetam 90% remit with AEDs but relapse if AED withdrawn GTCS on awakening 10–25 years GTCS, sometimes myoclonus Spike and wave on waking and sleep onset Sodium valproate Levetiracetam 65% controlled with AEDs but relapse off treatment (AED = antiepileptic drug; GTCS = generalised tonic–clonic seizure)

Epilepsy • 1101

Immediate care Little can or needs to be done for a person during a convulsive seizure except for first aid and common-sense manœuvres to limit damage or secondary complications (see Box 25.36). Advice should be given that on no account should anything be inserted into the patient’s mouth. The management of status epilepticus is described on page 1080. Lifestyle advice Patients should be advised to avoid activities where they might place themselves or others at risk if they have a seizure. This applies at work, at home and at leisure. At home, only shallow baths (or showers) should be taken. Prolonged cycle journeys should be discouraged until reasonable freedom from seizures has been achieved. Activities involving prolonged proximity to water (swimming, fishing or boating) should always be carried out in the company of someone who is aware of the risks and the potential need for rescue measures. Driving regulations vary between countries and the patient should be made aware of these (Box 25.38). Certain occupations, such as firefighter or airline pilot, are not open to those with a previous or active diagnosis of epilepsy; further information is available from epilepsy support organisations. The risk of harm from epilepsy should be discussed around the time of diagnosis. This should be done with care and sensitivity, and with the aim of motivating the patient to adapt habits and lifestyle to optimise epilepsy control and minimise risks of serious complications. Antiepileptic drugs Antiepileptic drugs (AEDs) should be considered where risk of seizure recurrence is high. A diagnosis of two or more seizures is justification enough but a prolonged inter-seizure interval may deter some patients and physicians. Treatment decisions should always be shared with the patient, to enhance adherence. A wide range of drugs is available. These agents either increase inhibitory neurotransmission in the brain or alter neuronal sodium channels to prevent abnormally rapid transmission of impulses. In the majority of patients, full control is achieved with a single drug. Dose regimens should be kept as simple as possible. Guidelines Epilepsy The same investigations are required in a patient with epilepsy (Box 25.34). The EEG may help to establish the type of epilepsy and guide therapy. Investigations should be revisited if the epilepsy is intractable to treatment. Inter-ictal EEG is abnormal in only about 50% of patients with recurrent seizures, so it cannot be used to exclude epilepsy. The sensitivity can be increased to about 85% by prolonging recording time and including a period of natural or drug-induced sleep, but this does not replace a well-taken history. Ambulatory EEG recording or video EEG monitoring may help with differentiation of epilepsy from other disorders if attacks are sufficiently frequent. Indications for imaging are summarised in Box 25.35. Imaging cannot establish a diagnosis of epilepsy but identifies any structural cause. It is not required if a confident diagnosis of a recognised GGE syndrome (e.g. juvenile myoclonic epilepsy) is made. While CT excludes a major structural cause of epilepsy, MRI is required to demonstrate subtle changes such as hippocampal sclerosis, which may direct or inform surgical intervention. Management It is important to explain the nature and cause of seizures to patients and their relatives, and to instruct relatives in the first aid management of seizures (Box 25.36). Many people with epilepsy feel stigmatised and may become unnecessarily isolated from work and social life. It is important to emphasise that epilepsy is a common disorder that affects 0.5–1% of the population, and that full control of seizures can be expected in approximately 70% of patients (Box 25.37). 25.36 How to administer first aid for seizures • Move the person away from danger (fire, water, machinery, furniture) • After convulsions cease, turn the person into the ‘recovery’ position (semi-prone) • Ensure the airway is clear but do NOT insert anything in the mouth (tongue-biting occurs at seizure onset and cannot be prevented by observers) • If convulsions continue for more than 5 mins or recur without the person regaining consciousness, summon urgent medical attention • Do not leave the person alone until fully recovered (drowsiness and delirium can persist for up to 1 hr) 25.35 Indications for brain imaging in epilepsy • Epilepsy starting after the age of 16 years • Seizures having focal features clinically • Electroencephalogram showing a focal seizure source • Control of seizures difficult or deteriorating 25.34 Investigation of epilepsy From where is the epilepsy arising? • Standard EEG • Sleep EEG • EEG with special electrodes (foramen ovale, subdural) What is the cause of the epilepsy? Structural lesion? • CT • MRI Metabolic disorder? • Urea and electrolytes • Liver function tests • Blood glucose • Serum calcium, magnesium Inflammatory or infective disorder? • Full blood count, erythrocyte sedimentation rate, C-reactive protein • Chest X-ray • Serology for syphilis, HIV, collagen disease • CSF examination Are the attacks truly epileptic? • Ambulatory EEG • Videotelemetry (CSF = cerebrospinal fluid; CT = computed tomography; EEG = electroencephalography; HIV = human immunodeficiency virus; MRI = magnetic resonance imaging) 25.37 Epilepsy: outcome after 20 years • 50% are seizure-free, without drugs, for the previous 5 years • 20% are seizure-free for the previous 5 years but continue to take medication • 30% continue to have seizures in spite of antiepileptic therapy

1102 • NEUROLOGY pharmacokinetics than the older ones and the only indication for measuring serum levels is if there is doubt about adherence. Blood levels need to be interpreted carefully and dose changes made to treat the patient rather than to bring a serum level into the ‘therapeutic range’. Some centres advocate serum level monitoring during pregnancy (notably with lamotrigine) but the evidence of benefit for this is not strong. Epilepsy surgery Some patients with drug-resistant epilepsy benefit from surgical resection of epileptogenic brain tissue. Less invasive treatments, including vagal nerve stimulation or deep brain stimulation, may also be helpful in some patients. All those who continue to experience seizures despite appropriate drug treatment should be considered for surgical treatment. Planning such interventions requires intensive specialist assessment and investigation to identify the site of seizure onset and the dispensability of any target areas for resection, i.e. whether the area of brain involved is necessary for a critical function such as vision or motor function. Withdrawing antiepileptic therapy Withdrawal of medication may be considered after a patient has been seizure-free for more than 2 years. Childhood-onset epilepsy, particularly classical absence seizures, carries the best prognosis for successful drug withdrawal. Other epilepsy syndromes, such as juvenile myoclonic epilepsy, have a marked tendency to recur after drug withdrawal. Focal epilepsies that begin in adult life are also likely to recur, especially if there is an identified structural lesion. Overall, the recurrence rate after drug withdrawal depends on the individual’s epilepsy history. An individualised estimate may be gained from the SIGN guideline tables (see ‘Further information’, p. 1146). Patients should be advised of the risks of recurrence, to allow them to decide whether or not they wish to withdraw. If undertaken, withdrawal should be done slowly, reducing the drug dose gradually over weeks or months. Withdrawal See Scottish Intercollegiate Guidelines Network SIGN 143 – Diagnosis and management of epilepsy in adults (May 2015). 25.39 Guidelines for antiepileptic drug therapy • Start with one first-line drug (see Box 25.40) • Start at a low dose; gradually increase dose until effective control of seizures is achieved or side-effects develop • Optimise adherence (use minimum number of doses per day) • If first drug fails (seizures continue or side-effects develop), start second first-line drug, followed if possible by gradual withdrawal of first • If second drug fails (seizures continue or side-effects develop), start second-line drug in combination with the preferred baseline drug at maximum tolerated dose (beware interactions) • If this combination fails (seizures continue or side-effects develop), replace second-line drug with alternative second-line drug • If this combination fails, check adherence and reconsider diagnosis (Are events seizures? Occult lesion? Treatment adherence/alcohol/ drugs confounding response?) • Consider alternative, non-drug treatments (e.g. epilepsy surgery, vagal nerve stimulation) • Use minimum number of drugs in combination at any one time 25.38 UK driving regulations The physician’s prime duty is to ensure the patient is aware of the legal obligation to inform the driving authority Private use Single seizure • Cease driving for 6 months; a longer period may be required if risk of recurrence is high Epilepsy (i.e. more than one seizure over the age of 5 years) • Cease driving immediately • Licence restored when patient is seizure-free for 1 year, or an initial sleep seizure is followed by exclusively sleep seizures for 1 year, or mixed awake and sleep seizures are followed by 3 years of exclusively sleep seizures • Licence will require renewal every 3 years thereafter until patient is seizure-free for 10 years Withdrawal of antiepileptic drugs • Cease driving during withdrawal period and for 6 months thereafter Vocational drivers (heavy goods and public service vehicles) • No licence permitted if any seizure has occurred after the age of 5 years until patient is off medication and seizure-free for more than 10 years, and has no potentially epileptogenic brain lesion are listed in Box 25.39. For focal epilepsies, one large study suggests that lamotrigine is the best-tolerated monotherapy, which, alongside its favourable adverse-effect profile and relative lack of pharmacokinetic interactions, makes it a good first-line drug, although caution must be exercised with oral contraceptive use. Unclassified or genetic generalised epilepsies respond best to valproate, although pregnancy-related problems mean that valproate should not be used in women of reproductive age unless the benefits outweigh the risks. The initial choice should be an established first-line drug (Box 25.40), with more recently introduced drugs as second choice. Monitoring therapy Some practitioners confuse epilepsy care with serum level monitoring. The newer drugs have much more predictable 25.40 Guidelines for choice of antiepileptic drug1 Epilepsy type First-line Second-line Third-line Focal onset and/or secondary GTCS Lamotrigine Carbamazepine Levetiracetam Sodium valproate Topiramate Zonisamide Lacosamide Clobazam Gabapentin Oxcarbazepine Phenobarbital Phenytoin Pregabalin Primidone Tiagabine GTCS2 Sodium valproate Levetiracetam Lamotrigine Topiramate Zonisamide Carbamazepine Phenytoin Primidone Phenobarbital Acetazolamide Absence2 Ethosuximide Sodium valproate Lamotrigine Clonazepam Myoclonic2 Sodium valproate Levetiracetam Clonazepam Lamotrigine Phenobarbital N.B. Use as few drugs as possible at the lowest possible dose. (GTCS = generalised tonic–clonic seizure) 1See Scottish Intercollegiate Guidelines Network SIGN 143 – Diagnosis and management of epilepsy in adults (May 2015). 2Genetic generalised epilepsies.

Epilepsy • 1103

Prognosis The outcome of newly diagnosed epilepsy is generally good. Overall, generalised epilepsies and generalised seizures are more readily controlled than focal seizures. The presence of a structural lesion reduces the chances of freedom from seizures. The overall prognosis for epilepsy is shown in Box 25.37. The particular problems that epilepsy poses in the elderly and in adolescents are summarised in Boxes 25.42 and 25.43, respectively. Status epilepticus Presentation and management are described on page 1080. While generalised status epilepticus is most easily recognised, non-convulsive status may be less dramatic and less easily diagnosed. It may cause only altered awareness, delirium or wandering with automatisms. In an intensive care unit setting, EEG monitoring is essential to ensure that diagnosis and treatment are optimised. Non-epileptic attack disorder (‘dissociative attacks’) The difficulty with nomenclature is discussed on page 1097. Patients may present with attacks that resemble epileptic seizures but are caused by psychological phenomena and may necessitate precautions around driving or occupation (see Box 25.38). Contraception Some AEDs induce hepatic enzymes that metabolise synthetic hormones, increasing the risk of contraceptive failure. This is most marked with carbamazepine, phenytoin and barbiturates, but clinically significant effects can be seen with lamotrigine and topiramate. If the AED cannot be changed, this can be overcome by giving higher-dose preparations of the oral contraceptive. Sodium valproate and levetiracetam have no interaction with hormonal contraception. Pregnancy and reproduction Epilepsy presents specific management problems during pregnancy (Box 25.41). There is usually concern about teratogenesis associated with AEDs. It is important to recognise proportionate risks: background risk of severe fetal malformation in the general population is around 2–3%, while the AED most associated with teratogenesis is sodium valproate, which, at high dose, increases the risk to around 6–7%. Long-term observational studies show that most of the commonly used AEDs can be given safely in pregnancy. Pre-conception treatment with folic acid (5 mg daily), along with use of the smallest effective doses of as few AEDs as possible, may reduce the risk of fetal abnormalities. The risks of abrupt AED withdrawal to the mother should be stressed. Seizures may become more frequent during pregnancy, particularly if pharmacokinetic changes decrease serum levels of AEDs (see Box 25.41). Menstrual irregularities and reduced fertility are more common in women with epilepsy, and are also increased by sodium valproate. Patients with epilepsy are at greater risk of osteoporosis, apparently independently of the drug used. Some centres advocate vitamin D supplementation in any patient with epilepsy but the higher female risk of osteoporosis makes this most important in women. Oral contraception can interact with individual AEDs (Box 25.41). 25.41 Epilepsy in pregnancy • Provision of pre-conception counselling is best practice: start folic acid (5 mg daily for 2 months) before conception to reduce the risk of fetal malformations. • Fetal malformation: risk is minimised if a single drug is used. Carbamazepine and lamotrigine have the lowest incidence of major fetal malformations. The risk with sodium valproate is higher but should be carefully balanced against its benefits. Levetiracetam may be safe but avoid other newer drugs if possible. • Learning difficulties in children: IQ may be lower when children are exposed to valproate in utero, so its use should always be considered carefully. • Haemorrhagic disease of the newborn: enzyme-inducing antiepileptic drugs increase risk. Give oral vitamin K (20 mg daily) to the mother during the last month of pregnancy and IM vitamin K (1 mg) to the infant at birth. • Increased frequency of seizures: where breakthrough seizures occur, monitor antiepileptic drug levels and adjust the dose regimen accordingly. • Pharmacokinetic effects of pregnancy: carbamazepine levels may fall in the third trimester. Lamotrigine and levetiracetam levels may fall early in pregnancy. Some advocate monitoring of levels. 25.43 Epilepsy in adolescence • Effect on school/education: seizures, antiepileptic drugs (AEDs) and psychological complications of epilepsy may hamper education. Fear may make some educational institutions unduly restrictive. • Effect on family relationships: parents may adopt a protective role, which can lead to epilepsy (and AEDs) becoming a point of assertion and rebellion. • Effect on career choice: epilepsy may exclude or restrict employment in the emergency services and armed forces. • Alcohol: may affect sleep pattern; excess may be associated with poor AED adherence. • Illicit drugs: may affect seizure threshold and be associated with poor AED adherence. • Sleep disturbance: may be worsened by social activities and computer games. • Oral contraception: interactions with AED can occur. Use may not always be disclosed to parents. 25.42 Epilepsy in old age • Incidence and prevalence: late-onset epilepsy is very common and the annual incidence in those over 60 years is rising. • Fits and faints: the features that usually differentiate these may be less definitive than in younger patients. • Non-convulsive status epilepticus: can present as delirium in the elderly. • Cerebrovascular disease: the underlying cause of seizures in 30–50% of patients over the age of 50 years. A seizure may occur with an overt stroke or with occult vascular disease. • Antiepileptic drug regimens: keep as simple as possible and take care to avoid interactions with other drugs being prescribed. • Carbamazepine-induced hyponatraemia: increases significantly with age; this is particularly important in patients on diuretics or those with heart failure. • Withdrawal of antiepileptic therapy: drug withdrawal should be attempted only where benefits exceed risk of harm from seizures.

1104 • NEUROLOGY within a few days, though head movement may continue to provoke transient symptoms (positional vertigo) for some time. During the acute attack, nystagmus (p. 1090) will be present for a few days. Cinnarizine, prochlorperazine or betahistine provide symptomatic relief but should not be used long-term, as this may delay recovery. A small proportion of patients fail to recover fully and complain of ongoing imbalance and dysequilibrium rather than vertigo; vestibular rehabilitation by a physiotherapist may help. Benign paroxysmal positional vertigo Benign paroxysmal positional vertigo (BPPV) is due to the presence of otolithic debris from the saccule or utricle affecting the free flow of endolymph in the semicircular canals (cupulolithiasis). It may follow minor head injury but typically is spontaneous. The history is diagnostic, with transient (seconds) vertigo precipitated by movement (typically, rolling over in bed or getting into or out of bed). Although it is benign, and usually self-limiting after weeks or months, patients are often alarmed by the symptoms. The diagnosis can be confirmed by the ‘Hallpike manœuvre’ to demonstrate positional nystagmus (Fig. 25.26). Treatment comprises explanation and reassurance, along with positioning procedures designed to return otolithic debris from the semicircular canal to saccule or utricle (such as the Epley manœuvre) and/or to re-educate the brain to cope with the inappropriate signals from the labyrinth (such as Cawthorne–Cooksey exercises: see ‘Further information’, p. 1146). Ménière’s disease This is due to an abnormality of the endolymph that causes episodes of vertigo accompanied by tinnitus and fullness in the ear, each attack typically lasting a few hours. Over the years, patients may develop progressive deafness (typically low-tone on audiometry). Examination is typically normal in between attacks. The diagnosis is clinical, supported by abnormal audiometry. Ménière’s disease is idiopathic but a similar syndrome may have no abnormal EEG discharges. Such attacks may be very prolonged, sometimes mimicking status epilepticus. Epileptic and non-epileptic attacks may coexist and time and effort are needed to clarify the relative contribution of each, allowing more accurate and comprehensive treatment. Non-epileptic attack disorder (NEAD) may be accompanied by dramatic flailing of the limbs and arching of the back, with side-to-side head movements and vocalising. Cyanosis and severe biting of the tongue are rare but incontinence can occur. Distress and crying are common following non-epileptic attacks. The distinction between epileptic attacks originating in the frontal lobes and non-epileptic attacks may be especially difficult, and may require videotelemetry with prolonged EEG recordings. Non-epileptic attacks are three times more common in women than in men and have been linked with a history of past or ongoing life trauma. They are not necessarily associated with formal psychiatric illness. Patients and carers may need reassurance that hospital admission is not required for every attack. Prevention requires psychotherapeutic interventions rather than drug therapy (p. 1202). Vestibular disorders Vertigo is the typical symptom caused by vestibular dysfunction, and most patients with vertigo have acute vestibular failure, benign paroxysmal positional vertigo or Ménière’s disease. Central (brain) causes of vertigo are rare by comparison, with the exception of migraine (p. 1095). Acute vestibular failure Although commonly called ‘labyrinthitis’ or ‘vestibular neuronitis’, acute vestibular failure is a more accurate term, as most cases are idiopathic. It usually presents as isolated severe vertigo with vomiting and unsteadiness. It begins abruptly, often on waking, and many patients are initially bed-bound. The vertigo settles Fig. 25.26 The Hallpike manœuvre for diagnosis of benign paroxysmal positional vertigo (BPPV). Patients are asked to keep their eyes open and look at the examiner as their head is swung briskly backwards through 120° to overhang the edge of the couch. A Perform first with the right ear down. B Perform next with the left ear down. The examiner looks for nystagmus (usually accompanied by vertigo). In BPPV, the nystagmus typically occurs in A or B only and is torsional, the fast phase beating towards the lower ear. Its onset is usually delayed a few seconds and it lasts 10–20 seconds. As the patient is returned to the upright position, transient nystagmus may occur in the opposite direction. Both nystagmus and vertigo typically decrease (fatigue) on repeat testing. B A

Disorders of sleep • 1105

Parasomnias Parasomnias are abnormal motor behaviours that occur around sleep. They may arise in either REM or non-REM sleep, with characteristic features and timing. Non-REM parasomnias tend to occur early in sleep. Parasomnias should be distinguished from other motor disturbances (such as periodic limb movements, hypnic jerks or sleep talking) and sleep-onset epileptic seizures (p. 1101). History from a sleeping partner or other witness is essential. Non-REM parasomnias These are due to incomplete arousal from non-REM sleep and manifest as night terrors, sleep walking and confusional arousals (sleep drunkenness). They typically occur within an hour or two of sleep onset, and are common in children and usually of no pathological significance. Rarely, they persist into adulthood and may become increasingly complex, including dressing, moving objects, eating, drinking or even acts of violence. Patients have little or no recollection of the episodes, even though they appear ‘awake’. The episodes may be triggered by alcohol or unfamiliar sleeping situations, and can be familial. Treatment is usually not required but clonazepam can be used. REM sleep behaviour disorder In REM sleep behaviour disorder (RBD), patients ‘act out’ their dreams during REM sleep, due to failure of the usual muscle atonia. Sleep partners provide typical histories of patients ‘fighting’ or ‘struggling’ in their sleep, sometimes causing injury to themselves or to their partner. They are easily roused from this state, with recollection of their dream, unlike in non-REM states. RBD is more common in men and may be an early symptom of neurodegenerative diseases such as alpha synucleinopathies (p. 1111), perhaps preceding more typical symptoms of these conditions by years. Polysomnography will confirm absence of atonia during REM sleep. Clonazepam is the most successful treatment. Restless legs syndrome Restless legs syndrome (RLS) is common, with a prevalence of up to 10%, but many patients never seek medical attention. It is characterised by unpleasant leg (rarely, arm) sensations that are eased by movement (motor restlessness); the diagnosis is be caused by middle ear trauma or infection. Imaging may be indicated to exclude other focal brainstem or cerebellopontine angle pathology but will be normal in Ménière’s disease. Management includes a low-salt diet, vestibular sedatives for acute attacks (e.g. cinnarizine or prochlorperazine), and occasionally surgery to increase endolymphatic drainage from the vestibular system. Migraine may also cause episodic vertigo, and can be confused with Ménière’s disease, although usually other migrainous features will appear in the history. Disorders of sleep Sleep disturbances include too much sleep (hypersomnolence or excessive daytime sleepiness), insufficient or poor-quality sleep (insomnia), and abnormal behaviour during sleep (parasomnias). Insomnia is usually caused by psychological or psychiatric disorders, shift work and other environmental causes, pain and so on, and will not be discussed further. Many symptoms and disorders may affect sleep and sleep quality (e.g. pain, depression/anxiety, parkinsonism). Excessive daytime sleepiness (hypersomnolence) There are primary and secondary causes (Box 25.44). The most common causes are impaired sleep due to lifestyle issues or sleep-disordered breathing (p. 622). Sleepiness may be measured using the Epworth Sleepiness Score (see Box 17.86, p. 623). Most causes will be identified by a detailed history from the patient and their bed partner, and a 2-week sleep diary. Narcolepsy This has a prevalence of about 1 in 2000, with peak onset in adolescence and early middle age. The key symptom is sudden, irresistible ‘sleep attacks’, often in inappropriate circumstances such as while eating or talking. Other characteristic features help distinguish this from excessive daytime sleepiness (Box 25.45). Symptoms may be due to loss of hypocretin-secreting hypothalamic neurons. Diagnosis requires sleep study with sleep latency testing (demonstrating rapid onset of REM sleep). Narcolepsy may respond to stimulants such as modafinil but more severe cases may require sodium oxybate, dexamfetamine, methylphenidate or selective serotonin reuptake inhibitor (SSRIs). Cataplexy can be debilitating and can respond to sodium oxybate or to antidepressants, such as clomipramine or venlafaxine. 25.44 Causes of hypersomnolence Primary causes • Narcolepsy • Idiopathic hypersomnolence • Brain injury Secondary causes (due to poor-quality sleep) • Obstructive sleep apnoea • Pain • Restless legs/periodic limb movements of sleep • Parkinsonism and other neurodegenerative diseases • Depression/anxiety • Medication • Environmental factors (noise, temperature etc.) 25.45 Narcolepsy symptoms Sleep attacks • Brief, frequent and unlike normal somnolence Cataplexy • Sudden loss of muscle tone triggered by surprise, laughter, strong emotion etc. Hypnagogic or hypnopompic hallucinations • Frightening hallucinations experienced during sleep onset or waking due to intrusion of REM sleep during wakefulness (can occur in normal people) Sleep paralysis • Brief paralysis on waking (can occur in normal people)

1106 • NEUROLOGY A) and CD226 genes. An immune hypothesis is supported by increased levels of activated T lymphocytes in the CSF and increased immunoglobulin synthesis within the CNS. Initial CNS inflammation in MS involves entry of activated T lymphocytes across the blood–brain barrier. These recognise myelin-derived antigens on the surface of the nervous system’s antigen-presenting cells, the microglia, and undergo clonal proliferation. The resulting inflammatory cascade releases cytokines and initiates destruction of the oligodendrocyte–myelin unit by macrophages. Histologically, the resultant lesion is a plaque of inflammatory demyelination, most commonly in the periventricular regions of the brain, the optic nerves and the subpial regions of the spinal cord (Fig. 25.27). This begins as a circumscribed area of disintegration of the myelin sheath, accompanied by infiltration by activated lymphocytes and macrophages, often with conspicuous perivascular inflammation. After the acute attack, gliosis follows, leaving a shrunken scar. Much of the initial acute clinical deficit is caused by the effect of inflammatory cytokines on transmission of the nervous impulse rather than structural disruption of myelin, and may explain the rapid recovery of some deficits and probably the acute benefit from glucocorticoids. In the long term, accumulating myelin loss reduces the efficiency of impulse propagation or causes complete conduction block, contributing to sustained impairment of CNS functions. Inflammatory mediators released during the acute attack (particularly nitric oxide) probably also initiate axonal damage, which is a feature of the latter stages of the disease. In established MS there is progressive axonal loss, probably due to the successive damage from acute attacks and the subsequent loss of neurotrophic factors from oligodendrocytes. This axonal loss may account for the phase of the disease characterised by progressive and persistent disability (Fig. 25.28). Clinical features The diagnosis of MS requires the demonstration of otherwise unexplained CNS lesions separated in time and space (Box 25.47); traditionally, this meant two or more clinical relapses affecting different parts of the nervous system, and the first ever episode was labelled ‘clinically isolated syndrome’ (CIS). Recent changes to diagnostic criteria mean that MS may be diagnosed after an isolated episode (i.e. at the CIS stage), provided that certain criteria are met (Box 25.47) The peak age of onset of MS is the fourth decade; onset before puberty or after the age of 60 years is rare. Symptoms and signs of MS usually evolve over days or weeks, resolving over weeks or months. Rarely, a more rapid stroke-like presentation may occur. About 85–90% of patients have an initial relapsing and remitting clinical course with variable intervening recovery, although the majority will eventually enter a secondary progressive phase. Most of the rest follow a slowly progressive clinical course (so-called primary progressive MS), while rare patients have a fulminant variety leading to early death (see Fig. 25.28). Frequent relapses with incomplete recovery indicate a poor prognosis. Some milder cases have an interval of years or even decades between attacks, while in others (particularly if optic neuritis is the initial manifestation) there is no recurrence of disease. There are a number of clinical symptoms and syndromes suggestive of MS, occurring either at presentation or during the course of the illness (Box 25.48). The physical signs observed in MS are determined by the anatomical site of demyelination. Combined spinal cord and brainstem signs are common, although evidence of previous optic neuritis may be found in the form of an afferent pupillary deficit. Significant intellectual impairment clinical (Box 25.46). It has a strong familial tendency and can present with daytime somnolence due to poor sleep. It is usually idiopathic but may be associated with iron deficiency, pregnancy, peripheral neuropathy, Parkinson’s disease or uraemia. It should be distinguished from akathisia, the daytime motor restlessness that is an adverse effect of antipsychotic drugs. Treatment, if required, is with dopaminergic drugs (dopamine agonists or levodopa, p. 1113) or benzodiazepines. Periodic limb movements in sleep Unlike RLS, periodic limb movements in sleep (PLMS) only occur during sleep and cause repetitive flexion movements of the limbs, usually in the early (non-REM) stages of sleep. Although patients are unaware of the symptoms, they may disrupt sleep quality and often disturb partners. The pathological significance of PLMS is uncertain and it often occurs in normal health. There is an overlap with RLS. Treatment is most successful with clonazepam or dopaminergic drugs. Neuro-inflammatory diseases Multiple sclerosis Multiple sclerosis (MS) is an important cause of long-term disability in adults, especially in the UK, where the prevalence is approximately 120 per 100 000. The annual incidence is around 7 per 100 000, while the lifetime risk of developing MS is about 1 in 400. The incidence of MS is higher in Northern Europeans and the disease is about twice as common in females. Pathophysiology There is evidence that both genetic and environmental factors play a causative role. The prevalence of MS is low near the equator and increases in the temperate zones of both hemispheres. People retain the risk of developing the disease in the zone in which they grew up, indicating that environmental exposures during growth and development are important. Prevalence also correlates with environmental factors, such as sunlight exposure, vitamin D (a controversial association) and exposure to Epstein–Barr virus (EBV), although causative mechanisms remain unclear. Genetic factors are also relevant; the risk of familial occurrence in MS is 15%, with highest risk in first-degree relatives (age-adjusted risk 4–5% for siblings and 2–3% for parents or offspring). Monozygotic twins have a concordance rate of 30%. The genes that predispose to MS are incompletely defined but inheritance appears to be polygenic, with influences from genes for human leucocyte antigen (HLA) typing, interleukin receptors, CLEC16A (C-type lectin domain family 16 member 25.46 Diagnostic criteria for restless legs syndrome A need to move the legs, usually accompanied or caused by uncomfortable, unpleasant sensations in the legs, with the following features: • only present or worse during periods of rest or inactivity such as lying or sitting • partially or totally relieved by movement such as walking or stretching, at least as long as the activity continues • generally worse or occurs only in the evening or night.

Neuro-inflammatory diseases • 1107

Fig. 25.27 Multiple sclerosis. A Photomicrograph from demyelinating plaque, showing perivascular cuffing of blood vessel by lymphocytes. B Brain magnetic resonance imaging in multiple sclerosis. Multiple high-signal lesions (arrows) seen particularly in the paraventricular region on T2 image. C In T1 image with gadolinium enhancement, recent lesions (A arrows) show enhancement, suggesting active inflammation (enhancement persists for 4 weeks); older lesions (B arrows) show no enhancement but low signal, suggesting gliosis. A B C A A A B B 25.47 The Macdonald criteria for the diagnosis of multiple sclerosis (2011)1 Clinical presentation2 Additional evidence required for diagnosis of MS Two or more attacks with either objective clinical evidence of at least 2 lesions or Objective clinical evidence of 1 attack with reasonable evidence (on clinical history) of at least 1 prior attack None Two or more attacks with objective clinical evidence of 1 lesion Dissemination in ‘space’ demonstrated by magnetic resonance imaging (MRI) ≥ 1 lesion in at least 2 of the MS-typical regions3 (multiple lesions in different sites) or Await further clinical attack at different anatomical site One attack with objective clinical evidence of ≥ 2 lesions Dissemination in ‘time’ demonstrated by evolving MRI showing combined enhancing (new) and non-enhancing (old) lesions or New T2 or enhancing lesion on repeat MRI or Await further (second) clinical attack at different anatomical site One attack with clinical evidence of only 1 lesion (clinically isolated syndrome) Dissemination in ‘space’ demonstrated by ≥ 1 T2 lesion in at least 2 MS-typical regions or Dissemination in ‘time’, demonstrated by simultaneous enhancing and non-enhancing lesions or New T2 or enhancing lesions on repeat MRI or Await further (second) clinical attack Insidious neurological progression suggestive of MS 1 year of progression plus 2 of the following: Evidence for dissemination in space with ≥ 1 T2 lesions in MS-typical regions Evidence for dissemination in space based on ≥ 2 lesions in the spinal cord Positive cerebrospinal fluid (evidence of oligoclonal band and/or elevated immunoglobulin G index) 1If the clinical presentation in the left-hand column is associated with the features in the right-hand column, the diagnosis is MS. If there is incomplete association, the diagnosis is ‘possible MS’. 2Assumes other possible causes for central nervous system inflammation (e.g. sarcoidosis, systemic lupus erythematosus) have been excluded. 3MS-typical regions = periventricular, juxtacortical, infratentorial, spinal cord. From Polman CH, Reingold SC, Branwell B, et al. Diagnostic criteria for multiple sclerosis. Ann Neurol 2011; 69:292–302.

1108 • NEUROLOGY Fig. 25.28 The progression of disability in fulminant, relapsing–remitting and progressive multiple sclerosis. Courtesy of Prof. D.A.S. Compston. Fulminant (< 10%) Relapsing– remitting (80%) Primary progressive (10–20%) Secondary progressive Disability Time Fig. 25.29 Investigations in a patient suspected of having multiple sclerosis. Exclude other structural disease and identify plaques of demyelination Image area of clinical involvement (magnetic resonance imaging, myelography) Demonstrate other sites of involvement Imaging (MRI) Visual evoked potentials Other evoked potentials Demonstrate inflammatory nature of lesion(s) Cerebrospinal fluid examination Cell count Protein electrophoresis (oligoclonal bands) Exclude other conditions Chest X-ray Serum angiotensin-converting enzyme Serum vitamin B12 Antinuclear antibodies Antiphospholipid antibodies 25.48 Clinical features of multiple sclerosis Common presentations of multiple sclerosis • Optic neuritis • Relapsing/remitting sensory symptoms • Subacute painless spinal cord lesion • Acute brainstem syndrome • Subacute loss of function of upper limb (dorsal column deficit) • 6th cranial nerve palsy Other symptoms and syndromes suggestive of central nervous system demyelination • Afferent pupillary defect and optic atrophy (previous optic neuritis) • Lhermitte’s symptom (tingling in spine or limbs on neck flexion) • Progressive non-compressive paraparesis • Partial Brown–Séquard syndrome (p. 1083) • Internuclear ophthalmoplegia with ataxia • Postural (‘rubral’, ‘Holmes’) tremor • Trigeminal neuralgia (p. 1096) under the age of 50 • Recurrent facial palsy appears only late in the disease, when loss of frontal lobe functions and impairment of memory are common. The prognosis for patients with MS is difficult to predict with confidence, especially early in the disease. Those with relapsing and remitting MS experience, on average, 1–2 relapses every 2 years, although this may decline with time. Approximately 5% of patients die within 5 years of disease onset, and slightly more have very good long-term outcome with little or no disability. Prognosis is good for patients with optic neuritis and only sensory relapses. Overall, about one-third of patients are disabled to the point of needing help with walking after 10 years, and this proportion rises to about half after 15 years. It would appear likely (though this is as yet unproven) that disease-modifying drugs will have an effect on long-term disability. Investigations There is no single diagnostic test that is definitive for MS and the results of investigation need to be combined with the clinical picture in order to make a diagnosis; MRI is the most important investigation (Fig. 25.29). MS mimics should be excluded (see below). Following the first clinical event (CIS), investigations may help prognosis by confirming the disseminated nature of the disease. MRI is the most sensitive technique for imaging lesions in brain and spinal cord (Fig. 25.30) and for excluding other causes that have provoked the neurological deficit. However, the MRI appearances in MS may be confused with those of small-vessel disease or cerebral vasculitis, and these diagnoses should be considered and excluded. Evoked potentials (visual, auditory or somatosensory) may detect clinically silent lesions but are rarely used nowadays with the advent of MRI. The CSF may show a lymphocytic pleocytosis in the acute phase and unique (i.e. absent from the serum) oligoclonal bands of IgG in 70–90% of patients between attacks. Oligoclonal bands are not specific for MS and denote only intrathecal inflammation, provided they are unique for the CSF. These can appear in other disorders, which should be excluded by examination and investigation. It is important to exclude other potentially treatable conditions, such as infection, vitamin B12 deficiency and spinal cord compression.

Neuro-inflammatory diseases • 1109

These drugs – available orally, as regular subcutaneous injections or as pulsed intravenous treatments – may be divided into two groups (Box 25.49). All DMTs have strict licensing criteria and are associated with a range of adverse effects, some occasionally fatal, especially the more effective drugs. Careful selection and counselling of patients are necessary and these drugs should be supervised by teams experienced in their use, as recommended in national guidelines. Clinical trials suggest that DMT options for primary and secondary progressive MS will be available in coming years. Clinical trials involving stem cells are ongoing. Special diets, including gluten-free regimens or linoleic acid supplements, and hyperbaric oxygen therapy are popular with patients but their efficacy has not been demonstrated. Treatment of symptoms, complications and disability Treatments for the complications of MS are summarised in Box 25.50. It is important to provide patients with a careful explanation of the nature of the disease and its outcome. When and if disability occurs, patients and their relatives need appropriate support. Specialist nurses working in a multidisciplinary team of health-care professionals are of great value in managing the chronic phase of the disease. Periods of physiotherapy and occupational therapy may improve functional capacity in those who become disabled, and guidance can be provided on the Management The management of MS involves four different strands: treatment of the acute episode, prevention of future relapses, treatment of complications, and management of the patient’s disability. The acute episode In a disabling exacerbation of MS, pulses of high-dose glucocorticoid, given either intravenously or orally over 3–5 days, will shorten the duration of the acute episode. Prolonged administration of glucocorticoids does not alter the long-term outcome and is associated with severe adverse effects; it should therefore be avoided. Pulses of glucocorticoids can be given up to three times in a year but use should be restricted to those individuals with significant function-threatening deficits. Prophylaxis to prevent glucocorticoid-induced osteoporosis (p. 1045) should be considered in patients requiring multiple courses of glucocorticoids. Disease-modifying treatment Until the 1990s, there were no effective disease-modifying treatments (DMTs) for MS; azathioprine showed some promise but this was offset by adverse effects and the drug was rarely used. The introduction of, initially, beta-interferons and glatiramer acetate paved the way for a new and exciting era of DMTs, which is still evolving. All reduce annual relapse rates and the number and size of lesions on MRI, and some may reduce disability. They are not indicated for treatment of early or pre-clinical MS. Fig. 25.30 Multiple sclerosis: demyelinating lesion in cervical spinal cord, high-signal T2 images (arrows). A Sagittal plane. B Axial plane. A B 25.49 Disease-modifying treatments in multiple sclerosis Treatment Route of administration/dosing Comment Moderate efficacy for less severe cases: average relapse rate reduction 30–50% Interferonbeta Alternate-day or weekly intramuscular or subcutaneous injection In widespread use for reducing relapse rate Glatiramer acetate Alternate-day subcutaneous injection Similar efficacy to interferon-beta Teriflunomide Daily oral May cause diarrhoea, alopecia, hepatotoxicity Highly teratogenic Dimethyl fumarate Daily oral May cause flushing and gastrointestinal disturbance Risk of PML Fingolimod Daily oral Superior efficacy to interferon-beta in randomised trials Cardiac conduction defects, especially with first dose High efficacy for severe cases: average relapse rate reduction

50% Alemtuzumab Intravenous infusion over two courses separated by 12 months; 5-day infusion initially, second course 3 days May precipitate autoimmune reactions, e.g. thyroid disease, ITP Natalizumab 4-weekly intravenous infusion Recently introduced; may be more effective than interferon-beta and glatiramer acetate Risk of PML (ITP = idiopathic thrombocytopenic purpura; PML = progressive multifocal leucoencephalopathy)

1110 • NEUROLOGY Investigations MRI shows multiple high-signal areas in a pattern similar to that of MS, although often with large confluent areas of abnormality. CSF may be normal or show an increase in protein and lymphocytes (occasionally > 100 × 106 cells/L). Oligoclonal bands may be found in the acute episode but, in contrast to MS, do not persist beyond clinical recovery. The clinical picture may be very similar to a first relapse of MS. Management The prognosis for acute disseminated encephalomyelitis is generally good, although occasionally it may be fatal (probably less than 10%). Treatment with high-dose intravenous methylprednisolone, using the same regimen as for a relapse of MS, is recommended. Transverse myelitis Transverse myelitis is an acute, usually monophasic, demyelinating disorder affecting the spinal cord. It is usually thought to be post-infectious in origin. It occurs at any age and presents with a subacute paraparesis with a sensory level, accompanied by severe pain in the neck or back at the onset. MRI should distinguish this from an external lesion affecting the spinal cord. CSF examination shows cellular pleocytosis, often with polymorphs at the onset. Oligoclonal bands are usually absent. Treatment is with high-dose intravenous methylprednisolone. The outcome is variable: one-third have static deficit, one-third go on to develop MS and one-third recover with no subsequent relapse. Some clinical features may suggest a higher risk of MS after transverse myelitis. Neuromyelitis optica Neuromyelitis optica (previously Devic’s disease) is the occurrence of transverse myelitis and bilateral optic neuritis. The disease has been recognised for many years, particularly in Asia. The majority of cases are associated with an antibody to a neuronal membrane channel, aquaporin 4. If changes are seen on brain MRI (this is variable), they are typically high-signal lesions restricted to periventricular regions. Spinal MRI scans show lesions that are typically longer than three spinal segments (unlike the shorter lesions of MS). Clinical deficits tend to recover less well than in MS, and the disease may be more aggressive with more frequent relapses. Treatment with glucocorticoids, azathioprine or cyclophosphamide, and/or plasmapheresis seems to be more effective than in MS. Paraneoplastic neurological disorders Neurological disease may occur with systemic malignant tumours in the absence of cerebral metastases. It is now recognised that, in the majority of these cases, antigen production in the body of the tumour leads to development of antibodies to parts of the CNS. Paraneoplastic conditions are increasingly recognised and the number of antibodies identified is also growing (Boxes 25.52 and 25.53). These syndromes are particularly associated with small-cell carcinoma of lung, ovarian tumours and lymphomas. Autoantibodies are found in the serum and/or CSF, and biopsy will show a lymphocytic infiltrate of the neural tissue affected. provision of aids at home, reducing handicap. Bladder care is particularly important. Urgency and frequency can be treated pharmacologically (see Box 25.25, p. 1094) but this may lead to a degree of retention with an attendant risk of infection. Urinary retention can be managed initially by intermittent urinary catheterisation (performed by the patient, if possible) but an in-dwelling catheter may become necessary. Sexual dysfunction is a frequent source of distress. Sildenafil or tadalafil helps impotence in men, and skilled counselling and prosthetic aids may be beneficial. Pregnancy does not increase the risk of progression of MS but relapses may occur post-partum (Box 25.51). Acute disseminated encephalomyelitis This is an acute monophasic demyelinating condition in which areas of perivenous demyelination are widely disseminated throughout the brain and spinal cord. The illness may arise spontaneously but often occurs a week or so after a viral infection, especially measles or chickenpox, or following vaccination, suggesting that it is immunologically mediated. Clinical features Headache, vomiting, pyrexia, delirium and meningism may be presenting features, often with focal or multifocal brain and spinal cord signs. Seizures or coma may occur. A minority of patients who recover have further episodes. 25.51 Multiple sclerosis in pregnancy • Counselling: provision of pre-conception counselling is best practice. • Relapse risk: endocrine effects on the immune system ensure that relapse risk drops during pregnancy. • Disease-modifying drugs: risk of teratogenicity means that all disease-modifying drugs should ideally be stopped 6–8 weeks before conception and recommenced after breastfeeding has stopped. • Post-partum relapse rate: rebound of immune system activity means that the highest risk of relapse is in the first year after delivery. 25.50 Treatment of complications in multiple sclerosis Spasticity • Physiotherapy • Baclofen (usually oral) • Dantrolene • Gabapentin • Sativex • Tizanidine • Intrathecal baclofen • Local (intramuscular) injection of botulinum toxin • Chemical neuronectomy Dysaesthesia • Carbamazepine • Gabapentin • Phenytoin • Amitriptyline Bladder symptoms • See Box 25.25 (p. 1094) Fatigue • Amantadine • Modafinil • Amitriptyline Erectile dysfunction • Sildenafil 50–100 mg/day • Tadalafil

Neurodegenerative diseases • 1111

disease has been proven, rather than when it is suspected. The CSF often shows an increased protein and lymphocyte count with oligoclonal bands. Treatment is directed at the primary tumour. Occasionally, successful therapy of the tumour is associated with improvement of the paraneoplastic syndrome. Some improvement may occur following administration of intravenous immunoglobulin. Neurodegenerative diseases While MS is the most common cause of disability in young people in the UK, vascular and neurodegenerative diseases are increasingly important in later life. The neurodegenerative diseases are united in having a pathological process that leads to specific neuronal death, causing relentlessly progressive symptoms, with Clinical features Clinical presentations are summarised in Boxes 25.52 and 25.53. In most instances, the neurological condition progresses quite rapidly over a few months, preceding the malignant disease in around half of cases. The range of clinical patterns is so wide that paraneoplastic disease should be considered in the diagnosis of any unusual progressive neurological syndrome. The paraneoplastic disorders of the peripheral nervous system particularly affect the synaptic cleft (p. 1065). Investigations and management The presence of characteristic autoantibodies in the context of a suspicious clinical picture may be diagnostic. The causative tumour may be very small and therefore CT of the chest or abdomen or PET scanning may be necessary to find it. These investigations should be pursued only when paraneoplastic 25.52 Paraneoplastic disorders of the central nervous system Clinical presentation Associated tumour Antibodies demonstrated Limbic encephalitis SCLC Anti-Hu, anti-CV2, PCA-2, anti-VGKC, anti-Ma1, anti-amphiphysin, anti-Ri, ANNA-3, anti-VGCC, anti-Zic4, anti-GluR1/2, anti-GABAR Testicular, breast Anti-Ma2, anti-GluR1/2 Thymoma Anti-VGKC, anti-CV2, anti-GluR1/2 Ovarian/testicular teratoma Anti-NMDAR Myelopathy SCLC, thymoma, others Anti-CV2, anti-amphiphysin, anti-aquaporin Motor neuron disease SCLC, others Anti-Hu Stiff person syndrome Breast, SCLC, thymoma, others Anti-amphiphysin, anti-Ri, anti-GAD, anti-GlyR Cerebellar degeneration Breast, ovarian, others Anti-Yo, anti-Ma1, anti-Ri SCLC, others Anti-Hu, anti-CV2, PCA-2, ANNA-3, anti-amphiphysin, anti-VGCC, anti-Ri, anti-Zic4, anti-GAD Lymphoma Anti-Tr, anti-mGluR1 Multifocal encephalomyelitis SCLC, thymoma Anti-Hu, anti-CV2, anti-VGKC, anti-Ma1, anti-amphiphysin, anti-Ri, ANNA-3 Opsoclonus–myoclonus Breast, ovarian Anti-Ri, anti-Yo, anti-amphiphysin SCLC Anti Hu, anti-Ri, anti-CV2, anti-amphiphysin, anti-VGCC Neuroblastoma Anti-Hu Testicular Anti-Ma1/2, anti-CV2 Extrapyramidal encephalitis SCLC, thymoma, testicular Anti-CV2, anti-Hu, anti-VGKC, anti-Ma Optic neuritis SCLC Anti-CV2, anti-aquaporin Retinal degeneration SCLC Anti-recoverin (ANNA = anti-neuronal nucleolar antibody; GABAR = GABA receptor; GAD = glutamic acid decarboxylase; GluR = glutamate receptor; GlyR = glycine receptor; NMDAR = N-methyl-D-aspartate receptor; PCA = Purkinje cell antibody; SCLC = small-cell lung cancer; VGCC = voltage-gated calcium channel; VGKC = voltage-gated potassium channel) 25.53 Paraneoplastic disorders of the peripheral nervous system Clinical presentation Associated tumour Antibodies demonstrated Neuromyotonia Thymoma, SCLC, others Anti-VGKC Myasthenia gravis Thymoma Anti-Achr, anti-MuSK Sensorimotor polyneuropathy Lymphoma, SCLC, others Anti-Hu, anti-CV2, ANNA-3, anti-Ma1, anti-amphiphysin Lambert–Eaton syndrome SCLC Anti-VGCC Motor neuropathy Lymphoma, SCLC, others Anti-Hu, anti-Yo, anti-CV2 Sensory neuropathy Lymphoma, SCLC, others Anti-Hu, anti-Yo, anti-CV2 Polymyositis/dermatomyositis Lung, breast Anti-Jo1 (MuSK = muscle-specific kinase; for other abbreviations, see Box 25.52)

1112 • NEUROLOGY be due to an environmental toxin but none has been convincingly identified. The pathological hallmarks of PD are depletion of the pigmented dopaminergic neurons in the substantia nigra and the presence of α-synuclein and other protein inclusions in nigral cells (Lewy bodies; Fig. 25.31). It is thought that environmental or genetic factors alter the α-synuclein protein, rendering it toxic and leading to Lewy body formation within the nigral cells. Lewy bodies are also found in the basal ganglia, brainstem and cortex, and increase with disease progression. PD is recognised as a synucleinopathy alongside multiple system atrophy and dementia with Lewy bodies. The loss of dopaminergic neurotransmission is responsible for many of the clinical features. Clinical features Non-motor symptoms, including reduction in sense of smell (hyposmia), anxiety/depression, constipation and REM sleep behavioural disturbance (RBD), may precede the development of typical motor features by many years but patients rarely present at this stage. The motor symptoms are almost always initially asymmetrical. The hallmark is bradykinesia, leading to classic symptoms such as increasingly small handwriting (‘micrographia’), difficulty tying shoelaces or buttoning clothes, and difficulty rolling over in bed. Tremor is an early feature but may not be present in at least 20% of people with PD. It is typically a unilateral rest tremor (p. 1085) affecting limbs, jaw and chin but not the head. In some patients, tremor remains the dominant symptom for many years. Rigidity causes stiffness and a flexed posture. Although postural righting reflexes are impaired early on in the disease, falls tend not to occur until later. As the disease advances, speech becomes softer and indistinct. There are a number of abnormalities on neurological examination (Box 25.55). Although features are initially unilateral, gradual bilateral involvement evolves with time. Cognition is spared in early disease; if impaired, it should trigger consideration of alternative diagnoses, such as dementia with Lewy bodies. Non-motor symptoms While non-motor symptoms may precede the onset of more typical symptoms by many years, for most patients these features become increasingly common and disabling as PD progresses. Cognitive impairment, including dementia, is the symptom most likely to impair quality of life for patients and their carers. Estimates of dementia frequency range from 30% to 80%, depending on definitions and length of follow-up. Other distressing Fig. 25.31 Parkinson’s disease. High power (× 400) view of substantia nigra of a patient with Parkinson’s disease showing classical Lewy body (haematoxylin and eosin). Courtesy of Dr J. Xuereb. 25.54 Causes of parkinsonism Idiopathic Parkinson’s disease (at least 80% of parkinsonism) Cerebrovascular disease Drugs and toxins • Antipsychotic drugs (older and ‘atypical’) • Metoclopramide, prochlorperazine • Tetrabenazine • Sodium valproate • Lithium • Manganese • MPTP Other degenerative diseases • Dementia with Lewy bodies • Progressive supranuclear palsy • Multiple system atrophy • Corticobasal degeneration • Alzheimer’s disease Genetic • Huntington’s disease • Fragile X tremor ataxia syndrome • Dopa-responsive dystonia • Spinocerebellar ataxias (particularly SCA 3) • Wilson’s disease Anoxic brain injury (MPTP = methyl-phenyl-tetrahydropyridine) incidence rising with age. The causes are not yet known, although genetic influences are important. Alzheimer’s disease (p. 1192) and Parkinson’s disease are the most common. Movement disorders Movement disorders present with a wide range of symptoms. They may be genetic or acquired, and the most important is Parkinson’s disease. Most movement disorders are categorised clinically, with few confirmatory investigations available other than for those with a known gene abnormality. Idiopathic Parkinson’s disease Parkinsonism is a clinical syndrome characterised primarily by bradykinesia (p. 1084), with associated increased tone (rigidity), tremor and loss of postural reflexes. There are many causes (Box 25.54) but the most common is Parkinson’s disease (PD). PD has an annual incidence of about 18/100 000 in the UK and a prevalence of about 180/100 000. Age has a critical influence on incidence and prevalence, the latter rising to 300–500/100 000 after 80 years of age. Average age of onset is about 60 years and fewer than 5% of patients present under the age of 40. Genetic factors are increasingly recognised and several single genes causing parkinsonism have been identified, although they account for a very small proportion of cases overall. Having a first-degree relative with PD confers a 2–3 times increased risk of developing the disorder. It is progressive and incurable, with a variable prognosis. While motor symptoms are the most common presenting features, non-motor symptoms (particularly cognitive impairment, depression and anxiety) become increasingly prominent as the disease progresses, and significantly reduce quality of life. Pathophysiology Although mutations in several genes have been identified in a few cases, in most patients the cause remains unknown. The discovery that methyl-phenyl-tetrahydropyridine (MPTP) caused severe parkinsonism in young drug users suggested that PD might

Neurodegenerative diseases • 1113

are neuroprotective. Levodopa (LD) remains the most effective treatment available but other agents include dopamine agonists, anticholinergics, inhibitors of monoamine oxidase (MAOI)-B and catechol-O-methyl-transferase (COMT), and amantadine. Debate continues about when and what treatment should be started. In general, most specialists recommend initiating treatment when symptoms are impacting on everyday life although some favour treatment as soon as the diagnosis is made. Whether it is best to start with LD, a dopamine agonist or MAOI-B remains unclear but most accept that the most effective, best-tolerated and cheapest drug is LD. Many motor symptoms, such as tremor, freezing, falling, head-drop and abnormal flexion, are quite resistant to treatment. Some non-motor symptoms, such as anxiety or depression, may respond to drug or non-drug treatments. In the UK, rivastigmine is licensed for use in PD-associated dementia, although its effect is modest. Many other non-motor symptoms are resistant to treatment. Drugs for PD should not be stopped abruptly, as this can precipitate malignant hyperthermia. Levodopa Levodopa is the precursor to dopamine. When administered orally, more than 90% is decarboxylated to dopamine peripherally in the gastrointestinal tract and blood vessels, and only a small proportion reaches the brain. This peripheral conversion is responsible for the high frequency of adverse effects. To avoid this, LD is combined with a dopa decarboxylase inhibitor (DDI); the inhibitor does not cross the blood–brain barrier, thus avoiding unwanted decarboxylation-blocking in the brain. Two DDIs, carbidopa and benserazide, are available as combination preparations with LD (Sinemet and Madopar, respectively). LD is most effective for relieving akinesia and rigidity; tremor response is often less satisfactory and it has no effect on many motor (posture, freezing) and non-motor symptoms. Failure of akinesia/rigidity to respond to LD (1000 mg/day) should prompt reconsideration of the diagnosis. Although controlled-release versions of LD exist, these are usually best reserved for use overnight, as their variable bioavailability makes them difficult to use throughout the day. Madopar is also available as a dispersible tablet for more rapid-onset effect. Adverse effects include postural hypotension, nausea and vomiting, which may be offset by domperidone. LD may exacerbate or trigger hallucinations, and abnormal LD-seeking behaviour (dopamine dysregulation syndrome), in which the patient takes excessive doses of LD, may occur uncommonly. As PD progresses, the response to LD becomes less predictable in many patients, leading to motor fluctuations. This end-of-dose deterioration is due to progressive loss of dopamine storage capacity by dwindling numbers of striatonigral neurons. 25.55 Physical signs in Parkinson’s disease General • Expressionless face (hypomimia) • Soft, rapid, indistinct speech (dysphonia) • Flexed (stooped) posture • Impaired postural reflexes Gait • Slow to start walking (failure of gait ignition) • Rapid, short stride length, tendency to shorten (festination) • Reduction of arm swing • Impaired balance on turning Tremor Resting (3–4 Hz, moderate amplitude): most common • Asymmetric, usually first in arm/hand (‘pill rolling’) • May affect legs, jaw and chin but not head • Intermittent, present at rest, often briefly abolished by movement of limb, exacerbated by walking Postural (6–8 Hz, moderate amplitude) • Present immediately on stretching out arms Re-emergent tremor (3–4 Hz, moderate amplitude) • Initially no tremor on stretching arms out, rest tremor re-emerges after a few seconds Rigidity • Cogwheel type, mostly upper limbs (due to tremor superimposed on rigidity) • Lead pipe type Akinesia (fundamental feature) • Slowness of movement • Fatiguing and decrease in size of repetitive movements Normal findings (if abnormal, consider other causes) • Power, deep tendon reflexes, plantar responses • Eye movements • Sensory and cerebellar examination non-motor symptoms include neuropsychiatric features (anxiety, depression, apathy, hallucinosis/psychosis), sleep disturbance and hypersomnolence, fatigue, pain, sphincter disturbance and constipation, sexual problems (erectile failure, loss of libido or hypersexuality), drooling and weight loss. Investigations The diagnosis is clinical. Structural imaging (CT or MRI) is usually normal for age and thus rarely helpful, although it may support a suspected vascular cause of parkinsonism. Functional dopaminergic imaging (SPECT or PET) is abnormal, even in the early stages (Fig. 25.32), but does not differentiate between the different forms of degenerative parkinsonism (see Box 25.54) and so is not specific for PD. In younger patients, specific investigations may be appropriate (e.g. exclusion of Huntington’s or Wilson’s diseases). Some patients with family histories may wish to consider genetic testing, although the role of genetic counselling is uncertain at present. Management Drug therapy Drug treatment for PD remains symptomatic rather than curative, and there is no evidence that any of the currently available drugs Fig. 25.32 Imaging in Parkinson’s disease. A Single photon emission computed tomography (SPECT) in Parkinson’s disease showing reduced dopamine activity in the basal ganglia. B Normal. A B

1114 • NEUROLOGY lack of efficacy (apart from an effect on tremor sometimes) and adverse effects, including dry mouth, blurred vision, constipation, urinary retention, delirium and hallucinosis, as well as long-term concerns regarding cognitive impairment. Several anticholinergics are available, including trihexyphenidyl (benzhexol) and orphenadrine. Surgery Destructive neurosurgery was commonly used before the introduction of LD. In the last 20 years, stereotactic surgery has emerged and most commonly involves deep brain stimulation (DBS), rather than the destructive approach of previous eras. Various targets have been identified, including the thalamus (only effective for tremor), globus pallidus and subthalamic nucleus. DBS is usually reserved for individuals with medically refractory tremor or motor fluctuations, and careful patient selection is vital to success. Intracranial delivery of fetal grafts or specific growth factors remains experimental. Physiotherapy, occupational therapy and speech therapy Patients at all stages of PD benefit from physiotherapy, which helps reduce rigidity and corrects abnormal posture. Occupational therapists can provide equipment to help overcome functional limitations, such as rails for stairs and the toilet, and bathing equipment. Speech therapy can help where dysarthria and dysphonia interfere with communication, and advice may also be provided to those with dysphagia. As with many complex neurological disorders, patients with PD should ideally be managed by a multidisciplinary team, including PD specialist nurses. Other parkinsonian syndromes Cerebrovascular disease and drug-induced parkinsonism are the most common alternative causes of parkinsonism (see Box 25.54). There are several degenerative conditions that cause parkinsonism, including multiple system atrophy, progressive supranuclear palsy and corticobasal degeneration. They typically have a more rapid progression than PD and tend to be resistant to treatment with LD. They are defined pathologically and identification during life is difficult. There are other conditions that may rarely manifest as parkinsonism, including Huntington’s and Wilson’s diseases. Multiple system atrophy Multiple system atrophy (MSA) is characterised by parkinsonism, autonomic failure and cerebellar symptoms, with either parkinsonism (MSA-P) or cerebellar features (MSA-C) predominating. It is much less common than PD, with a prevalence of about 4/100 000. Although early distinction between PD and MSA-P may be difficult, early falls, postural instability and lack of response to LD are clues. The pathological hallmark is α-synuclein-containing glial cytoplasmic inclusions found in the basal ganglia, cerebellum and motor cortex. Management is symptomatic and the prognosis is less good than for PD, with mean survival from symptom onset of fewer than 10 years and early disability. Cognition is usually unaffected. Progressive supranuclear palsy Progressive supranuclear palsy (PSP) presents with symmetrical parkinsonism, cognitive impairment, early falls and bulbar symptoms. The characteristic eye movement disorder, with slowed vertical saccades leading to impairment of up- and downgaze, may take years to emerge. PSP has different pathological LD-induced involuntary movements (dyskinesia) may occur as a peak-dose phenomenon or as a biphasic phenomenon (occurring during both the build-up and wearing-off phases). More complex fluctuations present as sudden, unpredictable changes in response, in which periods of parkinsonism (‘off’ phases) alternate with improved mobility but with dyskinesias (‘on’ phases). Motor complication management is difficult; wearing-off effects may respond to increased dose or frequency of LD or the addition of a COMT inhibitor (see below). More complex fluctuations may be improved by the addition of dopamine agonists (including continuous infusion of apomorphine), use of intraintestinal LD via a percutaneous endoscopic jejunostomy, or deep brain stimulator implantation. Dopamine receptor agonists Originally introduced in the hope of delaying the initiation of LD and thus delaying motor complications, several dopamine agonists are available, and may be delivered orally, transdermally or subcutaneously (Box 25.56). The ergot-derived agonists are no longer recommended because of rare but serious fibrotic effects. With the exception of apomorphine, all the agonists are considerably less effective than LD in relieving parkinsonism, have more adverse effects (nausea, vomiting, disorientation and hallucinations, impulse control disorders) and are more expensive. Their role in the management of PD (monotherapy or adjunctive) remains uncertain, and evidence suggests that their usefulness as initial monotherapy is short-lasting. MAOI-B inhibitors Monoamine oxidase type B facilitates breakdown of excess dopamine in the synapse. Two inhibitors are used in PD: selegiline and rasagiline. The effects of both are modest, although usually well tolerated. Neither is neuroprotective, despite initial hopes. COMT inhibitors Catechol-O-methyl-transferase (along with dopa decarboxylase) is involved in peripheral breakdown of LD. Two inhibitors are available: entacapone and tolcapone (which also inhibits central COMT). Entacapone has a modest effect and is most useful for early wearing-off. It is available either as a single tablet taken with each LD/DDI dose, or as a combination tablet with LD and DDI. The more potent tolcapone is less used because of rare but serious hepatotoxicity. Amantadine This has a mild, usually short-lived effect on bradykinesia and is rarely used unless patients are unable to tolerate other drugs. It is more commonly employed as a treatment for LD-induced dyskinesias, although again benefit is modest and short-lived. Adverse effects include livedo reticularis, peripheral oedema, delirium and other anticholinergic effects. Anticholinergic drugs These were the main treatment for PD prior to the introduction of LD. Their role now is limited by Oral unless otherwise stated. 25.56 Dopamine agonists Ergot-derived • Bromocriptine • Lisuride • Pergolide • Cabergoline Non-ergot-derived • Ropinirole • Pramipexole • Rotigotine (transdermal patch) • Apomorphine (subcutaneous)

Neurodegenerative diseases • 1115

is wide (Boxes 25.57 and 25.58), and diagnosis is guided by age of onset, evolution and clinical features. A significant proportion of cases remain idiopathic despite investigation. The hereditary ataxias are a group of inherited disorders in which degenerative changes occur to varying extents in the cerebellum, brainstem, pyramidal tracts, spinocerebellar tracts and optic and peripheral nerves, and influence the clinical manifestations. Onset ranges from infancy to adulthood, with recessive, sex-linked or dominant inheritance (see Box 25.58). While the genetic abnormality has been identified for some, allowing diagnostic testing, this is not currently the case for many of the hereditary ataxias. Tremor disorders Tremor (p. 1085) is a feature of many disorders but the most important clinical syndromes are PD, essential tremor, druginduced tremors (Box 25.59) and functional (psychogenic) tremors. Essential tremor This has a prevalence of about 300/100 000 and may display a dominant pattern of inheritance, although no genes have thus far been identified. It may present at any age with a bilateral arm tremor (8–10 Hz), rarely at rest but typical with movement. The head and voice may be involved. The tremor improves in about 50% of patients with small amounts of alcohol. There are no specific tests and essential tremor should be distinguished from other tremor syndromes, including dystonic tremor. Beta-blockers and primidone are sometimes helpful, and DBS of the thalamus is an effective treatment for severe cases. features, being associated with abnormal accumulation of tau (τ) proteins and degeneration of the substantia nigra, subthalamic nucleus and mid-brain. It is therefore a tauopathy rather than synucleinopathy. The prevalence is about 5/100 000, with average survival similar to that in MSA. There is no treatment, and the parkinsonism usually does not respond to LD. Corticobasal degeneration Corticobasal degeneration (CBD) is less common than MSA or PSP, and the clinical manifestations are variable, including parkinsonism, dystonia, myoclonus and ‘alien limb’ phenomenon, whereby a limb (usually upper) moves about or interferes with the other limb without apparent conscious control. Cortical symptoms, including dementia and especially apraxia, are common and may be the only features in some cases. A number of other diseases may present with a corticobasal syndrome, including other dementias. CBD is a tauopathy with widespread deposition throughout the brain, and has similar survival rates to MSA and PSP. Wilson’s disease This is an autosomal recessive disorder resulting from mutation in the ATP7B gene, causing a defect of copper metabolism (p. 896). It is a treatable cause of various movement disorders, including tremor, dystonia, parkinsonism and ataxia; psychiatric symptoms may also occur. Wilson’s disease should always be excluded in patients under the age of 50 presenting with any movement disorder. Huntington’s disease Huntington’s disease (HD) is an autosomal dominant disorder, presenting in adults usually but occasionally in children. It is due to expansion of a trinucleotide CAG repeat in the Huntingtin gene on chromosome 4 (p. 43). The disease frequently demonstrates the phenomenon of anticipation, in which there is a younger age at onset as the disease is passed through generations, due to progressive expansion of the repeat. The prevalence is about 4–8/100 000. Clinical features HD typically presents with a progressive behavioural disturbance, abnormal movements (usually chorea), and cognitive impairment leading to dementia. Onset under 18 years is rare but patients may then present with parkinsonism rather than chorea (the ‘Westphal variant’). There is always a family history, although this may be concealed. Investigations and management The diagnosis is confirmed by genetic testing; pre-symptomatic testing for other family members is available but must be preceded by appropriate counselling (p. 59). Brain imaging may show caudate atrophy but is not a reliable test. There are a number of HD mimics. Management is symptomatic. The chorea may respond to neuroleptics such as risperidone or sulpiride, or tetrabenazine. Depression and anxiety are common and may be helped by medication. Ataxias The ataxias are a heterogeneous group of inherited and acquired disorders, presenting either with pure ataxia or in association with other neurological and non-neurological features. The differential 25.57 Causes of acquired ataxia Structural • Brain tumour • Brain abscess Toxic • Drugs: lithium, phenytoin, amiodarone, toluene, 5-fluorouracil, cytosine arabinoside • Alcohol • Heavy metals/chemicals: mercury, lead, thallium Infection/post-infectious • HIV • Varicella zoster • Whipple’s disease • Miller Fisher syndrome (p. 1140) Degenerative • Multiple system atrophy • Sporadic Creutzfeldt–Jakob disease • Idiopathic (or sporadic) late-onset cerebellar ataxia Inflammatory/immune-mediated • Multiple sclerosis • Gluten ataxia (coeliac disease) • Paraneoplastic ataxia • Hashimoto encephalopathy Metabolic • Vitamin B1 or E deficiency • Hypothyroidism • Hypoparathyroidism Vascular • Stroke (ischaemic or haemorrhagic) • Vascular malformations • Superficial siderosis

1116 • NEUROLOGY arterial loop irritating the 7th nerve just outside the pons. It may, however, be symptomatic and secondary to structural lesions. Drug treatment is not effective but injections of botulinum toxin into affected muscles help, although these usually have to be repeated every 3 months or so. In refractory cases, microvascular decompression may be considered. Motor neuron disease Motor neuron disease (MND) is a neurodegenerative condition caused by loss of upper and lower motor neurons in the spinal cord, cranial nerve nuclei and motor cortex. Annual incidence is about 2/100 000, with a prevalence of about 7/100 000. Most cases are sporadic but 10% of cases are familial. Abnormalities in the superoxide dismutase (SOD1) gene account for about 20% of such cases, and an expanded repeat sequence in the C9orf72 gene on chromosome 9 is associated with MND and frontotemporal dementia. The most common form of MND (Fig. 25.33) is amyotrophic lateral sclerosis (ALS), and many use the terms MND and ALS interchangeably. ALS is characterised by a combination of upper and lower motor neuron signs; there are rarer, pure lower (progressive muscular atrophy) or upper (progressive lateral sclerosis) motor neuron variants of MND. The average age of onset is 65, with 10% presenting before 45 years. Clinical features Diagnosis can be difficult and is often delayed. MND typically presents focally, either with limb onset (e.g. foot drop or loss of manual dexterity) or with bulbar symptoms (dysarthria, swallowing difficulty); respiratory onset is rare but type II respiratory failure is a common terminal event. Sensory, autonomic and visual symptoms do not occur, although cramp is common (Box 25.60). Examination reveals a combination of lower and upper Dystonia Dystonia is characterised by a focal increase in tone affecting muscles in the limbs or trunk. It may be a feature of a number of neurological conditions (PD, Wilson’s disease), or occur secondary to brain damage (trauma, stroke) or drugs (tardive syndromes). Dystonia also occurs as a primary disorder. With childhood onset the cause is usually genetic and dystonia is generalised, but adult onset is usually focal; examples include a twisted neck (torticollis), repetitive blinking (blepharospasm) or tremor. Task-specific symptoms (e.g. writer’s cramp, musician’s dystonia) are often dystonic. Treatment is difficult but botulinum toxin injections or DBS may be useful. Hemifacial spasm This usually presents after middle age with intermittent twitching around one eye, spreading ipsilaterally to other facial muscles. The spasms are exacerbated by talking, eating and stress. Hemifacial spasm is usually idiopathic, similar to trigeminal neuralgia; it has been suggested that it may be due to an aberrant Drugs causing parkinsonism and associated tremor are listed in Box 25.54. 25.59 Drug-induced tremor (usually postural) • β-agonists (e.g. salbutamol) • Theophylline • Sodium valproate • Thyroxine • Lithium • Tricyclic antidepressants • Recreational drugs (e.g. amphetamines) • Alcohol • Caffeine 25.58 Inherited ataxias Inheritance pattern Age of onset Clinical features Autosomal dominant Episodic ataxias Childhood and early adulthood Brief episodes of ataxia, sometimes induced by stress or startle. May develop progressive ataxia Spinocerebellar ataxias (SCAs) Childhood to middle age Over 30 subtypes identified thus far. Progressive ataxia, sometimes associated with other features, including retinitis pigmentosa, pyramidal tract abnormalities, peripheral neuropathy and cognitive deficits Dentato-rubro-pallidoluysian atrophy (DRPLA) Childhood to middle age Children present with myoclonic epilepsy and progressive ataxia. Adults have progressive ataxia with psychiatric features, dementia and choreoathetosis Autosomal recessive Friedreich’s ataxia Childhood/adolescence (late onset possible) Ataxia, nystagmus, dysarthria, spasticity, areflexia, proprioceptive impairment, diabetes mellitus, optic atrophy, cardiac abnormalities. Usually chair-bound Ataxia telangiectasia Childhood Progressive ataxia, athetosis, telangiectasia on conjunctivae, impaired DNA repair, immune deficiency, tendency to malignancies Abetalipoproteinaemia Childhood Steatorrhoea, sensorimotor neuropathy, retinitis pigmentosa, malabsorption of vitamins A, D, E and K Hereditary ataxia with vitamin E deficiency < 20 years Similar to Friedreich’s ataxia, visual loss or retinitis pigmentosa, chorea Others Usually young onset Numerous, with genes identified only in some X-linked Fragile X tremor ataxia syndrome

50 years Tremor, ataxia, parkinsonism, autonomic failure, cognitive impairment and dementia Adrenoleukodystrophy Childhood to adult Impaired adrenal and cognitive function, sometimes spastic paraparesis Mitochondrial disease Various Ataxia features in several mitochondrial diseases, including Kearns–Sayre syndrome, MELAS, MERRF, Leigh’s syndrome (p. 49) (MELAS = mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes; MERRF = myoclonic epilepsy with ragged red fibres)

Infections of the nervous system • 1117

tests are usually normal, other than a mildly raised creatine kinase. Sensory and motor nerve conduction studies are normal but there may be reduction in amplitude of motor action potentials due to axonal loss. EMG will usually confirm the typical features of widespread denervation and re-innervation. Spinal fluid analysis is not usually necessary. Genetic testing is increasing in importance, with mutations found in SOD1, FUS, TARDBP and C9orf72 that may help predict risk and phenotype of disease in those with a family history of MND. Management Patients should be managed within a multidisciplinary service, including physiotherapists, speech and occupational therapists, dietitians, ventilatory and feeding support, and palliative care teams, with neurological and respiratory input. Riluzole, a glutamate release antagonist, is licensed for ALS but has only a modest effect, prolonging median survival by about 2–3 months. Non-invasive ventilation significantly prolongs survival and improves or maintains quality of life in people with ALS. Survival and some measures of quality of life are significantly improved in the subgroup of people with better baseline bulbar function but not in those with severe bulbar impairment. Feeding by percutaneous gastrostomy may improve quality of life and prolong survival, even when done at a late stage. Rapid access to palliative care teams is essential for patients as they enter the terminal stages of MND. Spinal muscular atrophy This is a group of genetically determined disorders affecting spinal and cranial lower motor neurons, characterised by proximal and distal wasting, fasciculation and weakness of muscles. Involvement is usually symmetrical but occasional localised forms occur. With the exception of the infantile form, progression is slow and the prognosis better than for MND. Infections of the nervous system The clinical features of nervous system infections depend on the location of the infection (the meninges or the parenchyma of the brain and spinal cord), the causative organism (virus, bacterium, 25.60 Clinical features of motor neuron disease Onset • Usually after the age of 50 years • Very uncommon before the age of 30 years • Affects males more commonly than females Symptoms • Limb muscle weakness, cramps, occasionally fasciculation • Disturbance of speech/swallowing (dysarthria/dysphagia) • Cognitive and behavioural features common (similar to frontotemporal dementia) Signs • Wasting and fasciculation of muscles • Weakness of muscles of limbs, tongue, face and palate • Pyramidal tract involvement, causing spasticity, exaggerated tendon reflexes, extensor plantar responses • External ocular muscles and sphincters usually remain intact • No objective sensory deficit • Evidence of cognitive impairment with frontotemporal dominance Course • Symptoms often begin focally in one part and spread gradually but relentlessly to become widespread Fig. 25.33 Patterns of involvement in motor neuron disease. (LMN = lower motor neuron; UMN = upper motor neuron) Motor neuron disease Primary lateral sclerosis Progressive muscular atrophy Predominantly LMN Weakness and wasting of distal limb muscles initially Fasciculation Tendon reflexes may be present Mixed LMN and UMN Distal and proximal muscle wasting and weakness Fasciculation Spasticity, exaggerated reflexes, extensor plantars Bulbar and pseudobulbar palsy follow eventually Pyramidal tract features may predominate Predominantly UMN Spasticity–few lower motor neuron signs Gradual progression Predominantly cranial nerves Early involvement of tongue, palate and pharyngeal muscles Dysarthria/dysphagia Wasting and fasciculation of tongue Pyramidal signs may be present Progressive bulbar palsy Amyotrophic lateral sclerosis motor neuron signs (e.g. brisk reflexes in wasted, fasciculating muscles) without sensory involvement (Fig. 25.33). Cognitive impairment is under-recognised in MND: up to 50% will have a mainly executive impairment on formal testing, and around 10% develop a frontotemporal dementia (FTD). About 10% of patients presenting with FTD will develop ALS within a few years of dementia onset. Even with treatment, MND is relentlessly progressive, but median survival is improved with specialist follow-up offering non-invasive ventilation, feeding measures and access to pharmacological treatment. Investigations Clinical features are often typical but alternative diagnoses should be excluded. Exclusion of treatable causes, such as immunemediated multifocal motor neuropathy with conduction block (p. 1140) and cervical myeloradiculopathy, is essential. Blood

1118 • NEUROLOGY Where specific immunisation is not employed, the mumps virus is a common cause. Clinical features Viral meningitis occurs mainly in children or young adults, with acute onset of headache and irritability and the rapid development of meningism. The headache is usually the most severe feature. There may be a high pyrexia but focal neurological signs are rare. Investigations The diagnosis is made by lumbar puncture. CSF usually contains an excess of lymphocytes. While glucose and protein levels are commonly normal, the latter may be raised. It is important to verify that the patient has not received antibiotics (for whatever cause) prior to the lumbar puncture, as CSF lymphocytosis can also be found in partially treated bacterial meningitis. Management There is no specific treatment and the condition is usually benign and self-limiting. The patient should be treated symptomatically in a quiet environment. Recovery usually occurs within days, although a lymphocytic pleocytosis may persist in the CSF. Meningitis may also occur as a complication of a systemic viral infection such as mumps, measles, infectious mononucleosis, herpes zoster and hepatitis. Whatever the virus, complete recovery without specific therapy is the rule. Bacterial meningitis Many bacteria can cause meningitis but geographical patterns vary, as does age-related sensitivity (Box 25.63). In the ‘meningitis belt’ of sub-Saharan Africa, drought and dust storms are often associated with meningococcal outbreaks (Harmattan meningitis). Bacterial meningitis is usually part of a bacteraemic illness, although direct spread from an adjacent focus of infection in the ear, skull fracture or sinus can be causative. Antibiotics have rendered this less common but mortality and morbidity remain fungus or parasite), and whether the infection is acute or chronic. The major infections of the nervous system are listed in Box 25.61. The frequency of these varies geographically. Helminthic infections, such as cysticercosis and hydatid disease, and protozoal infections are described in Chapter 11. Meningitis Acute infection of the meninges presents with a characteristic combination of pyrexia, headache and meningism. Meningism consists of headache, photophobia and stiffness of the neck, often accompanied by other signs of meningeal irritation, including Kernig’s sign (extension at the knee with the hip joint flexed causes spasm in the hamstring muscles) and Brudzinski’s sign (passive flexion of the neck causes flexion of the hips and knees). Meningism is not specific to meningitis and can occur in patients with subarachnoid haemorrhage. The severity of clinical features varies with the causative organism, as does the presence of other features such as a rash. Abnormalities in the CSF (see Box 25.6, p. 1078) are important in distinguishing the cause of meningitis. Causes of meningitis are listed in Box 25.62. Viral meningitis Viruses are the most common cause of meningitis, usually resulting in a benign and self-limiting illness requiring no specific therapy. It is much less serious than bacterial meningitis unless there is associated encephalitis. A number of viruses can cause meningitis (see Box 25.62), the most common being enteroviruses. 25.62 Causes of meningitis Infective Bacteria (see Box 25.63) Viruses • Enteroviruses (echo, Coxsackie, polio) • Mumps • Influenza • Herpes simplex • Varicella zoster • Epstein–Barr • HIV • Lymphocytic choriomeningitis • Mollaret’s meningitis (herpes simplex virus type 2) Protozoa and parasites • Cysticerci • Amoeba Fungi • Cryptococcus neoformans • Candida • Histoplasma • Blastomyces • Coccidioides • Sporothrix Non-infective (‘sterile’) Malignant disease • Breast cancer • Bronchial cancer • Leukaemia • Lymphoma Inflammatory disease (may be recurrent) • Sarcoidosis • Systemic lupus erythematosus • Behçet’s disease 25.61 Infections of the nervous system Bacterial infections • Meningitis • Suppurative encephalitis • Brain abscess • Paravertebral (epidural) abscess • Tuberculosis (p. 588) • Neurosyphilis • Leprosy (Hansen’s disease) (peripheral nerves)* • Diphtheria (peripheral nerves)* • Tetanus (motor cells) Viral infections • Meningitis • Encephalitis • Transverse myelitis • Progressive multifocal leucoencephalopathy • Poliomyelitis • Subacute sclerosing panencephalitis (late sequel) • Rabies • HIV infection (Ch. 12) Prion diseases • Creutzfeldt–Jakob disease • Kuru Protozoal infections • Malaria* • Toxoplasmosis (in immune-suppressed)* • Trypanosomiasis* • Amoebic abscess* Helminthic infections • Schistosomiasis (spinal cord)* • Cysticercosis* • Hydatid disease* • Strongyloidiasis* Fungal infections • Candida meningitis or brain abscess • Cryptococcal meningitis *These infections are discussed in Chapter 11.

Infections of the nervous system • 1119

with recurrent fever, sweating, joint pains and transient rash. It usually occurs in the middle-aged and elderly, and in those who have previously had a splenectomy. In pneumococcal and Haemophilus infections there may be an accompanying otitis media. Pneumococcal meningitis may be associated with pneumonia and occurs especially in older patients and alcoholics, as well as those with hyposplenism. Listeria monocytogenes is an increasing cause of meningitis and rhombencephalitis (brainstem encephalitis) in the immunosuppressed, people with diabetes, alcoholics and pregnant women (p. 259). It can also cause meningitis in neonates. Investigations Lumbar puncture is mandatory unless there are contraindications (p. 1077). If the patient is drowsy and has focal neurological signs or seizures, is immunosuppressed, has undergone recent neurosurgery or has suffered a head injury, it is wise to obtain a CT to exclude a mass lesion (such as a cerebral abscess) before lumbar puncture because of the risk of coning. This should not, however, delay treatment of presumed meningitis. If lumbar puncture is deferred or omitted, it is essential to take blood cultures and to start empirical treatment (Fig. 25.34). Lumbar 25.63 Bacterial causes of meningitis Age of onset Common Less common Neonate Gram-negative bacilli (Escherichia coli, Proteus) Group B streptococci Listeria monocytogenes Pre-school child Haemophilus influenzae Neisseria meningitidis (subtypes B, C, Y, W) Streptococcus pneumoniae Mycobacterium tuberculosis Older child and adult N. meningitidis (subtypes B, C, Y, W) Strep. pneumoniae L. monocytogenes M. tuberculosis Staphylococcus aureus (skull fracture) H. influenzae significant. An important factor in determining prognosis is early diagnosis and the prompt initiation of appropriate therapy. The meningococcus and other common causes of meningitis are normal commensals of the upper respiratory tract. New and potentially pathogenic strains are acquired by the air-borne route but close contact is necessary. Epidemics of meningococcal meningitis occur, particularly in cramped living conditions or where the climate is hot and dry. The organism invades through the nasopharynx, producing sepsis and leading to meningitis. Pathophysiology The meningococcus (Neisseria meningitidis) is now the most common cause of bacterial meningitis in Western Europe after Streptococcus pneumoniae, while in the USA Haemophilus influenzae remains common. In India, H. influenzae B and Strep. pneumoniae are probably the most common causes of bacterial meningitis, especially in children. Streptococcus suis is a rare zoonotic cause of meningitis associated with porcine contact. Infection stimulates an immune response, causing the pia–arachnoid membrane to become congested and infiltrated with inflammatory cells. Pus then forms in layers, which may later organise to form adhesions. These may obstruct the free flow of CSF, leading to hydrocephalus, or they may damage the cranial nerves at the base of the brain. Hearing loss is a frequent complication. The CSF pressure rises rapidly, the protein content increases, and there is a cellular reaction that varies in type and severity according to the nature of the inflammation and the causative organism. An obliterative endarteritis of the leptomeningeal arteries passing through the meningeal exudate may produce secondary cerebral infarction. Pneumococcal meningitis is often associated with a very purulent CSF and a high mortality, especially in older adults. Clinical features Headache, drowsiness, fever and neck stiffness are the usual presenting features. In severe bacterial meningitis the patient may be comatose, later developing focal neurological signs. Ninety per cent of patients with meningococcal meningitis will have two of the following: fever, neck stiffness, altered consciousness and rash. When accompanied by sepsis, presenting signs may evolve rapidly, with abrupt onset of obtundation due to cerebral oedema. Complications of meningococcal sepsis are listed in Box 25.64. Chronic meningococcaemia is a rare condition in which the patient can be unwell for weeks or even months 25.64 Complications of meningococcal sepsis • Meningitis • Rash (morbilliform, petechial or purpuric) • Shock • Intravascular coagulation • Renal failure • Peripheral gangrene • Arthritis (septic or reactive) • Pericarditis (septic or reactive) Fig. 25.34 The investigation of meningitis. Resuscitate and stabilise patient Initial tests (blood culture and polymerase chain reaction, throat swab) Empirical antibiotics (Box 25.65) Transfer to critical care facility Drowsy, focal signs? (possible mass lesion, hydrocephalus or cerebral oedema) No Yes Lumbar puncture No other contraindication to lumbar puncture Computed tomography brain No mass lesion, hydrocephalus or other contraindication to lumbar puncture seen

1120 • NEUROLOGY The only contraindication is a history of penicillin anaphylaxis. Recommended empirical therapies are outlined in Box 25.65, and the preferred antibiotic when the organism is known after CSF examination is stipulated in Box 25.66. Adjunctive glucocorticoid therapy is useful in reducing hearing loss and neurological sequelae in both children and adults in developed countries where the incidence of penicillin resistance is low, but its role where there are high rates of resistance or in countries where there are high rates of untreated HIV is unclear. In meningococcal disease, mortality is doubled if the patient presents with features of sepsis rather than meningitis. Individuals likely to require intensive care facilities and expertise include those with cardiac, respiratory or renal involvement, and those with CNS depression prejudicing the airway. Early endotracheal intubation and mechanical ventilation protect the airway and may prevent the development of the acute respiratory distress syndrome (ARDS, p. 198). Adverse prognostic features include hypotensive shock, a rapidly developing rash, a haemorrhagic diathesis, multisystem failure and age over 60 years. Prevention of meningococcal infection Close contacts of patients with meningococcal infection (Box 25.67) should be given 2 days of oral rifampicin. In adults, a single dose of ciprofloxacin is an alternative. If not treated with ceftriaxone, the index case should be given similar treatment to clear infection from the nasopharynx before hospital discharge. Vaccines are available for most meningococcal subgroups but not group B, which is one of the most common serogroups isolated in many countries. Tuberculous meningitis Tuberculous meningitis is now uncommon in developed countries except in immunocompromised individuals, although it is still seen in those born in endemic areas and in developing countries. It is seen more frequently as a secondary infection in patients with the acquired immunodeficiency syndrome (AIDS). Pathophysiology Tuberculous meningitis most commonly occurs shortly after a primary infection in childhood or as part of miliary tuberculosis (p. 588). The usual local source of infection is a caseous focus in puncture will help differentiate the causative organism: in bacterial meningitis the CSF is cloudy (turbid) due to the presence of many neutrophils (often > 1000 × 106 cells/L), the protein content is significantly elevated and the glucose reduced. Gram film and culture may allow identification of the organism. Blood cultures may be positive. PCR techniques can be used on both blood and CSF to identify bacterial DNA. These methods are useful in detecting meningococcal infection and in typing the organism. Management There is an untreated mortality rate of around 80%, so action must be swift. In suspected bacterial meningitis the patient should be given parenteral benzylpenicillin immediately (intravenous is preferable) and prompt hospital admission should be arranged. 25.65 Treatment of pyogenic meningitis of unknown cause

  1. Adults aged 18–50 years with or without a typical meningococcal rash • Cefotaxime 2 g IV 4 times daily or • Ceftriaxone 2 g IV twice daily
  2. Patients in whom penicillin-resistant pneumococcal infection is suspected, or in areas with a significant incidence of penicillin resistance in the community As for (1) but add: • Vancomycin 1 g IV twice daily or • Rifampicin 600 mg IV twice daily
  3. Adults aged > 50 years and those in whom Listeria monocytogenes infection is suspected (brainstem signs, immunosuppression, diabetic, alcoholic) As for (1) but add: • Ampicillin 2 g IV 6 times daily or • Co-trimoxazole 5 mg/kg IV daily in two divided doses
  4. Patients with a clear history of anaphylaxis to β-lactams • Chloramphenicol 25 mg/kg IV 4 times daily plus • Vancomycin 1 g IV twice daily
  5. Adjunctive treatment (see text) • Dexamethasone 0.15 mg/kg 4 times daily for 2–4 days 25.66 Chemotherapy of bacterial meningitis when the cause is known Pathogen Regimen of choice Alternative agents Neisseria meningitidis Benzylpenicillin 2.4 g IV 6 times daily for 5–7 days Cefuroxime, ampicillin Chloramphenicol* Streptococcus pneumoniae (sensitive to β-lactams, MIC < 1 mg/L) Cefotaxime 2 g IV 4 times daily or Ceftriaxone 2 g IV twice daily for 10–14 days Chloramphenicol* Strep. pneumoniae (resistant to β-lactams) As for sensitive strains but add: Vancomycin 1 g IV twice daily or Rifampicin 600 mg IV twice daily Vancomycin plus rifampicin* Moxifloxacin Gatifloxacin Haemophilus influenzae Cefotaxime 2 g IV 4 times daily or Ceftriaxone 2 g IV twice daily for 10–14 days Chloramphenicol* Listeria monocytogenes Ampicillin 2 g IV 6 times daily plus Gentamicin 5 mg/kg IV daily Ampicillin 2 g IV 4-hourly plus Co-trimoxazole 50 mg/kg daily in two divided doses Streptococcus suis Cefotaxime 2 g IV 4 times daily or Ceftriaxone 2 g IV twice daily for 10–14 days Chloramphenicol* *For patients with a history of anaphylaxis to β-lactam antibiotics. (MIC = minimum inhibitory concentration)

Infections of the nervous system • 1121

protein and a marked fall in glucose. The tubercle bacillus may be detected in a smear of the centrifuged deposit from the CSF but a negative result does not exclude the diagnosis. The CSF should be cultured but, as this result will not be known for up to 6 weeks, treatment must be started without waiting for confirmation. Brain imaging may show hydrocephalus, brisk meningeal enhancement on enhanced CT or MRI, and/or an intracranial tuberculoma. Management As soon as the diagnosis is made or strongly suspected, chemotherapy should be started using one of the regimens that include pyrazinamide, described on page 592. The use of glucocorticoids in addition to antituberculous therapy has been controversial. Recent evidence suggests that it improves mortality, especially if given early, but not focal neurological damage. Surgical ventricular drainage may be needed if obstructive hydrocephalus develops. Skilled nursing is essential during the acute phase of the illness, and adequate hydration and nutrition must be maintained. Other forms of meningitis Fungal meningitis (especially cryptococcosis; p. 302) usually occurs in patients who are immunosuppressed and is a recognised complication of HIV infection (p. 321). The CSF findings are similar to those of tuberculous meningitis, but the diagnosis can be confirmed by microscopy or specific serological tests. In some areas, meningitis may be caused by spirochaetes (leptospirosis, Lyme disease and syphilis; pp. 257, 255 and 337), rickettsiae (typhus fever; p. 270) or protozoa (amoebiasis; p. 286). Meningitis can also be due to non-infective pathologies. This is seen in recurrent aseptic meningitis resulting from systemic lupus erythematosus (SLE), Behçet’s disease or sarcoidosis, as well as a condition of previously unknown origin known as Mollaret’s syndrome, in which the recurrent meningitis is associated with epithelioid cells in the spinal fluid (‘Mollaret’ cells). Recent evidence suggests that this condition may be due to herpes simplex virus type 2 and is therefore infective after all. Meningitis can also be caused by direct invasion of the meninges by neoplastic cells (‘malignant meningitis’; see Box 25.62). Parenchymal viral infections Infection of the substance of the nervous system will produce symptoms of focal dysfunction (deficits and/or seizures) with general signs of infection, depending on the acuteness of the infection and the type of organism. Viral encephalitis A range of viruses can cause encephalitis but only a minority of patients report recent systemic viral infection. In Europe, the most serious cause of viral encephalitis is herpes simplex (p. 247), which probably reaches the brain via the olfactory nerves. Varicella zoster is also an important cause. The development of effective therapy for some forms of encephalitis has increased the importance of clinical diagnosis and virological examination of the CSF. In some parts of the world, viruses transmitted by mosquitoes and ticks (arboviruses) are an important cause of encephalitis. The epidemiology of some of these infections is changing. Japanese encephalitis (p. 249) has spread relentlessly across Asia to Australia, and there have been outbreaks of West Nile encephalitis in Romania, Israel and New York. Zika virus has the meninges or brain substance adjacent to the CSF pathway. The brain is covered by a greenish, gelatinous exudate, especially around the base, and numerous scattered tubercles are found on the meninges. Clinical features The clinical features and staging criteria are listed in Box 25.68. Onset is much slower than in other bacterial meningitis – over 2–8 weeks. If untreated, tuberculous meningitis is fatal in a few weeks but complete recovery is usual if treatment is started at stage I (Box 25.68). When treatment is initiated later, the rate of death or serious neurological deficit may be as high as 30%. Investigations Lumbar puncture should be performed if the diagnosis is suspected. The CSF is under increased pressure. It is usually clear but, when allowed to stand, a fine clot (‘spider web’) may form. The fluid contains up to 500 × 106 cells/L, predominantly lymphocytes, but can contain neutrophils. There is a rise in 25.67 Chemoprophylaxis following meningococcal exposure Close contacts warranting chemoprophylaxis • Household contacts (including persons who ate or slept in the same dwelling as the patient during the 7 days prior to disease onset) • Child-care and nursery-school contacts • Persons having contact with patient’s oral secretions during the 7 days prior to disease onset: Kissing Sharing of toothbrushes Sharing of eating utensils Mouth-to-mouth resuscitation Unprotected contact during endotracheal intubation • Aircraft contacts for persons seated next to the patient for > 8 hrs Persons at low risk in whom chemoprophylaxis is not recommended • Casual contact (e.g. at school or work) without direct exposure to patient’s oral secretions • Indirect contact only (contact with a high-risk contact and not a case) • Health-care worker without direct exposure to patient’s oral secretions 25.68 Clinical features and staging of tuberculous meningitis Symptoms • Headache • Vomiting • Low-grade fever • Lassitude • Depression • Delirium • Behaviour changes Signs • Meningism (may be absent) • Oculomotor palsies • Papilloedema • Depression of conscious level • Focal hemisphere signs Staging of severity • Stage I (early): non-specific symptoms and signs without alteration of consciousness • Stage II (intermediate): altered consciousness without coma or delirium plus minor focal neurological signs • Stage III (advanced): stupor or coma, severe neurological deficits, seizures or abnormal movements

1122 • NEUROLOGY usually conveyed by saliva through bites or licks on abrasions or on intact mucous membranes. Humans are most frequently infected from dogs and bats. In Europe, the maintenance host is the fox. The incubation period varies in humans from a minimum of 9 days to many months but is usually between 4 and 8 weeks. Severe bites, especially if on the head or neck, are associated with shorter incubation periods. Human rabies is a rare disease, even in endemic areas. However, because it is usually fatal, major efforts are directed at limiting its spread and preventing its importation into uninfected countries, such as the UK. Clinical features At the onset there may be fever, and paraesthesia at the site of the bite. A prodromal period of 1–10 days, during which the patient becomes increasingly anxious, leads to the characteristic ‘hydrophobia’. Although the patient is thirsty, attempts at drinking provoke violent contractions of the diaphragm and other inspiratory muscles. Delusions and hallucinations may develop, accompanied by spitting, biting and mania, with lucid intervals in which the patient is markedly anxious. Cranial nerve lesions develop and terminal hyperpyrexia is common. Death ensues, usually within a week of the onset of symptoms. Investigations During life, the diagnosis is usually made on clinical grounds but rapid immunofluorescent techniques can detect antigen in corneal impression smears or skin biopsies. Management Established disease Only a few patients with established rabies have survived. All received some post-exposure prophylaxis (see below) and needed intensive care facilities to control cardiac and respiratory failure. Otherwise, only palliative treatment is possible once symptoms have appeared. The patient should be heavily sedated with diazepam, supplemented by chlorpromazine if needed. Nutrition and fluids should be given intravenously or through a gastrostomy. Pre-exposure prophylaxis Pre-exposure prophylaxis is required by those who handle potentially infected animals professionally, work with rabies virus in laboratories or live at special risk in rabies-endemic areas. Protection is afforded by intradermal injections of human diploid cell strain vaccine, or two intramuscular injections given 4 weeks apart, followed by yearly boosters. Post-exposure prophylaxis The wounds should be thoroughly cleaned, preferably with a quaternary ammonium detergent or soap; damaged tissues should be excised and the wound left unsutured. Rabies can usually be prevented if treatment is started within a day or two of biting. Delayed treatment may still be of value. For maximum protection, hyperimmune serum and vaccine are required. The safest antirabies antiserum is human rabies immunoglobulin. The dose is 20 IU/kg body weight; half is infiltrated around the bite and half is given intramuscularly at a different site from the vaccine. Hyperimmune animal serum may be used but hypersensitivity reactions, including anaphylaxis, are common. The safest vaccine, free of complications, is human diploid cell strain vaccine; 1.0 mL is given intramuscularly on days 0, 3, 7, 14, 30 and 90. In developing countries, where human rabies globulin may not be obtainable, 0.1 mL of vaccine may be given mutated in the last decades and become a more significant global health problem. HIV may cause encephalitis with a subacute or chronic presentation but occasionally has an acute presentation with seroconversion. Pathophysiology The infection provokes an inflammatory response that involves the cortex, white matter, basal ganglia and brainstem. The distribution of lesions varies with the type of virus. For example, in herpes simplex encephalitis, the temporal lobes are usually primarily affected, whereas cytomegalovirus can involve the areas adjacent to the ventricles (ventriculitis). Inclusion bodies may be present in the neurons and glial cells, and there is an infiltration of polymorphonuclear cells in the perivascular space. There is neuronal degeneration and diffuse glial proliferation, often associated with cerebral oedema. Clinical features Viral encephalitis presents with acute onset of headache, fever, focal neurological signs (aphasia and/or hemiplegia, visual field defects) and seizures. Disturbance of consciousness ranging from drowsiness to deep coma supervenes early and may advance dramatically. Meningism occurs in many patients. Rabies presents a distinct clinical picture and is described below. Investigations Imaging by CT scan may show low-density lesions in the temporal lobes but MRI is more sensitive in detecting early abnormalities. Lumbar puncture should be performed once imaging has excluded a mass lesion. The CSF usually contains excess lymphocytes but polymorphonuclear cells may predominate in the early stages. The CSF may be normal in up to 10% of cases. Some viruses, including the West Nile virus, may cause a sustained neutrophilic CSF. The protein content may be elevated but the glucose is normal. The EEG is usually abnormal in the early stages, especially in herpes simplex encephalitis, with characteristic periodic slowwave activity in the temporal lobes. Virological investigations of the CSF, including PCR, may reveal the causative organism but treatment initiation should not await this. Management Optimum treatment for herpes simplex encephalitis (aciclovir 10 mg/kg IV 3 times daily for 2–3 weeks) has reduced mortality from 70% to around 10%. This should be given early to all patients suspected of having viral encephalitis. Some survivors will have residual epilepsy or cognitive impairment. For details of post-infectious encephalomyelitis, see page 1110. Antiepileptic treatment may be required (p. 1101) and raised intracranial pressure may indicate the need for dexamethasone. Brainstem encephalitis This presents with ataxia, dysarthria, diplopia or other cranial nerve palsies. The CSF is lymphocytic, with a normal glucose. The causative agent is presumed to be viral. However, Listeria monocytogenes may cause a similar syndrome with meningitis (and often a polymorphonuclear CSF pleocytosis) and requires specific treatment with ampicillin (500 mg 4 times daily; see Box 25.66). Rabies Rabies is caused by a rhabdovirus that infects the central nervous tissue and salivary glands of a wide range of mammals. It is

Infections of the nervous system • 1123

not regain useful function. Second attacks are very rare but occasionally patients show late deterioration in muscle bulk and power many years after the initial infection (this is termed the ‘post-polio syndrome’). Investigations The CSF shows a lymphocytic pleocytosis, a rise in protein and a normal sugar content. Poliomyelitis virus may be cultured from CSF and stool. Management Established disease In the early stages, bed rest is imperative because exercise appears to worsen the paralysis or precipitate it. At the onset of respiratory difficulties, a tracheostomy and ventilation are required. Subsequent treatment is by physiotherapy and orthopaedic measures. Prophylaxis Prevention of poliomyelitis is by immunisation with live (Sabin) vaccine. In developed countries where polio is now very rare, the live vaccine has been replaced by the killed vaccine in childhood immunisation schedules. Herpes zoster (shingles) Herpes zoster is the result of reactivation of the varicella zoster virus that has lain dormant in a nerve root ganglion following chickenpox earlier in life. Reactivation may be spontaneous (as usually occurs in the middle-aged or elderly) or due to immunosuppression (as in patients with diabetes, malignant disease or AIDS). Full details are given on page 239. Subacute sclerosing panencephalitis This is a rare, chronic, progressive and eventually fatal complication of measles, presumably a result of an inability of the nervous system to eradicate the virus. It occurs in children and adolescents, usually many years after the primary virus infection. There is generalised neurological deterioration and onset is insidious, with intellectual deterioration, apathy and clumsiness, followed by myoclonic jerks, rigidity and dementia. The CSF may show a mild lymphocytic pleocytosis and the EEG demonstrates characteristic periodic bursts of triphasic waves. Although there is persistent measles-specific IgG in serum and CSF, antiviral therapy is ineffective and death ensues within a few years. Progressive multifocal leucoencephalopathy This was originally described as a rare complication of lymphoma, leukaemia or carcinomatosis but has become more frequent as a feature of AIDS (p. 319) or secondary to immunosuppression, e.g. following organ transplantation or use of disease-modifying drugs for MS. It is an infection of oligodendrocytes by human polyomavirus JC, causing widespread demyelination of the white matter of the cerebral hemispheres. Clinical signs include dementia, hemiparesis and aphasia, which progress rapidly, usually leading to death within weeks or months. Areas of low density in the white matter are seen on CT but MRI is more sensitive, showing diffuse high signal in the cerebral white matter on T2-weighted images. The only treatment available is restoration of the immune response (by treating AIDS or reversing immunosuppression). intradermally into eight sites on day 1, with single boosters on days 7 and 28. Where human products are not available and when risk of rabies is slight (licks on the skin, or minor bites of covered arms or legs), it may be justifiable to delay starting treatment while observing the biting animal or awaiting examination of its brain, rather than use the older vaccine. Poliomyelitis Pathophysiology Disease is caused by one of three polioviruses, which constitute a subgroup of the enteroviruses. Poliomyelitis has become much less common in developed countries following the widespread use of oral vaccines but is still a problem in the developing world, especially parts of Africa. Infection usually occurs through the nasopharynx. The virus causes a lymphocytic meningitis and infects the grey matter of the spinal cord, brainstem and cortex. There is a particular propensity to damage anterior horn cells, especially in the lumbar segments. Clinical features The incubation period is 7–14 days. Figure 25.35 illustrates the various features of the infection. Many patients recover fully after the initial phase of a few days of mild fever and headache. In other individuals, after a week of well-being, there is a recurrence of pyrexia, headache and meningism. Weakness may start later in one muscle group and can progress to widespread paresis. Respiratory failure may supervene if intercostal muscles are paralysed or the medullary motor nuclei are involved. Epidemics vary widely in terms of the incidence of non-paralytic cases and in mortality rate. Death occurs from respiratory paralysis. Muscle weakness is maximal at the end of the first week and gradual recovery may then take place over several months. Muscles showing no signs of recovery after a month will probably Fig. 25.35 Poliomyelitis. Possible consequences of infection. Infection Asymptomatic seroconversion Aseptic meningitis (encephalitis) Febrile illness

Anterior horn cell infection Recovery Lower motor neuron paralysis Recovery Death Residual disability Complete Late deterioration

1124 • NEUROLOGY Parenchymal bacterial infections Cerebral abscess Bacteria may enter the cerebral substance through penetrating injury, by direct spread from paranasal sinuses or the middle ear, or secondary to sepsis. Untreated congenital heart disease is a recognised risk factor. The site of abscess formation and the likely causative organism are both related to the source of infection (Box 25.69). Initial infection leads to local suppuration followed by loculation of pus within a surrounding wall of gliosis, which in a chronic abscess may form a tough capsule. Haematogenous spread may lead to multiple abscesses. Clinical features A cerebral abscess may present acutely with fever, headache, meningism and drowsiness, but more commonly presents over days or weeks as a cerebral mass lesion with little or no evidence of infection. Seizures, raised intracranial pressure and focal hemisphere signs occur alone or in combination. Distinction from a cerebral tumour may be impossible on clinical grounds. Investigations Lumbar puncture is potentially hazardous in the presence of raised intracranial pressure and CT should always precede it. CT reveals single or multiple low-density areas, which show ring enhancement with contrast and surrounding cerebral oedema (Fig. 25.36). There may be an elevated white blood cell count and ESR in patients with active local infection. The possibility of cerebral toxoplasmosis or tuberculous disease secondary to HIV infection (p. 320) should always be considered. Management and prognosis Antimicrobial therapy is indicated once the diagnosis is made. The likely source of infection should guide the choice of antibiotic (see Box 25.69). In neurosurgical patients, the addition of vancomycin should be considered. Surgical drainage by burr-hole aspiration or excision may be necessary, especially where the presence of a capsule may lead to a persistent focus of infection. Epilepsy frequently develops and is often resistant to treatment. Despite advances in therapy, mortality remains 10–20% and may partly relate to delay in diagnosis and treatment. 25.69 Aetiology and treatment of bacterial cerebral abscess Site of abscess Source of infection Likely organisms Recommended treatment Frontal lobe Paranasal sinuses Teeth Streptococci Anaerobes Cefotaxime 2–3 g IV 4 times daily plus Metronidazole 500 mg IV 3 times daily Temporal lobe Middle ear Streptococci Enterobacteriaceae Ampicillin 2–3 g IV 3 times daily plus Metronidazole 500 mg IV 3 times daily plus either Cerebellum Sphenoid sinus Mastoid/middle ear Pseudomonas spp. Anaerobes Ceftazidime 2 g IV 3 times daily or Gentamicin* 5 mg/kg IV daily Any site Penetrating trauma Staphylococci Flucloxacillin 2–3 g IV 4 times daily or Cefuroxime 1.5 g IV 3 times daily Multiple Metastatic and cryptogenic Streptococci Anaerobes Benzylpenicillin 1.8–2.4 g IV 4 times daily if endocarditis or cyanotic heart disease Otherwise cefotaxime 2–3 g IV 4 times daily plus Metronidazole 500 mg IV 3 times daily *Monitor gentamicin levels. Fig. 25.36 Right temporal cerebral abscess (arrows), with surrounding oedema and midline shift to the left. A Unenhanced computed tomography (CT) image. B Contrastenhanced CT image. A B

Infections of the nervous system • 1125

involvement is suspected. Active disease is suggested by an elevated cell count, usually lymphocytic, and the protein content may be elevated to 0.5–1.0 g/L with an increased gamma globulin fraction. Serological tests in CSF are usually positive but progressive disease can occur with negative CSF serology. Management The injection of procaine benzylpenicillin (procaine penicillin) and probenecid for 17 days is essential in the treatment of neurosyphilis of all types (p. 338). Further courses of penicillin must be given if symptoms are not relieved, if the condition continues to advance or if the CSF continues to show signs of active disease. The cell count returns to normal within 3 months of completion of treatment, but the elevated protein takes longer to subside and some serological tests may never revert to normal. Evidence of clinical progression at any time is an indication for renewed treatment. Diseases caused by bacterial toxins Tetanus This disease results from infection with Clostridium tetani, a commensal in the gut of humans and domestic animals that is found in soil. Infection enters the body through wounds, which may be trivial. It is rare in the UK, occurring mostly in gardeners and farmers, but a recent increase has been seen in intravenous drug misusers. By contrast, the disease is common in many developing countries, where dust contains spores derived from animal and human excreta. Unhygienic practices soon after birth may lead to infection of the umbilical stump or site of circumcision, causing tetanus neonatorum. Tetanus is still one of the major killers of adults, children and neonates in developing countries, where the mortality rate can be nearly 100% in the newborn and around 40% in others. In circumstances unfavourable to growth of the organism, spores are formed and these may remain dormant for years in the soil. Spores germinate and bacilli multiply only in the anaerobic conditions that occur in areas of tissue necrosis or if the oxygen tension is lowered by the presence of other organisms, particularly if aerobic. The bacilli remain localised but produce an exotoxin with an affinity for motor nerve endings and motor nerve cells. Subdural empyema This is a rare complication of frontal sinusitis, osteomyelitis of the skull vault or middle ear disease. A collection of pus in the subdural space spreads over the surface of the hemisphere, causing underlying cortical oedema or thrombophlebitis. Patients present with severe pain in the face or head and pyrexia, often with a history of preceding paranasal sinus or ear infection. The patient then becomes drowsy, with seizures and focal signs such as a progressive hemiparesis. The diagnosis rests on a strong clinical suspicion in patients with a local focus of infection. Careful assessment with contrastenhanced CT or MRI may show a subdural collection with underlying cerebral oedema. Management requires aspiration of pus via a burr hole and appropriate parenteral antibiotics. Any local source of infection must be treated to prevent re-infection. Spinal epidural abscess The characteristic clinical features are pain in a root distribution and progressive transverse spinal cord syndrome with paraparesis, sensory impairment and sphincter dysfunction. Features of the primary focus of infection may be less obvious and thus can be overlooked. The resurgence of resistant staphylococcal infection and intravenous drug misuse has contributed to a recent marked rise in incidence. X-ray changes occur late, if present, so MRI or myelography should precede urgent neurosurgical intervention. Decompressive laminectomy with abscess drainage relieves the pressure on the dura. Organisms may be grown from the pus or blood. Surgery, together with appropriate antibiotics, may prevent complete and irreversible paraplegia. Lyme disease Infection with Borrelia burgdorferi can cause numerous neurological problems, including polyradiculopathy, meningitis, encephalitis and mononeuritis multiplex (p. 255). Neurosyphilis Neurosyphilis may present as an acute or chronic process and may involve the meninges, blood vessels and/or parenchyma of the brain and spinal cord. The decade to 2008 saw a 10-fold increase in the incidence of syphilis, mostly as a result of misguided relaxation of safe sex measures with the advent of effective antiretroviral treatments for AIDS. Paralleled future increases in neurosyphilis are inevitable. The clinical manifestations are diverse and early diagnosis and treatment are essential. Clinical features The clinical and pathological features of the three most common presentations are summarised in Box 25.70. Neurological examination reveals signs indicative of the anatomical localisation of lesions. Delusions of grandeur suggest general paresis of the insane, but more commonly there is simply progressive dementia. Small and irregular pupils that react to convergence but not light, as described by Argyll Robertson (see Box 25.22, p. 1092), may accompany any neurosyphilitic syndrome but most commonly tabes dorsalis. Investigations Routine screening for syphilis is warranted in many neurological patients. Treponemal antibodies (p. 338) are positive in the serum in most patients, but CSF examination is essential if neurological 25.70 Clinical and pathological features of neurosyphilis Type and interval from primary infection Pathology Clinical features Meningovascular (5 years)* Endarteritis obliterans Meningeal exudate Granuloma (gumma) Stroke Cranial nerve palsies Seizures/mass lesion General paralysis of the insane (5–15 years)* Degeneration in cerebral cortex/ cerebral atrophy Thickened meninges Dementia Tremor Bilateral upper motor signs Tabes dorsalis (5–20 years)* Degeneration of sensory neurons Wasting of dorsal columns Optic atrophy Lightning pains Sensory ataxia Visual failure Abdominal crises Incontinence Trophic changes Any of the above Argyll Robertson pupils (p. 1092)

1126 • NEUROLOGY Prevention Tetanus can be prevented by immunisation and prompt treatment of contaminated wounds by débridement and antibiotics. In patients with a contaminated wound, the immediate danger of tetanus can be greatly reduced by the injection of 1200 mg of penicillin followed by a 7-day course of oral penicillin. For those allergic to penicillin, erythromycin should be used. When the risk of tetanus is judged to be present, an intramuscular injection of 250 IU of human tetanus antitoxin should be given, along with toxoid, which should be repeated 1 month and 6 months later. For those already immunised, only a booster dose of toxoid is required. Botulism Botulism is caused by the neurotoxins of Clostridium botulinum, which are extremely potent and cause disease after ingestion of even picogram amounts. Its classical form is an acute onset of bilateral cranial neuropathies associated with symmetric descending weakness. Anaerobic conditions are necessary for the organism’s growth. It may contaminate and thrive in many foodstuffs, where sealing and preserving provide the requisite conditions. Contaminated honey has been implicated in infant botulism, in which the organism colonises the gastrointestinal tract. Wound botulism is a growing problem in injection drug-users. The toxin causes predominantly bulbar and ocular palsies (difficulty in swallowing, blurred or double vision, ptosis), progressing to limb weakness and respiratory paralysis. Criteria for the clinical diagnosis are shown in Box 25.72. The anterior horn cells are affected after the exotoxin has passed into the blood stream and their involvement results in rigidity and convulsions. Symptoms first appear from 2 days to several weeks after injury: the shorter the incubation period, the more severe the attack and the worse the prognosis. Clinical features By far the most important early symptom is trismus – spasm of the masseter muscles, which causes difficulty in opening the mouth and in masticating; hence the name ‘lockjaw’. Lockjaw in tetanus is painless, unlike the spasm of the masseters due to dental abscess, septic throat or other causes. Conditions that can mimic tetanus include hysteria and phenothiazine overdosage, or overdose in intravenous drug misusers. In tetanus, the tonic rigidity spreads to involve the muscles of the face, neck and trunk. Contraction of the frontalis and the muscles at the angles of the mouth leads to the so-called ‘risus sardonicus’. There is rigidity of the muscles at the neck and trunk of varying degree. The back is usually slightly arched (‘opisthotonus’) and there is a board-like abdominal wall. In the more severe cases, violent spasms lasting for a few seconds to 3–4 minutes occur spontaneously, or may be induced by stimuli such as movement or noise. These episodes are painful and exhausting, and suggest a grave outlook, especially if they appear soon after the onset of symptoms. They gradually increase in frequency and severity for about 1 week and the patient may die from exhaustion, asphyxia or aspiration pneumonia. In less severe illness, periods of spasm may not commence until a week or so after the first sign of rigidity, and in very mild infections they may never appear. Autonomic involvement may cause cardiovascular complications, such as hypertension. Rarely, the only manifestation of the disease may be ‘local tetanus’ – stiffness or spasm of the muscles near the infected wound – and the prognosis is good if treatment is commenced at this stage. Investigations The diagnosis is made on clinical grounds. It is rarely possible to isolate the infecting organism from the original locus of entry. Management Established disease Management of established disease should begin as soon as possible, as shown in Box 25.71. 25.71 Treatment of tetanus Neutralise absorbed toxin • Give IV injection of 3000 IU of human tetanus antitoxin Prevent further toxin production • Débride wound • Give benzylpenicillin 600 mg IV 4 times daily (metronidazole if patient is allergic to penicillin) Control spasms • Nurse in a quiet room • Avoid unnecessary stimuli • Give IV diazepam • If spasms continue, paralyse patient and ventilate General measures • Maintain hydration and nutrition • Treat secondary infections 25.72 US Centers for Disease Control (CDC) definition of botulism Three main syndromes • Infantile • Food-borne • Wound infection Clinical features • Absence of fever • Symmetrical neurological deficits • Patient remains responsive • Normal or slow heart rate and normal blood pressure • No sensory deficits with the exception of blurred vision Management includes assisted ventilation and general supportive measures until the toxin eventually dissociates from nerve endings 6–8 weeks following ingestion. A polyvalent antitoxin is available for post-exposure prophylaxis and for the treatment of suspected botulism. It specifically neutralises toxin types A, B and E and is not effective against infantile botulism (in which active growth of the organism allows continued toxin production). Prion diseases Prions are unique amongst infectious agents in that they are devoid of any nucleic acid. They appear to be transmitted by acquisition of a normal mammalian protein (prion protein, PrPC) that is in an abnormal conformation (PrPSC, containing an excess of beta-sheet protein); the abnormal protein inhibits the 26S

Intracranial mass lesions and raised intracranial pressure • 1127

earlier. Patients affected by vCJD are typically younger than those with sporadic CJD and present with neuropsychiatric changes and sensory symptoms in the limbs, followed by ataxia, dementia and death. Progression is slightly slower than in patients with sporadic CJD (mean time to death is over a year). Characteristic EEG changes are not present, but MRI brain scans show characteristic high-signal changes in the pulvinar thalami in a high proportion of cases (Fig. 25.37). Brain histology is distinct, with very florid plaques containing the prion proteins. Abnormal prion protein has been identified in tonsil specimens from patients with vCJD, leading to the suggestion that the disease could be transmitted by reticulo-endothelial tissue (like TSEs in animals but unlike sporadic CJD in humans). It was the emergence of this form of the disorder that led to the changes in public health and farming policy in the UK; while the incidence of vCJD has declined dramatically, surveillance and research continue. Intracranial mass lesions and raised intracranial pressure Many different types of mass lesion may arise within the intracranial cavity (Box 25.74). In developing countries tuberculoma and other infections are frequent causes, but in the West intracranial haemorrhage and brain tumours are more common. The clinical features depend on the site of the mass, its nature and its rate of expansion. Symptoms and signs (see Box 25.75) are produced by a number of mechanisms. Raised intracranial pressure Raised intracranial pressure (RICP) may be caused by mass lesions, cerebral oedema, obstruction to CSF circulation leading proteasome, which can degrade misfolded proteins, leading to accumulation of the abnormally configured PrPSC protein instead of normal PrPC. The result is accumulation of protein that forms amyloid in the CNS, causing a transmissible spongiform encephalopathy (TSE) across several species. Human prion diseases (Box 25.73) are characterised by the histopathological triad of cortical spongiform change, neuronal cell loss and gliosis. Associated with these changes there is deposition of amyloid, made up of an altered form of a normally occurring protein, the prion protein. Prion proteins are not inactivated by cooking or conventional sterilisation, and transmission is thought to occur by consumption of infected CNS tissue or by inoculation (e.g. via depth EEG electrodes, corneal grafts, cadaveric dura mater grafts and pooled cadaveric growth hormone preparations). The same diseases can occur in an inherited form, due to mutations in the PrP gene. The apparent transmission of bovine spongiform encephalopathy (BSE) to humans was thought to be responsible for the emergence of a new variant of CJD (vCJD) in the UK (see below). This outbreak led to nationwide precautionary measures, such as leucodepletion of all blood used for transfusion, and the mandatory use of disposable surgical instruments wherever possible for tonsillectomy, appendicectomy and ophthalmological procedures. Creutzfeldt–Jakob disease Creutzfeldt–Jakob disease (CJD) is the best-characterised human TSE. Some 10% of cases arise from a mutation in the gene coding for the prion protein. The sporadic form is the most common, occurring in middle-aged to elderly patients. Clinical features usually involve a rapidly progressive dementia, with myoclonus and a characteristic EEG pattern (repetitive slow-wave complexes), although a number of other features, such as visual disturbance or ataxia, may also be seen. These are particularly common in CJD transmitted by inoculation (e.g. by infected dura mater grafts). Death occurs after a mean of 4–6 months. There is no effective treatment. Variant Creutzfeldt–Jakob disease This type of CJD (vCJD) emerged in the late 1990s, affecting a small number of patients in the UK. The causative agent appears to be identical to that causing BSE in cows, and the disease may have been a result of the epidemic of BSE in the UK a decade 25.73 Prion diseases affecting humans Disease Mechanism Creutzfeldt–Jakob disease Sporadic Unknown: spontaneous PrPC to PrPSC conversion or somatic mutation Familial Genetic: mutations in the PrP gene Variant Dietary ingestion: infection from bovine spongiform encephalopathy Gerstmann–Sträussler– Scheinker disease Genetic: mutations in the PrP gene Fatal familial insomnia Genetic: mutations in the PrP gene Sporadic fatal insomnia Genetic: spontaneous PrPC to PrPSC conversion or somatic mutation Kuru Dietary: ingestion of affected human brain Fig. 25.37 Magnetic resonance imaging in variant Creutzfeldt–Jakob disease. Arrows indicate bilateral pulvinar hyperintensity.

1128 • NEUROLOGY a large hemisphere mass may cause ‘temporal coning’ (Fig. 25.38). This may stretch the 3rd and/or 6th cranial nerves or cause pressure on the contralateral cerebral peduncle (giving rise to ipsilateral upper motor neuron signs), and is usually accompanied by progressive coma. Downward movement of the cerebellar tonsils through the foramen magnum may compress the medulla – ‘tonsillar coning’ (Fig. 25.39). This may result in brainstem haemorrhage and/or acute obstruction of the CSF pathways. As coning progresses, coma and death occur unless the condition is rapidly treated. Management Primary management of RICP should be targeted at relieving the cause (e.g. surgical decompression of mass lesion, glucocorticoids to reduce vasogenic oedema or shunt procedure to relieve hydrocephalus). Supportive treatment includes maintenance of to hydrocephalus, impaired CSF absorption and cerebral venous obstruction (see Box 25.74). Clinical features In adults, intracranial pressure is less than 10–15 mmHg. The features of RICP are listed in Box 25.75. The speed of pressure increase influences presentation. If slow, compensatory mechanisms may occur, including alteration in the volume of fluid in CSF spaces and venous sinuses, minimising symptoms. Rapid pressure increase (as in aggressive tumours) does not permit these compensatory mechanisms to take place, leading to early symptoms, including sudden death. Papilloedema is not always present, either because the pressure rise has been too rapid or because of anatomical anomalies of the meningeal sheath of the optic nerve. A false localising sign is one in which the pathology is remote from the site of the expected lesion; in RICP, the 6th cranial nerve (unilateral or bilateral) is most commonly affected but the 3rd, 5th and 7th nerves may also be involved. Sixth nerve palsies are thought to be due either to stretching of the long slender nerve or to compression against the petrous temporal bone ridge. Transtentorial herniation of the uncus may compress the ipsilateral 3rd nerve and usually involves the pupillary fibres first, causing a dilated pupil; however, a false localising contralateral 3rd nerve palsy may also occur, perhaps due to extrinsic compression by the tentorial margin. Vomiting, coma, bradycardia and arterial hypertension are later features of RICP. The rise in intracranial pressure from a mass lesion may cause displacement of the brain. Downward displacement of the medial temporal lobe (uncus) through the tentorium due to 25.74 Common causes of raised intracranial pressure Mass lesions • Intracranial haemorrhage (traumatic or spontaneous): Extradural haematoma Subdural haematoma Intracerebral haemorrhage • Cerebral tumour (particularly posterior fossa lesions or high-grade gliomas: see Box 25.76) • Infective: Cerebral abscess Tuberculoma Cysticercosis (p. 298) Hydatid cyst (p. 299) • Colloid cyst (in ventricles) Disturbance of cerebrospinal fluid circulation • Obstructive (non-communicating) hydrocephalus: obstruction within ventricular system • Communicating hydrocephalus: site of obstruction outside ventricular system Obstruction to venous sinuses • Cerebral venous thrombosis • Trauma (depressed fractures overlying sinuses) Diffuse brain oedema or swelling • Meningo-encephalitis • Trauma (diffuse head injury, near-drowning) • Subarachnoid haemorrhage • Metabolic (e.g. water intoxication) • Idiopathic intracranial hypertension 25.75 Clinical features of intracranial mass lesions Presentation Features Seizures Focal onset ± generalised spread Focal symptoms Progressive loss of function Weakness Numbness Dysphasia Cranial neuropathy False localising signs Unilateral/bilateral 6th nerve palsies Contralateral 3rd nerve (usually pupil first) Raised intracranial pressure (usually aggressive tumours causing vasogenic oedema or obstructive hydrocephalus) Headache worse on lying/straining Vomiting Diplopia (6th nerve involvement) Papilloedema Bradycardia, raised blood pressure Impaired conscious level Stroke/TIA-like symptoms Acute haemorrhage into tumour Paroxysmal ‘tumour attacks’ Cognitive/behavioural change Usually frontal mass lesions Endocrine abnormalities Pituitary tumours Incidental finding Asymptomatic but identified on imaging (meningiomas commonly) (TIA = transient ischaemic attack) Fig. 25.38 Cerebral tumour displacing medial temporal lobe and causing pressure on the mid-brain and 3rd cranial nerve. 3rd nerve deformed Cerebral tumour Mid-brain distorted Tentorial margin

Intracranial mass lesions and raised intracranial pressure • 1129

isolated stable headache is almost never due to intracranial tumour. The size of the primary tumour is of far less prognostic significance than its location within the brain. Tumours within the brainstem will result in early neurological deficits, while those in the frontal region may be quite large before symptoms occur. fluid balance, blood pressure control, head elevation, and use of diuretics such as mannitol. Intensive care support may be needed (p. 208). Brain tumours Primary brain tumours are a heterogeneous collection of neoplasms arising from the brain tissue or meninges, and vary from benign to highly malignant. Primary malignant brain tumours (Box 25.76) are rare, accounting for 1% of all adult tumours but a higher proportion in children. The most common benign brain tumour is a meningioma. Primary brain tumours do not metastasise due to the absence of lymphatic drainage in the brain. There are rare pathological subtypes, however, such as medulloblastoma, which do have a propensity to metastasise; the reasons for this are not clear. Most cerebral tumours are sporadic but may be associated with genetic syndromes such as neurofibromatosis or tuberous sclerosis. Brain tumours are not classified by the usual TNM system but by the World Health Organisation (WHO) grading I–IV; this is based on histology (e.g. nuclear pleomorphism, presence of mitoses and presence of necrosis), with grade I the most benign and grade IV the most malignant. Gliomas account for 60% of brain tumours, with the aggressive glioblastoma multiforme (WHO grade IV) the most common glioma, followed by meningiomas (20%) and pituitary tumours (10%). Although the lower-grade gliomas (I and II) may be very indolent, with prognosis measured in terms of many years, these may transform to higher-grade disease at any time, with a resultant sharp decline in life expectancy. Most malignant brain tumours are due to metastases, with intracranial metastases complicating about 20% of extracranial malignancies. The rate is higher with primaries in the bronchus, breast and gastrointestinal tract (Fig. 25.40). Metastases usually occur in the white matter of the cerebral or cerebellar hemispheres but there are diffuse leptomeningeal types. Clinical features The presentation is variable and usually influenced by the rate of growth. High-grade disease (WHO grades III and IV) tends to present with a short (weeks) history of mass effect (headache, nausea secondary to RICP), while more indolent tumours can present with slowly progressive focal neurological deficits, depending on their location (see Box 25.75); generalised or focal seizures are common in either. Headache, if present, is usually accompanied by focal deficits or seizures, and Fig. 25.39 Tonsillar cone. Downward displacement of the cerebellar tonsils below the level of the foramen magnum. Cerebellar tonsil Level of foramen magnum Fourth ventricle Atlas Axis 25.76 Primary brain tumours Histological type Common site Age Malignant Glioma (astrocytoma) Cerebral hemisphere Cerebellum Brainstem Adulthood Childhood/adulthood Childhood/young adulthood Oligodendroglioma Cerebral hemisphere Adulthood Medulloblastoma Posterior fossa Childhood Ependymoma Posterior fossa Childhood/adolescence Cerebral lymphoma Cerebral hemisphere Adulthood Benign Meningioma Cortical dura Parasagittal Sphenoid ridge Suprasellar Olfactory groove Adulthood (often incidental finding) Neurofibroma Acoustic neuroma Adulthood Craniopharyngioma Suprasellar Childhood/adolescence Pituitary adenoma Pituitary fossa Adulthood Colloid cyst Third ventricle Any age Pineal tumours Quadrigeminal cistern Childhood (teratomas) Young adulthood (germ cell) Fig. 25.40 Contrast-enhanced computed tomogram of the head showing a large metastasis within the left hemisphere (large arrow). There is surrounding cerebral oedema, and a smaller metastasis (small arrow) within the wall of the right lateral ventricle. The primary lesion was a lung carcinoma.

1130 • NEUROLOGY the sphenoid ridge, when partial excision is often all that is possible. Thereafter, post-operative surveillance may be required, as radiotherapy is effective at preventing further growth of residual tumour. Pituitary adenomas may be removed by a trans-sphenoidal route, avoiding the need for a craniotomy. Unfortunately, gliomas, which account for the majority of brain tumours, cannot be completely excised, since infiltration spreads well beyond the apparent radiological boundaries of the intracranial mass. Recurrence is therefore the rule, even if the mass of the tumour is apparently removed completely; partial excision (‘debulking’) may be useful in alleviating symptoms caused by RICP, but although there is increasing evidence that the degree of surgical excision may have a positive influence on survival, this has not yet been convincingly demonstrated. Radiotherapy and chemotherapy In the majority of primary CNS tumours, radiation and chemotherapy are used to control disease and extend survival rather than for cure. Meningioma and pituitary adenoma offer the Investigations Diagnosis is by neuroimaging (Figs 25.41 and 25.42) and pathological grading following biopsy or resection where possible. The more malignant tumours are more likely to demonstrate contrast enhancement on imaging. If the tumour appears metastatic, further investigation to find the primary is required. Management Brain tumours are treated with a combination of surgery, radiotherapy and chemotherapy, depending on the type of tumour and the patient. Advancing age is the most powerful negative prognostic factor in CNS tumours, so best supportive care (including glucocorticoid therapy) may be most appropriate in older patients with metastases or high-grade disease. Treatment may not always be indicated in low-grade gliomas and watchful waiting may be appropriate, although a more aggressive approach is increasingly favoured. Dexamethasone given orally (or intravenously where RICP is acutely or severely raised) may reduce the vasogenic oedema typically associated with metastases and high-grade gliomas. Prolactin- or growth hormone-secreting pituitary adenomas (p. 683) may respond well to treatment with dopamine agonists (such as bromocriptine, cabergoline or quinagolide); in this situation, imaging and hormone levels may be all that is required to establish a formal diagnosis, precluding the need for surgery. Surgical The mainstay of primary treatment is surgery, either resection (full or partial debulking) or biopsy, depending on the site and likely radiological diagnosis. Clearly, if a tumour occurs in an area of brain that is highly important for normal function (e.g. motor strip), then biopsy may be the only safe surgical intervention but, in general, maximal safe resection is the optimal surgical management. Meningiomas and acoustic neuromas offer the best prospects for complete removal and thus cure. Some meningiomas can recur, however, particularly those of Fig. 25.41 Magnetic resonance image showing a meningioma in the frontal lobe (arrow A) with associated oedema (arrow B). A B Fig. 25.42 Magnetic resonance image of an acoustic neuroma (arrows) in the posterior fossa compressing the brainstem. A Axial image. B Coronal image. A B

Intracranial mass lesions and raised intracranial pressure • 1131

2 (see below). When sporadic, acoustic neuroma occurs after the third decade and is more frequent in females. The tumour commonly arises near the nerve’s entry point into the medulla or in the internal auditory meatus, usually on the vestibular division. Acoustic neuromas account for 80–90% of tumours at the cerebellopontine angle. Clinical features Acoustic neuroma typically presents with unilateral progressive hearing loss, sometimes with tinnitus. Vertigo is an unusual symptom, as slow growth allows compensatory brainstem mechanisms to develop. In some cases, progressive enlargement leads to distortion of the brainstem and/or cerebellar peduncle, causing ataxia and/or cerebellar signs in the limbs. Distortion of the fourth ventricle and cerebral aqueduct may cause hydrocephalus (see below), which may be the presenting feature. Facial weakness is unusual at presentation but facial palsy may follow surgical removal of the tumour. The tumour may be identified incidentally on cranial imaging. Investigations MRI is the investigation of choice (see Fig. 25.42). Management Surgery is the treatment of choice. If the tumour can be completely removed, the prognosis is excellent, although deafness is a common complication of surgery. Stereotactic radiosurgery (radiotherapy) may be appropriate for some lesions. Neurofibromatosis Neurofibromatosis encompasses two clinically and genetically separate conditions, with an autosomal dominant pattern of inheritance. The more common neurofibromatosis type 1 (NF1) is caused by mutations in the NF1 gene on chromosome 17, half of which are new mutations. NF1 is characterised by neurofibromas (benign peripheral nerve sheath tumours) and skin involvement (Fig. 25.43), and may affect numerous systems (Box 25.77). best chance of life-long remission. The gliomas are incurable; high-grade, WHO grade IV disease still carries a median survival of just over 1 year. In this situation, patient and family should always be involved in decisions regarding treatment. The diagnosis, and often the symptoms, are devastating, and support from palliative care and social work is crucial at an early stage. In WHO grade III disease, prognosis is a little better (2–4 years), and in rarer, more indolent tumours very prolonged survival is possible. Advances have been made recently in terms of therapeutic outcome. Standard care for WHO grade IV glioblastoma multiforme is now combination radiotherapy with temozolomide chemotherapy; although this improves median survival of the population from only 12 to 14.5 months, up to 25% of patients survive for more than 2 years (compared to approximately 10% with radiotherapy alone). Ten percept will survive more than 5 years with temozolomide (virtually unheard of with radiotherapy alone). Benefits are more likely in well-debulked patients who are younger and fitter. Implantation of chemotherapy gives a small survival benefit. Understanding of the molecular biology of brain tumours has allowed the use of biomarkers to guide therapy and prognostic discussions. In patients with methylation of the promoter region of the MGMT (methyl guanine methyl transferase) gene (about 30% of the population), 2-year survival is almost 50%. MGMT reduces the cytotoxicity of temozolomide and this mutation also reduces the enzyme’s activity, rendering the tumour more sensitive to chemotherapy. In grade II and III gliomas, the presence of the loss of heterozygosity (LOH) 1p19q chromosomal abnormality confers chemosensitivity and thus improves prognosis. The presence of a rare mutation in the IDH-1 (isocitrate dehydrogenase) gene confers a more favourable prognosis in patients with glioblastoma. There is a small group of highly malignant grade IV tumours that can be cured with aggressive therapy. Medulloblastomas have a good chance of long-term remission with maximal surgery followed by irradiation of the whole brain and spine; younger patients may also benefit from concomitant and adjuvant chemotherapy. Older patients do not tolerate this, however. Once tumours relapse, chemotherapy response rates are low and survival is short in high-grade disease. In the more uncommon low-grade tumours, repeated courses of chemotherapy can result in much more prolonged survival. In metastatic disease, radiotherapy offers a modest improvement in survival but with costs in terms of quality of life; treatment therefore needs careful discussion with the patient. Benefits may be superior in breast cancer but there is little to separate other pathologies. Occasional chemosensitive cancers, such as small-cell lung cancer, may benefit from systemic chemotherapy but intracerebral metastases represent a late stage of disease and have a short prognosis. Prognosis The WHO histological grading system is a powerful predictor of prognosis in primary CNS tumours, though it does not yet take account of individual biomarkers. For each tumour type and grade, advancing age and deteriorating functional status are the next most important negative prognostic features. The overall 5-year survival rate of about 14% in adults masks a wide variation that depends on tumour type. Acoustic neuroma This is a benign tumour of Schwann cells of the 8th cranial nerve, which may arise in isolation or as part of neurofibromatosis type Fig. 25.43 A café au lait spot (arrow A) and subcutaneous nodules (arrows B) on the forearm of a patient with neurofibromatosis type 1. B B A

1132 • NEUROLOGY Neurofibromatosis type 2 (NF2) is caused by mutations of the NF2 gene on chromosome 22, and is characterised by schwannomas (benign peripheral nerve sheath tumours comprising Schwann cells only) with little skin involvement; the clinical manifestations are more restricted to the eye and nervous system (Box 25.77). Malignant change may occur in NF1 neurofibromas but is rare in NF2 schwannomas. The prevalence of NF1 and NF2 is about 20–50 per 100 000 and 1.5 per 100 000, respectively. Von Hippel–Lindau disease This rare autosomal dominant disease is caused by mutations of the VHL tumour suppressor gene on chromosome 3. It promotes development of tumours affecting the kidney, adrenal gland, CNS, eye, inner ear, epididymis and pancreas, which may undergo malignant change. Benign haemangiomas and haemangioblastomas affect about 80% of patients, and are mostly cerebellar and retinal. 25.77 Neurofibromatosis types 1 and 2: clinical features Neurofibromatosis 1 Neurofibromatosis 2 Skin Cutaneous/subcutaneous neurofibromas Angiomas Café au lait patches (> 6) Axillary/groin freckling Hypopigmented patches Much less commonly affected than in NF1 Café au lait patches (usually < 6) Cutaneous schwannomas: plaque lesions Subcutaneous schwannomas Eyes Lisch nodules (iris fibromas) Glaucoma Congenital ptosis Cataracts Retinal hamartoma Optic nerve meningioma Nervous system Plexiform neurofibromas Malignant peripheral nerve sheath tumours Aqueduct stenosis Slight tonsillar descent Cognitive impairment Epilepsy Vestibular schwannomas Cranial nerve schwannomas (not 1 and 2) Spinal schwannomas Peripheral nerve schwannomas Cranial meningiomas Spinal meningiomas Spinal/brainstem ependymomas Spinal/cranial astrocytoma Bone Scoliosis Osteoporosis Pseudoarthrosis Cardiorespiratory systems Pulmonary stenosis Hypertension Renal artery stenosis Compression from neurofibroma causing restrictive lung defect Gastrointestinal system Gastrointestinal stromal tumour (GIST) Duodenal/ampullary neuroendocrine tumour Fig. 25.44 The circulation of cerebrospinal fluid (CSF). (1) CSF is synthesised in the choroid plexus of the ventricles and flows from the lateral and third ventricles through the aqueduct to the fourth ventricle. (2) At the foramina of Luschka and Magendie it exits the brain, flowing over the hemispheres (3) and down around the spinal cord and roots in the subarachnoid space. (4) It is then absorbed into the dural venous sinuses via the arachnoid villi. Choroid plexus

25.78 Causes of hydrocephalus Congenital malformations • Aqueduct stenosis • Chiari malformations • Dandy–Walker syndrome • Benign intracranial cysts • Vein of Galen aneurysms • Congenital central nervous system infections • Craniofacial anomalies Acquired causes • Mass lesions (especially those in the posterior fossa) • Tumour • Colloid cyst of third ventricle • Abscess • Haematoma • Absorption blockages due to: Inflammation (e.g. meningitis, sarcoidosis) Intracranial haemorrhage Paraneoplastic neurological disease Paraneoplastic neurological syndromes often present before the underlying tumour declares itself and cause considerable disability. They are discussed in full on page 1110. Hydrocephalus Hydrocephalus is the excessive accumulation of CSF within the brain, and may be caused either by increased CSF production, by reduced CSF absorption, or by obstruction of the circulation (Fig. 25.44). Symptoms range from none to sudden death, depending on the speed at which and degree to which hydrocephalus develops. The causes are listed in Box 25.78. The terms ‘communicating’ and ‘non-communicating’ (also known as obstructive) hydrocephalus refer to blockage either outside or within the ventricular system, respectively (Fig. 25.45). Normal pressure hydrocephalus Normal pressure hydrocephalus (NPH) is a controversial entity, said to involve intermittent rises in CSF pressure, particularly at night. It is described in old age as being associated with a triad of gait apraxia, dementia and urinary incontinence.

Intracranial mass lesions and raised intracranial pressure • 1133

villi. A number of drugs may be associated, including tetracycline, vitamin A and retinoid derivatives. Clinical features The usual presentation is with headache, sometimes accompanied by diplopia and visual disturbance (most commonly, transient obscurations of vision associated with changes in posture). Clinical examination reveals papilloedema but little else. False localising cranial nerve palsies (usually of the 6th nerve) may be present. It is important to record visual fields accurately for future monitoring. Investigations Brain imaging is required to exclude a structural or other cause (e.g. cerebral venous sinus thrombosis, p. 1162). The ventricles are typically normal in size or small (‘slit’ ventricles). The diagnosis may be confirmed by lumbar puncture, which shows raised normal CSF constituents at increased pressure (usually

30 cmH2O CSF). Management Management can be difficult and there is no evidence to support any specific treatment. Weight loss in overweight patients may be helpful if it can be achieved. Acetazolamide or topiramate may help to lower intracranial pressure, the latter perhaps aiding weight loss in some patients. Repeated lumbar puncture is an effective treatment for headache but may be technically difficult in obese individuals and is often poorly tolerated. Patients failing to respond, in whom chronic papilloedema threatens vision, may require optic nerve sheath fenestration or a lumbo-peritoneal shunt. Head injury Diagnosis of head trauma is usually clear – either from the history or from signs of external trauma to the head. Brain injury is more likely with skull fracture but can occur without. Individual cranial nerves may be damaged in fractures of the facial bones or skull base. Intracranial effects can be substantial and take several forms: extradural haematoma (collection of blood between the skull and dura); subdural haematoma (collection of blood between the dura and the surface of the brain); intracerebral haematoma; or diffuse axonal injury. Whatever pathology occurs, the resultant RICP may lead to coning (see Figs 25.38 and 25.39). Haematomas are identified by CT and management is by surgical drainage, usually via a burr hole. Penetrating skull fractures lead to increased infection risk. Long-term sequelae include headache, cognitive decline and depression, all contributing to significant social, work, personality and family difficulties. Subdural haematoma may occur spontaneously, particularly in patients on anticoagulants, in old age, and with alcohol misuse. There may or may not be a history of trauma. Patients present with subacute impairment of brain function, both globally (obtundation and coma) and focally (hemiparesis, seizures). Headache may not be present. The diagnosis should always be considered in those who present with reduced conscious level. Beyond the immediate consequences of brain injury, there is increasing suspicion of long-term consequences, including dementia, postulated after either single (moderate or severe) injuries or even after multiple mild injuries, such as in boxers. If substantiated, this would encourage more effort to go into prevention of repeated brain injury in sporting contexts. Fig. 25.45 Magnetic resonance image of hydrocephalus due to aqueduct stenosis. A Axial T2-weighted image (cerebrospinal fluid appears white): note the dilated lateral ventricles. B Sagittal T1-weighted image (cerebrospinal fluid appears black): note the dilated ventricles (top arrow) and narrowed aqueduct (bottom arrow). A B Management Diversion of the CSF by means of a shunt placed between the ventricular system and the peritoneal cavity or right atrium may result in rapid relief of symptoms in obstructive hydrocephalus. The outcome of shunting in NPH is much less predictable and, until a good response can be predicted, the management of individual cases will remain uncertain. Idiopathic intracranial hypertension This usually occurs in obese young women. The annual incidence is about 3 per 100 000. RICP occurs in the absence of a structural lesion, hydrocephalus or other identifiable cause. The aetiology is uncertain but there is an association with obesity in females, perhaps inducing a defect of CSF reabsorption by the arachnoid

1134 • NEUROLOGY may be lower motor neuron signs, including weakness, wasting and reflex impairment (Fig. 25.47). Investigations Where there is no trauma, imaging should not be carried out for isolated cervical pain. MRI is the investigation of choice in those with radicular symptoms. X-rays offer limited benefit, except in excluding destructive lesions, and electrophysiological studies rarely add to clinical examination with MRI. Management Conservative treatment with analgesics and physiotherapy results in resolution of symptoms in the great majority of patients, but a few require surgery in the form of discectomy or radicular decompression. Cervical myelopathy Dorsomedial herniation of a disc and the development of transverse bony bars or posterior osteophytes may result in pressure on the spinal cord or the anterior spinal artery, which supplies the anterior two-thirds of the cord (see Fig. 25.46). Disorders of cerebellar function Cerebellar dysfunction can manifest as incoordination of limb function, gait ataxia (p. 1087), speech or eye movements. Acute dysfunction may be caused by alcohol or prescription drugs (especially the sodium channel-blocking antiepileptic drugs phenytoin and carbamazepine). Inflammatory changes in the cerebellum may cause symptoms in the aftermath of some infections (especially herpes zoster) or as a paraneoplastic phenomenon. The hereditary spinocerebellar ataxias are described on page 1115; they manifest as progressive ataxias in middle and old age, often with other neurological features that aid specific diagnosis. Disorders of the spine and spinal cord The spinal cord and spinal roots may be affected by intrinsic disease or by disorders of the surrounding meninges and bones. The clinical presentation of these conditions depends on the anatomical level at which the cord or roots are affected, as well as the nature of the pathological process involved. It is important to recognise when the spinal cord is at risk of compression (p. 1136) so that urgent action can be taken. Cervical spondylosis Cervical spondylosis is the result of osteoarthritis in the cervical spine. It is characterised by degeneration of the intervertebral discs and osteophyte formation. Such ‘wear and tear’ is extremely common and radiological changes are frequently found in asymptomatic individuals over the age of 50. Spondylosis may be associated with neurological dysfunction. In order of frequency, the C5/6, C6/7 and C4/5 vertebral levels affect C6, C7 and C5 roots, respectively (Fig. 25.46). Cervical radiculopathy Acute onset of compression of a nerve root occurs when a disc prolapses laterally. More gradual onset may be due to osteophytic encroachment of the intervertebral foramina. Clinical features The patient complains of pain in the neck that may radiate in the distribution of the affected nerve root. The neck is held rigidly and neck movements may exacerbate pain. Paraesthesia and sensory loss may be found in the affected segment and there Fig. 25.46 Magnetic resonance image showing cervical cord compression (arrow) in cervical spondylosis. Fig. 25.47 Findings in cervical nerve root compression. Biceps, deltoid and spinati Biceps C5 Brachioradialis Supinator C6 Triceps, fingers and wrist extensors Triceps C7 Reflex loss Muscle weakness Sensory loss (see Fig 25.10, p. 1071) Root

Disorders of the spine and spinal cord • 1135

Pathophysiology The altered mechanics of the lumbar spine result in loss of lumbar lordosis and there may be spasm of the paraspinal musculature. Root pressure is suggested by limitation of flexion of the hip on the affected side if the straight leg is raised (Lasègue’s sign). If the third or fourth lumbar root is involved, Lasègue’s sign may be negative, but pain in the back may be induced by hyperextension of the hip (femoral nerve stretch test). The roots most frequently affected are S1, L5 and L4; the signs of root pressure at these levels are summarised in Figure 25.48. Clinical features The onset may be sudden or gradual. Alternatively, repeated episodes of low back pain may precede sciatica by months or years. Constant aching pain is felt in the lumbar region and may radiate to the buttock, thigh, calf and foot. Pain is exacerbated by coughing or straining but may be relieved by lying flat. Investigations MRI is the investigation of choice if available, since soft tissues are well imaged. Plain X-rays of the lumbar spine are of little value in the diagnosis of disc disease, although they may demonstrate conditions affecting the vertebral body. CT can provide helpful images of the disc protrusion and/or narrowing of exit foramina. Management Some 90% of patients with sciatica recover following conservative treatment with analgesia and early mobilisation; bed rest does not help recovery. The patient should be instructed in backstrengthening exercises and advised to avoid physical manœuvres likely to strain the lumbar spine. Injections of local anaesthetic or glucocorticoids may be useful adjunctive treatment if symptoms are due to ligamentous injury or joint dysfunction. Surgery may have to be considered if there is no response to conservative treatment or if progressive neurological deficits develop. Central disc prolapse with bilateral symptoms and signs and disturbance of sphincter function requires urgent surgical decompression. Lumbar canal stenosis This occurs with a congenitally narrowed lumbar spinal canal, exacerbated by the degenerative changes that commonly occur with age. Pathophysiology The symptoms of spinal stenosis are thought to be due to local vascular compromise secondary to the canal stenosis, rendering Clinical features The onset is usually insidious and painless but acute deterioration may occur after trauma, especially hyperextension injury. Upper motor neuron signs develop in the limbs, with spasticity of the legs usually appearing before the arms are involved. Sensory loss in the upper limbs is common, producing tingling, numbness and proprioception loss in the hands, with progressive clumsiness. Sensory manifestations in the legs are much less common. Neurological deficit usually progresses gradually and disturbance of micturition is a very late feature. Investigations MRI (see Fig. 25.46) (or rarely myelography) will direct surgical intervention. The former provides information on the state of the spinal cord at the level of compression. Management Surgical procedures, including laminectomy and anterior discectomy, may arrest progression of disability but neurological improvement is not the rule. The decision as to whether surgery should be undertaken may be difficult. Manual manipulation of the cervical spine is of no proven benefit and may precipitate acute neurological deterioration. Prognosis The prognosis of cervical myelopathy is variable. In many patients, the condition stabilises or even improves without intervention. If progression results in sphincter dysfunction or pyramidal signs, surgical decompression should be considered. Lumbar spondylosis This term covers degenerative disc disease and osteoarthritic change in the lumbar spine. Pain in the distribution of the lumbar or sacral roots (‘sciatica’) is almost always due to disc protrusion but can be a feature of other rare but important disorders, including spinal tumour, malignant disease in the pelvis and tuberculosis of the vertebral bodies. Lumbar disc herniation While acute lumbar disc herniation is often precipitated by trauma (usually lifting heavy weights while the spine is flexed), genetic factors may also be important. The nucleus pulposus may bulge or rupture through the annulus fibrosus, giving rise to pressure on nerve endings in the spinal ligaments, changes in the vertebral joints or pressure on nerve roots. Fig. 25.48 Findings in lumbar nerve root compression. Knee extension Knee Femoral nerve L4 Ankle dorsiflexion Ankle inversion None L5 Plantar flexion Ankle S1 Reflex loss Muscle weakness Sensory loss (see Fig 25.10, p. 1071) Root L3/L4 L4/L5 L5/S1 Disc level

1136 • NEUROLOGY the nerve roots ischaemic and intolerant of the increased demand that occurs on exercise. Clinical features Patients, who are usually elderly, develop exercise-induced weakness and paraesthesia in the legs (‘spinal claudication’). These symptoms progress with continued exertion, often to the point that the patient can no longer walk, but are quickly relieved by a short period of rest. Physical examination at rest shows preservation of peripheral pulses with absent ankle reflexes. Weakness or sensory loss may only be apparent if the patient is examined immediately after exercise. Investigations The investigation of first choice is MRI, but contraindications (body habitus, metallic implants) may make CT or myelography necessary. Management Lumbar laminectomy may provide relief of symptoms and recovery of normal exercise tolerance. Spinal cord compression Spinal cord compression is one of the more common neurological emergencies encountered in clinical practice and the usual causes are listed in Box 25.79. A space-occupying lesion within the spinal canal may damage nerve tissue either directly by pressure or indirectly by interference with blood supply. Oedema from venous obstruction impairs neuronal function, and ischaemia from arterial obstruction may lead to necrosis of the spinal cord. The early stages of damage are reversible but severely damaged neurons do not recover; hence the importance of early diagnosis and treatment. Clinical features The onset of symptoms of spinal cord compression is usually slow (over weeks) but can be acute as a result of trauma or metastases (see Figs 25.46, 25.49 and 25.50), especially if there is associated arterial occlusion. The symptoms are shown in Box 25.80. Pain and sensory symptoms occur early, while weakness and sphincter dysfunction are usually late manifestations. The signs vary according to the level of the cord compression and the 25.79 Causes of spinal cord compression Site Frequency Causes Vertebral 80% Trauma (extradural) Intervertebral disc prolapse Metastatic carcinoma (e.g. breast, prostate, bronchus) Myeloma Tuberculosis Meninges (intradural, extramedullary) 15% Tumours (e.g. meningioma, neurofibroma, ependymoma, metastasis, lymphoma, leukaemia) Epidural abscess Spinal cord (intradural, intramedullary) 5% Tumours (e.g. glioma, ependymoma, metastasis) 25.80 Symptoms of spinal cord compression Pain • Localised over the spine or in a root distribution, which may be aggravated by coughing, sneezing or straining Sensory • Paraesthesia, numbness or cold sensations, especially in the lower limbs, which spread proximally, often to a level on the trunk Motor • Weakness, heaviness or stiffness of the limbs, most commonly the legs Sphincters • Urgency or hesitancy of micturition, leading eventually to urinary retention 25.82 Investigation of acute spinal cord syndrome • Magnetic resonance imaging of spine or myelography • Plain X-rays of spine • Chest X-ray • Cerebrospinal fluid • Serum vitamin B12 25.81 Signs of spinal cord compression Cervical, above C5 • Upper motor neuron signs and sensory loss in all four limbs • Diaphragm weakness (phrenic nerve) Cervical, C5–T1 • Lower motor neuron signs and segmental sensory loss in the arms; upper motor neuron signs in the legs • Respiratory (intercostal) muscle weakness Thoracic cord • Spastic paraplegia with a sensory level on the trunk • Weakness of legs, sacral loss of sensation and extensor plantar responses Cauda equina • Spinal cord ends approximately at the T12/L1 spinal level and spinal lesions below this level can cause lower motor neuron signs only by affecting the cauda equina structures involved. There may be tenderness to percussion over the spine if there is vertebral disease and this may be associated with a local kyphosis. Involvement of the roots at the level of the compression may cause dermatomal sensory impairment and corresponding lower motor signs. Interruption of fibres in the spinal cord causes sensory loss (p. 1083) and upper motor neuron signs below the level of the lesion, and there is often disturbance of sphincter function. The distribution of these signs varies with the level of the lesion (Box 25.81). The Brown–Séquard syndrome (see Fig. 25.18E, p. 1084) results if damage is confined to one side of the cord; the findings are explained by the anatomy of the sensory tracts (see Fig. 25.11, p. 1072). With compressive lesions, there is usually a band of pain at the level of the lesion in the distribution of the nerve roots subject to compression. Investigations Patients with a history of acute or subacute spinal cord syndrome should be investigated urgently, as listed in Box 25.82. The

Disorders of the spine and spinal cord • 1137

good functional recovery can be expected unless a marked neurological deficit has developed before diagnosis. Extradural compression due to malignancy is the most common cause of spinal cord compression in developed countries and has a poor prognosis. Useful function can be regained if treatment, such as radiotherapy, is initiated within 24 hours of the onset of severe weakness or sphincter dysfunction; management should involve close cooperation with both oncologists and neurosurgeons. Spinal cord compression due to tuberculosis is common in some areas of the world and may require surgical treatment. This should be followed by appropriate antituberculous chemotherapy (p. 592) for an extended period. Traumatic lesions of the vertebral column require specialised neurosurgical treatment. Intrinsic diseases of the spinal cord There are many disorders that interfere with spinal cord function due to non-compressive involvement of the spinal cord itself. A list of these disorders is given in Box 25.83. The symptoms and signs are generally similar to those that would occur with extrinsic compression (see Boxes 25.80 and 25.81), although a suspended sensory loss (see Fig. 25.18F, p. 1084) can occur only with intrinsic disease such as syringomyelia. Urinary symptoms usually occur earlier in the course of an intrinsic cord disorder than with compressive disorders. Investigation of intrinsic disease starts with imaging to exclude a compressive lesion. MRI provides most information about structural lesions, such as diastematomyelia, syringomyelia (Fig. 25.51) or intrinsic tumours. Non-specific signal change may be seen in the spinal cord in inflammatory (see Fig. 25.30, p. 1109) or infective conditions and metabolic disorders such as vitamin B12 deficiency. Lumbar puncture or blood tests may be required to make a specific diagnosis. investigation of choice is MRI (Fig. 25.49), as it can define the extent of compression and associated soft-tissue abnormality (Fig. 25.50). Plain X-rays may show bony destruction and soft-tissue abnormalities. Routine investigations, including chest X-ray, may provide evidence of systemic disease. If myelography is performed, CSF should be taken for analysis; in cases of complete spinal block, this shows a normal cell count with a very elevated protein causing yellow discoloration of the fluid (Froin’s syndrome). The risk of acute deterioration after myelography in spinal cord compression means that the neurosurgeons should be alerted before it is undertaken. Where a secondary tumour is causing the compression, needle biopsy may be required to establish a tissue diagnosis. Management Treatment and prognosis depend on the nature of the underlying lesion. Benign tumours should be surgically excised, and a Fig. 25.49 Axial magnetic resonance image of thoracic spine. A neurofibroma (N) is compressing the spinal cord (SC) and emerging in a ‘dumbbell’ fashion through the vertebral foramen into the paraspinal space. SC N Fig. 25.50 Computed tomographic myelogram of cervical spine at the level of C2 showing bony erosion of vertebra by a metastasis (arrow). Fig. 25.51 Sagittal magnetic resonance image showing descent of cerebellar tonsils and central syrinx. The MRI shows descent of the cerebellar tonsils (top arrow), with a large central cord syrinx extending down from the cervical cord (middle arrow) to the thoracic cord (bottom arrow).

1138 • NEUROLOGY studies and EMG, p. 1076). Neuropathies can occur in association with many systemic diseases, toxins and drugs (Box 25.85). Clinical features Motor nerve involvement produces features of a lower motor neuron lesion (p. 1082). Symptoms and signs of sensory nerve involvement depend on the type of sensory nerve involved (p. 1083); small-fibre neuropathies are often painful. Autonomic involvement may cause postural hypotension, disturbance of sweating, cardiac rhythm and gastrointestinal, bladder and sexual functions; isolated autonomic neuropathies are rare and more commonly complicate other neuropathies. Investigations The investigations required reflect the wide spectrum of causes (Box 25.86). Neurophysiological tests are key in discriminating between demyelinating and axonal neuropathies, and in identifying entrapment neuropathies. Most neuropathies are of the chronic axonal type. Diseases of peripheral nerves Disorders of the peripheral nervous system are common and may affect the motor, sensory or autonomic components, either in isolation or in combination. The site of pathology may be nerve root (radiculopathy), nerve plexus (plexopathy) or nerve (neuropathy). Neuropathies may present as mononeuropathy (single nerve affected), multiple mononeuropathies (‘mononeuritis multiplex’) or a symmetrical polyneuropathy (Box 25.84). Cranial nerves 3–12 share the same tissue characteristics as peripheral nerves elsewhere and are subject to the same range of diseases. Pathophysiology Damage may occur to the nerve cell body (axon) or the myelin sheath (Schwann cell), leading to axonal or demyelinating neuropathies. The distinction is important, as only demyelinating neuropathies are usually susceptible to treatment. Making the distinction requires neurophysiology (nerve conduction 25.83 Intrinsic diseases of the spinal cord Type of disorder Condition Clinical features Congenital Diastematomyelia (spina bifida) Features variably present at birth and deteriorate thereafter LMN features, deformity and sensory loss of legs Impaired sphincter function Hairy patch or pit over low back Incidence reduced by increased maternal intake of folic acid during pregnancy Hereditary spastic paraplegia Onset usually in adult life Autosomal dominant inheritance usual Slowly progressive UMN features affecting legs > arms Little or no sensory loss Infective/inflammatory Transverse myelitis due to viruses (HZV), schistosomiasis, HIV, MS, sarcoidosis Weakness and sensory loss, often with pain, developing over hours to days UMN features below lesion Impaired sphincter function Paraneoplastic May predate tumour diagnosis Vascular Anterior spinal artery infarct due to atherosclerosis, aortic dissection, embolus Abrupt onset Anterior horn cell loss (LMN) at level of lesion UMN features below it Spinothalamic sensory loss below lesion but dorsal column sensation spared Spinal AVM/dural fistula Onset variable (acute to slowly progressive) Variable LMN, UMN, sensory and sphincter disturbance Symptoms and signs often not well localised to site of AVM Neoplastic Glioma, ependymoma Weakness and sensory loss often with pain, developing over months to years UMN features below lesion in cord; additional LMN features in conus Impaired sphincter function Metabolic Vitamin B12 deficiency (subacute combined degeneration) Progressive spastic paraparesis with proprioception loss Absent reflexes due to peripheral neuropathy ± Optic nerve and cerebral involvement (p. 715) Copper deficiency Excess dietary zinc Nitrous oxide toxicity Modifies vitamin B12 metabolism Degenerative Motor neuron disease Relentlessly progressive LMN and UMN features, associated bulbar weakness No sensory involvement (p. 1116) Syringomyelia Gradual onset over months or years, pain in cervical segments Anterior horn cell loss (LMN) at level of lesion, UMN features below it Suspended spinothalamic sensory loss at level of lesion, dorsal columns preserved (see Figs 25.18F (p. 1084) and 25.51) (AVM = arteriovenous malformation; HIV = human immunodeficiency virus; HZV = herpes zoster virus; LMN = lower motor neuron; MS = multiple sclerosis; UMN = upper motor neuron)

Diseases of peripheral nerves • 1139

25.84 Causes of polyneuropathy Genetic • Charcot–Marie–Tooth disease (CMT) • Hereditary neuropathy with liability to pressure palsies (HNPP) • Hereditary sensory ± autonomic neuropathies (HSN, HSAN) • Familial amyloid polyneuropathy • Hereditary neuralgic amyotrophy Drugs • Amiodarone • Antibiotics (dapsone, isoniazid, metronidazole, ethambutol) • Antiretrovirals • Chemotherapy (cisplatin, vincristine, thalidomide) • Phenytoin Toxins • Alcohol • Nitrous oxide (recreational use) • Rarely: lead, arsenic, mercury, organophosphates, solvents Vitamin deficiencies • Thiamin • Pyridoxine • Vitamin B12 • Vitamin E Infections • HIV • Leprosy • Brucellosis Inflammatory • Guillain–Barré syndrome • Chronic inflammatory demyelinating polyradiculoneuropathy • Vasculitis (polyarteritis nodosa, granulomatosis with polyangiitis (also known as Wegener’s granulomatosis), rheumatoid arthritis, systemic lupus erythematosus) • Paraneoplastic (antibody-mediated) Systemic medical conditions • Diabetes • Renal failure • Sarcoidosis Malignant disease • Infiltration Others • Paraproteinaemias • Amyloidosis • Critical illness polyneuropathy/ myopathy 25.85 Common causes of axonal and demyelinating chronic polyneuropathies Axonal • Diabetes mellitus • Alcohol • Uraemia • Cirrhosis • Amyloid • Myxoedema • Acromegaly • Paraneoplasm • Drugs and toxins (see Box 25.84) • Deficiency states (see Box 25.84) • Hereditary factors • Infection (see Box 25.84) • Idiopathic factors Demyelinating • Chronic inflammatory demyelinating polyradiculoneuropathy • Multifocal motor neuropathy • Paraprotein-associated demyelinating neuropathy • Charcot–Marie–Tooth disease type I and type X 25.86 Investigation of peripheral neuropathy Initial tests • Glucose (fasting) • Erythrocyte sedimentation rate, C-reactive protein • Full blood count • Urea and electrolytes • Liver function tests • Serum protein electrophoresis • Vitamin B12, folate • ANA, ANCA • Chest X-ray • HIV testing If initial tests are negative • Nerve conduction studies • Vitamins E and A • Genetic testing (see Box 25.84) • Lyme serology (p. 256) • Serum angiotensin-converting enzyme • Serum amyloid (ANCA = antineutrophil cytoplasmic antibody; ANA = antineutrophil antibody) 25.87 Symptoms and signs in common entrapment neuropathies Nerve Symptoms Muscle weakness/ muscle-wasting Area of sensory loss Median (at wrist) (carpal tunnel syndrome) Pain and paraesthesia on palmar aspect of hands and fingers, waking patient from sleep. Pain may extend to arm and shoulder Abductor pollicis brevis Lateral palm and thumb, index, middle and lateral half fourth finger Ulnar (at elbow) Paraesthesia on medial border of hand, wasting and weakness of hand muscles All small hand muscles, excluding abductor pollicis brevis Medial palm and little finger, and medial half fourth finger Radial Weakness of extension of wrist and fingers, often precipitated by sleeping in abnormal posture, e.g. arm over back of chair Wrist and finger extensors, supinator Dorsum of thumb Common peroneal Foot drop, trauma to head of fibula Dorsiflexion and eversion of foot Nil or dorsum of foot Lateral cutaneous nerve of the thigh (meralgia paraesthetica) Tingling and dysaesthesia on lateral border of thigh Nil Lateral border of thigh Entrapment neuropathy Focal compression or entrapment is the usual cause of a mononeuropathy. Symptoms and signs of entrapment neuropathy are listed in Box 25.87. Entrapment neuropathies may affect anyone but diabetes, excess alcohol or toxins, or genetic syndromes may be predisposing causes. Unless axonal loss

1140 • NEUROLOGY Clinical features Distal paraesthesia and pain precede muscle weakness that ascends rapidly from lower to upper limbs and is more marked proximally than distally. Facial and bulbar weakness commonly develops, and respiratory weakness requiring ventilatory support occurs in 20% of cases. Weakness progresses over a maximum of 4 weeks (usually less). Rapid deterioration to respiratory failure can develop within hours. Examination shows diffuse weakness with loss of reflexes. Miller Fisher syndrome presents with internal and external ophthalmoplegia, ataxia and areflexia. Investigations The CSF protein is raised, but may be normal in the first 10 days. There is usually no increase in CSF white cell count (> 10 × 106 cells/L suggests an alternative diagnosis). Electrophysiological changes may emerge after a week or so, with conduction block and multifocal motor slowing, sometimes most evident proximally as delayed F waves (p. 1076). Antibodies to the ganglioside GM1 are found in about 25%, usually the motor axonal form. Other causes of an acute neuromuscular paralysis should be excluded (e.g. poliomyelitis, botulism, diphtheria, spinal cord syndromes or myasthenia), via the history and examination rather than investigations. Management Active treatment with plasma exchange or intravenous immunoglobulin therapy shortens the duration of ventilation and improves prognosis. In severe GBS, both intravenous immunoglobulin (IVIg) and plasma exchange started within 2 weeks of onset hasten recovery with similar rates of adverse effects but IVIg treatment is significantly more likely to be completed than plasma exchange. Overall, 80% of patients recover completely within 3–6 months, 4% die and the remainder suffer residual neurological disability, which can be severe. Adverse prognostic features include older age, rapid deterioration to ventilation and evidence of axonal loss on EMG. Supportive measures to prevent pressure sores and deep venous thrombosis are essential. Regular monitoring of respiratory function (vital capacity) is needed in the acute phase, as respiratory failure may develop with little warning. Chronic polyneuropathy The most common axonal and demyelinating causes of polyneuropathy are shown in Box 25.85. A chronic symmetrical axonal polyneuropathy, evolving over months or years, is the most common form of chronic neuropathy. Diabetes mellitus is the most common cause but in about 25–50% no cause can be found. Hereditary neuropathy Charcot–Marie–Tooth disease (CMT) is an umbrella term for the inherited neuropathies. The members of this group of syndromes have different clinical and genetic features. The most common CMT is the autosomal dominantly inherited CMT type 1, usually caused by a mutation in the PMP-22 gene. Common signs are distal wasting (‘inverted champagne bottle’ legs), often with pes cavus, and predominantly motor involvement. X-linked and recessively inherited forms of CMT, causing demyelinating or axonal neuropathies, also occur. has occurred, entrapment neuropathies will recover, provided the primary cause is removed, either by avoiding the precipitation of activity or by surgical decompression. Multifocal neuropathy Multifocal neuropathy (mononeuritis multiplex) is characterised by lesions of multiple nerve roots, peripheral nerves or cranial nerves (Box 25.88). Vasculitis is a common cause, either as part of a systemic disease or isolated to the nerves, or it may arise on a background of a polyneuropathy (e.g. diabetes). Multifocal motor neuropathy (MMN) with conduction block is a rare pure motor neuropathy, typically affecting the arms; it is associated with anti-GM1 antibodies in about 50% and responds to intravenous immunoglobulin. Polyneuropathy A polyneuropathy is typically associated with a ‘length-dependent’ pattern, occurring in the longest peripheral nerves first and affecting the distal lower limbs before the upper limbs. Sensory symptoms and signs develop in an ascending ‘glove and stocking’ distribution (p. 1083). In inflammatory demyelinating neuropathies, the pathology may be more patchy, affecting the upper rather than lower limbs. Guillain–Barré syndrome Guillain–Barré syndrome (GBS) is a heterogeneous group of immune-mediated conditions with an incidence of 1–2/100 000/ year. In Europe and North America, the most common variant is an acute inflammatory demyelinating polyneuropathy (AIDP). Axonal variants, either motor (acute motor axonal neuropathy, AMAN) or sensorimotor (acute motor and sensory axonal neuropathy, AMSAN), are more common in China and Japan, and account for 10% of GBS in Western countries (often associated with Campylobacter jejuni). The hallmark is an acute paralysis evolving over days or weeks with loss of tendon reflexes. About twothirds of those with AIDP have a prior history of infection, and an autoimmune response triggered by the preceding infection causes demyelination. A number of GBS variants have been described, associated with specific anti-ganglioside antibodies; the best recognised is Miller Fisher syndrome, which involves anti-GQ1b antibodies. 25.88 Causes of multifocal mononeuropathy Axonal (defined on nerve conduction studies) • Vasculitis (systemic or non-systemic) • Diabetes mellitus • Sarcoidosis • Infection (HIV, hepatitis C, Lyme disease, leprosy, diphtheria) Focal demyelination with/without conduction block • Multifocal motor neuropathy • Multiple compression neuropathies (usually in association with underlying disease, such as diabetes or alcoholism) • Multifocal acquired demyelinating sensory and motor neuropathy (MADSAM) • Hereditary neuropathy with a predisposition to pressure palsy (autosomal dominant, peripheral myelin protein 22 gene) • Lymphoma

Diseases of the neuromuscular junction • 1141

Chronic demyelinating polyneuropathy The acquired chronic demyelinating neuropathies include chronic inflammatory demyelinating peripheral neuropathy (CIDP), multifocal motor neuropathy (see above) and paraproteinassociated demyelinating neuropathy. CIDP typically presents with relapsing or progressive motor and sensory changes, evolving over more than 8 weeks (in distinction to the more acute GBS). It is important to recognise, as it usually responds to glucocorticoids, plasma exchange or intravenous immunoglobulin. Some 10% of patients with acquired demyelinating polyneuropathy have an abnormal serum paraprotein, sometimes associated with a lymphoproliferative malignancy. They may also demonstrate positive antibodies to myelin-associated glycoprotein (anti-MAG antibodies). Brachial plexopathy Trauma usually damages either the upper or the lower parts of the brachial plexus, according to the mechanics of the injury. The clinical features depend on the anatomical site of the damage (Box 25.89). Lower parts of the brachial plexus are vulnerable to infiltration from breast or apical lung tumours (Pancoast tumour, p. 600) or damage by therapeutic irradiation. The lower plexus may also be compressed by a cervical rib or fibrous band between C7 and the first rib at the thoracic outlet. Neuralgic amyotrophy (also known as brachial neuritis) presents as an acute brachial plexopathy of probable inflammatory origin. Severe shoulder pain precedes the appearance of a patchy upper brachial plexus lesion, with motor and/or sensory involvement. There is no specific treatment and recovery is often incomplete; it may recur in about 25% and there is a rare autosomal dominant hereditary form. The appearance of vesicles should indicate the alternative diagnosis of motor zoster. 25.89 Physical signs in brachial plexus lesions Site Affected muscles Sensory loss Upper plexus (Erb–Duchenne) Biceps, deltoid, spinati, rhomboids, brachioradialis (triceps, serratus anterior) Patch over deltoid Lower plexus (Déjerine–Klumpke) All small hand muscles, claw hand (ulnar wrist flexors) Ulnar border of hand/forearm Thoracic outlet syndrome Small hand muscles, ulnar forearm Ulnar border of hand/forearm/ upper arm Spinal root lesions Spinal root lesions (radiculopathy) are described above. Clinical features include muscle weakness and wasting and dermatomal sensory and reflex loss, which reflect the pattern of the roots involved. Pain in the muscles innervated by the affected roots may be prominent. Diseases of the neuromuscular junction Myasthenia gravis This is the most common cause of acutely evolving, fatigable weakness and preferentially affects ocular, facial and bulbar muscles. Pathophysiology Myasthenia gravis is an autoimmune disease, most commonly (80% of cases) caused by antibodies to acetylcholine receptors in the post-junctional membrane of the neuromuscular junction. The resultant blockage of neuromuscular transmission and complement-mediated inflammatory response reduces the number of acetylcholine receptors and damages the end plate (Fig. 25.52). Other antibodies can produce a similar clinical picture, most notably autoantibodies to muscle-specific kinase (MuSK), which is involved in the regulation and maintenance of acetylcholine receptors. About 15% of patients (mainly those with late onset) have a thymoma, most of the remainder displaying thymic follicular hyperplasia. Myasthenic patients are more likely to have associated organ-specific autoimmune diseases. Triggers are not always evident but some drugs (e.g. penicillamine) can precipitate an antibody-mediated myasthenic syndrome that may persist after drug withdrawal. Other drugs, especially aminoglycosides and quinolones, may exacerbate the neuromuscular blockade and should be avoided in patients with myasthenia. Clinical features Myasthenia gravis usually presents between the ages of 15 and 50 years and there is a female preponderance in younger patients. In older patients, males are more commonly affected. It tends to run a relapsing and remitting course. The most evident symptom is fatigable muscle weakness; movement is initially strong but rapidly weakens as muscle use continues. Worsening of symptoms towards the end of the day or following exercise is characteristic. There are no sensory signs or signs of involvement of the CNS, although weakness of the oculomotor muscles may mimic a central eye movement disorder. The first symptoms are usually intermittent ptosis or diplopia but weakness of chewing, swallowing, speaking or limb movement also occurs. Resting of the eyelids (looking downwards) may be followed by increased reflex elevation with up-gaze (so-called Cogan’s lid twitch sign). Any limb muscle may be affected, most commonly those of the shoulder girdle; the patient is unable to undertake tasks above shoulder level, such as combing the hair, without frequent rests. Respiratory muscles may be involved and respiratory failure is an avoidable cause of death. Aspiration may occur if the cough is ineffectual. Ventilatory support is required where weakness is severe or of abrupt onset. Lumbosacral plexopathy Lumbosacral plexus lesions may be caused by neoplastic infiltration or compression by retroperitoneal haematomas. A small-vessel vasculopathy can produce a unilateral or bilateral lumbar plexopathy in association with diabetes mellitus (‘diabetic amyotrophy’) or an idiopathic form in nondiabetic patients. This presents with painful wasting of the quadriceps with weakness of knee extension and an absent knee reflex.

1142 • NEUROLOGY Fig. 25.52 Myasthenia gravis and Lambert–Eaton myasthenic syndrome (LEMS). In myasthenia there are antibodies to the acetylcholine receptors on the post-synaptic membrane, which block conduction across the neuromuscular junction (NMJ). Myasthenic symptoms can be transiently improved by inhibition of acetylcholinesterase (e.g. with Tensilon – edrophonium bromide), which normally removes the acetylcholine. A cell-mediated immune response produces simplification of the post-synaptic membrane, further impairing the ‘safety factor’ of neuromuscular conduction. In LEMS, antibodies to the pre-synaptic voltage calcium channels impair release of acetylcholine from the motor nerve ending; calcium is required for the acetylcholine-containing vesicle to fuse with the pre-synaptic membrane for release into the NMJ. Motor neuron Lambert–Eaton syndrome Antibodies to pre-synaptic calcium channels Acetylcholine packets released by calcium influx Acetylcholine Ca2+ Voltage-gated calcium channel Acetylcholine receptor Acetylcholinesterase removes acetylcholine from neuromuscular junction Sodium channels in clefts amplify potential change Depolarisation of muscle membrane In myasthenia end plate is subject to cell-mediated immune assault (end plate simplified) Myasthenia gravis Antibodies to acetylcholine receptors Investigations Intravenous injection of the short-acting anticholinesterase edrophonium bromide (the Tensilon test) is less widely used than before. Improvement in muscle function occurs within 30 seconds and usually persists for 2–3 minutes but the test is not entirely specific or sensitive. Cover with intravenous atropine is necessary to avoid bradycardia. Planning assessment beforehand (e.g. speech or limb movements) allows some objectivity in gauging the effect. Repetitive stimulation during nerve conduction studies may show a characteristic decremental response (p. 1076) if the muscle has been clinically affected. Anti-MuSK antibodies are more common in acetylcholine receptor antibody-negative patients with prominent bulbar involvement. All patients should have a thoracic CT to exclude thymoma, especially those without anti-acetylcholine receptor antibodies. Screening for associated autoimmune disorders, particularly thyroid disease, is important. Management The goals of treatment are to maximise the activity of acetylcholine at remaining receptors in the neuromuscular junctions and to limit or abolish the immunological attack on motor end plates. The duration of action of acetylcholine is prolonged by inhibiting acetylcholinesterase. The most commonly used anticholinesterase drug is pyridostigmine. Muscarinic side-effects, including diarrhoea and colic, may be controlled by propantheline. Overdosage of anticholinesterase drugs may cause a ‘cholinergic crisis’ due to depolarisation block of motor end plates, with muscle 25.90 Immunological treatment of myasthenia Acute treatments Intravenous immunoglobulin • Lowers production of antibodies and rapidly reduces weakness Plasma exchange • Removing antibody from the blood may produce marked improvement; this is usually brief, so is normally reserved for myasthenic crisis or for pre-operative preparation Long-term treatments Glucocorticoid treatment • Improvement is commonly preceded by marked exacerbation of myasthenic symptoms, so treatment should be initiated in hospital • Usually necessary to continue treatment for months or years, risking adverse effects Pharmacological immunosuppression treatment • Azathioprine 2.5 mg/kg daily reduces the necessary dosage of glucocorticoids and may allow their withdrawal. Effect on clinical features may be delayed for months • Mycophenolate mofetil: less commonly used Thymectomy • Should be considered in any antibody-positive patient under 45 years with symptoms not confined to extraocular muscles, unless the disease has been established for more than 7 years • Likely to be required for thymoma

Diseases of muscle • 1143

Diseases of muscle Muscle disease, either hereditary or acquired, is rare. Most typically, it presents with a proximal symmetrical weakness. Diagnosis is dependent on recognition of clinical clues, such as cardiorespiratory involvement, evolution, family history, exposure to drugs, the presence of contractures, myotonia and other systemic features, and on investigation findings, most importantly EMG and muscle biopsy. Hereditary syndromes include the muscular dystrophies, muscle channelopathies, metabolic myopathies (including mitochondrial diseases) and congenital myopathies. Muscular dystrophies These are inherited disorders with progressive muscle destruction and may be associated with cardiac and/or respiratory involvement and sometimes non-myopathic features (Box 25.91). Myotonic dystrophy is the most common, with a prevalence of about 12/100 000. Clinical features The pattern of the clinical features is defined by the specific syndromes. Onset is often in childhood, although some patients, especially those with myotonic dystrophy, may present as adults. Wasting and weakness are usually symmetrical, without fasciculation or sensory loss, and tendon reflexes are usually preserved until a late stage. Weakness is usually proximal, except in myotonic dystrophy type 1, when it is distal. Investigations The diagnosis can be confirmed by specific molecular genetic testing, supplemented with EMG and muscle biopsy if necessary. Creatine kinase is markedly elevated in the dystrophinopathies 25.91 The muscular dystrophies Type Genetics Age of onset Muscles affected Other features Myotonic dystrophy (DM1) Autosomal dominant; expanded triplet repeat chromosome 19q Any Face (including ptosis), sternomastoids, distal limb, generalised later Myotonia, cognitive impairment, cardiac conduction abnormalities, lens opacities, frontal balding, hypogonadism Proximal myotonic myopathy (PROMM; DM2) Autosomal dominant; quadruplet repeat expansion in Zn finger protein 9 gene chromosome 3q 8–50 years Proximal, especially thigh, sometimes muscle hypertrophy As for DM1 but cognition not affected Muscle pain Duchenne X-linked; deletions in dystrophin gene Xp21 < 5 years Proximal and limb girdle Cardiomyopathy and respiratory failure Becker X-linked; deletions in dystrophin gene Xp21 Childhood/early adulthood Proximal and limb girdle Cardiomyopathy common but respiratory failure uncommon Limb girdle Many mutations on different chromosomes Childhood/early adulthood Limb girdle Very variable depending on genetic subtype, some involve cardiac and respiratory systems Facioscapulohumeral (FSH) Autosomal dominant; tandem repeat deletion chromosome 4q35 7–30 years Face and upper limb girdle, distal lower limb weakness Pain in shoulder girdle common, deafness Cardiorespiratory involvement rare Oculopharyngeal Autosomal dominant and recessive; triplet repeat expansion in PABP2 gene chromosome 14q 30–60 years Ptosis, external ophthalmoplegia, dysphagia, tongue weakness Mild lower limb weakness Emery–Dreifuss X-linked recessive; mutations in emerin gene 4–5 years Humero-peroneal, proximal limb girdle later Contractures develop early Cardiac involvement leads to sudden death fasciculation, paralysis, pallor, sweating, excessive salivation and small pupils. This may be distinguished from severe weakness due to exacerbation of myasthenia (‘myasthenic crisis’) by the clinical features and, if necessary, by the injection of a small dose of edrophonium. Immunological treatment of myasthenia is outlined in Box 25.90. Thymectomy may improve overall prognosis but awaits clinical trial confirmation. Prognosis is variable and remissions may occur spontaneously. When myasthenia is entirely ocular, prognosis is excellent and disability slight. Young female patients with generalised disease may benefit from thymectomy, while older patients are less likely to have a remission despite treatment. Rapid progression of the disease more than 5 years after onset is uncommon. Lambert–Eaton myasthenic syndrome Other rarer conditions can present with muscle weakness due to impaired transmission across the neuromuscular junction. The most common of these is the Lambert–Eaton myasthenic syndrome (LEMS), which can occur as an inflammatory or paraneoplastic phenomenon. Antibodies to pre-synaptic voltagegated calcium channels (see Fig. 25.52) impair transmitter release. Patients may have autonomic dysfunction (e.g. dry mouth) in addition to muscle weakness but the cardinal clinical sign is absence of tendon reflexes, which return after sustained contraction of the relevant muscle. The condition is associated with underlying malignancy in a high percentage of cases and investigation must be directed towards identifying any neoplasm. Diagnosis is made electrophysiologically on the presence of post-tetanic potentiation of motor response to nerve stimulation at a frequency of 20–50/sec. Treatment is with 3,4-diaminopyridine, or pyridostigmine and immunosuppression.

1144 • NEUROLOGY Mitochondrial dysfunction can be caused by alterations in either mitochondrial DNA or genes encoding for oxidative processes. Genetic abnormalities or mutations in mitochondrial DNA may affect single individuals and single tissues (most commonly muscle). Thus, patients with exercise intolerance, myalgia and sometimes recurrent myoglobinuria may have isolated pathogenic mutations in genes encoding for oxidation pathways. Inherited disorders of the oxidative pathways of the respiratory chain in mitochondria cause a group of disorders, either restricted to the muscle or associated with non-myopathic features (Box 25.93). Many of these mitochondrial disorders are inherited via the mitochondrial genome, down the maternal line (p. 49). Diagnosis is based on clinical appearances, supported by muscle biopsy appearance (usually with ‘ragged red’ and/or cytochrome oxidase-negative fibres), and specific mutations either on blood or, more reliably, muscle testing. Mutations may be due either to point mutations or to deletions of mitochondrial DNA. A disorder called Leber hereditary optic neuropathy (LHON) is characterised by acute or subacute loss of vision, most frequently in males, due to bilateral optic atrophy. Three point mutations account for more than 90% of LHON cases. Channelopathies Inherited abnormalities of the sodium, calcium and chloride ion channels in striated muscle produce various syndromes of familial periodic paralysis, myotonia and malignant hyperthermia, which may be recognised by their clinical characteristics and potassium abnormalities (Box 25.94). Genetic testing is available. Acquired myopathies These include the inflammatory myopathies, or myopathy associated with a range of metabolic and endocrine disorders or drug and toxin exposure (Fig. 25.53). (Duchenne and Becker) but is normal or moderately elevated in the other dystrophies. Screening for an associated cardiac abnormality (cardiomyopathy or dysrhythmia) is important. Management There is no specific therapy for most of these conditions but physiotherapy and occupational therapy help patients cope with their disability. Glucocorticoids can be used in Duchenne muscular dystrophy but side-effects should be anticipated and avoided by dose modification. Ataluren is a compound given by infusion to affected individuals that may ‘override’ the stop sign in Duchenne, theoretically leading to normalisation of muscle proteins and potentially reducing or arresting functional deteriorations. Treatment of associated cardiac failure or arrhythmia (with pacemaker insertion if necessary) may be required; similarly, management of respiratory complications (including nocturnal hypoventilation) can improve quality of life. Improvements in non-invasive ventilation have led to significant improvements in survival for patients with Duchenne muscular dystrophy. Genetic counselling is important. Inherited metabolic myopathies There are a large number of rare inherited disorders that interfere with the biochemical pathways that maintain the energy supply (adenosine triphosphate, ATP) to muscles. These are mostly recessively inherited deficiencies in the enzymes necessary for glycogen or fatty acid (β-oxidation) metabolism (Box 25.92). They typically present with muscle weakness and pain. Mitochondrial disorders Mitochondrial diseases are discussed on page 49. Mitochondria are present in all tissues and dysfunction causes widespread effects on vision (optic atrophy, retinitis pigmentosa, cataracts), hearing (sensorineural deafness) and the endocrine, cardiovascular, gastrointestinal and renal systems. Any combination of these should raise the suspicion of a mitochondrial disorder, especially if there is evidence of maternal transmission. 25.92 Inherited disorders of muscle metabolism Disease Clinical features Diagnosis Carbohydrate (glycogen) metabolism Myophosphorylase deficiency (McArdle’s disease): autosomal recessive Exercise-induced myalgia, stiffness, weakness (with ‘second wind’ phenomenon), myoglobinuria Creatine kinase (CK) elevated Muscle biopsy Enzyme assay Acid maltase deficiency (Pompe’s disease): autosomal recessive Infantile form: death within 2 years Childhood: death in twenties or thirties Adult: progressive proximal myopathy with respiratory failure CK elevated Blood lymphocyte analysis for glycogen granules Muscle biopsy Enzyme assay Lipid metabolism (β-oxidation) Carnitine-palmitoyl transferase (CPT) deficiency Myalgia after exercise, myoglobinuria, weakness CK normal between attacks Urinary organic acids Enzyme assays Muscle biopsy 25.93 Mitochondrial syndromes Syndrome Clinical features Myoclonic epilepsy with ragged red fibres (MERRF) Myoclonic epilepsy, cerebellar ataxia, dementia, sensorineural deafness ± peripheral neuropathy, optic atrophy and multiple lipomas Mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS) Episodic encephalopathy, stroke-like episodes often preceded by migraine-like headache, nausea and vomiting Chronic progressive external ophthalmoplegia (CPEO) Progressive ptosis and external oculomotor palsy, proximal myopathy ± deafness, ataxia and cardiac conduction defects Kearns–Sayre syndrome Like CPEO but early age of onset (< 20 years), heart block, pigmentary retinopathy Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) Progressive ptosis, external oculomotor palsy, gastrointestinal dysmotility (often pseudo-obstruction), diffuse leucoencephalopathy, thin body habitus, peripheral neuropathy and myopathy Neuropathy, ataxia and retinitis pigmentosa (NARP) Weakness, ataxia and progressive loss of vision, along with dementia, seizures and proximal weakness

Diseases of muscle • 1145

25.94 Muscle channelopathies Channel Muscle disease Gene and inheritance Clinical features Sodium Paramyotonia congenita SCN4A (17q35) Autosomal dominant Cold-evoked myotonia with episodic weakness provoked by exercise and cold Potassium-aggravated myotonia SCN4A Pure myotonia without weakness provoked by potassium Hyperkalaemic periodic paralysis SCN4A Autosomal dominant Brief (mins to hours), frequent episodes of weakness provoked by rest, cold, potassium, fasting, pregnancy, stress Less common than hypokalaemic periodic paralysis Hypokalaemic periodic paralysis SCN4A Autosomal dominant (one-third new mutations) Longer (hours to days) episodic weakness triggered by rest, carbohydrate loading, cold Chloride Myotonia congenita: Thomsen’s disease CLCN1 Autosomal dominant Myotonia usually mild, little weakness Becker’s disease CLCN1 Autosomal recessive Myotonia often severe, transient weakness Calcium Hypokalaemic periodic paralysis CACNA1S Autosomal dominant Episodic weakness triggered by carbohydrate meal Malignant hyperthermia CACNA1S, CACNL2A Autosomal dominant Hyperpyrexia due to excess muscle activity, precipitated by drugs, usually anaesthetic agents; most common cause of death during general anaesthetic Potassium Andersen–Tawil syndrome KCNJ2 Autosomal dominant Similar to hypokalaemic periodic paralysis, associated with cardiac and non-myopathic features (skeletal and facial) Ryanodine receptor Malignant hyperthermia Central core and multicore disease RYR1 (19q13) RYR1 Mostly autosomal dominant As malignant hyperthermia above Present in infancy with mild progressive weakness Fig. 25.53 Causes of acquired proximal myopathy. Inflammatory • Polymyositis • Dermatomyositis • Inclusion body myositis (predominantly distal effects) Drugs • Glucocorticoids • Statins • Amiodarone • β-blockers • Opiates • Chloroquine • Ciclosporin • Vincristine • Clofibrate • Zidovudine Paraneoplastic • Carcinomatous neuromyopathy • Dermatomyositis Toxic • Alcohol (chronic and acute syndromes) • Amphetamines/cocaine/heroin • Vitamin E • Organophosphates • Snake venoms Endocrine/metabolic • Hypothyroidism • Hyperthyroidism • Acromegaly • Cushing’s syndrome (including iatrogenic) • Addison’s disease • Conn’s syndrome • Osteomalacia • Hypokalaemia (liquorice, diuretic and purgative abuse) • Hypercalcaemia (disseminated bony metastases)

1146 • NEUROLOGY epilepsydiagnosis.org International League Against Epilepsy: free access to videos of different seizure types and clinical summaries of the epilepsies. headinjurysymptoms.org Symptoms and management of mild and moderate head injury. ihs-classification.org/en/ International Headache Society: full access to 3rd edition of International Classification of Headache Disorders. neurosymptoms.org Advice on managing functional neurological symptoms. ninds.nih.gov National Institute of Neurological Disorders and Stroke. sign.ac.uk Scottish Intercollegiate Guidelines network: SIGN 107 Diagnosis and management of headache in adults; SIGN 110 Early management of patients with a head injury; SIGN 113 Diagnosis and pharmacological management of Parkinson’s disease; SIGN 143 Diagnosis and management of epilepsy in adults. wfneurology.org World Federation of Neurology. Further information Journal articles Scolding N, Barnes D, Cader S, et al. Association of British Neurologists: revised (2015) guidelines for prescribing diseasemodifying treatments in multiple sclerosis. Pract Neurol 2015; 0:1–7. Websites aneuroa.org/ American Neurological Association. brainandspine.org.uk and dizziness-and-balance.com/disorders Diagnosing benign paroxysmal positional vertigo.

Ch04-3 Clinical Medicine

16-26 Stroke medicine

26 Stroke medicine

Stroke medicine P Langhorne Clinical examination in stroke disease 1148 Functional anatomy and physiology 1150 Investigations 1151 Presenting problems 1152 Weakness 1152 Speech disturbance 1152 Visual deficit 1152 Visuo-spatial dysfunction 1152 Ataxia 1153 Headache 1153 Seizure 1153 Coma 1153 Stroke 1153 Pathophysiology 1153 Clinical features 1155 Investigations 1157 Management 1158 Subarachnoid haemorrhage 1160 Clinical features 1161 Investigations 1161 Management 1162 Cerebral venous disease 1162 Clinical features 1162 Investigations and management 1162

1148 • STROKE MEDICINE Clinical examination in stroke disease Blood pressure and cardiac auscultation Higher cerebral function Speech and language Attention and neglect Abbreviated mental test Cranial nerve function Neck stiffness/pain Visual fields Nerve palsy, e.g. 3rd, 6th, 7th or 12th General appearance Conscious level Posture: leaning to one side? Facial symmetry

Gait Able to weight-bear? Ataxic Hemiparetic gait pattern Sensory system Touch sensation Cortical sensory function: sensory inattention or neglect Joint position sense

Motor system Muscle bulk Abnormal posture or movements Tone Strength, including pronator drift Co-ordination Tendon reflexes Plantar reflexes

Hemiparetic posture Left pronator drift Visual field defect Mitral stenosis Extensor plantar reflex Fanning of toes Up Atrial fibrillation Left facial (7th nerve) palsy Pulse Rate and rhythm Loud Loud OS A2P2 MDM

Clinical examination in stroke disease • 1149

Rapid assessment of suspected stroke Rosier scale Can be used by emergency staff to indicate probability of a stroke in acute presentations: Unilateral facial weakness +1 Loss of consciousness −1 Unilateral grip weakness +1 Seizure −1 Unilateral arm weakness +1 Unilateral leg weakness +1 Speech loss +1 Visual field defect +1 Total (−2 to +6); score of > 0 indicates stroke is possible cause Exclusion of hypoglycaemia • Bedside blood glucose testing with BMstix Language deficit • History and examination may indicate a language deficit • Check comprehension (‘lift your arms, close your eyes’) to identify a receptive dysphasia • Ask patient to name people/objects (e.g. nurse, watch, pen) to identify a nominal dysphasia • Check articulation (ask patient to repeat phrases after you) for dysarthria Motor deficit Subtle pyramidal signs: • Check for pronator drift: ask patient to hold out arms and maintain their position with eyes closed (see opposite) • Check for clumsiness of fine finger movements Sensory and visual inattention • Establish that sensation/visual field is intact on testing one side at a time • Retest sensation/visual fields on simultaneous testing of both sides; the affected side will no longer be felt/seen • Perform clock drawing test (see below) Truncal ataxia • Check if patient can sit up or stand without support General examination Skin • Xanthelasma • Rash (arteritis, splinter haemorrhages) • Colour change (limb ischaemia, deep vein thrombosis) • Pressure injury Eyes • Arcus senilis • Diabetic retinopathy • Hypertensive retinopathy • Retinal emboli Cardiovascular system • Heart rhythm (?atrial fibrillation) • Blood pressure (high or low) • Carotid bruit • Jugular venous pulse (raised in heart failure, low in hypovolaemia) • Murmurs (source of embolism) • Peripheral pulses and bruits (?generalised arteriopathy) Respiratory system • Signs of pulmonary oedema or infection • Oxygen saturation Abdomen • Palpable bladder (urinary retention) Locomotor system • Injuries sustained during collapse • Comorbidities that influence recovery, e.g. osteoarthritis Clock drawing test A An image drawn by a doctor. B An image drawn by a patient with left-sided neglect. A B

1150 • STROKE MEDICINE Functional anatomy and physiology The main arterial supply of the brain comes from the internal carotid arteries, which supply the anterior brain through the anterior and middle cerebral arteries, and the vertebral and basilar arteries (vertebrobasilar system), which provide the posterior circulation to the posterior cerebral arteries. The anterior and middle cerebral arteries supply the frontal and parietal lobes, while the posterior cerebral artery supplies the occipital lobe. The vertebral and basilar arteries perfuse the brainstem, mid-brain and cerebellum (Fig. 26.2). The functions of each of these Cerebrovascular disease is the third most common cause of death in high-income countries after cancers and ischaemic heart disease, and the most common cause of severe physical disability. It includes a range of disorders of the central nervous system (Fig. 26.1). Stroke is the most common clinical manifestation of cerebrovascular disease and results in episodes of brain dysfunction due to focal ischaemia or haemorrhage. Subarachnoid haemorrhage (SAH) and cerebral venous thrombosis (CVT) will be discussed separately, since their pathophysiology, clinical manifestations and management are distinct from those of stroke. Vascular dementia is described on page 1191. Fig. 26.1 A classification of stroke disease. Stroke (acute, focal brain dysfunction due to vascular disease) Total anterior circulation stroke (TACS) (15%) Partial anterior circulation stroke (PACS) (30%) Lacunar stroke (LACS) (20%) Posterior circulation stroke (POCS) (20%) Intracerebral haemorrhage (10%) Subarachnoid haemorrhage (5%) Central venous thrombosis (<1%) Anterior (carotid) circulation (65%) Posterior (vertebrobasilar circulation) (20%) Brain parenchyma (10%) Subarachnoid space (5%) Venous system Infarct (85%) Arterial (>99%) Haemorrhage (15%) Infarct (often develops secondary haemorrhage) Venous (<1%) • Embolism (cardiac, major vessels) • Thrombosis in situ Clinical classification Site of lesion Pathology Vascular system Common pathophysiology • Thrombosis in situ • Thrombosis • Embolism (cardiac) • Vascular degeneration • Aneurysm • Arteriovenous malformation • Aneurysm • Arteriovenous malformation • Vascular degeneration • Thrombosis in situ Fig. 26.2 Arterial circulation of the brain. A Horizontal view. B Lateral view. Anterior (carotid) circulation Posterior (vertebrobasilar) circulation Anterior cerebral artery (ACA) Posterior communicating artery (PCoA) Posterior cerebral artery (PCA) Small perforating vessels Anterior communicating artery (ACoA) Basilar artery (BA) Vertebral arteries (VA) Internal carotid arteries (ICA) Middle cerebral artery (MCA) PCA PCoA BA VA ICA ACA MCA A B

Investigations • 1151

Neuroimaging Computed tomography (CT) scanning is the mainstay of emergency stroke imaging. It allows the rapid identification of intracerebral bleeding and stroke ‘mimics’ (i.e. pathologies other than stroke that have similar presentations), such as tumours. Magnetic resonance imaging (MRI) is used when there is diagnostic uncertainty or delayed presentation, and when more information on brain structure and function is required (Fig. 26.4). Contraindications to MRI include cardiac pacemakers and claustrophobia on entering the scanner. CT angiography (CTA) and CT perfusion are now being used to characterise the cerebral circulation and areas of ischaemia better (p. 1072). Vascular imaging Various techniques are used to obtain images of extracranial and intracranial blood vessels (Fig. 26.5). The least invasive is ultrasound (Doppler or duplex scanning), which is used to image the carotid and the vertebral arteries in the neck. In skilled hands, reliable information can be provided about the degree of arterial stenosis and the presence of ulcerated plaques. Blood flow in the intracerebral vessels can be examined using transcranial Doppler. While the anatomical resolution is limited, it is improving and many centres no longer require formal angiography before proceeding to carotid endarterectomy (see below). Blood flow can also be detected by specialised sequences in MR angiography (MRA) or CTA but the anatomical resolution is still not as good as that of intra-arterial angiography, which outlines blood vessels by the injection of radio-opaque contrast intravenously or intra-arterially. The X-ray images obtained can be enhanced by the use of computer-assisted digital subtraction or spiral CT. Because of the significant risk of complications, intra-arterial contrast angiography is reserved for use when non-invasive methods have provided a contradictory picture or incomplete information, or when it is necessary to image the intracranial circulation in detail, e.g. to delineate a saccular aneurysm, an arteriovenous malformation or vasculitis. Blood tests These identify underlying causes of cerebrovascular disease, e.g. blood glucose (diabetes mellitus), triglycerides and cholesterol (hyperlipidaemia) or full blood count (polycythaemia). Erythrocyte Fig. 26.3 Venous circulation of the brain. Posterior Superior sagittal sinus Cavernous sinus Transverse sinus Jugular vein Anterior Fig. 26.4 Acute stroke seen on computed tomography (CT) scan with corresponding magnetic resonance imaging (MRI) appearance. A CT may show no evidence of early infarction. B A corresponding image seen on MRI diffusion weighted imaging (DWI) with changes of infarction in the middle cerebral artery (MCA) territory (arrows). A and B, Courtesy of Dr A. Farrell and Prof. J. Wardlaw. A B areas of the brain are described on page 1064. Communicating arteries provide connections between the anterior and posterior circulations and between left and right hemispheres, creating protective anastomotic connections that form the circle of Willis. In health, regulatory mechanisms maintain a constant cerebral blood flow across a wide range of arterial blood pressures to meet the high resting metabolic activity of brain tissue; cerebral blood vessels dilate when systemic blood pressure is lowered and constrict when it is raised. This autoregulatory mechanism can be disrupted after stroke. The venous collecting system is formed by a collection of sinuses over the surface of the brain, which drain into the jugular veins (Fig. 26.3). Investigations A range of investigations may be required to answer specific questions about brain structure and function and about the function of the vascular system.

1152 • STROKE MEDICINE are initially reduced but then become increased with a spastic pattern of increased tone (see Box 25.14, p. 1082). Upper motor neuron weakness of the face (7th cranial nerve) is often present. Speech disturbance Dysphasia and dysarthria are the most common presentations of disturbed speech in stroke (p. 1087). Dysphasia indicates damage to the dominant frontal or parietal lobe (see Box 25.2, p. 1066), while dysarthria is a non-localising feature that reflects weakness or incoordination of the face, pharynx, lips, tongue or palate. Visual deficit Visual loss can be due to unilateral optic ischaemia (called amaurosis fugax if transient), caused by disturbance of blood flow in the internal carotid artery and ophthalmic artery, leading to monocular blindness. Ischaemia of the occipital cortex or post-chiasmic nerve tracts results in a contralateral hemianopia (p. 1088). Visuo-spatial dysfunction Damage to the non-dominant cortex often results in contralateral visuo-spatial dysfunction, e.g. sensory or visual neglect and apraxia (inability to perform complex tasks despite normal motor, sensory and cerebellar function; p. 1086), sometimes misdiagnosed as delirium. sedimentation rate (ESR) and immunological tests, such as antineutrophil cytoplasmic antibodies (ANCAs, p. 992), may be required when vasculitis is suspected. Genetic testing for rarer inherited conditions, such as CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy), may be indicated. Lumbar puncture Lumbar puncture (p. 1077) is reserved for investigation of SAH. Cardiovascular investigations Electrocardiography (ECG; p. 448), including ECG monitoring and echocardiography (p. 451), may reveal abnormalities that may cause cardiac embolism in stroke. Presenting problems Most vascular lesions develop suddenly within a matter of minutes or hours, and so should be considered in the differential diagnosis of patients with any acute neurological presentation. Weakness Unilateral weakness is the classical presentation of stroke and, much more rarely, of CVT. The weakness is sudden, progresses rapidly and follows a hemiplegic pattern (see Fig. 25.17, p. 1082). There is rarely any associated abnormal movement. Reflexes Fig. 26.5 Different techniques for imaging blood vessels. A Doppler scan showing 80% stenosis of the internal carotid artery (arrow). B Three-dimensional reconstruction of CT angiogram showing stenosis at the carotid bifurcation (arrow). C MR angiogram showing giant aneurysm at the middle cerebral artery bifurcation (arrow). D Intra-arterial angiography showing arteriovenous malformation (arrow). A–D, Courtesy of Dr D. Collie. A B C D

Stroke • 1153

However, if and when these homeostatic mechanisms fail, the process of ischaemia starts, and ultimately leads to infarction unless the vascular supply is restored. As the cerebral blood flow declines, different neuronal functions fail at various thresholds (Fig. 26.7). Once blood flow falls below the threshold for the maintenance of electrical activity, neurological deficit develops. At this level of blood flow, neurons are still viable; if blood flow increases again, function returns and the patient will have had a Fig. 26.6 Homeostatic responses to falling perfusion pressure in the brain following arterial occlusion. Vasodilatation initially maintains cerebral blood flow (A), but after maximal vasodilatation further falls in perfusion pressure lead to a decline in blood flow. An increase in tissue oxygen extraction, however, maintains the cerebral metabolic rate for oxygen (B). Still further falls in perfusion, and therefore blood flow, cannot be compensated; cerebral oxygen availability falls and symptoms appear, then infarction (C). Symptoms Infarction Cerebral oxygen extraction Cerebral blood volume Cerebral oxygen metabolism Blood flow Perfusion pressure Vasodilatation A B C Time (mins/hrs) 26.1 Risk factors for stroke Fixed risk factors • Age • Gender (male > female except at extremes of age) • Race (Afro-Caribbean > Asian

European) • Previous vascular event: Myocardial infarction Stroke Peripheral vascular disease • Heredity • Sickle cell disease • High fibrinogen Modifiable risk factors • Blood pressure • Cigarette smoking • Hyperlipidaemia • Diabetes mellitus • Heart disease: Atrial fibrillation Congestive cardiac failure Infective endocarditis • Excessive alcohol intake • Oestrogen-containing drugs: Oral contraceptive pill Hormone replacement therapy • Polycythaemia Ataxia Stroke causing damage to the cerebellum and its connections can present as an acute ataxia (p. 1086) and there may be associated brainstem features such as diplopia (p. 1088) and vertigo (p. 1086). The differential diagnosis includes vestibular disorders (p. 1104). Headache Sudden severe headache is the cardinal symptom of SAH but also occurs in intracerebral haemorrhage. Although headache is common in acute ischaemic stroke, it is rarely a dominant feature (p. 1080). Headache also occurs in cerebral venous disease. Seizure Seizure is unusual in acute stroke but may be generalised or focal (especially in cerebral venous disease). Coma Coma is uncommon, though it may occur with a brainstem event. If present in the first 24 hours, it usually indicates a subarachnoid or intracerebral haemorrhage (see Box 10.26, p. 194). Stroke Stroke is a common medical emergency. The incidence rises steeply with age, and in many lower- and middle-income countries it is rising in association with less healthy lifestyles. About 20% of stroke patients die within a month of the event and at least half of those who survive are left with physical disability. Pathophysiology Of the 180–300 patients per 100 000 population presenting annually with a stroke, 85% sustain a cerebral infarction due to inadequate blood flow to part of the brain, and most of the remainder have an intracerebral haemorrhage (see Fig. 26.1). Cerebral infarction Cerebral infarction is mostly caused by thromboembolic disease secondary to atherosclerosis in the major extracranial arteries (carotid artery and aortic arch). About 20% of infarctions are due to embolism from the heart, and a further 20% are due to thrombosis in situ caused by intrinsic disease of small perforating vessels (lenticulostriate arteries), producing so-called lacunar infarctions. The risk factors for ischaemic stroke reflect the risk factors for the underlying vascular disease (Box 26.1). About 5% are due to rare causes, including vasculitis (p. 1040), endocarditis (p. 527) and cerebral venous disease (see below). Cerebral infarction takes some hours to complete, even though the patient’s deficit may be maximal shortly after the vascular occlusion. After the occlusion of a cerebral artery, infarction may be forestalled by the opening of anastomotic channels from other arterial territories that restore perfusion to its territory. Similarly, reduction in perfusion pressure leads to compensatory homeostatic changes to maintain tissue oxygenation (Fig. 26.6). These compensatory changes can sometimes prevent occlusion of even a carotid artery from having any clinically apparent effect.

1154 • STROKE MEDICINE of the excitatory neurotransmitter glutamate into the extracellular fluid. Glutamate opens membrane channels, allowing influx of calcium and more sodium into the neurons. Calcium activates intracellular enzymes that complete the destructive process. The release of inflammatory mediators by microglia and astrocytes causes death of all cell types in the area of maximum ischaemia. The infarction process is worsened by anaerobic production of lactic acid (Fig. 26.8) and consequent fall in tissue pH. There have been attempts to develop neuroprotective drugs to slow down the processes leading to irreversible cell death but so far these have proved disappointing. The final outcome of occlusion of a cerebral blood vessel thus depends on the competence of circulatory homeostatic mechanisms, the metabolic demand, and the severity and duration of the reduction in blood flow. Higher brain temperature, e.g. in fever, and higher blood glucose have both been associated with a greater volume of infarction for a given reduction in cerebral blood flow. Subsequent restoration of blood flow may cause haemorrhage into the infarcted area (‘haemorrhagic transformation’). This is particularly likely in patients given antithrombotic or thrombolytic drugs, and in patients with larger infarcts. Radiologically, a cerebral infarct can be seen as a lesion that comprises a mixture of dead brain tissue that is already undergoing autolysis, and tissue that is ischaemic and swollen but recoverable (the ‘ischaemic penumbra’). The infarct swells with time and is at its maximal size a couple of days after stroke onset. At this stage, it may be big enough to exert mass effect both clinically and radiologically; sometimes, decompressive craniectomy is required (see below). After a few weeks, the oedema subsides and the infarcted area is replaced by a sharply defined fluid-filled cavity. Intracerebral haemorrhage Intracerebral haemorrhage causes about 10% of acute stroke events but is more common in low-income countries. It usually results from rupture of a blood vessel within the brain parenchyma but may also occur in a patient with SAH (see transient ischaemic attack (TIA). However, if blood flow falls further, a level is reached at which irreversible cell death starts. Hypoxia leads to an inadequate supply of adenosine triphosphate (ATP), which leads to failure of membrane pumps, thereby allowing influx of sodium and water into cells (cytotoxic oedema) and release Fig. 26.8 The process of neuronal ischaemia and infarction. (1) Reduction of blood flow reduces supply of oxygen and hence adenosine triphosphate (ATP). H+ is produced by anaerobic metabolism of available glucose. (2) Energy-dependent membrane ionic pumps fail, leading to cytotoxic oedema and membrane depolarisation, allowing calcium entry and releasing glutamate. (3) Calcium enters cells via glutamate-gated channels and (4) activates destructive intracellular enzymes (5), destroying intracellular organelles and cell membrane, with release of free radicals. Free fatty acid release activates pro-coagulant pathways that exacerbate local ischaemia. (6) Glial cells take up H+, can no longer take up extracellular glutamate and also suffer cell death, leading to liquefactive necrosis of whole arterial territory. (AMPA = α-amino-3-hydroxy-5-methyl-4isoxazolepropionic acid receptor; NMDA = N-methyl-D-aspartate; NO = nitric oxide) ↓Oxygen +glucose Anaerobic metabolism ↓ATP H+ Ca2+ Na+/K+ ATPase↓ Lipid peroxidases Proteases NO synthase Ca2+ Na+ AMPA NMDA Glutamate ↓Glutamate uptake by glia H+ K+ Glia Fe + H Water Na+ Oedema Free radicals Ca2+

Thromboxane Prostaglandins Free fatty acids Depolarisation Fig. 26.7 Thresholds of cerebral ischaemia. Symptoms of cerebral ischaemia appear when the blood flow has fallen to less than half of normal and energy supply is insufficient to sustain neuronal electrical function. Full recovery can occur if this level of flow is returned to normal but not if it is sustained. Further blood flow reduction below the next threshold causes failure of cell ionic pumps and starts the ischaemic cascade, leading to cell death.

Increased oxygen extraction Failure of electrical function Failure of ionic pumps Potassium efflux Sodium influx Cerebral blood flow mL/100 g/min Symptoms Cell death

Stroke • 1155

such as abnormal movement). Provided there is a clear history of this, the chance of a brain lesion being anything other than vascular is 5% or less (Box 26.3). If symptoms progress over hours or days, other diagnoses must be excluded. Delirium and memory or balance disturbance are more often due to stroke mimics. Transient symptoms, e.g. syncope, amnesia, delirium and dizziness, do not reflect focal cerebral dysfunction but are often mistakenly attributed to TIA (see Fig. 10.3, p. 182, and Box 26.4). Campaigns to raise public awareness of the emergency nature of stroke exploit the fact that weakness of the face or arm, or disturbance of speech is the most common presentation. The clinical presentation of stroke depends on which arterial territory is involved and the size of the lesion (see Fig. 26.1). These will both have a bearing on management, such as suitability for carotid endarterectomy. The neurological deficit can be identified Fig. 26.9 CT scans showing intracerebral haemorrhage. A Basal ganglia haemorrhage with intraventricular extension. B Small cortical haemorrhage. A and B, Courtesy of Dr A. Farrell and Prof. J. Wardlaw. A B 26.3 Differential diagnosis of stroke and transient ischaemic attack ‘Structural’ stroke mimics • Primary cerebral tumours • Metastatic cerebral tumours • Extradural or subdural haematoma • Demyelination • Peripheral nerve lesions (vascular or compressive) • Cerebral abscess ‘Functional’ stroke mimics • Todd’s paresis (after epileptic seizure) • Hypoglycaemia • Migrainous aura (with or without headache) • Focal seizures • Ménière’s disease or other vestibular disorder • Conversion disorder (p. 1202) • Encephalitis 26.2 Causes of intracerebral haemorrhage and associated risk factors Disease Risk factors Complex small-vessel disease with disruption of vessel wall Age Hypertension High cholesterol Amyloid angiopathy Familial (rare) Age Impaired blood clotting Anticoagulant therapy Blood dyscrasia Thrombolytic therapy Vascular anomaly Arteriovenous malformation Cavernous haemangioma Substance misuse Alcohol Amphetamines Cocaine below) if the artery ruptures into the brain substance as well as the subarachnoid space. Haemorrhage frequently occurs into an area of brain infarction and, if the volume of haemorrhage is large, it may be difficult to distinguish from primary intracerebral haemorrhage both clinically and radiologically (Fig. 26.9). The risk factors and underlying causes of intracerebral haemorrhage are listed in Box 26.2. Explosive entry of blood into the brain parenchyma causes immediate cessation of function in that area as neurons are disrupted and white-matter fibre tracts are split apart. The haemorrhage itself may expand over the first minutes or hours, or it may be associated with a rim of cerebral oedema, which, along with the haematoma, acts like a mass lesion to cause progression of the neurological deficit. If big enough, this can cause shift of the intracranial contents, producing transtentorial coning and sometimes rapid death (p. 1127). If the patient survives, the haematoma is gradually absorbed, leaving a haemosiderin-lined slit in the brain parenchyma. Clinical features Both acute stroke and transient ischaemic attack (TIA) are characterised by a rapid-onset, focal deficit of brain function and can be considered as a spectrum of symptoms from transient (TIA) to persistent (stroke). The typical presentation occurs over minutes, affects an identifiable area of brain and is ‘negative’ in character (i.e. abrupt loss of function without positive features 26.4 Characteristic features of stroke and non-stroke syndromes (‘stroke mimics’) Feature Stroke Stroke mimics Symptom onset Sudden (minutes) Often slower onset Symptom progression Rapidly reaches maximum severity Often gradual onset Severity of deficit Unequivocal May be variable/uncertain Pattern of deficit Hemispheric pattern May be non-specific with delirium, memory loss, balance disturbance Loss of consciousness Uncommon More common

1156 • STROKE MEDICINE hypoxia or severe systemic infection. The combination of severe headache and vomiting at the onset of the focal deficit is suggestive of intracerebral haemorrhage. General examination may provide clues to the cause and identify important comorbidities and complications. Several terms have been used to classify strokes, often based on the duration and evolution of symptoms: • Transient ischaemic attack (TIA) describes a stroke in which symptoms resolve within 24 hours – an arbitrary cut-off that has little value in practice, apart from perhaps indicating that underlying cerebral haemorrhage or extensive cerebral infarction is extremely unlikely. The term from the patient’s history and (if it is persistent) the neurological examination. The presence of a unilateral motor deficit, a higher cerebral function deficit such as aphasia or neglect, or a visual field defect usually places the lesion in the cerebral hemisphere. Ataxia, diplopia, vertigo and/or bilateral weakness usually indicate a lesion in the brainstem or cerebellum. Different combinations of these deficits define several stroke syndromes (Fig. 26.10), which reflect the site and size of the lesion and may provide clues to the underlying pathology. Reduced conscious level usually indicates a large-volume lesion in the cerebral hemisphere but may result from a lesion in the brainstem or complications such as obstructive hydrocephalus, Fig. 26.10 Clinical and radiological features of the stroke syndromes. The top three diagrams show coronal sections of the brain and the bottom one shows a sagittal section. The anatomical locations of cerebral functions are shown with the nerve tracts in green. A motor (or sensory) deficit (shown by the areas shaded red) can occur with damage to the relevant cortex (PACS), nerve tracts (LACS) or both (TACS). The corresponding CT scans show horizontal slices at the level of the lesion, highlighted by the arrows. Combination of: Hemiparesis Higher cerebral dysfunction (e.g. aphasia) Hemisensory loss Homonymous hemianopia (damage to optic radiations) Leg Total anterior circulation syndrome (TACS) Clinical syndrome Common symptoms Common cause CT scan features Arm Higher cerebral functions Face Optic radiations Middle cerebral artery occlusion (Embolism from heart or major vessels) Isolated motor loss (e.g. leg only, arm only, face) Isolated higher cerebral dysfunction (e.g. aphasia, neglect) Mixture of higher cerebral dysfunction and motor loss (e.g. aphasia with right hemiparesis) Leg Partial anterior circulation syndrome (PACS) Arm Higher cerebral functions Face Optic radiations Occlusion of a branch of the middle cerebral artery or anterior cerebral artery (Embolism from heart or major vessels) Pure motor stroke – affects two limbs Pure sensory stroke Sensory-motor stroke No higher cerebral dysfunction or hemianopia Leg Lacunar syndrome (LACS) Posterior circulation stroke (POCS) (lateral view) Arm Higher cerebral functions Visual cortex Cerebellum Cranial nerve nuclei Face Optic radiations Thrombotic occlusion of small perforating arteries (Thrombosis in situ) Homonymous hemianopia (damage to visual cortex) Cerebellar syndrome Cranial nerve syndromes Occlusion in vertebral, basilar or posterior cerebral artery territory (Cardiac embolism or thrombosis in situ)

Stroke • 1157

Neuroimaging Brain imaging with either CT or MRI should be performed in all patients with acute stroke. Exceptions are where results would not influence management, such as in the advanced stage of a terminal illness. CT remains the most practical and widely available method of imaging the brain. It will usually exclude non-stroke lesions, including subdural haematomas and brain tumours, and will demonstrate intracerebral haemorrhage within minutes of stroke onset (see Fig. 26.9). However, especially within the first few hours after symptom onset, CT changes in cerebral infarction may be completely absent or only very subtle. Changes often develop over time (see Fig. 26.13) but small cerebral infarcts may never show up on CT scans. For some purposes, a CT scan performed within 24 hours is adequate TIA traditionally also includes patients with amaurosis fugax, usually due to a vascular occlusion in the retina. • Stroke describes those events in which symptoms last more than 24 hours. The differential diagnosis of patients with symptoms lasting a few minutes or hours is similar to those with persisting symptoms (see Box 26.3). The term ‘minor stroke’ is sometimes used to refer to symptoms lasting over 24 hours but not causing significant disability. • Progressing stroke (or stroke in evolution) describes a stroke in which the focal neurological deficit worsens after the patient first presents. Such worsening may be due to increasing volume of infarction, haemorrhagic transformation or increasing cerebral oedema. • Completed stroke describes a stroke in which the focal deficit persists and is not progressing. When assessing a patient within hours of symptom onset, it is not possible to distinguish stroke from TIA unless symptoms have already resolved. In clinical practice, it is important to distinguish those patients with strokes who have persisting focal neurological symptoms when seen from those whose symptoms have already resolved. Investigations Investigation of acute stroke aims to confirm the vascular nature of a lesion, distinguish infarction from haemorrhage and identify the underlying vascular disease and risk factors (Box 26.5). Risk factor analysis Initial investigation includes a range of simple blood tests to detect common vascular risk factors and markers of rarer causes, along with an ECG and brain imaging. Where there is uncertainty about the nature of the stroke, further investigations are indicated. This especially applies to younger patients, who are less likely to have atherosclerotic disease (Box 26.6). 26.5 Investigation of a patient with an acute stroke Diagnostic question Investigation Is it a vascular lesion? CT/MRI Is it ischaemic or haemorrhagic? CT/MRI Is it a subarachnoid haemorrhage? CT/lumbar puncture Is there any cardiac source of embolism? ECG Holter monitoring Echocardiogram What is the underlying vascular disease? Duplex ultrasound of carotids MRA CTA Contrast angiography What are the risk factors? Full blood count Cholesterol Blood glucose Is there an unusual cause? ESR Serum protein electrophoresis Clotting/thrombophilia screen (CT = computed tomography; CTA = computed tomographic angiography; ECG = electrocardiogram; ESR = erythrocyte sedimentation rate; MRA = magnetic resonance angiography; MRI = magnetic resonance imaging) 26.6 Causes and investigation of acute stroke in young patients Cause Investigation Cerebral infarct Cardiac embolism Echocardiography (including transoesophageal) Premature atherosclerosis Serum lipids Arterial dissection MRI CTA Reversible cerebral vasoconstriction syndromes MRI CTA Thrombophilia Protein C, protein S Antithrombin III Factor V Leiden, prothrombin Homocystinuria (p. 369) Urinary amino acids Methionine loading test Antiphospholipid antibody syndrome (p. 977) Anticardiolipin antibodies/lupus anticoagulant Systemic lupus erythematosus ANA Vasculitis (e.g. primary angiitis of the central nervous system) ESR CRP ANCA CADASIL CARASIL MRI brain Genetic analysis Skin biopsy Mitochondrial cytopathy Serum lactate White cell mitochondrial DNA Muscle biopsy Mitochondrial molecular genetics Fabry’s disease Alpha-galactosidase levels Sickle cell disease Sickle cell studies Neurovascular syphilis Syphilis serology Primary intracerebral haemorrhage AVM MRI/MRA Drug misuse Drug screen (amphetamine, cocaine) Coagulopathy PT and APTT Platelet count Subarachnoid haemorrhage Saccular (‘berry’) aneurysm MRI/MRA AVM MRI/MRA Vertebral dissection MRI/MRA (ANA = antinuclear antibody; ANCA = antineutrophil cytoplasmic antibody; APTT = activated partial thromboplastin time; AVM = arteriovenous malformation; CADASIL/CARASIL = cerebral autosomal dominant/recessive arteriopathy with subcortical infarcts and leucoencephalopathy; CRP = C-reactive protein; CTA = computed tomographic angiography; ESR = erythrocyte sedimentation rate; MRA = magnetic resonance angiography; MRI = magnetic resonance imaging; PT = prothrombin time)

1158 • STROKE MEDICINE disability and handicap through rehabilitation, and reducing the risk of recurrent stroke or other vascular events. With TIA there is no persisting brain damage and disability, so the priority is to reduce the risk of further vascular events. Supportive care Rapid admission of patients to a specialised stroke unit facilitates coordinated care from a specialised multidisciplinary team, and has been shown to reduce both mortality and residual disability amongst survivors. For every 1000 patients managed in a stroke unit, an extra 50 will avoid death or long-term disability, compared to those managed in general wards. Consideration of a patient’s rehabilitation needs should commence at the same time as acute medical management. Dysphagia is common and can be detected by an early bedside test of swallowing. This allows hydration, feeding and medication to be given safely, if necessary by nasogastric tube or intravenously. In the acute phase, a checklist may be useful (Box 26.8) to ensure that all the factors that might influence outcome have been addressed. In recent years, many services have developed hyperacute stroke units (HASUs) to ensure that patients are given immediate access to these interventions, as well as urgent medical treatments. The patient’s neurological deficits may worsen during the first few hours or days after their onset. This may be due to extension of the area of infarction, haemorrhage transformation of an infarction, or the development of oedema with consequent mass effect. It is important to distinguish these patients from those who Fig. 26.11 Emergency management of stroke. Varies with patient selection and delay in treatment. (NNT = number needed to treat to avoid one death or long-term disability) Haemorrhagic stroke Neuroimaging Ischaemic stroke Reverse coagulation abnormality Eligible for urgent reperfusion therapy? Yes (20%) No (80%) Aspirin (NNT 80) Intravenous thrombolysis (NNT 9–20) and/or Mechanical thrombectomy (NNT 8–10)* Acute stroke unit care (NNT 20) Identify cause and plan secondary prevention Clinical diagnosis of stroke (Box 26.4) 26.7 Indications for immediate CT/MRI in acute stroke • Patient on anticoagulants or with abnormal coagulation • Consideration for reperfusion (thrombolysis) or immediate anticoagulation • Deteriorating conscious level or rapidly progressing deficits • Suspected cerebellar haematoma, to exclude hydrocephalus but there are certain circumstances in which an immediate CT scan is essential (Box 26.7). Even in the absence of changes suggesting infarction, abnormal perfusion of brain tissue can be imaged with CT after injection of contrast media (i.e. CT perfusion scanning). This can be useful in guiding immediate treatment of ischaemic stroke. MRI is not as widely available as CT and scanning times are longer. However, MRI diffusion weighted imaging (DWI) can detect ischaemia earlier than CT, and other MRI sequences can also be used to demonstrate abnormal perfusion (see Fig. 26.4). MRI is more sensitive than CT in detecting strokes affecting the brainstem and cerebellum, and, unlike CT, can reliably distinguish haemorrhagic from ischaemic stroke even several weeks after the onset. CT and MRI may reveal clues as to the nature of the arterial lesion. For example, there may be a small, deep lacunar infarct indicating small-vessel disease, or a more peripheral infarct suggesting an extracranial source of embolism (see Fig. 26.10). In a haemorrhagic lesion, the location might indicate the presence of an underlying vascular malformation, saccular aneurysm or amyloid angiopathy. More recently, CTA is being used to show vessel occlusion suitable for clot retrieval (see later). Vascular imaging Many ischaemic strokes are caused by atherosclerotic thromboembolic disease of the major extracranial vessels. Detection of extracranial vascular disease can help establish why the patient has had an ischaemic stroke and, in selected patients, may lead on to specific treatments, including carotid endarterectomy to reduce the risk of further stroke (see below). The presence or absence of a carotid bruit is not a reliable indicator of the degree of carotid stenosis. Extracranial arterial disease can be non-invasively identified with duplex ultrasound, MRA or CTA (see Fig. 26.5), or occasionally by intra-arterial contrast radiography as above. Cardiac investigations Approximately 20% of ischaemic strokes are due to embolism from the heart. The most common causes are atrial fibrillation, prosthetic heart valves, other valvular abnormalities and recent myocardial infarction. These may be identified by clinical examination and ECG, but a transthoracic or transoesophageal echocardiogram is also required to confirm the presence of a clinically apparent cardiac source or to identify an unsuspected source such as endocarditis, atrial myxoma, intracardiac thrombus or patent foramen ovale. Such findings may lead on to specific cardiac treatment. Management Management (Fig. 26.11) is aimed at identifying the cause, minimising the volume of brain that is irreversibly damaged, preventing complications (Fig. 26.12), reducing the patient’s

Stroke • 1159

mannitol or artificial ventilation. Surgical decompression to reduce intracranial pressure should be considered in appropriate patients. Reperfusion (thrombolysis and thrombectomy) Rapid reperfusion in ischaemic stroke can reduce the extent of brain damage. Intravenous thrombolysis with recombinant tissue Fig. 26.12 Complications of acute stroke. Nurse semi-erect Avoid aspiration (nil by mouth, nasogastric tube, possible gastrostomy) Complications Prevention Treatment Epileptic seizures Maintain cerebral oxygenation Avoid metabolic disturbance Anticonvulsants Depression and anxiety Maintain positive attitude and provide information Antidepressants Painful shoulder Avoid traction injury Shoulder/arm supports Physiotherapy Physiotherapy Local glucocorticoid injections Chest infection Antibiotics Physiotherapy Appropriate aperients and diet Constipation Appropriate aperients Avoid catheterisation if possible Use penile sheath Urinary infection Antibiotics Frequent turning Monitor pressure areas Avoid urine damage to skin Pressure sores Nursing care Pressure-relieving mattress Maintain hydration Early mobilisation Heparin (for high-risk patients only) Deep vein thrombosis/ pulmonary embolism Anticoagulation (exclude haemorrhage first) are deteriorating as a result of complications such as hypoxia, sepsis, epileptic seizures or metabolic abnormalities that may be reversed more easily. Patients with cerebellar haematomas or infarcts with mass effect may develop obstructive hydrocephalus and some will benefit from insertion of a ventricular drain and/or decompressive surgery (see Fig. 26.11). Some patients with large haematomas or infarction with massive oedema in the cerebral hemispheres may benefit from anti-oedema agents, such as Blood glucose • Check blood glucose and treat when levels are ≥11.1 mmol/L (200 mg/dL) (by insulin infusion or glucose/potassium/insulin (GKI) • Monitor closely to avoid hypoglycaemia Temperature • If pyrexic, investigate and treat underlying cause • Control with antipyretics, as raised brain temperature may increase infarct volume Pressure areas • Reduce risk of skin breakdown: Treat infection Maintain nutrition Provide pressure-relieving mattress Turn immobile patients regularly Incontinence • Check for constipation and urinary retention; treat these appropriately • Avoid urinary catheterisation unless patient is in acute urinary retention or incontinence is threatening pressure areas Mobilisation • Avoid bed rest Airway • Perform bedside screen and keep patient nil by mouth if swallowing unsafe or aspiration occurs Breathing • Check respiratory rate and give oxygen if saturation < 95% Circulation • Check peripheral perfusion, pulse and blood pressure, and treat abnormalities with fluid replacement, anti-arrhythmics and inotropic drugs as appropriate Hydration • If signs of dehydration, give fluids parenterally or by nasogastric tube Nutrition • Assess nutritional status and provide supplements if needed • If dysphagia persists for >48 hrs, start feeding via nasogastric tube Medication • If dysphagic, consider other routes for essential medications Blood pressure • Unless there is heart or renal failure, evidence of hypertensive encephalopathy or aortic dissection, do not lower blood pressure abruptly in first week as it may reduce cerebral perfusion. Blood pressure often returns towards patient’s normal level within days 26.8 How to manage a patient with acute stroke

1160 • STROKE MEDICINE haemorrhage. The potential gain from good secondary prevention can be expressed as the number needed to treat (NNT) to avoid a recurrent stroke. Patients with ischaemic events should be put on long-term antiplatelet drugs (NNT 100) and statins (NNT 60) to lower cholesterol. For patients in atrial fibrillation, the risk can be reduced substantially (NNT 15) by using oral anticoagulation with warfarin to achieve an international normalised ratio (INR) of 2–3. The newer direct oral anticoagulants (such as dabigatran, rivaroxaban and apixaban) are now widely used, offering improved safety and effectiveness at increased drug cost. The risk of recurrence after both ischaemic and haemorrhagic strokes can be reduced by blood pressure reduction, even for those with relatively normal blood pressures (NNT 50). Carotid endarterectomy and angioplasty A small proportion of patients with a carotid territory ischaemic stroke or TIA will have more than 50% stenosis of the carotid artery on the side of the brain lesion. Such patients have a greater than average risk of stroke recurrence. For those without major residual disability, removal of the stenosis has been shown to reduce the overall risk of recurrence (NNT 15), although the operation itself carries about a 5% risk of stroke. Surgery is most effective in patients with more severe stenoses (70–99%) and when it is performed within the first couple of weeks after the TIA or ischaemic stroke. Carotid angioplasty and stenting are technically feasible but have not been shown to be as effective as endarterectomy for the majority of eligible patients. Endarterectomy of asymptomatic carotid stenosis has been shown to reduce the subsequent risk of stroke but the small absolute benefit does not justify its routine use. Unusual causes A minority of strokes are caused by arterial dissection of the carotid (carotid dissection) or vertebral artery (vertebral artery dissection). The presenting history often includes minor injury and face or neck pain. After confirmation on angiography (MRA or CTA), treatment is with either antiplatelet drugs or anticoagulation. Reversible vasoconstriction syndromes require good physiological control (particularly blood pressure). Subarachnoid haemorrhage Subarachnoid haemorrhage (SAH) is less common than ischaemic stroke or intracerebral haemorrhage (see Fig. 26.1) and affects about 6/100 000 of the population. Women are affected more commonly than men and the condition usually presents before the age of 65. The immediate mortality of aneurysmal SAH is about 30%; survivors have a recurrence (or rebleed) rate of about 40% in the first 4 weeks and 3% annually thereafter. Some 85% of cases of SAH are caused by saccular or ‘berry’ aneurysms arising from the bifurcation of cerebral arteries (see Fig. 26.2), particularly in the region of the circle of Willis. The most common sites are in the anterior communicating artery (30%), posterior communicating artery (25%) or middle cerebral artery (20%). There is an increased risk in first-degree relatives of those with saccular aneurysms, and in patients with polycystic kidney disease (p. 405) and congenital connective tissue defects such as Ehlers–Danlos syndrome (p. 970). In about 10% of cases, SAHs are non-aneurysmal haemorrhages (so-called peri-mesencephalic haemorrhages), which have a very characteristic appearance on CT and a benign outcome in terms of mortality and recurrence. 26.9 Anticoagulation in old age • Increased risk: older age and previous stroke increase the risk of stroke in the presence of atrial fibrillation, and bleeding risk with anticoagulation. • Falls risk: elderly patients are more prone to falls, including head injuries, which increase bleeding risk. • Monitoring of therapy: fine adjustments to daily dose of warfarin may be more difficult, as may monitoring of therapy. • Impact of comorbidities: the presence of conditions such as chronic renal impairment, diabetes or heart failure may affect the risk:benefit ratio, and decisions to use anticoagulation must be weighed carefully. Decision aids have been developed to assist (see ‘Further information’). plasminogen activator (rt-PA) increases the risk of haemorrhagic transformation of the cerebral infarct with potentially fatal results. The main contraindications are bleeding risk (recent haemorrhage, anticoagulant therapy) and delay to treatment; the earlier treatment is given, the greater the benefit. However, if given within 4.5 hours of symptom onset to carefully selected patients, the haemorrhagic risk is offset by an improved overall outcome. Recently mechanical clot retrieval (thrombectomy) in patients with a large-vessel occlusion can greatly improve the chances of avoiding disability (see Fig. 26.11). Aspirin In the absence of contraindications, aspirin (300 mg daily) should be started immediately after an ischaemic stroke unless rt-PA has been given, in which case it should be withheld for at least 24 hours. Aspirin reduces the risk of early recurrence and has a small but clinically worthwhile effect on long-term outcome (see Fig. 26.11); it may be given by rectal suppository or by nasogastric tube in dysphagic patients. Heparin Anticoagulation with heparin has been widely used to treat acute ischaemic stroke in the past. While it reduces the risk of early ischaemic recurrence and venous thromboembolism, it increases the risk of both intracranial and extracranial haemorrhage. Furthermore, routine use of heparin does not result in better long-term outcomes, and therefore it should not be used in the routine management of acute stroke. It is unclear whether heparin might provide benefit in selected patients, such as those with recent myocardial infarction, arterial dissection or progressing strokes. Intracranial haemorrhage must be excluded on brain imaging before considering anticoagulation. Coagulation abnormalities In those with intracerebral haemorrhage, coagulation abnormalities should be reversed as quickly as possible to reduce the likelihood of the haematoma enlarging. This most commonly arises in those on warfarin therapy. There is no evidence that clotting factors are useful in the absence of a clotting defect. Management of risk factors The approaches used are summarised in Figure 26.13. The average risk of a further stroke is 5–10% within the first week of a stroke or TIA, perhaps 15% in the first year and 5% per year thereafter. The risks are not substantially different for intracerebral

Subarachnoid haemorrhage • 1161

present at onset if there is an associated intracerebral haematoma. A third nerve palsy may be present due to local pressure from an aneurysm of the posterior communicating artery, but this is rare. Fundoscopy may reveal a subhyaloid haemorrhage, which represents blood tracking along the subarachnoid space around the optic nerve. Investigations CT brain scanning and lumbar puncture are required. The diagnosis of SAH can be made by CT but a negative result does not completely exclude it, since small amounts of blood in the subarachnoid space cannot be detected by CT (see Fig. 26.14). Lumbar puncture should be performed 12 hours after symptom onset if possible, to allow detection of xanthochromia (p. 1077). If either of these tests is positive, cerebral angiography (see Fig. 26.5) is required to determine the optimal approach to prevent recurrent bleeding. Around 5% of SAHs are due to arteriovenous malformations and vertebral artery dissection. Clinical features SAH typically presents with a sudden, severe, ‘thunderclap’ headache (often occipital), which lasts for hours or even days, often accompanied by vomiting, raised blood pressure and neck stiffness or pain. It commonly occurs on physical exertion, straining and sexual excitement. There may be loss of consciousness at the onset, so SAH should be considered if a patient is found comatose. About 1 patient in 8 with a sudden severe headache has SAH and, in view of this, all who present in this way require investigation to exclude it (Fig. 26.14). On examination, the patient is usually distressed and irritable, with photophobia. There may be neck stiffness due to subarachnoid blood but this may take some hours to develop. Focal hemisphere signs, such as hemiparesis or aphasia, may be Fig. 26.13 Strategies for secondary prevention of stroke. (1) Lower blood pressure with caution in patients with postural hypotension, renal impairment or bilateral carotid stenosis. (2) Other statins can be used as an alternative to simvastatin in patients on warfarin or digoxin. (3) Warfarin and aspirin have been used in combination in patients with prosthetic heart valves. (4) The combination of aspirin and clopidogrel is indicated only in patients with unstable angina or those with a temporary high risk of recurrence (e.g. carotid stenosis). (ACE = angiotensin-converting enzyme; BP = blood pressure; CT = computed tomography; ECG = electrocardiogram; MRI = magnetic resonance imaging; TIA = transient ischaemic attack; U&Es = urea and electrolytes) Antiplatelet drugs4 • Aspirin 300 mg at once then 75 mg daily • Clopidogrel 75 mg daily is effective alternative Lower cholesterol2 if total cholesterol

3.5 mmol/L (135 mg/dL) with simvastatin 40 mg nocte, after checking liver function tests Anticoagulation if no contraindications. Warfarin with target INR 2–3 (or 3.5 if mechanical prosthetic valve). Direct oral anticoagulants (DOACs) offer safe, effective alternative Consider • Cardioversion • Anti-arrhythmic Carotid endarterectomy Refer if > 70% stenosis on symptomatic side Carotid duplex Lower BP1 if BP > 130/70 mmHg 1–2 weeks after onset • Thiazide diuretic • ACE inhibitor (check U&Es) • Other agents Lifestyle • Smoking cessation • Lower salt intake • Lower fat intake • Lower excess alcohol intake • Increase exercise • Lose excess weight Haemorrhagic Sinus rhythm If contraindications to anticoagulation, e.g. bleeding, falls, binge drinking, poor adherence Thyroid function tests and echocardiogram Atrial fibrillation ECG Ischaemic Single typical TIA Stroke or atypical or multiple cerebral TIAs CT brain scan within 24 hours of onset; MRI if later than 7 days

1162 • STROKE MEDICINE (focal or generalised). The deficit can increase if spreading thrombophlebitis occurs. Investigations and management MR venography demonstrates a filling defect in the affected vessel. Anticoagulation, initially with heparin followed by warfarin, is beneficial, even in the presence of venous haemorrhage. In selected patients, endovascular thrombolysis has been advocated. Management of underlying causes and complications, such as persistently raised intracranial pressure, is important. About 10% of cerebral venous sinus thrombosis, particularly cavernous sinus thrombosis, is associated with infection (most commonly Staphylococcus aureus), needing antibiotic treatment. Otherwise, the treatment of choice is anticoagulation. Further information Websites eso-stroke.org European Stroke Organisation guidelines. nhs.uk/actfast FAST (face, arms, speech, time) campaign to raise public awareness of the emergency nature of stroke. nice.org.uk/guidance National Institute for Health and Care Excellence CG180 ‘Tools and resources’ includes a patient decision aid – Atrial fibrillation: medicines to help reduce your risk of a stroke – what are the options? rcplondon.ac.uk/resources/stroke-guidelines Royal College of Physicians of London clinical guideline. stroke.cochrane.org Systematic reviews of stroke treatments. stroketraining.org Stroke Training and Awareness Resources. Fig. 26.14 Investigation of subarachnoid haemorrhage. (CSF = cerebrospinal fluid; CT = computed tomography) Emergency CT Traumatic lumbar punctures do not cause xanthochromia in that specimen Negative (<10% of subarachnoid haemorrhage) Shows subarachnoid haemorrhage Blood/xanthochromia CSF (after 12 hours) If CT and CSF at 12 hours are negative the patient has not had a subarachnoid haemorrhage Refer to neurosurgeons Resuscitate Nimodipine 60 mg 26.11 Clinical features of cerebral venous thrombosis Cavernous sinus thrombosis • Proptosis, ptosis, headache, external and internal ophthalmoplegia, papilloedema, reduced sensation in trigeminal first division • Often bilateral, patient ill and febrile Superior sagittal sinus thrombosis • Headache, papilloedema, seizures • Clinical features may resemble idiopathic intracranial hypertension (p. 1133) • May involve veins of both hemispheres, causing advancing motor and sensory focal deficits Transverse sinus thrombosis • Hemiparesis, seizures, papilloedema • May spread to jugular foramen and involve cranial nerves 9, 10 and 11 26.10 Causes of cerebral venous thrombosis Predisposing systemic causes • Dehydration • Pregnancy • Behçet’s disease (p. 1043) • Thrombophilia (p. 922) • Hypotension • Oral contraceptive use Local causes • Paranasal sinusitis • Meningitis, subdural empyema • Penetrating head and eye wounds • Facial skin infection • Otitis media, mastoiditis • Skull fracture Management Nimodipine (30–60 mg IV for 5–14 days, followed by 360 mg orally for a further 7 days) is usually given to prevent delayed ischaemia in the acute phase. Insertion of platinum coils into an aneurysm (via an endovascular procedure) or surgical clipping of the aneurysm neck reduces the risk of both early and late recurrence. Coiling is associated with fewer perioperative complications and better outcomes than surgery; where feasible, it is now the procedure of first choice. Arteriovenous malformations can be managed either by surgical removal, by ligation of the blood vessels that feed or drain the lesion, or by injection of material to occlude the fistula or draining veins. Treatment may also be needed for complications of SAH, which include obstructive hydrocephalus (that may require drainage via a shunt), delayed cerebral ischaemia due to vasospasm (which may be treated with vasodilators), hyponatraemia (best managed by fluid restriction) and systemic complications associated with immobility, such as chest infection and venous thrombosis. Cerebral venous disease Thrombosis of the cerebral veins and venous sinuses (cerebral venous thrombosis) is much less common than arterial thrombosis. However, it has been recognised with increasing frequency in recent years, as access to non-invasive imaging of the venous sinuses using MR venography has increased. The main causes are listed in Box 26.10. Clinical features Cerebral venous sinus thrombosis usually presents with symptoms of raised intracranial pressure, seizures and focal neurological symptoms. The clinical features vary according to the sinus involved (Box 26.11 and see Fig. 26.3). Cortical vein thrombosis presents with focal cortical deficits such as aphasia and hemiparesis (depending on the area affected), and epilepsy

Ch04-3 Clinical Medicine

17-27 Medical ophthalmology

27 Medical ophthalmology

Medical ophthalmology J Olson Functional anatomy and physiology 1164 Investigation of visual disorders 1168 Perimetry 1168 Imaging 1168 Visual electrophysiology 1169 Presenting problems in ophthalmic disease 1169 Watery/dry eye 1170 Pruritus 1170 Pain/headache 1170 Photophobia/glare 1170 Photopsia 1170 Blurred vision 1170 Loss of vision 1170 Distortion of vision 1171 Eyelid retraction 1171 Optic disc swelling 1171 Proptosis 1171 Specialist ophthalmological conditions 1171 Ocular inflammation 1171 Infectious conditions 1173 Cataract 1174 Diabetic eye disease 1174 Retinal vascular occlusion 1177 Age-related macular degeneration 1178

1164 • MEDICAL OPHTHALMOLOGY Lacrimal gland/lacrimal drainage The lacrimal gland lies within the periorbita of the anterolateral roof of the orbit. Its secretions (tears) wash away surface irritants and convey emotion. Excess tears drain, via canaliculi in the lids, into the lacrimal sac, nasolacrimal duct and inferior nasal meatus. Extraocular muscles The extraocular muscles (Fig. 27.1) consist of four recti, two obliques and one levator. The recti originate from a circular condensation of periorbita, the annulus of Zinn, which encircles the superior orbital fissure and the optic canal. They extend forwards to insert into the anterior sclera. The levator palpebrae superioris originates above the optic canal and inserts into the tarsal plate and overlying skin of the upper eyelid. The superior tarsal muscle (Müller’s muscle) originates from the inferior aspect of the levator and also inserts into the tarsal plate. The superior oblique originates superonasal to the recti, and runs along the roof of the orbit, its tendon passing horizontally through the trochlea at the orbital rim to insert into the anterior sclera. The inferior oblique originates from the floor of the anterior orbit, just posterior to the lacrimal sac. It turns horizontally, passing beneath the inferior rectus, to insert into the inferior anterior sclera. Eye The optic vesicle develops from the diencephalon. The eye is therefore contiguous with the brain. This is reflected in the three-layer structure of the eye: The ability to see is an important aspect of everyday life. Although rarely a cause of mortality, visual impairment can have a profoundly negative impact on socioeconomic status. Globally, although refractive errors and cataract remain the main causes of visual impairment, significant progress has occurred in prevention and treatment. Public health measures have reduced diseases of poor hygiene and unclean water, such as trachoma and onchocerciasis, and greater access to surgery has reduced the burden of untreated cataract and glaucoma. However, conditions associated with longevity, such as age-related macular degeneration, diabetic retinopathy and retinal vein occlusion, for which scientific advances have led to effective but expensive therapies requiring frequent and long-term attendance, are increasing in frequency. Traditionally, ophthalmology relied on other specialties to undertake extraocular investigation and treatment. Medical ophthalmology bypasses that co-dependence, allowing patients with visual disorders to receive overarching care within ophthalmology. As such, it requires a good grounding in medicine, particularly dermatology, diabetes and endocrinology, infectious diseases, medical genetics, neurology, rheumatology and stroke medicine. Medical ophthalmology presents a challenge for a medical textbook, as it overlaps with almost all other specialties, but particularly neurology. In this book neuro-ophthalmology is covered in Chapter 25. This chapter concentrates mainly on intraocular inflammation, which was the prime drive to create the specialty, and conditions that require intravitreal injection therapy. It does not therefore represent the totality of the medical ophthalmologist’s workload. Ophthalmological conditions that are usually managed within non-ophthalmological specialties are discussed in the corresponding chapters, although for ease of reference the more common ophthalmic features of nonophthalmological conditions are listed throughout this chapter (haematological disease in Box 27.1, diabetes and endocrine disease in Box 27.2, cardiovascular disease in Box 27.3, respiratory disease in Box 27.4, rheumatological/musculoskeletal disease in Box 27.5, gastrointestinal disease in Box 27.6 and skin disease in Box 27.7). Functional anatomy and physiology Visual pathways, innervation of the eye and the control of eye movement are discussed in Chapter 25. Orbit The orbit is the fat-filled cavity in which the eye is suspended. It is shaped like a hollow square pyramid, its base the orbital rim. The orbital periosteum (‘periorbita’) is continuous with the periosteal layer of cranial dura mater. The dura and arachnoid form the optic nerve sheath, its subarachnoid space containing cerebrospinal fluid in continuity with the third ventricle. Eyelid/orbital septum/conjunctiva In primary gaze, the eyelids just cover the superior and inferior cornea. The eyelids contain the orbital septum and the tarsal plate. Within the tarsal plates, modified sebaceous (Meibomian) glands produce an oily surfactant to slow tear evaporation. The conjunctiva, a mucous membrane, lines the posterior surface of the eyelid, adhering only to the tarsal plates and the scleral/corneal junction. The accessory lacrimal glands provide basal tear production; mucus produced by goblet cells stabilises the tear film by lowering surface tension. 27.1 Ophthalmic features of haematological disease Condition Ophthalmic findings Severe anaemia of any cause (retinopathy of anaemia) Flame haemorrhages Cotton wool spots Roth spots Pre-retinal haemorrhage Megaloblastic anaemia Optic neuropathy Sickle cell anaemia Conjunctival vasculopathy Peripheral retinal neovascularisation Thalassaemia Desferrioxamine-associated pigmentary retinopathy Leukaemia (leukaemic retinopathy) Pseudohypopyon Flame haemorrhages Roth spots Retinal oedema Retinal vein occlusion Lymphoma Non-Hodgkin lymphoma Central nervous system lymphoma Lacrimal gland infiltration Posterior uveitis (atypical choroiditis) Myeloproliferative disorders Hyperviscosity Cerebral venous thrombosis Retinal vein occlusion Papilloedema Paraproteinaemias Waldenström’s macroglobulinaemia Multiple myeloma Retinal vein engorgement/ occlusion Thrombophilia Cerebral venous thrombosis Papilloedema

Functional anatomy and physiology • 1165

27.3 Ophthalmic features of cardiovascular disease Condition Ophthalmic findings Arteriosclerosis Arteriovenous nipping Retinal vein occlusion, caused by arteriovenous nipping Retinal artery macroaneurysm Ischaemic optic neuropathy Pupil-sparing third and/or sixth nerve palsy, caused by infarction of the vasa nervosum Hypertension Hypertensive retinopathy Cotton wool spots Flame haemorrhages Optic disc oedema, with or without macular oedema Infective endocarditis Flame haemorrhages Roth spots Endophthalmitis, caused by haematogenous spread of infection Drugs Vortex keratopathy (corneal epithelial deposits), caused by amiodarone (also seen in Fabry’s disease, p. 370) Bilateral optic neuropathy, caused by amiodarone Thromboembolic disorders (including thromboembolus from atrial fibrillation) Retinal artery occlusion, caused by artery-to-artery embolism Homonymous hemianopia, caused by embolic stroke (p. 1088) 27.2 Ophthalmic features of diabetes and other endocrine disease Condition Ophthalmic findings Diabetes Proliferative retinopathy Macular oedema Small pupils (autonomic neuropathy) Cataract (including ‘snowflake’ cataract) Thyrotoxicosis (any cause) Eyelid retraction Graves’ disease (TSH receptor antibody-positive) Exposure keratopathy Conjunctival and periorbital oedema Restrictive ocular motility Proptosis Optic neuropathy Parathyroid disease Band keratopathy Corneal calcium deposition Phaeochromocytoma Hypertensive retinopathy Cotton wool spots Flame haemorrhages Optic disc oedema with or without macular oedema Cushing’s syndrome Posterior subcapsular cataract Diabetic retinopathy Central serous retinopathy Thyroid carcinoma Horner’s syndrome with absent unilateral facial sweating (TSH = thyroid stimulating hormone) Fig. 27.1 The extraocular musculature (right eye). Adapted from Batterbury M, Bowling B, Murphy C. Ophthalmology. An illustrated colour text, 3rd edn. Churchill Livingstone, Elsevier Ltd; 2009. Medial rectus Superior rectus Superior oblique Inferior oblique Orbicularis oculi muscle (palpebral portion) Inferior rectus Lateral rectus (cut) Levator palpebrae superioris 27.4 Ophthalmic features of respiratory disease Condition Ophthalmic findings Chronic obstructive pulmonary disease (p. 573) Optic disc oedema (type 2 respiratory failure) Cystic fibrosis (p. 580) Diabetic retinopathy Tuberculosis (p. 588) Anterior uveitis Choroidal granuloma Serpiginous choroiditis Peripheral retinal arteritis Optic neuropathy, visual loss and disturbance of colour vision (adverse effects of ethambutol and isoniazid) Sarcoidosis (p. 608) Anterior uveitis (granulomatosis) Mutton fat keratitic precipitates Iris nodules Choroidal granuloma Panuveitis Multifocal choroiditis Retinal periphlebitis Sicca syndrome, caused by lacrimal gland infiltration Exposure keratopathy, caused by corneal exposure secondary to facial nerve palsy Optic neuropathy, caused by optic disc oedema secondary to meningeal infiltration Lung cancer (p. 928) Horner’s syndrome (p. 1091) Cancer-associated retinopathy • the sclera/cornea, a fibrous outer layer analogous to the meningeal dura • the choroid, ciliary body and iris (together known as the uveal tract), a vascular middle layer analogous to the pia-arachnoid • the retina, an inner layer analogous to white matter. The major structures of the eye are shown in Figure 27.2. During embryogenesis, overlying ectoderm sinks into the neuroectoderm of the optic vesicle to form the lens vesicle, thus inducing the optic vesicle to form the two-layered optic cup. The inner and outer layers form the neurosensory retina and the retinal pigment epithelium, respectively. The intervening space is continuous with the third ventricle of the diencephalon,

1166 • MEDICAL OPHTHALMOLOGY The limbus lies at the junction between the cornea and sclera, and contains stem cells and Schlemm’s canal. The stem cells allow continuous regeneration of the corneal epithelium. Schlemm’s canal, with its overlying trabecular meshwork, drains aqueous fluid from the anterior chamber into the external veins of the episclera and conjunctiva. The avascular cornea is nourished by diffusion from the anterior chamber, limbal capillaries and oxygen dissolved in the tear film. The cornea, assisted by the lens and the length of the eye, determines the refractive ability of the eye. the cilia of the third ventricle continuing as cilia on the outer neurosensory retina. Laterally, these cilia form the outer segments of the photoreceptors. Initially, the hyaloid artery supplies the lens and vitreous. In its final form, the vitreous develops from the retina and the hyaloid artery regresses, leaving only the central retinal artery and its branches. Mesenchyme forms the tarsal plates of the eyelid, the stroma and the endothelium of the cornea, the sclera and the choroid. Surface ectoderm, as well as forming the lens, forms the epidermis of the eyelid, the conjunctiva, the epithelium of the cornea and the lacrimal gland. Sclera/cornea The sclera lends shape to the eye and provides attachment for the ocular musculature. It makes up five-sixths of the eyeball, the other sixth being formed by transparent cornea. 27.5 Ophthalmic features of rheumatological/ musculoskeletal disease Rheumatoid arthritis • Keratoconjunctivitis sicca • Peripheral ulcerative keratitis (‘corneal melt’) • Painless episcleritis • Scleritis and scleromalacia Seronegative spondyloarthropathies • Conjunctivitis (chlamydiaassociated reactive arthritis) • Anterior uveitis Connective tissue diseases Dermatomyositis • Periorbital oedema with violaceous eyelid rash Sjögren’s syndrome • Dry eyes Treatment effects • Bull’s eye maculopathy (hydroxychloroquine) • Viral retinitis (immunosuppression) Systemic vasculitides Giant cell arteritis • Central/branch retinal artery occlusion • Ischaemic optic neuropathy Behçet’s disease • Occlusive retinal vasculitis (posterior uveitis) • Anterior uveitis with hypopyon Granulomatosis with polyangiitis (Wegener’s) • Scleritis with involvement of adjacent cornea (sclerokeratitis) • Retro-orbital inflammation (see Fig. 25.49) Polyarteritis nodosa • Peripheral ulcerative keratitis • Scleritis • Retinal arteritis Others/non-specific • Necrotising scleritis/ sclerokeratitis/peripheral ulcerative keratitis • Anterior ischaemic optic neuropathy • Extraocular myositis (painful diplopia) • Retinal arteritis • Pupil-sparing 3rd nerve palsy • 6th nerve palsy • Proptosis • Occipital lobe infarction Diseases of bone Paget’s disease, polyostotic fibrous dysplasia • Optic neuropathy Others/non-specific • Anterior uveitis (adverse effect of bisphosphonates) 27.7 Ophthalmic features of skin disease Rosacea • Posterior blepharitis • Keratitis Acne vulgaris • Dry eye (adverse effect of isotretinoin) • Papilloedema (adverse effect of tetracycline) Psoriasis • Anterior uveitis Eczema • Atopic keratoconjunctivitis Urticaria • Angioedema Bullous diseases • Ocular cicatricial pemphigoid • Stevens–Johnson syndrome Alopecia areata • Eyebrow and eyelash loss Cutaneous melanoma • Melanoma-associated retinopathy Skin tumours • Eyelid tumours (basal cell carcinoma, squamous cell carcinoma, keratoacanthoma, naevus, melanoma) Skin infections • Stye (eyelash folliculitis) • Acute blepharoconjunctivitis (herpes simplex) • Chronic conjunctivitis (molluscum contagiosum) 27.6 Ophthalmic features of gastrointestinal disease Malabsorption • Corneal and conjunctival keratinisation • Rod photoreceptor loss Chronic pancreatitis • Diabetic retinopathy Inflammatory bowel disease • Episcleritis • Non-necrotising scleritis • Anterior uveitis Large bowel tumours • Atypical congenital retinal pigment epithelium hypertrophy (familial adenomatous polyposis) Inherited liver disease • Kayser–Fleischer corneal rings, sunflower cataracts (Wilson’s disease) • Diabetic retinopathy (haemochromatosis)

Functional anatomy and physiology • 1167

Histologically, the centre of the retina is termed the macula lutea, its yellowish appearance caused by the presence of the xanthophylls (yellow pigments) lutein and zeaxanthin. At the centre of the macula, the neurosensory retina dips to form the fovea. The single-layered retinal pigment epithelium is highly metabolically active and is essential for the maintenance and survival of the overlying photoreceptors. The neurosensory retina initiates the visual pathway. Its photoreceptors synapse with radially arranged bipolar neurons, which in turn synapse with circumferentially arranged optic nerve ganglion cells. ‘Horizontal’ and amacrine cells within the plexiform layers modulate neuronal activity between bipolar cells, photoreceptors and the ganglion cells. At the fovea, a one-to-one relationship between cones, bipolar neurons and ganglion cells leads to the highest acuity. In the peripheral retina, many rods converge on to a bipolar neuron, and many bipolar neurons converge on to a ganglion cell, leading to lower acuity. In effect, the peripheral retina conveys black-and-white sentinel vision, alerting the brain to move the higher-acuity colour vision of the fovea into gaze. Photoreceptors are specialised neurons that cause neurotransmitters to be released in response to light (‘phototransduction’). There are three types of photoreceptors: namely, rods, cones and ganglion cells, the latter of which independently respond to blue light, influencing circadian rhythms. The sclera is pierced posteriorly by the optic nerve at the lamina cribrosa, a sieve-like conduit. Its outer layer, the episclera, consists of loose connective tissue, separating it from Tenon’s capsule, the soft-tissue socket of the eye. Choroid, ciliary body and iris – the uveal tract Posteriorly, the choroid acts as a conduit for branches of the ophthalmic artery and veins. The choriocapillaris, a network of widebore, fenestrated capillaries, abuts the retinal pigment epithelium. The ciliary body forms the junction between the choroid and the iris, and lies just inferior to the limbus. Anteriorly, its ciliary processes produce aqueous (fluid) that circulates through the pupil into the anterior chamber. Posteriorly, it constitutes the pars plana and forms the attachments for the suspensory ligaments of the lens. The ciliary muscle encircles the eye within the ciliary body. Contraction of this muscle relaxes the suspensory ligaments of the lens, bringing near objects into focus. The iris bows gently forwards as it lies against the lens. It is divided into a pupillary zone, containing the circumferential sphincter pupillae muscle, and a ciliary zone, containing the dilator pupillae. Retina The retina consists of the neurosensory retina and the retinal pigment epithelium. The two layers are adherent only adjacent to the optic disc and at the edge of the pars plana. Fig. 27.2 The main structures of the eye. The inset shows the arrangement of the retinal cells. Inset adapted from Douglas G, Nicol F, Robertson C (eds). Macleod’s Clinical examination, 13th edn. Churchill Livingstone, Elsevier Ltd; 2013. Limbus Sclera Choroid Retina Fovea Hyaloid canal Retinal vessels Optic nerve Extraocular muscle Optic nerve fibres Ganglion cell Amacrine cell Bipolar cell Horizontal cell Cone Rod Pigment epithelium Cornea Iris Pupil Lens Anterior chamber (aqueous) Ciliary muscle Ciliary body Conjunctiva Vitreous gel Suspensory ligaments

1168 • MEDICAL OPHTHALMOLOGY The tangent screen is a piece of black cloth attached to a wall, in front of which the operator introduces moving targets into the patient’s field of view. It retains an important role in the positive identification of functional peripheral field loss (tunnel vision) versus pathological field loss (funnel vision), although the results are somewhat operator-dependent. Goldmann perimetry is a mechanical improvement on tangent screen perimetry, which utilises targets of varying size and illumination. An automated version is available. Automated threshold perimetry Automated visual fields test the threshold of the eye’s ability to see at various points within the visual field, forming complex outputs that can be stored digitally. Internal quality assurance mechanisms monitor stability of fixation, false positives due to trigger-happy patients and false negatives due to performance fatigue. Many patients need practice before accurate results are obtained; first-time fields are rarely reliable and often show spurious and misleading findings. Most automated perimetry assesses only central vision. Few neurological disorders start peripherally, the exception being unilateral loss of peripheral field with disease of the anterior pole of the occipital lobe. However, retinal pathology, such as retinal detachment and retinitis pigmentosa, may be missed if reliance is placed on automated perimetry rather than clinical examination. Visual field defects on perimetry that affect the whole of the superior or inferior half of the visual field need to be differentiated by confrontation into arcuate visual field defects, which affect central field only, and altitudinal field defects, which affect both central and peripheral vision. Arcuate visual fields defects localise a lesion to the optic nerve head, whereas a lesion anywhere along the optic nerve can cause an altitudinal defect. Imaging See Figure 27.4. Photography Digital photography is utilised to document surface anatomy. Colour images are ideal for lesions affecting the skin and cornea. For the retina, however, red-free imaging brings additional benefits, particularly for discriminating red haemorrhages or abnormal new vessels from the red background of the retina. Lens The lens is a transparent flexible structure suspended between the iris and the vitreous. Its flexibility enables objects over a range of distances to be focused on the retina. It has a capsule, a central nucleus and a peripheral cortex. It continues to grow throughout life, becoming less flexible with age. Vitreous The vitreous gel is 99% water and 1% collagen/hyaluronic acid. The outer edge (cortex) of the vitreous condenses to form the anterior and posterior hyaloid membranes. The base of the vitreous strongly adheres to the ora serrata/pars plana and the optic disc rim, where the internal limiting membrane of the retina is thinnest. Lesser degrees of adhesion occur at the parafoveal retina and along the retinal vessels. Blood supply of the orbit/eye The main blood supply of the orbit originates from the intracranial internal carotid artery. The ophthalmic artery, the first branch of the internal carotid artery, traverses the subarachnoid space to enter the optic canal within the dural sheath of the optic nerve. On leaving the optic canal, it emerges from the dural sheath to course briefly along, and then over, the optic nerve and reach the medial wall of the orbit. Several arterial circles are formed. The major arterial circle of the iris is formed within the ciliary body by anterior ciliary arteries anastomosing with the posterior ciliary arteries. The pial branches of the optic nerve and the short ciliary arteries join together, as the circle of Zinn, to supply the intraocular optic nerve. The infraorbital artery, a branch of the maxillary artery, also contributes to the orbital blood supply, in particular the inferior rectus, the inferior oblique and the lacrimal sac. The orbit is drained by the superior and inferior ophthalmic veins, which converge to drain through the superior orbital fissure into the cavernous sinus. Investigation of visual disorders History is the key to diagnosing visual disorders, with examination and investigations used to confirm or refute the expectations formed by the history. Perimetry In the era before modern radiology, manual perimetry was utilised as a non-invasive form of ‘neuroimaging’. Nowadays, perimetry is largely automated and its main role lies in the monitoring of glaucoma; it also has a lesser role in assessing neuro-ophthalmic disorders. All methods of perimetry are subjective and rely on patient cooperation and mental agility. Amsler chart The Amsler chart (Fig. 27.3) is the simplest method of documenting the visual field, and is easy for both patient and clinician to understand and perform. It can be used for all forms of visual field loss but is best suited to follow up the central scotomata of macular disorders, which are often too subtle for other methods of perimetry. Tangent/Goldmann kinetic perimetry Manual perimetry methods, such as tangent screen and Goldmann kinetic perimetry, appeal to the non-specialist, as they produce easily interpretable contoured maps of the visual field. Fig. 27.3 Amsler chart. The Amsler chart is a grid of 0.5 cm squares with a dot in the centre. The subject is asked to fix on the central dot with one eye and any distorted or missing lines are recorded.

Presenting problems in ophthalmic disease • 1169

Ocular ultrasound The main role of ultrasound is where the retina is obscured: for instance, by cataract or vitreous haemorrhage. It also has an important role in diagnosing choroidal melanoma, based on its distinctive internal reflectivity. Visual electrophysiology Electrophysiology is used to localise disorders to the photoreceptors (electroretinogram), the retinal ganglion cells (pattern electroretinogram) or the optic pathways (visual evoked potential). The site of photoreceptor involvement can be further localised to specific regions of the retina (multifocal electroretinogram) or the macula itself (pattern electroretinogram). Electrophysiology requires cooperation, correction of refractive errors and the ability to fixate. Voluntary suppression of the electrical responses is possible by simply not focusing on the target. Despite this, it remains the investigation of choice for visual symptoms unexplained by clinical examination. Presenting problems in ophthalmic disease Presenting problems that are ophthalmological manifestations of predominantly neurological disease (e.g. ptosis, diplopia, oscillopsia, nystagmus and pupillary abnormalities) are discussed in Chapter 25. Optical coherence tomography Optical coherence tomography is the optical equivalent of ultrasound, using light rather than sound waves to create its images. It is invaluable, not least for assessing the integrity of the layers of the retina and detecting macular oedema of any cause. Autofluorescence The retinal pigment epithelium contains autofluorescent lipofuscin, which can be excited by blue- and green-coloured light and captured by digital imaging. Increased autofluorescence occurs when there is abnormal accumulation of lipofuscin, as seen with certain inherited retinal dystrophies; excess retinal pigment epithelium metabolic activity, such as at the edge of evolving atrophic macular degeneration; or drug deposition, such as with hydoxychloroquine. Fundus angiography Fluorescein angiography is an invasive technique with risks including local extravasation of dye at the site of intravenous injection and anaphylaxis. Currently, its role is limited to the diagnosis of retinal vasculitis, retinal and choroidal neovascularisation, and capillary occlusion. Non-invasive angiography is now possible using optical coherence tomography, but its applicability is limited by small field of view and inability to demonstrate flow or leakage. Indocyanine angiography directly images the choroidal circulation and is particularly useful in guiding laser treatment for the choroidal polyps of polypoidal choroidal vasculopathy. Fig. 27.4 Ocular imaging. A Colour retinal photograph from a healthy subject. B Red-free retinal photograph from a healthy subject. C Optical coherence tomogram of a normal eye, showing the layers of the retina. In this image, the macula shows normal foveal indentation. D Fundus autofluorescence (FAF) of the right eye in a normal subject. Distribution of FAF intensity shows typical background signal with reduced signal at the optic disc (absence of autofluorescent material) and retinal vessels (absorption). Intensity is markedly decreased over the fovea due to the absorption of the blue light by yellow macular pigment. E Fundal fluorescein angiogram of a normal adult retina. F Ocular ultrasound image showing typical biconvex appearance of a choroidal melanoma. A, B, C and F, Courtesy of Aberdeen Royal Infirmary. D, From Schmitz-Valckenberg S, Fleckenstein M, Hendrik PN, et al. Fundus autofluorescence and progression of age-related macular degeneration. Survey Ophthalmol 2009; 54(1):96–117. E, From Witmer MT, Szilárd K. Wide-field imaging of the retina. Survey Ophthalmol 2013; 58(2):143–154. A B C D E F

1170 • MEDICAL OPHTHALMOLOGY Photophobia may also be a feature of meningitis, usually with accompanying neck stiffness and headache (meningism, p. 1118). Glare is a common early feature of cataract, particularly triggered by oncoming car headlights when driving at night. It is a relatively common indication for surgery. It may also be an issue where there is insufficient melanin in the retinal pigment epithelium, e.g. in atrophic age-related macular degeneration, in ocular albinism or following extensive pan-retinal laser therapy. If surgery is not an option, or while surgery is awaited, the symptom of glare may be reduced by wearing a broad-brimmed hat. Photopsia A flickering light sensation is indicative of photoreceptor activity, either through traction, as in the setting of posterior vitreous detachment, or inflammation, as in the setting of autoimmune or paraneoplastic retinopathy. Rarely, photopsia is a symptom of occipital lobe epilepsy, in which case there is usually an accompanying homonymous hemianopia. Blurred vision Blurred vision describes the situation in which patients are able to see what they are looking at, but what they are looking at is out of focus. The most common cause of intermittent blurred vision is dry eye; the most common cause of permanent blurred vision is cataract. If blurred vision is worse in the morning and eases as the day progresses, this suggests macular oedema. Loss of vision In visual loss, patients are no longer able to see all or part of what they are looking at. Some symptoms associated with visual loss require urgent ophthalmological assessment (Box 27.8). Watery/dry eye The most common cause of a watery eye is a dry eye triggering reflex lacrimation. Patients with dry eye may complain of a foreign body or gritty sensation in the eye or intermittent visual blurring, triggered by reduced blinking, as occurs when reading or when concentrating on a distant object, such as the television. Pruritus Common causes of itch are an acute allergic response to either airborne allergens or direct contact. A significant proportion of people are allergic to topical chloramphenicol, a first-line treatment for many minor ocular ailments. Pain/headache The key consideration in deciding whether or not ocular pain and/or headache originates from the eye is whether there is a ciliary flush (red eye) or no ciliary flush (white eye). Red eye The presence of a ciliary flush in the region of the limbus is a key finding in intraocular causes of pain. The presence of watering or watery discharge is not a discriminatory feature, and over-reliance on this symptom often results in anterior uveitis being misdiagnosed as viral conjunctivitis. White eye In the absence of a ciliary flush, ocular or periorbital pain is most commonly caused by migraine. Pain on eye movement is a cardinal feature of optic neuritis and scleritis. In optic neuritis the eye is white, whereas in scleritis, except for posterior scleritis, it is red. Posterior scleritis, in which the visible sclera is white, should be diagnosed only in the setting of positive signs such as disc swelling and exudative retinal detachment, or with confirmation by ocular ultrasound. A more common cause of severe ocular/ periocular pain, with associated photophobia and lacrimation, is cluster headache (p. 1096), which is often misdiagnosed as scleritis. Just like scleritis, cluster headache responds to oral glucocorticoids, adding to the diagnostic confusion. Intermittent, subacute angle closure glaucoma can cause headache, but usually accompanying corneal oedema causes haloes (a form of glare with rainbow colours), elicited by looking at lights or blurring of vision. Giant cell arteritis is an uncommon, but usually striking, cause of headache, predominantly seen in the elderly. Rarely, it presents with sudden painless visual loss in the absence of raised inflammatory markers. Diagnosis can be made by demonstrating choroidal shutdown on fluorescein angiography. Photophobia/glare Excessive sensitivity to light, rather than fear of light, usually indicates ciliary muscle spasm due to inflammation in the iris. Common causes are corneal abrasion, acute anterior uveitis and contact lens-related keratitis. Occasionally, photophobia can be a symptom of congenital retinal dystrophies, especially cone photoreceptor deficiency. 27.8 Red flag symptoms in visual loss* Symptom Possible causes Sudden onset Retinal artery occlusion Ischaemic optic neuropathy Headache Giant cell arteritis if age > 55 years Eye pain Angle closure glaucoma Keratitis Scleritis Anterior uveitis Pain on eye movement Optic neuritis Scleritis Distortion Choroidal neovascular membrane: Age-related macular degeneration Pathological myopia Posterior uveitis Idiopathic Macular hole Epiretinal membrane Worse in the morning Macular oedema: Diabetic macular oedema Retinal vein occlusion Uveitis *The presence of any of these symptoms in a patient with visual loss requires emergency referral to an ophthalmologist.

Specialist ophthalmological conditions • 1171

most common cause is thyroid eye disease, when proptosis is termed exophthalmos. Proptosis is a sign of retro-orbital expansion and may be intraconal or extraconal. When expansion is within the cone of extraocular muscles, then movement forwards will be in line with the visual axis. When outside, the eye is additionally displaced to the side. The primary clinical concern is whether vision is at risk due to optic nerve compression or corneal exposure. In addition, there may be double vision. In thyroid eye disease, diplopia may be absent if the disease is symmetrical. Instead, restricted ocular movements make patients move their head en bloc when looking at objects deviating from the primary position of gaze. To the patient, however, the overarching concern is often the change in appearance. Specialist ophthalmological conditions Ocular inflammation Inflammation can affect any part of the eye. In structures in direct contact with the environment, particularly the cornea and the conjunctiva, inflammation is most likely to be caused by infection. In other structures, such as the uveal tract and sclera, inflammation is more likely to be caused by autoimmune conditions, although it may also be a manifestation of infection or malignancy. Although the latter conditions may present with indicative ocular signs, their presence is often appreciated only retrospectively, after failure to respond to immunosuppression. Most non-infective forms of ocular inflammation are idiopathic; all are more common in the presence of other autoimmune conditions. Some may be directly associated but asynchronous in disease activity, such as the anterior uveitis of ankylosing spondylitis (p. 1028). Others are direct manifestations of an overarching, underlying, inflammatory condition such as the keratoscleritis of granulomatosis with polyangiitis (formerly known as Wegener’s granulomatosis). Sjögren’s syndrome Sjögren’s syndrome is the archetypal autoimmune disease and its secondary form is associated with a large number of other autoimmune conditions (see Box 24.64, p. 1039). The cardinal features are inflammation of the lacrimal gland, its conjunctival accessory glands and the parotid gland, leading to hyposecretion of tears and saliva. Involvement of the lacrimal gland alone causes keratoconjunctivitis sicca, a syndrome of dry eyes and corneal and conjunctival irritation. Keratoconjunctivitis sicca, however, can also be caused by reduced function of the lacrimal glands and/or lacrimal ducts from other causes. Treatment of the ophthalmological manifestations of Sjögren’s syndrome is symptomatic, and consists of supplementing tear production with artificial tears (e.g. hypromellose) and reducing tear loss by humidification and avoidance of dry environments. If these measures are insufficient, tear drainage may be reduced with surgical options such as punctal plugs and punctal occlusion. Peripheral ulcerative keratitis Peripheral ulcerative keratitis (‘corneal melting’) is an autoimmune disorder affecting the corneal limbus, where it may be The most common cause of transient visual loss is the aura of migraine, usually a positive phenomenon with the object of regard seemingly hidden by something in the way, rather than a negative phenomenon in which part or all of what is being looked at is missing. With positive visual phenomena the obstruction is often white or coloured, expanding across the visual field, or in a constant position but shimmering. Negative visual phenomena are a cardinal feature of ocular, usually retinal, ischaemia, with complete absence of vision (blackness) occupying part or all the visual field. Transient ocular ischaemia is usually embolic in nature but is occasionally seen in giant cell arteritis, where it suggests critical optic nerve ischaemia. Permanent monocular negative visual phenomena usually indicate previous optic nerve or retinal infarction. Tiny negative visual phenomena may also be seen in capillary disorders such as diabetic retinopathy, where patchy macular capillary occlusion may, for instance, cause letters to be missing from words on reading. Distortion of vision Distortion is a cardinal symptom of disruption of foveal photoreceptor alignment. The most common cause is choroidal neovascularisation. Less commonly, it can be caused by epiretinal membrane formation, where posterior hyaloid surface scarring causes foveal traction. Usually with distortion, objects are not only misshapen but also smaller (micropsia), due to the photoreceptors being pulled apart. Macropsia, where objects look bigger than normal, is uncommon. It is sometimes seen in the ‘Alice in Wonderland’ syndrome, a paediatric variant of migraine where there is altered visual perception of body images. Eyelid retraction Eyelid retraction is usually caused by inflammatory thyroid eye disease or thyrotoxicosis (see pp. 631 and 645, and Fig. 18.8). The first muscle to be affected in thyroid eye disease is the inferior rectus. The enlarged muscle tethers the eye and restricts upgaze. Compensatory increased innervation to the superior rectus and the levator palpebrae superioris, as well as direct inflammation, leads to eyelid retraction. In thyrotoxicosis, increased sympathetic nervous activity leads to bilateral eyelid retraction. This, however, resolves with beta-blockade and treatment of thyrotoxicosis. Rarely, bilateral eyelid retraction is a sign of dorsal midbrain pathology (Collier’s sign), where it is accompanied by a supranuclear upgaze palsy and convergence-retraction nystagmus. Optic disc swelling Optic disc swelling can be a developmental variant of normal (pseudopapilloedema) or caused by optic nerve pathology, or reflect more widespread nerve fibre oedema as with retinal vein occlusion. Neurological causes of optic disc swelling are discussed in on page 1090. Proptosis Proptosis, particularly if bilateral and symmetrical, is often first recognised when it is quite advanced. Accompanying eyelid retraction is a typical feature of thyroid eye disease. By far the

1172 • MEDICAL OPHTHALMOLOGY may induce active systemic infection. Furthermore, the most commonly used biologic for uveitis – anti-tumour necrosis factor therapy (e.g. adalimumab, infliximab) – may trigger demyelination. The most common form of uveitis is anterior uveitis, which is usually idiopathic but may be associated with other autoimmune conditions, particularly HLA-B27-related spondyloarthropathies (p. 1027); it is rarely caused directly by infection. Acutely, dilating drops are used to prevent the inflamed iris from sticking to the lens (posterior synechiae) and obstructing the outflow of aqueous fluid, while a tapering dose of topical glucocorticoids, usually over 4–6 weeks, mitigates the local signs and symptoms of the self-resolving inflammation. Inadequate treatment can lead to pupil block glaucoma and cataract. Posterior complications can also develop, predominantly macular oedema, the main cause of visual impairment in all forms of uveitis. With intermediate uveitis, inflammation occurs at the pars plana, with most symptoms, predominantly floaters, being a result of inflammation of the vitreous base. Unlike anterior uveitis, pure intermediate uveitis is not associated with iris inflammation; instead, white blood cells are seen predominantly in the anterior vitreous, with a lesser amount overspilling into the anterior chamber. Treatment is challenging. Topical therapy is ineffective, as it does not penetrate beyond the anterior chamber, but symptoms of floaters are not often sufficient to justify systemic immunosuppression. In some cases, vitritis (vitreous inflammation), or more commonly macular oedema, may cause visual impairment. Occasionally, retinal neovascular proliferation may occur, either as an inflammatory response or as a direct result accompanied by adjacent scleritis. It may be directly associated with inflammatory disorders in which immune complexes are formed, particularly rheumatoid arthritis, systemic lupus erythematosus and granulomatosis with polyangiitis. Pain and redness are helpful indicators but may not always be present. Systemic immunosuppression is always required but topical glucocorticoids should be used cautiously due to the risk of aggravating keratolysis (corneal thinning). Secondary infection should be prevented with topical antibiotics and attention should be paid to corneal hydration, through the use of artificial tears and lubricants. More common causes of peripheral corneal ulceration are blepharitis and acne rosacea, causing ocular irritation rather than frank pain. Hypersensitivity to staphylococcal exotoxin leads to stromal infiltrate adjacent to, but sparing, the limbus (marginal keratitis). Resolution of this self-limiting condition can be assisted by the use of topical chloramphenicol, with or without topical glucocorticoids. Prevention is through management of the underlying condition, usually with ocular lid hygiene for simple blepharitis and metronidazole gel for rosacea. Scleritis Scleritis is usually accompanied by severe pain, worse on eye movement and often waking the patient through the night. Diagnosis of anterior scleritis is usually straightforward, with the eye showing diffuse or nodular erythema (although it may have to be searched for under the eyelids). Posterior uveitis is often accompanied by reduced vision and oedema of the retina, choroid and extraocular muscles. White patches of necrosis (pallor) within the erythema are an ominous sign, indicative of systemic vasculitis. Non-necrotising scleritis is commonly idiopathic but may be associated with other autoimmune conditions, particularly rheumatoid arthritis and inflammatory bowel disease. It is also common with herpes zoster ophthalmicus, intraocular involvement being indicated by the involvement of the lateral external nose (Hutchison’s sign). Necrotising scleritis requires aggressive immunosuppression; non-necrotising scleritis can occasionally be managed by topical glucocorticoids or non-steroidal anti-inflammatory drugs (NSAIDs) but usually requires oral glucocorticoids. Some patients with recurrent episodes of scleritis, or in whom inflammation is gradual and prolonged, may develop scleral thinning (scleromalacia), revealing the underlying blue choroid. Episcleritis Episcleritis is a benign self-limiting condition of uncertain aetiology, occasionally associated with other inflammatory disorders. Sectoral redness of the episclera is usual, although nodules can form. Often confused with scleritis, although usually less symptomatic, the diagnostic topical application of phenylephrine turns the inflamed episclera white but has no effect on the redness of scleritis. Treatment is with cold artificial tears, although occasionally topical NSAIDs or topical glucocorticoids are required. Uveitis Uveitis is an overarching term for inflammation anywhere in the uveal tract, retina or vitreous. It may be classified according to speed of onset, location, specific features, or aetiology (Box 27.9). Syphilis can cause all forms of uveitis. Active tuberculosis may present with an occlusive vasculitis or serpiginous (snake-like) choroiditis emanating from the optic disc. Latent tuberculosis is a particular concern because treatment of the uveitis with biologics 27.9 Aetiology of uveitis Idiopathic • Anterior uveitis often associated with the HLA-B27 haplotype, even in the absence of other manifestations Primary ophthalmic conditions • Trauma, including penetrating injury and ophthalmic surgery • Fuchs’ heterochromic cyclitis • Posner–Schlossman syndrome Rheumatological • HLA-B27-associated (seronegative) spondyloarthropathies: ankylosing spondylitis, psoriatic arthritis, reactive arthritis • Juvenile idiopathic arthritis Systemic vasculitides • Behçet’s disease • Polyarteritis nodosa • Granulomatosis with polyangiitis (Wegener’s) Systemic infections (only the more common causes are listed) • Brucellosis • Herpes virus infections (cytomegalovirus, herpes simplex virus, varicella zoster virus) • Leptospirosis • Lyme borreliosis • Syphilis • Toxoplasmosis • Tuberculosis • Whipple’s disease Gastrointestinal conditions • Inflammatory bowel disease (Crohn’s disease, ulcerative colitis) Malignancy • Primary central nervous system lymphoma (rare) Systemic conditions of unknown cause • Multiple sclerosis • Sarcoidosis

Specialist ophthalmological conditions • 1173

All layers of the cornea may be involved: the epithelium in the form of dendritic ulceration; the stroma in the form of white infiltrate and occasionally necrosis; and the endothelium in the form of localised oedema and keratitic precipitates. Loss of corneal sensation is common following herpes simplex keratitis, and occasionally neurotrophic keratopathy may result. Epithelial disease is self-limiting but treatment with topical or oral antivirals reduces the risk of stromal involvement and scarring. Stromal and endothelial disease requires additional topical glucocorticoids, but only once any epithelial defect has healed. Herpes simplex keratitis is analogous to herpes labialis; recurrences are therefore common and, if frequent, may warrant long-term oral antivirals. Corneal grafting may be required but the risk of recurrence remains. Bacteria also cause infectious keratitis, especially following corneal trauma or contact lens misuse. Other risk factors for microbial keratitis include topical glucocorticoids and pre-existing ocular surface disease. Bacterial keratitis has many causes, some of which do not respond to chloramphenicol, so topical quinolones are used as first-line agents. Rarely, the free-living amoeba Acanthamoeba castellanii may be a cause of contact lens-associated keratitis, presenting subacutely and leading to corneal nerve infiltration, keratitis and accompanying scleritis. Fungal keratitis is the most common cause of infectious keratitis in developing countries, particularly if there has been corneal trauma and contact with soil or plant matter. It is usually caused by Fusarium. Fungal keratitis has no particular distinguishing features and delayed diagnosis is common. If it is suspected, cultures should be undertaken and antifungal treatment, which is hampered by poor corneal penetration of antifungals, started promptly. Corneal transplantation is often required. Endophthalmitis Endophthalmitis is infection of the anterior and posterior chambers of the eye. It may be exogenous (e.g. from penetrating trauma or following surgery) or, less commonly, endogenous, caused by haematogenous spread of microorganisms within the blood, which gain entry to the eye via the choroid and ciliary body. The causes of endogenous endophthalmitis are therefore the causes of bacteraemia and fungaemia (p. 225). Gram-positive of capillary occlusion. Intermediate uveitis may be associated with demyelination, sarcoidosis and inflammatory bowel disease. Posterior uveitis tends to present with visual impairment secondary to macular oedema, vitritis or choroiditis. More chronic forms also exist and these tend to present with photopsia, visual field defects or distortion inducing choroidal neovascular membranes. Infectious conditions Conjunctivitis Conjunctivitis is predominantly caused by bacteria or viruses, and is usually self-limiting in 7–10 days. Bacterial conjunctivitis is associated with a purulent discharge and viral conjunctivitis with a watery discharge, the latter often being confused with the photophobia and reflex lacrimation of anterior uveitis. Underlying chlamydial infection should always be considered if there is a persistent thick, mucopurulent discharge (p. 340). Allergic conjunctivitis is also common, either as a component of hay fever (allergic rhinitis, p. 622) or as an allergy to chloramphenicol, which is commonly used to treat conjunctivitis. Rarely, conjunctivitis may be associated with inflammatory systemic mucus membrane disorders, such as ocular mucus membrane (cicatricial) pemphigoid or Stevens–Johnson syndrome (pp. 1254 and 1264). The secondary effects of loss of conjunctival function can be devastating to the cornea. Other causes of conjunctival scarring include trachoma (p. 273), chemical burns and orbital radiotherapy. Infectious keratitis/corneal ulceration Inflammation of the cornea should always raise concern about underlying infection (Box 27.10). Central ulceration is always more serious than peripheral, through involvement of the visual axis. Cultures from corneal scraping or biopsy may be required, although much infectious keratitis is treated empirically on the basis of site, morphology and response to treatment. In the West, the most common cause of infectious keratitis is herpes simplex virus type 1 (occasionally type 2) (Fig. 27.5). 27.10 Common causes of infectious keratitis Organism Features/comments Treatment Viruses Herpes simplex Characteristic ‘dendritic’ ulcer is the most common form, often recurrent Topical/systemic aciclovir (with topical glucocorticoid for stromal keratitis once the epithelium is healed) Varicella zoster Herpes zoster ophthalmicus Systemic aciclovir Bacteria Pseudomonas aeruginosa Staphylococcus aureus Coagulase-negative staphylococci Propionibacterium spp. Coagulase-negative staphylococci and Propionibacterium spp. are members of the skin flora, and must not be dismissed as contaminants Topical fluoroquinolone with Gram-positive and Gramnegative cover (e.g. ofloxacin) Subsequent treatment depends on sensitivity testing results Fungi Fusarium sp. Aspergillus sp. Candida sp. Fusarium and Aspergillus keratitis are often associated with soil and/or corneal trauma; may also be contact lens-related Candida causes post-keratoplasty keratitis Options include topical natamycin (if available), amphotericin B, voriconazole and other azoles (e.g. econazole), and systemic fluconazole or voriconazole Parasites Acanthamoeba castellanii (free-living amoeba) Associated with poor contact lens hygiene Topical polyhexamethylene biguanide Onchocerca volvulus (nematode) See page 292

1174 • MEDICAL OPHTHALMOLOGY Fig. 27.5 Infective keratitis. A Herpes simplex dendritic ulcer stained with fluorescein. B Fusarium keratitis. An irregularly edged lesion suggests a fungal cause but is not pathognomonic. A, Courtesy of McPherson Optometry, Aberdeen. B, From Macsai MS, Fontes BM. Rapid diagnosis in ophthalmology: anterior segment. Elsevier Inc.; 2008. (Courtesy of the External Eye Disease and Cornea Section, Federal University of São Paulo, Brazil.) A B Fig. 27.6 Focal chorioretinitis in clinically suspected endogenous Candida endophthalmitis. This patient was an intravenous drug user and improved with empirical oral fluconazole. From Ryan SJ (ed). Retina, 5th edn. Saunders, Elsevier Inc.; 2013. (Case courtesy of Jeffrey K. Moore, MD.) Fig. 27.7 Sunflower cataract and Kayser–Fleischer ring (arrow) in Wilson’s disease. From Kaiser PK, Friedman NJ (eds). Massachusetts Eye and Ear Infirmary Illustrated manual of ophthalmology, 4th edn. Saunders, Elsevier Inc.; 2014. bacteria are most common, followed by Gram-negative bacteria and then fungi. Clinical presentation is with visual blurring and/or visual loss, which are usually unilateral. Ocular findings range from a few deposits in the retina/choroid (chorioretinitis) to panendophthalmitis, in which there is a severe inflammatory reaction in both the anterior and posterior chambers. A specific appearance of the retina is described for Candida endophthalmitis, which characteristically causes creamy-white retinal or chorioretinal lesions (Fig. 27.6). It is vitally important to sample the vitreous, as this may provide the only opportunity to determine the most appropriate therapy. Treatment is with systemic and/or intravitreal antibiotics or antifungal agents, depending on the cause and severity. Vitrectomy may also be required. Cataract Cataract is permanent opacity of the lens (Fig. 27.7). Globally, untreated cataract is the most common cause of visual impairment, although in countries where surgery is available, age-related macular degeneration is a more common cause. The normal lens thickens and opacifies with age, and cataract can be detected in more than half the population over the age 65 (senile cataract). Many ocular and systemic diseases can predispose to cataract formation, the most common being uveitis and diabetes mellitus. Wilson’s disease (hepatolenticular degeneration, p. 896) causes a characteristic ‘sunflower’ cataract. Excessive exposure to ultraviolet light, ionising radiation and glucocorticoid therapy are also predisposing factors. The characteristic symptoms of cataract are progressive loss of vision and glare. If these become serious enough to require treatment, surgical intervention will be required, usually in the form of ultrasonic phacoemulsification with intraocular lens (IOL) implant. Other common ophthalmological findings in old age are shown in Box 27.11. Diabetic eye disease Diabetic retinopathy Diabetic retinopathy is one of the most common causes of visual impairment in people of working age in developed countries. The prevalence of diabetic retinopathy increases with the duration of diabetes. Almost all individuals with type 1 diabetes, and most of those with type 2 diabetes, will have some degree of

Specialist ophthalmological conditions • 1175

retinopathy after 20 years. Fortunately, most patients develop only mild forms of retinopathy. Pathogenesis The underlying pathogenesis of diabetic retinopathy is local vascular endothelial growth factor production initiated by hyperglycaemia-induced capillary occlusion. This occlusion stimulates increased production of retinal vascular endothelial growth factor, which not only increases capillary permeability, leading to retinal oedema, but also stimulates angiogenesis, leading to new vessel formation. Clinical features The initial clinical feature of diabetic retinopathy, capillary occlusion, is visible only on retinal angiography. Capillaries adjacent to the occluded capillary form discrete swellings (microaneurysms), which leak fluid and blood, causing oedema and retinal haemorrhages (Fig. 27.8). Clinically, microaneurysms appear as isolated red dots, the capillaries being too small to visualise. At the edge of any leaking fluid, lipids precipitate out to form exudate, like the tidemark of the sea. In turn, capillaries with microaneurysms also occlude, their microaneurysms turning white before disappearing entirely from clinical view. As more and more capillaries occlude, larger patches of retinal ischaemia form, leading to sufficient vascular endothelial growth factor production to induce the growth of new vessels at the border of diseased and undiseased retina. Within patches of retinal ischaemia, diseased remnants of partially perfused capillaries form intraretinal microvascular abnormalities (IRMAs) and retinal veins develop multiple diffuse swellings (venous beading). These signs are best seen on fluorescein angiography. 27.11 Common ophthalmological findings in old age • Small pupils that dilate poorly with mydriatics: common neurodegenerative finding, particularly with diabetes. • Spurious findings on automated perimetry: decreasing manual dexterity and cognitive function often render automated perimetry findings unreliable. • Lens opacities: cataract is ubiquitous but requires treatment only if symptomatic. • Drusen: common from mid-life onwards. Larger (soft) drusen are more likely to herald age-related macular degeneration than smaller (hard) drusen. • Glaucoma: angle closure glaucoma is more common as the increasing size of the lens shallows the anterior chamber. Once it is identified, both eyes are always treated to prevent development/ recurrence. Chronic open angle glaucoma is more common in those with a family history or ocular hypertension (isolated raised intraocular pressure). • Impaired upgaze: common. It is differentiated from progressive supranuclear palsy (p. 1114) by the doll’s head manœuvre, the full range of vertical movement being retained in progressive supranuclear palsy PSP. • Ptosis: mechanical ptosis is common due to degenerative disinsertion of the levator palpebrae superioris aponeurosis. A high skin crease and preserved ability to elevate help differentiate it from other causes (p. 1090). • Late-onset presentation of congenital conditions: adult pseudovitelliform macular ‘degeneration’ is an autosomal dominant retinal dystrophy, which causes mild visual impairment. Oculopharyngeal muscular dystrophy is an autosomal dominant condition characterised by later-onset chronic progressive external ophthalmoparesis and swallowing difficulties. 27.12 Medical ophthalmology in adolescence Inherited conditions • Stargardt’s disease: autosomal recessive macular dystrophy that commonly presents in adolescence/early adulthood, causing significant bilateral impairment of central vision. Developmental anomalies • Pathological myopia: due to elongated ocular axial length rather than refractive index of cornea and lens. Increased risk of retinal detachment and choroidal neovascular membrane formation. • Optic disc drusen: come to prominence during adolescence and usually first detected during routine examination. Often mistaken for papilloedema, particularly in the setting of coincidental daily headache. • Amblyopia: occasionally detected after the age of 7 years, particularly in the absence of pre-school screening, when it is unlikely to respond to patching of the other eye. • Keratoconus: presents with increasing astigmatism (distortion of vision due to abnormal corneal topography). Hard contact lenses are the mainstay of therapy. Further progression may be prevented through ‘cross-linking’ surgery. Deterioration of existing conditions • Diabetic retinopathy: in type 1 diabetes, retinopathy usually first presents at least 5 years after diagnosis, which often coincides with adolescence. Puberty may accelerate progression. Greatest risk is disengagement with diabetes care, including retinal screening, significantly increasing later presentation with advanced symptomatic retinopathy. • Adult manifestations of retinopathy of prematurity: clinical features depend on the type of treatment used in the neonatal period and include retinal detachment, angle closure glaucoma, severe myopia and cataract. Sexual activity • Chlamydia conjunctivitis: onset of sexual activity may lead to this ocular condition, which is associated with reactive arthritis (p. 1031). Untreated coexistent genital tract infection may cause infertility. Transition to adult services • Neurofibromatosis type 1: see page 1131. • Optic nerve astrocytoma/glioma: often develops in late childhood or early adolescence. Sports medicine • Contact sports: eye protection is important for all, especially if there is only one functional eye, e.g. with amblyopia. 27.13 Visual disorders and pregnancy • Ocular inflammation: pregnancy appears to have a protective effect on many inflammatory disorders, although not systemic lupus erythematosus. Most patients can taper treatment during pregnancy. Mycophenolate mofetil is teratogenic. Glucocorticoids and tacrolimus appear safe. The use of biologics during pregnancy should be based on a balance of risks, and professional guidelines should be consulted. • Diabetic retinopathy: may be accelerated during pregnancy because the placenta is a potent source of angiogenic growth factors. Retinal screening each trimester is recommended. • HELLP/pre-eclampsia/eclampsia (p. 1284): retinal features of accelerated hypertension (p. 514) may be seen, including optic disc oedema, flame haemorrhages and cotton wool spots. Occasionally, exudative retinal detachments occur. Vasogenic oedema (posterior reversible encephalopathy syndrome), affecting the posterior occipital and parietal lobes, may cause cortical visual impairment. All features tend to resolve with delivery or control of blood pressure.

1176 • MEDICAL OPHTHALMOLOGY Fig. 27.8 Diabetic retinopathy. A Colour photograph of severe background diabetic retinopathy: multiple blot haemorrhages indicative of capillary occlusion; dot haemorrhages indistinguishable from microaneurysms or microaneurysmal bleeds; and cotton wool spots indicative of arteriolar occlusion. B Red-free image shows the presence of extensive haemorrhages more clearly; the more haemorrhages, the greater the degree of likely capillary occlusion. C Fluorescein angiogram now reveals extensive entrapment of fluorescein within multiple microaneurysms. D Colour photograph showing three cardinal consequences of capillary occlusion: intra-retinal microvascular anomalies occurring within an area of capillary occlusion (top arrow); venous reduplication (rare finding), with venous beading, extending from the reduplication towards the optic disc, occurring where capillaries are occluded either side of the vein (middle arrow); and new vessel formation occurring at the border between the diseased and health retina (bottom arrow). E Red-free image shows these features, particularly intra-retinal microvascular anomalies, more clearly. Note the relative pallor compared to the right-hand side of the image, which is indicative of widespread capillary occlusion. Absolute pallor never occurs, as it is ‘masked’ by the highly vascularised choroid lying underneath. A–E, Courtesy of Aberdeen Royal Infirmary. A B C D E secondary optic atrophy and night blindness (nyctalopia), which interfered with the ability to drive. Modern application of laser is lighter, more tailored to the sites of underlying capillary ischaemia and relatively free of side-effects, only occasionally resulting in loss of the ability to drive. In the UK there is a requirement to inform the driver licensing authority if retinopathy is (or has been) present in both eyes, irrespective of treatment history. Intravitreal injections of anti-vascular endothelial growth factor (e.g. ranibizumab, aflibercept, bevacizumab) also cause temporary regression of proliferative retinopathy, whereas, after pan-retinal laser therapy, background and proliferative types of retinopathy regress permanently. If both eyes have been treated with laser, patients can be safely discharged to a retinal screening programme. Management of diabetic macular oedema Traditionally, oedema seen on slit-lamp biomicroscopy was categorised according to three patterns of leakage elucidated from fluorescein angiogram studies: • focal leakage from microaneurysms • diffuse leakage from diseased capillaries • ischaemia (no leakage) from thrombosis of the perifoveal capillaries. Laser was applied, either directly on leaking microaneurysms or empirically by placing a grid of burns on the affected macula, to reduce leakage. The main aim was to treat oedema before the fovea was affected, as laser therapy for oedema affecting the fovea was never particularly effective. New vessels and their glial tissue (like a cabbage leaf) grow from retinal veins, through the overlying internal limiting membrane into the vitreous, triggering local inflammation and contracting scars. The vitreous is strongly adherent to the pars plana. It pulls back on the new vessel, triggering further bleeding, growth, inflammation and scarring. If the scarring is sufficient, then tractional retinal detachment and complete blindness may occur. Other retinal lesions, not unique to capillary occlusion, are also seen in diabetic retinopathy. These include flame haemorrhages and cotton wool spots (soft exudates). Flame haemorrhages are horizontal streaky haemorrhages in the retinal nerve-fibre layer. They are also seen in any severe anaemia, e.g. bacterial endocarditis and leukaemia. Cotton wool spots are also situated in the nerve-fibre layer and are usually most numerous nasal to the optic disc, where the nerve fibres crowd together. They are also seen in accelerated hypertension, after severe hypoglycaemia and occasionally in giant cell arteritis. A cotton wool spot combined with an enclosing flame haemorrhage is termed a Roth spot. Roth spots have traditionally been associated with endocarditis, although they may be seen with any cause of a flame haemorrhage. Management of proliferative diabetic retinopathy If untreated, proliferative retinopathy eventually causes severe visual impairment through recurrent vitreous haemorrhage and retinal detachment. Pan-retinal laser photocoagulation therapy is extremely effective at preserving vision, if applied before complications set in. Historically, laser therapy was used empirically to ablate the retina extensively outside the macula. However, this caused

Specialist ophthalmological conditions • 1177

hypertension, hyperlipidaemia and smoking), all of which are prevalent in people with type 2 diabetes. In diabetes, metabolic changes in the lens (which are not yet fully elaborated) cause premature and/or accelerated cataract formation. A rare type of ‘snowflake’ cataract occurs in young patients with poorly controlled diabetes. This does not usually affect vision but tends to make fundal examination difficult. The indications for cataract surgery in diabetes are similar to those in the non-diabetic population, but an additional indication in diabetes is when adequate assessment of the fundus and/or retinal laser therapy becomes impossible. Retinal vascular occlusion Retinal vein occlusion (thrombosis) Retinal vein occlusion is an important vascular cause of visual impairment, visual loss resulting from macular oedema or occasionally from neovascularisation, both of which are managed in a similar way to diabetic macular oedema or proliferative diabetic retinopathy. Although pathogenesis of retinal vein occlusion is not fully understood, the most common mechanism is believed to be compression of a vein by an adjacent arteriosclerotic artery. Retinal vessels are unusual in that, where the arteries and veins cross over each other, they share a common outer layer (tunica adventitia). This means that arteriosclerotic thickening of an artery leads directly to compression of the adjacent vein (arteriovenous nipping). A less common cause of retinal vein occlusion is inflammation of the retinal vein (periphlebitis), also called retinal vasculitis (unlike systemic vasculitis, the arterial system is not involved). Periphlebitis should be suspected in younger patients and in patients with no obvious risk factors for arteriosclerosis. Diagnosis is made by fluorescein angiography and treatment is with systemic immunosuppression, with or without adjunctive intravitreal therapy. Retinal vein occlusion is associated with systemic hypertension and may rarely result from hyperviscosity due to a myeloproliferative disorder, multiple myeloma, Waldenström’s macroglobulinaemia or leukaemia. Glaucoma is associated with retinal vein occlusion but whether this is a direct cause or merely a comorbidity in the elderly is not known. Clinical presentation is with unilateral painless loss of central vision (central retinal vein thrombosis) or an area of peripheral vision (branch retinal vein thrombosis). Fundoscopic features include flame haemorrhages, cotton wool spots, macular oedema and a swollen optic disc (Fig. 27.9). However, retinal screening programmes have demonstrated that extrafoveal macular oedema often resolves spontaneously, and the introduction of intravitreal injection therapy, which rescues vision in 50% of those treated regardless of the mechanism of oedema, has led to a paradigm shift in management. Now, rather than laser treatment of asymptomatic oedema that does not involve the centre of the fovea, the emphasis has shifted to treating those who are symptomatic from centre-involving foveal oedema (confirmed on optical coherence tomography) with anti-vascular endothelial growth factor injections. Although this method of treatment is more effective, monthly injections may be required indefinitely. Prevention There is a clear relationship between glycaemic control and the incidence of diabetic retinopathy. A combination of good glycaemic and blood pressure control also slows the progression of retinopathy. When blood glucose is rapidly lowered in patients with type 1 diabetes, however, there can be a transient deterioration of retinopathy, predominantly in the form of cotton wool spot formation, but occasionally triggering new vessel formation. The trigger is believed to be increased systemic insulin growth factor release, which is most likely to occur with sudden correction of eating disorders or reinstitution of insulin therapy in those who miss out injections, often to induce weight loss. This often occurs during hospitalisation for other reasons. Although, ideally, any improvement in glycaemic control should be gradual, in many circumstances this is hard to achieve, particularly if the patient suddenly decides to comply with treatment, leading to dramatic improvement in glycaemic control. Screening Systematic screening for asymptomatic proliferative retinopathy has been shown to be cost-effective. It has led to the introduction of population-based screening programmes in the UK and other countries, where health care is funded centrally. There is little evidence that screening asymptomatic patients for macular oedema is cost-effective, although a by-product of screening is that suspected macular oedema has become the most common reason for referral from retinal screening to ophthalmology. Although hand-held ophthalmoscopy has been shown to have poor sensitivity compared to examination by slit-lamp biomicroscopy or retinal photography, any form of screening is better than none where resources are scarce. Currently, optical coherence tomography is being added to the screening pathway to reduce false-negative referrals for macular oedema. Historically, annual screening has been advocated. However, evidence now indicates that patients with repeated normal screens, particularly those with type 2 diabetes, can be safely screened every 2 years. In pregnancy, the placenta is a source of angiogenic growth factors. For this reason, although the risk of developing significant retinopathy during pregnancy remains low, pregnant women should be screened every trimester until the placenta is delivered. Other causes of visual loss in people with diabetes Around 50% of visual loss in people with type 2 diabetes results from causes other than diabetic retinopathy. These include cataract, age-related macular degeneration, retinal vein occlusion, retinal arterial occlusion, non-arteritic ischaemic optic neuropathy and glaucoma. Some of these conditions are to be expected in this group, as they relate to cardiovascular risk factors (e.g. Fig. 27.9 Central retinal vein occlusion (thrombosis), showing flame haemorrhages, cotton wool spots, macular oedema and a swollen optic disc. Courtesy of Aberdeen Royal Infirmary.

1178 • MEDICAL OPHTHALMOLOGY epithelium (‘drusen’), often followed by the development of focal areas of macular hypo- and hyperpigmentation, where diseased retinal pigment epithelial cells have precipitated their pigment (age-related maculopathy). The atrophic form presents with gradual onset of central visual blurring, accompanied, to a lesser degree, by visual distortion. Large (geographic), central patches of atrophy are seen with areas of adjacent hyperpigmentation. In the neovascular form, sudden onset of central distortion, progressing within weeks, is the predominant symptom. Apart from age the main risk factor appears to be smoking. The advent of anti-vascular endothelial growth factor injectors has led to effective therapy for the neovascular form, in many but not all. Unfortunately, treatment is expensive and requires considerable financial and staff resources to treat in timely fashion; delayed treatment can lead to irreversible visual loss. For whichever type, whether treatable or not, visual rehabilitation, through the use of appropriate magnifiers, alteration in lighting and specialised adaptation of everyday living objects, remains important adjunctive therapy. Further information Websites jrcptb.org.uk/specialties/medical-ophthalmology How to train in medical ophthalmology in the UK. ndrs-wp.scot.nhs.uk Scottish Diabetic Retinopathy Screening Collaborative: aspects of screening for diabetic retinopathy, including rationale, organisation, delivery and an on-line training handbook. rcophth.ac.uk/standards-publications-research/clinical-guidelines Royal College of Ophthalmologists, London: as part of its role in championing excellence, produces a range of pragmatic surgical and medical guidelines. sun.scot.nhs.uk Scottish Uveitis Network: standards of care, treatment guidelines and information leaflets. The management of retinal vein occlusion is twofold: management of the underlying aetiology and management of the consequences of retinal vein occlusion. Where an underlying risk factor for arteriosclerosis is clearly present (p. 484), then secondary prevention measures should be commenced. However, the role of secondary prevention of arteriosclerosis in isolated retinal vein occlusion, although common practice by some, remains controversial. Retinal artery occlusion Retinal artery occlusion is usually an embolic phenomenon. Common predisposing factors are therefore (predominantly carotid) atherosclerosis valvular heart disease, arrhythmias and infective endocarditis. The next most common cause is vasculitis, mainly giant cell arteritis (p. 1042). Retinal artery occlusion presents with painless unilateral visual loss, the extent and location of which depend on whether there is a central occlusion or a branch occlusion (peripheral occlusions may be asymptomatic). Transient occlusion of the internal carotid or ophthalmic artery causes transient visual loss, or amaurosis fugax (p. 1152). The typical fundoscopic finding in a central occlusion is a transiently pale retina with a ‘cherry-red’ spot at the macula, the appearance developing over an hour or so after the occlusion (Fig. 27.10). In branch occlusions there is no cherry-red spot and the retinal pallor is regional. Age-related macular degeneration Age-related macular degeneration is the most common cause of visual impairment in the Western world. There are two basic forms: atrophic (dry) and neovascular (wet). The underlying mechanism is dysfunction of the retinal pigment epithelium, leading to overlying photoreceptor death. Choroidal neovascularisation, growing under and into the overlying retina, may occur, distorting the anatomy of the photoreceptors and ending in scar formation. Both forms are preceded by deposits under the retinal pigment Fig. 27.10 Retinal artery occlusion. A Colour fundus photograph of central retinal artery occlusion, showing a classic cherry-red spot and a superior optic disc haemorrhage. B Superior branch retinal artery occlusion due an embolus at the disc branch retinal artery occlusion, showing a pale segment of retina. A, From Duker JS, Waheed NK, Goldman DR. Handbook of retinal OCT. Saunders, Elsevier Inc.; 2014. B, From Bowling B. Kanski’s Clinical ophthalmology, 8th edn. Elsevier Ltd; 2016. A B

Ch04-3 Clinical Medicine

18-28 Medical psychiatry

28 Medical psychiatry

Medical psychiatry RM Steel SM Lawrie Clinical examination 1180 The psychiatric interview 1181 The mental state examination 1181 Investigations in medical psychiatry 1183 Functional anatomy and physiology 1183 Biological factors 1183 Psychological and behavioural factors 1183 Social and environmental factors 1184 Presenting problems in psychiatric illness 1184 Delirium 1184 Alcohol misuse 1184 Substance misuse 1184 Delusions and hallucinations 1184 Low mood 1185 Elevated mood 1186 Anxiety 1186 Psychological factors affecting medical conditions 1186 Medically unexplained somatic symptoms 1187 Self-harm 1187 Disturbed and aggressive behaviour 1188 Principles of management of psychiatric disorders 1189 Pharmacological treatments 1190 Electroconvulsive therapy 1190 Other forms of electromagnetic stimulation 1190 Surgery 1190 Psychological therapies 1190 Social interventions 1191 Psychiatric disorders 1191 Dementia 1191 Alcohol misuse and dependence 1194 Substance misuse disorder 1195 Schizophrenia 1196 Mood disorders 1198 Anxiety disorders 1200 Obsessive–compulsive disorder 1201 Stress-related disorders 1201 Somatoform disorders 1202 Eating disorders 1203 Personality disorders 1204 Factitious disorders and malingering 1205 Puerperal psychiatric disorders 1206 Psychiatry and the law 1207

1180 • MEDICAL PSYCHIATRY Psychiatric disorders have traditionally been considered as ‘mental’ rather than as ‘physical’ illnesses. This is because they manifest with disordered functioning in the areas of emotion, perception, thinking and memory, and formerly had no clearly biological basis. However, as biochemical and structural abnormalities of the brain are identified in an increasing number of psychiatric disorders, and psychological and behavioural factors are identified in many medical illnesses, the distinction between mental and physical illness has become questionable. The World Health Organisation (WHO) periodically publishes its International Classification of Disease (ICD), which provides definitions for every recognised clinical condition. The current edition (ICD-10) comprises 22 chapters. The diagnoses listed in Chapter V, ‘Mental and behavioural disorders’ (Box 28.1), are used by psychiatrists around the world in everyday clinical practice and it is these conditions that provide the focus for this chapter. Psychiatric disorders are among the most common of all human illnesses. The WHO’s Global Burden of Disease study found ‘Mental, neurological and substance misuse disorders’ to be the leading cause of ‘Years lost to disability’ (YLDs), accounting for 28.5% of global YLDs. As with most clinical conditions, the prevalence of mental disorders varies with the setting. In the general population, depression, anxiety disorders and adjustment disorders are most common (>10%) and psychosis is rare (<2%); in acute medical wards of general hospitals, organic disorders such as delirium are very common, with prevalence highest among sick, elderly patients; in specialist general psychiatric services, psychoses are the most common disorders (Box 28.2). Clinical examination As in other areas of medicine, the psychiatric assessment comprises a structured clinical history and examination followed by appropriate investigations. However, psychiatric assessment differs from a standard medical assessment in the following ways: • There is greater emphasis on the history and relatively less reliance on investigations. • A large part of the clinical examination component is conducted as the history is being taken rather than as a discrete set of procedures afterwards. 28.1 World Health Organisation classification of psychiatric disorders Chapter V (F00–F99) Mental and behavioural disorders Examples F00–F09 Organic mental disorders Dementias Delirium Other mental disorders due to brain damage or disease F10–F19 Disorders due to psychoactive substances: alcohol, opioids, cannabinoids etc. Intoxication Harmful use Dependence Withdrawal F20–F29 Schizophrenia and delusional disorders Schizophrenia F30–F39 Mood [affective] disorders Depression Bipolar affective disorder F40–F48 Neurotic, stress-related and somatoform disorders Phobias Generalised anxiety disorder Obsessive–compulsive disorder Post-traumatic stress disorder Adjustment disorders Somatoform disorders F50–F59 Behavioural syndromes associated with physiological disturbances Eating disorders: anorexia and bulimia nervosa Sexual dysfunction F60–F69 Disorders of adult personality and behaviour Specific personality disorders Trichotillomania Gender identity disorders F70–F79 Mental retardation Mild, moderate, severe or profound F80–F89 Disorders of psychological development Autism Asperger’s syndrome F90–F98 Behavioural and emotional disorders of childhood Hyperkinetic disorders Tic disorders From WHO. International Classification of Disease, 10th edn (ICD-10). 28.2 Prevalence of psychiatric disorders by medical setting Medical/surgical General psychiatric services General practice Outpatients Inpatients Delirium – – +++ – Alcohol/substance abuse ++ ++ +++ +++ Schizophrenia – – – +++ Bipolar affective disorder – – – +++ Depression ++ ++ +++ +++ Anxiety disorders ++ ++ ++ +++ Adjustment disorders ++ ++ +++ + Somatoform disorders + +++ ++ – Personality disorders + + + +++ − ‘rare’ (<2%); + ‘uncommon’ (2–5%); ++ ‘common’ (5–10%); +++ ‘very common’ (>10%)

Clinical examination • 1181

28.3 How to structure a psychiatric interview Presenting problem Reason for referral • Why the patient has been referred and by whom Presenting complaints • The patient should be asked to describe the main problems for which help is requested and what they want the doctor to do History of present illness • The patient should be asked to describe the course of the illness from when symptoms were first noticed • The interviewer asks direct questions to determine the nature, duration and severity of symptoms, and any associated factors Background Family history • Description of parents and siblings, and a record of any mental illness in relatives Personal history • Birth and early developmental history, major events in childhood, education, occupational history, relationship(s), marriage, children, current social circumstances Previous medical and psychiatric history • Previous health, accidents and operations • Use of alcohol, tobacco and other drugs • Direct questions may be needed concerning previous psychiatric history since this may not be volunteered: ‘Have you ever been treated for depression or nerves?’ or ‘Have you ever suffered a nervous breakdown?’ Previous personality • The patterns of behaviour and thinking that characterise a person, including their relationships with other people and reactions to stress (useful information may be obtained from an informant who has known the patient well for many years) • It commonly includes the interviewing of an informant, usually a relative or friend who knows the patient, especially when the illness affects the patient’s ability to give an accurate history. A full psychiatric history (Box 28.3) incorporating a detailed mental state examination may take an hour or more because of its complexity. A brief mental state examination, usually taking no more than a few minutes (see below), should be part of the assessment of all patients, not merely those deemed to have psychiatric illnesses. The psychiatric interview The aims of the interview are to: • establish a therapeutic relationship with the patient • elicit the symptoms, history and background information (Box 28.3) • examine the mental state • provide information, reassurance and advice. state may be observed as the history is being taken, specific enquiries about important features should always be made. General appearance and behaviour Any abnormalities of alertness or motor behaviour, such as restlessness or retardation, should be noted. The level of consciousness should be determined, especially in the assessment of possible delirium. Speech Speed and fluency should be observed, including slow (retarded) speech and word-finding difficulty. ‘Pressure of speech’ describes rapid speech that is difficult to interrupt. Mood This can be judged by facial expression, posture and movements. Patients should also be asked if they feel sad or depressed and if they lack ability to experience pleasure (anhedonia). Are they anxious, worried or tense? Is mood elevated with excess energy and a reduced need for sleep, as in (hypo)mania? Thoughts The content of thought can be elicited by asking ‘What are your main concerns?’. Is thinking negative, guilty or hopeless, suggesting depression? Are there thoughts of self-harm? If so, enquiry should be made about plans. Are patients excessively worried about many things, suggesting anxiety? Do they think that they are especially powerful, important or gifted (grandiose thoughts), suggesting mania? The form of thinking may also be abnormal. In schizophrenia, patients may display loosened associations between ideas, making it difficult to follow their train of thought. There may also be abnormalities of thought possession, when patients experience the intrusion of alien thoughts into their mind or the broadcasting of their own thoughts to other people (p. 1196). Abnormal beliefs A delusion is a false belief, out of keeping with a patient’s cultural background, which is held with conviction despite evidence to the contrary (p. 1184). Abnormal perceptions Illusions are misperceptions of real stimuli. Hallucinations are sensory perceptions that occur in the absence of external stimuli, such as hearing voices when no one is present (p. 1184). Cognitive function Cognitive function has many components: memory, concentration, visuospatial abilities, executive function and so on. In most cases, a brief assessment of orientation (person, place and time – the patent is asked their name, age, date of birth, what building they are in, the current date and day of the week) and attention (‘serial 7s’ – the patient is asked to subtract 7 from 100 and then 7 from the answer, and so on) is sufficient to exclude clinically significant cognitive impairment. Where there is reason to suspect cognitive impairment, however, a standardised screening tool should be used. In delirium, cognitive impairment typically fluctuates over time so may be missed by a single assessment. The Montreal Cognitive Assessment (MoCA) is a useful screening questionnaire that covers all the main domains of cognitive function (Fig. 28.1). It is designed to be easy to use and is freely available online in many different languages. Another widely used screening test is the Mini-Mental State Examination (MMSE), although this is subject to copyright, unlike the MoCA. The mental state examination The mental state examination (MSE) is a systematic examination of the patient’s thinking, emotion and behaviour. As with the clinical examination in other areas of medicine, the aim is to elicit objective clinical signs. While many aspects of the patient’s mental

1182 • MEDICAL PSYCHIATRY Fig. 28.1 Montreal Cognitive Assessment (MoCA). A widely used screening tool for cognitive impairment. © Z. Nasreddine MD, www.mocatest.org. VISUOSPATIAL/EXECUTIVE NAMING M E MO RY ATTENTION LANGUAGE ABSTRACTION ORIENTATION Optional © Z.Nasreddine MD www.mocatest.org DELAYED RECALL NAME: Education: Sex: Copy cube Contour FACE 1st trial

2nd trial FBACMNAAJKLBAFAKDEAAAJAMOFAAB VELVET CHURCH DAISY RED No points Read list of words, subject must repeat them. Do 2 trials, even if 1st trial is successful. Do a recall after 5 minutes. Read list of digits (1 digit/ sec.) Repeat: I only know that John is the one to help today. The cat always hid under the couch when dogs were in the room. Serial 7 subtraction starting at 100 Fluency / Name maximum number of words in one minute that begin with the letter F Similarity between e.g. banana – orange = fruit Has to recall words WITH NO CUE Category cue Points for UNCUED recall only Multiple choice cue Administered by: 4 or 5 correct subtractions: 3 pts, 2 or 3 correct: 2 pts, 1 correct: 1 pt, 0 correct: 0 pt Read list of letters. The subject must tap with his hand at each letter A. No points if ≥ 2 errors Subject has to repeat them in the forward order Subject has to repeat them in the backward order Numbers Hands POINTS /5 Draw CLOCK (Ten past eleven) (3 points) End Begin E A

B

D C Date of birth: DATE: Date Month Year Day Place TOTAL City Add 1 point if ≤ 12 yr edu Normal ≥ 26 / 30

FACE VELVET CHURCH DAISY RED train – bicycle watch – ruler

(N ≥ 11 words) /3 /2 2 1 8 5 4 7 4 2 /1 /3 /2 /1 /2 /5 /6 /30

Functional anatomy and physiology • 1183

Brain structure and function Brain structure is grossly normal in most psychiatric disorders, although abnormalities may be observed in some conditions, such as generalised atrophy in Alzheimer’s disease and enlarged ventricles with a slight decrease in brain size in schizophrenia. The functioning of the brain, however, is commonly altered due to changes in neurotransmitters such as dopamine, noradrenaline (norepinephrine) and 5-hydroxytryptamine (5-HT, serotonin). Functional differences in specific areas of the brain are increasingly being recognised using advanced imaging techniques. For example, positron emission tomography (PET) studies of dopamine ligand binding in schizophrenia has consistently demonstrated increased dopamine synthesis in the striatum, even in untreated patients, while a smaller body of PET evidence points towards reductions in 5-HT transporter binding in the mid-brain and amygdala in depression. Pattern classification approaches to structural magnetic resonance imaging (MRI) data can accurately predict the development of schizophrenia in at-risk populations, and generalised grey matter loss over time is a poor prognostic guide. Increased anterior cingulate activity in depression is a consistent predictor of good response to both antidepressants and cognitive behaviour therapy. While these and other imaging techniques show potential as diagnostic, prognostic and therapeutic aids, they remain research tools at the present time. It is also increasingly clear that psychiatric disorders are associated with disruptions in neuronal systems rather than single sites. These can be characterised using diffusion tensor imaging (DTI) of white-matter projection fibres and resting-state/task-based functional MRI (fMRI) studies of inter-regional connectivity. For example, DTI has shown reduced white-matter density in limbic (‘emotional’) system tracts, such as the fornix and cingulum, in many disorders. Resting-state fMRI studies consistently identify ‘default mode’, salience and executive control networks of interconnected neuronal populations for certain mental activities. These pathways are implicated in several psychiatric disorders but, as yet, in non-specific ways. Psychological and behavioural factors Early environment Early childhood adversity, such as emotional deprivation or abuse, predisposes to most psychiatric disorders, such as depression, eating disorders and personality disorders in adulthood. Personality The relationship between personality and psychiatric disorder can be difficult to assess because the development of psychiatric disorder can impact on a patient’s personality. Some personality types predispose the individual to develop a psychiatric disorder, however; for example, an obsessional (‘anankastic’) personality increases the risk of obsessive–compulsive disorder. A disordered personality may also perpetuate a psychiatric disorder once it is established, leading to a poorer prognosis. Behaviour A person’s behaviour may predispose to the development or perpetuation of a disorder. Examples include excess alcohol intake leading to dependence, dieting in anorexia or persistent avoidance of the feared situation in phobia. The Addenbrooke’s Cognitive Examination – 3rd edition (ACE-III) offers a more comprehensive assessment and brief training courses for clinicians wishing to use it. These resources are available online (see ‘Further information’). Patients’ own understanding of their symptoms Patients should be asked what they think their symptoms are due to and whether they warrant treatment. The failure of a patient to understand their own symptoms is referred to as ‘lack of insight’. Psychotic patients characteristically have lack of insight and fail to accept that they are in need of treatment. Investigations in medical psychiatry In many areas of medicine, laboratory or radiological tests play a central role in diagnosis. Such tests are often performed in psychiatry but are typically used to exclude non-psychiatric illness rather than to confirm a psychiatric diagnosis. For example, in a patient presenting with symptoms of anxiety it may be appropriate to check thyroid function to exclude thyrotoxicosis as a cause of their symptoms. Specific investigations are recommended in certain psychiatric conditions such as dementia, delirium and substance misuse. These will be discussed later in this chapter. Functional anatomy and physiology Most psychiatric disorders result from a complex interplay between psychological, social, environmental and genetic factors. Each of these factors may play a role in predisposing to, precipitating or perpetuating a disorder (Box 28.4). Biological factors Genetic Genetic factors play a predisposing role in many psychiatric disorders, including schizophrenia and bipolar affective disorder. However, while some disorders, such as Huntington’s disease, are due to mutations in a single gene, the genetic contribution to most psychiatric disorders is polygenic in nature and mediated by the combined effects of several genetic variants, each with modest effects and modulated by environmental factors. 28.4 Classification of risk factors for psychiatric disorders Classification Examples Predisposing Established in utero or in childhood Genetic and epigenetic factors Congenital defects Increase susceptibility to psychiatric disorder Disturbed family background Operate throughout patient’s lifetime Chronic physical illness Precipitating Trigger an episode of illness Determine its time of onset Stressful life events Acute physical illness Misuse of alcohol or drugs Perpetuating Delay recovery from illness Lack of social support Chronic physical illness

1184 • MEDICAL PSYCHIATRY (p. 1194), there are two additional sets of problems associated with drug misuse (Box 28.5): • problems linked with the route of administration, such as intravenous injection • problems arising from pressure applied to doctors to prescribe the misused substances. Assessment and management are described on page 1195. Delusions and hallucinations Delusions and hallucinations are abnormal beliefs and perceptions that have no rational basis. They are often due to psychiatric illness but can be secondary to substance misuse, physical illness or neurological disorders, such as epilepsy. Delusions A delusion is a false belief, out of keeping with a patient’s cultural background, which is held with conviction despite evidence to the contrary. It is common to classify delusions on the basis of their content. They may be: • persecutory – such as a conviction that others are out to harm one • hypochondriacal – such as an unfounded conviction that one has cancer • grandiose – such as a belief that one has special powers or status • nihilistic – such as ‘My head is missing’, ‘I have no body’ or ‘I am dead’. Hallucinations Hallucinations are defined as sensory perceptions occurring without external stimuli. They can occur in any sensory modality but most commonly are visual or auditory. Typical examples are hearing voices when no one else is present, or seeing ‘visions’. Hallucinations have the quality of ordinary perceptions and are perceived as originating in the external world, not in the patient’s own mind (when they are termed ‘pseudo-hallucinations’). Those occurring when falling asleep (‘hypnagogic’) and on waking (‘hypnopompic’) are a normal phenomenon and not pathological. Hallucinations should be distinguished from illusions, which are misperceptions of real external stimuli (such as mistaking a shrub for a person in poor light). Social and environmental factors Social isolation The lack of a close, confiding relationship predisposes to some psychiatric disorders, such as depression. The reduced social support resulting from having a psychiatric disorder may also act to perpetuate it. Stressors Social and environmental stressors often play an important role in precipitating psychiatric disorder in those who are predisposed, such as trauma in post-traumatic stress disorder, losses (such as bereavement) in depression, and events perceived as threatening (such as potential loss of employment) in anxiety. Presenting problems in psychiatric illness Delirium Delirium is a medical disorder that is common in the elderly and in patients in high-dependency and intensive care units. The causes, assessment and management are described on page 209. Alcohol misuse Misuse of alcohol is a major problem worldwide. It presents in a multitude of ways, which are discussed further on page 1194 and in Box 28.22. In many cases, the link to alcohol is obvious; in others, it may not be, since denial and concealment of alcohol intake are common. Clinical assessment The patient should be asked to describe a typical week’s drinking, quantified in terms of units of alcohol (1 unit contains approximately 8 g alcohol and is the equivalent of half a pint of beer, a single measure of spirits or a small glass of wine). The history from the patient may need corroboration by the GP, earlier medical records and family members. Investigations Abnormalities in routine biochemistry and haematology can support the diagnosis of alcohol excess (such as the finding of a raised mean cell volume (MCV) and/or raised γ-glutamyl transferase (GGT)), but such tests are abnormal in only half of problem drinkers; consequently, normal results on these tests do not exclude an alcohol problem. When abnormal, these measures may be helpful in challenging denial and monitoring treatment response. Transient elastography (also known as FibroScan) is an ultrasound-based technique that measures fibrosis and steatosis. It is used in specialist services to complement information derived from tests of MCV and GGT. Management The prevention and management of alcohol-related problems are discussed on page 1195. Substance misuse The misuse of drugs of all kinds is also widespread. As well as the general headings listed for alcohol problems in Box 28.22 28.5 Substance misuse: additional presenting problems Complications arising from the route of use Intravenous • Local: abscesses, cellulitis, thrombosis • Systemic: bacterial (endocarditis), viral (hepatitis, human immunodeficiency virus (HIV)) Nasal ingestion • Erosion of nasal septum, epistaxis Smoking • Oral, laryngeal and lung cancer Inhalation • Burns, chemical pneumonitis, rashes Pressure to prescribe misused substance • Manipulation, deceit and threats • Factitious description of illness • Malingering

Presenting problems in psychiatric illness • 1185

Clinical assessment Depression is a relatively common illness, with a prevalence of approximately 5% in the general population and 10–20% in medical patients. It is important to note that depression has physical as well as mental symptoms (Box 28.6). The diagnosis of depression in the medically ill, who may have physical symptoms of disease such as weight loss, fatigue, disturbed sleep, reduced appetite and so on that overlap with the physical symptoms of depression, relies on detection of the core psychological symptoms of ‘anhedonia’ (inability to experience pleasure) and the negative cognitive triad (see Box 28.17). In some cases, depression may occur as a result of a direct effect of a medical condition or its treatment on the brain, when it is referred to as an ‘organic mood disorder’ (Box 28.7). Investigations When a patient appears to be low in mood, it is good practice to ask them specifically about their mood. Do they feel low (nausea, over-sedation, parkinsonism and so on can all cause a patient to appear low in mood). If so, how long have they been feeling low? Are they still able to enjoy things? To what do they attribute their low mood? If the low mood is persistent, not adequately explained by circumstances and/or associated with anhedonia, the patient should be investigated for depression (p. 1199). Where a patient’s mood is extremely low, the clinician should ask about suicide. Asking about suicide does not increase the risk of it occurring, whereas failure to enquire denies the opportunity to prevent it. The assessment of suicide risk is described on page 1185. Clinical assessment Careful and tactful enquiry is required because agitation, terror or the fear of being thought ‘mad’ may make patients unable or unwilling to volunteer or describe their abnormal beliefs or perceptions. The nature of hallucinations can be important diagnostically; for example, ‘running commentary’ voices that discuss the patient are strongly associated with schizophrenia. In general, auditory hallucinations suggest schizophrenia, while hallucinations in other sensory modalities, especially vision but also taste and smell, suggest an organic cause, such as substance misuse, delirium or temporal lobe epilepsy. Hallucinations and delusions often co-occur. If their content is consistent with coexisting emotional symptoms, they are described as ‘mood-congruent’. Thus, patients with severely depressed mood may believe themselves responsible for all the evils in the world, and hear voices saying, ‘You are worthless. Go and kill yourself.’ In this case, the diagnosis of depressive psychosis is made on the basis of the congruence of different phenomena (mood, delusion and hallucination). Incongruence between hallucinations, delusions and mood suggests schizophrenia. Investigations The presence of hallucinations and/or delusions should not automatically trigger a round of expensive investigations; rather, careful clinical assessment of the nature, extent and time course of the patient’s symptoms will generate a list of likely diagnoses, and investigations can then be intelligently deployed to differentiate between these. When hallucinations and/or delusions arise in the context of disturbed consciousness and impaired cognition, the diagnosis is usually an organic disorder, most commonly delirium and/or dementia, and should be investigated accordingly (pp. 184 and 1192). Management The management of hallucinations and/or delusions is primarily the management of the underlying condition (such as delirium, schizophrenia, mania or psychotic depression). Certain principles apply, however, whatever the underlying cause. Hallucinations and delusions can be very real to, and often frightening for, the person who is experiencing them. Patients will often seek reassurance from the doctor. The doctor should acknowledge that these experiences are real for the patient while avoiding being drawn into colluding with the patient’s false beliefs or perceptions. Statements such as ‘Sometimes when we are unwell our brain plays tricks on us’ can help to reassure a patient. Where the patient lacks insight, however, a more neutral ‘We will have to agree to disagree’ may be necessary to avoid conflict. Antipsychotic medication can reduce psychotic symptoms, such as hallucinations and delusion, and is often used in combination with other sedating medication (such as a benzodiazepine) to alleviate acute distress and reduce behavioural disturbance (p. 1197). Low mood It is not uncommon for general hospital patients to report low mood. It is important to differentiate an understandable, selflimiting reaction to adversity (such as physical illness or bad news), which is normal and requires support rather than ‘treatment’, from a depressive disorder (p. 1198), which is characterised by a more severe and persistent disturbance of mood and requires specific treatment. Diseases that may cause organic affective disorders by direct action on the brain. 28.7 Organic mood disorders Neurological • Cerebrovascular disease • Cerebral tumour • Multiple sclerosis • Parkinson’s disease • Huntington’s disease • Alzheimer’s disease • Epilepsy Endocrine • Hypothyroidism • Hyperthyroidism • Cushing’s syndrome • Addison’s disease • Hyperparathyroidism Malignant disease Infections • Infectious mononucleosis • Herpes simplex • Brucellosis • Typhoid • Toxoplasmosis Connective tissue disease • Systemic lupus erythematosus Drugs • Phenothiazines • Phenylbutazone • Glucocorticoids, oral contraceptives • Interferon 28.6 Symptoms of depressive disorders Psychological • Depressed mood • Reduced self-esteem • Pessimism • Guilt • Loss of interest • Loss of enjoyment (anhedonia) • Suicidal thinking Somatic • Reduced appetite • Weight change • Disturbed sleep • Fatigue • Loss of libido • Bowel disturbance • Motor retardation (slowing of activity)

1186 • MEDICAL PSYCHIATRY stressful events: adjustment disorders (p. 1201). Other more persistent forms of anxiety are described in detail on page 1200. Investigations Anxiety may occasionally be a manifestation of a medical condition such as thyrotoxicosis (Box 28.9). Tests to exclude or confirm these conditions should be considered, particularly if anxiety is a new symptom that has arisen in the absence of an obvious stressor. Management The management of specific anxiety disorders is discussed later in this chapter (p. 1200). Benzodiazepines and related drugs, while extremely effective in the short term, cause tolerance and unpleasant or even dangerous withdrawal syndromes if used for more than a few weeks. Psychological factors affecting medical conditions Psychological factors may influence the presentation, management and outcome of medical conditions. Specific factors are shown in Box 28.10. The most common psychiatric diagnoses in the medically ill are anxiety and depressive disorders. Often these appear understandable as adjustments to illness and its treatment; however, if the anxiety and depression are severe and persistent, they may complicate the management of the medical condition and active management is required. Anxiety may present as an increase in somatic symptoms, such as breathlessness, tremor or palpitations, or as the avoidance of medical treatment. It is most common in those facing difficult or painful treatments, deterioration of their illness or death. Depression may manifest as increased physical symptoms, such as pain, fatigue and disability, as well as with depressed mood and loss of interest and pleasure. It is most common in patients who have suffered Management The management of depression is discussed on page 1199. Where a patient’s low mood is an understandable reaction to adversity, the clinical team can support the patient by minimising uncertainty through open and effective clinical communication and by addressing isolation (allowing access to visitors, telephone and so on). Elevated mood Elevated mood is much less common than depressed mood, and in medical settings is often secondary to drug or alcohol misuse, an organic disorder or medical treatment. Where none of these applies, the patient may be experiencing a manic (or, if less severe, ‘hypomanic’) episode as part of a bipolar affective disorder (p. 1199). Mania is the converse of depression. It may manifest as infectious joviality, over-activity, lack of sleep and appetite, undue optimism, over-talkativeness, irritability, and recklessness in spending and sexual behaviour. When elated mood is severe, psychotic symptoms are often evident, like delusions of grandeur such as believing erroneously that one is royalty. Investigations The first investigation for any medical patient presenting with persistent and inexplicable elevated mood in the absence of a history of bipolar affective disorder is a medication review. Mania is a relatively common side-effect of certain classes of drug, such as glucocorticoids, and is a rare side-effect of many other drugs. Recreational, herbal and over-the-counter preparations should also be considered. Second-line investigations include tests for Cushing’s disease (p. 666), thyrotoxicosis (p. 635), syphilis (p. 337) and encephalitis (p. 1121). Management The management of bipolar affective disorder is discussed on page 1200. Management of organic mania involves identifying and addressing the underlying cause. The management of disturbed or aggressive behaviour is discussed on page 1188. Anxiety Anxiety may be transient, persistent, episodic or limited to specific situations. The symptoms of anxiety are both psychological and physical (Box 28.8). The differential diagnosis of anxiety is shown in Box 28.9. Most anxiety is part of a transient adjustment to 28.10 Risk factors for psychological problems associated with medical conditions • Previous history of depression or anxiety • Lack of social support • New diagnosis of a serious medical condition • Deterioration of, or failure of treatment for, a medical condition • Unpleasant, disabling or disfiguring treatment • Change in medical care, such as discharge from hospital • Impending death 28.9 Differential diagnosis of anxiety • Normal response to threat • Adjustment disorder • Generalised anxiety disorder • Panic disorder • Phobic disorder • Organic (medical) cause: Hyperthyroidism Paroxysmal arrhythmias Phaeochromocytoma Alcohol and benzodiazepine withdrawal Hypoglycaemia Temporal lobe epilepsy 28.8 Symptoms of anxiety disorder Psychological • Apprehension • Irritability • Worry • Poor concentration • Fear of impending disaster • Depersonalisation Somatic • Palpitations • Fatigue • Tremor • Dizziness • Sweating • Diarrhoea • Frequent desire to pass urine • Chest pain • Initial insomnia • Breathlessness • Headache

Presenting problems in psychiatric illness • 1187

The incidence of SH varies over time and between countries. In the UK, the lifetime prevalence of suicidal ideation is 15% and that of acts of SH is 4%. SH is more common in women than men, and in young adults than the elderly. (In contrast, completed suicide is more common in men and the elderly; Box 28.12.) There is a higher incidence of SH among lower socioeconomic groups, particularly those living in crowded, socially deprived urban areas. There is also an association with alcohol misuse, child abuse, unemployment and recently broken relationships. Clinical assessment The main differential diagnosis is from accidental poisoning and so-called ‘recreational’ overdose in drug users. It must be remembered that SH is not a diagnosis but a presentation, and may be associated with any psychiatric diagnosis, the most common being adjustment disorder, substance and alcohol misuse, depressive disorder and personality disorder. In many cases, however, no psychiatric diagnosis can be made. Management A thorough psychiatric and social assessment should be attempted in all cases (Fig. 28.2), although some patients will discharge themselves before this can take place. The need for psychiatric assessment should not delay urgent medical or surgical treatment, though, and may need to be deferred until the patient is well enough for interview. The purpose of the psychiatric assessment is to: • establish the short-term risk of suicide • identify potentially treatable problems, whether medical, psychiatric or social. Topics to be covered when assessing a patient are listed in Box 28.13. The history should include events occurring immediately actual or anticipated losses, such as receiving a terminal diagnosis or undergoing disfiguring surgery. Treatment is by psychological and/or pharmacological therapies, as described on page 1189. Care is required when prescribing psychotropic drugs to the medically ill in order to avoid exacerbation of the medical condition and harmful interactions with other prescribed drugs. Medically unexplained somatic symptoms Patients commonly present to doctors with physical symptoms. While these symptoms may be an expression of a medical condition, they often are not (see Fig. 28.6). They may then be referred to as ‘medically unexplained symptoms’ (MUS), which are very common in patients attending general medical outpatient clinics. Almost any symptom can be medically unexplained. They include: • pain (including back, chest, abdominal, pelvic and headache) • fatigue • fits, ‘funny turns’, dizziness and feelings of weakness. Patients with MUS may receive a medical diagnosis of a so-called ‘functional somatic syndrome’, such as irritable bowel syndrome (Box 28.11), and may also merit a psychiatric diagnosis on the basis of the same symptoms. The most frequent psychiatric diagnoses associated with MUS are anxiety or depressive disorders. When these are absent, a diagnosis of somatoform disorder may be appropriate. Somatoform disorders are discussed in more detail on page 1202. 28.12 Risk factors for suicide • Psychiatric illness (depressive illness, schizophrenia) • Older age • Male sex • Living alone • Unemployment • Recent bereavement, divorce or separation • Chronic physical ill health • Drug or alcohol misuse • Suicide note written • History of previous attempts (especially if a violent method was used) 28.11 Functional somatic syndromes Medical specialty Somatic syndromes Gastroenterology Irritable bowel syndrome, functional dyspepsia Gynaecology Pre-menstrual syndrome, chronic pelvic pain Rheumatology Fibromyalgia Cardiology Atypical or non-cardiac chest pain Respiratory medicine Hyperventilation syndrome Infectious diseases Chronic (post-viral) fatigue syndrome Neurology Tension headache, non-epileptic attacks, functional gait disorder Dentistry Temporomandibular joint dysfunction, atypical facial pain Ear, nose and throat Globus syndrome Allergy medicine Multiple chemical sensitivity 28.13 Assessment of patients after self-harm Current attempt • Patient’s account • Degree of intent at the time: preparations, plans, precautions against discovery, note • Method used, particularly whether violent • Degree of intent now • Symptoms of psychiatric illness Background • Previous attempts and their outcome • Family and personal history • Social support • Previous response to stress • Extent of drug and alcohol misuse Self-harm Self-harm (SH) is a common reason for presentation to medical services. The term ‘attempted suicide’ is potentially misleading, as most of these patients are not trying to kill themselves. Most cases of SH involve overdose, of either prescribed or non-prescribed drugs (Ch. 7). Less common methods include asphyxiation, drowning, hanging, jumping from a height or in front of a moving vehicle, and the use of firearms. Methods that carry a high chance of being fatal are more likely to be associated with serious psychiatric disorder. Self-cutting is common and often repetitive, but rarely leads to contact with medical services.

1188 • MEDICAL PSYCHIATRY ward is necessary only for persons who display one or more of the following: • an acute psychiatric disorder • high short-term risk of suicide • need for temporary respite from intolerable circumstances • requirement for further assessment of their mental state. Approximately 20% of SH patients make a repeat act during the following year and 1–2% kill themselves. Factors associated with suicide after an episode of SH are listed in Box 28.12. Disturbed and aggressive behaviour Disturbed and aggressive behaviour is common in general hospitals, especially in emergency departments. Most behavioural disturbance arises not from medical or psychiatric illness, but from alcohol intoxication, reaction to the situation and personality characteristics. Clinical assessment The key principles of management are, firstly, to establish control of the situation rapidly and thereby ensure the safety of the patient and others; and secondly, to try to determine the cause of the disturbance in order to remedy it. Establishing control requires the presence of an adequate number of trained staff, an appropriate physical environment and sometimes sedation (Fig. 28.3). The assistance of hospital security staff and sometimes the police may be required. In all cases, the staff approach is important; a calm, non-threatening manner expressing understanding of the patient’s concerns is often all that is required to defuse potential aggression (Box 28.14). An attempt should be made to try to identify the factors that are contributing to the disturbed behaviour. When the patient is cooperative, these are best determined at interview. Other sources of information about the patient include medical and psychiatric records, and discussion with nursing staff, family members and other informants, including the patient’s GP. The following information should be sought: • psychiatric, medical (especially neurological) and criminal history • current psychiatric and medical treatment • alcohol and drug misuse • recent stressors • the time course and accompaniments of the current episode in terms of mood, belief and behaviour. Observation of the patient’s behaviour may also yield useful clues. Do they appear to be responding to hallucinations? Are they alert or variably drowsy and confused? Are there physical features suggestive of drug or alcohol misuse or withdrawal? Are there new injuries or old scars, especially on the head? Do they smell of alcohol or solvents? Do they bear the marks of drug injection? Are they unwashed and unkempt, suggesting a gradual development of their condition? Investigations Depending on the results of clinical assessment, routine biochemistry, haematology and analysis of blood or urine for illicit drugs or alcohol may be required. Management Measures such as restraint and sedation may be required in patients with acute behavioural disturbance in order to Fig. 28.2 Assessment of patients admitted following self-harm. No Yes Patient admitted following deliberate self-harm Urgent medical treatment needed? Medical assessment to determine need for urgent medical treatment Medical treatment Psychiatric assessment Immediate and significant suicide risk No Yes Plan to minimise risk: • remove methods of self-harm • arrange for special support • consider use of mental health legislation Assess for significant psychiatric illness Suspected? No Yes Assess and arrange management for other problems Consider: • psychiatric admission (using mental health legislation if necessary) • referral to psychiatric service for outpatient treatment before and after the act, and especially any evidence of planning. The nature and severity of any current psychiatric symptoms must be assessed, along with the personal and social supports available to the patient outside hospital. Most SH patients have depressive and anxiety symptoms on a background of chronic social and personal difficulties (often complicated by use of alcohol or other substances), but no psychiatric disorder. They do not usually require psychotropic medication or specialised psychiatric treatment but may benefit from personal support and practical advice from a GP, social worker or community psychiatric nurse. Admission to a psychiatric

Principles of management of psychiatric disorders • 1189

can be achieved with antipsychotic drugs (such as haloperidol) and/or benzodiazepines (such as lorazepam or diazepam). The choice of drug, dose, route and rate of administration depends on the patient’s age, gender and physical health, as well as the likely cause of the disturbed behaviour. The benefits of sedation must always be balanced against the potential risks. When prescribing benzodiazepines, consider the risk of respiratory depression (particularly in patients with lung disease) and encephalopathy (in those with liver disease). When prescribing antipsychotic drugs for acute sedation, consider the risk of acute dystonias (such as ‘oculogyric crisis’) and acute arrhythmias (in patients with heart disease). Thus for a frail elderly woman with emphysema and delirium, sedation may be achieved with a low dose (0.5 mg) of oral haloperidol, while for a strong young man with an acute psychotic episode, 10 mg or more of intravenous diazepam and a similar dose of haloperidol may be required. A parenterally administered anticholinergic agent, such as procyclidine, should be available to treat extrapyramidal effects from haloperidol if they arise. Flumazenil (p. 142) can be used to reverse respiratory depression caused by benzodiazepines. If the initial assessment suggests that the patient has an acute psychiatric disorder, then admission to a psychiatric facility may be indicated. If a medical cause is more likely, psychiatric transfer is usually inappropriate and the patient should be managed in a medical setting, with whatever nursing and security support is required. Where it is clear that there is no medical or psychiatric illness, the person should be removed from the hospital, to police custody if necessary. Many countries, such as the UK, also have specific mental health legislation that may be used to detain patients if necessary. Principles of management of psychiatric disorders The multifactorial origin of most psychiatric disorders means that there are multiple potential targets for treatment. It is useful to consider management strategies within a bio-psycho-social framework. This can help to address the biological factors that contribute to the illness with medication and other physical treatments such as electroconvulsive therapy, while also considering the potential role for psychological therapies and changes to the patient’s social environment. Fig. 28.3 Acute management of disturbed behaviour. Yes No Yes No Yes No Disturbed behaviour Does it seem likely to be caused by mental disorder? Consider calling security/police Is the behaviour putting the patient or others at risk? Monitor and review Monitor and review

  1. Ensure availability of adequate personnel to provide ‘overwhelming force’
  2. Try to attain a safe and quiet environment
  3. Consider emergency sedation with haloperidol (0.5– 5 mg IM/orally) and/or benzodiazepine (diazepam 5–10 mg IV slowly in view of risk of respiratory depression or lorazepam 1–2 mg IM/orally) Consult with senior staff Consider repeating drug, increasing dose or using other agents such as midazolam or paraldehyde Are measures effective? 28.15 Medical psychiatry in old age • Organic psychiatric disorders: especially common, so cognitive function should always be assessed; if impaired, an associated medical condition or adverse drug effect should be suspected. • Disturbed behaviour: delirium is the most common cause. • Depression: common. Just because a person is old and frail does not mean that depression is ‘to be expected’ and that it should not be treated. • Self-harm: associated with an increased risk of completed suicide. • Medically unexplained symptoms: common and often associated with depressive disorder. • Loneliness, poverty and lack of social support: must be taken into consideration in management decisions. 28.14 Psychiatric emergencies • Intervene as necessary to reduce the risk of harm to the patient and to others • Adopt a calm, non-threatening approach • Arrange availability of other staff and parenteral medication • Consider diagnostic possibilities of drug intoxication, acute psychosis and delirium • Involve friends and relatives as appropriate identify the cause and to protect the patient and other people from harm. While this potentially raises legal issues, in most countries, including the UK, common law confers on doctors the right, and indeed the duty, to intervene against a patient’s wishes if this is necessary. Sedation may be required and

1190 • MEDICAL PSYCHIATRY 28.17 The negative cognitive triad associated with depression Cognitive error Example Negative view of self ‘I am no good’ Negative view of current life experiences ’The world is an awful place’ Negative view of the future ’The future is hopeless’ Pharmacological treatments These aim to relieve psychiatric disorder by modifying brain function. The main biological treatments are psychotropic drugs. These are widely used for various purposes; a pragmatic classification is set out in Box 28.16. It should be noted that some drugs have applications to more than one condition; for example, antidepressants are also widely used in the treatment of anxiety and chronic pain. The specific subgroups of psychotropic drugs are discussed in the sections on the appropriate disorders below. Electroconvulsive therapy Electroconvulsive therapy (ECT) entails producing a convulsion by the brief administration of a high-voltage direct-current impulse to the head while the patient is anaesthetised and paralysed by muscle relaxant. If properly administered, it is remarkably safe, has few side-effects, and is of proven efficacy for severe depressive illness. There may be headaches and amnesia for events occurring a few hours before ECT (retrograde) and after it (anterograde). Pronounced amnesia can occur but is infrequent and difficult to distinguish from the effects of severe depression. Other forms of electromagnetic stimulation Clinical trials of transcranial magnetic stimulation (TMS) and vagal nerve stimulation (VNS) suggest they may have a limited role in patients with depression refractory to conventional treatments. Surgery Surgery to the brain (psychosurgery) has a very limited place and then only in the treatment of severe chronic psychiatric illness resistant to other measures. Frontal lobotomies are never done now, and pre-frontal leucotomies are very rare. Operations these days usually target specific sub-regions and tracts of the brain. Psychological therapies These treatments are useful in many psychiatric disorders and also in non-psychiatric conditions. They are based on talking with patients, either individually or in groups. Sometimes discussion is supplemented by ‘homework’ or tasks to complete between treatment sessions. Psychological treatments take a number of forms based on the duration and frequency of contact, the specific techniques applied and their underlying theory. General psychotherapy General psychotherapy should be part of all medical treatment. It involves empathic listening to the patient’s account of their symptoms and associated fears and concerns, followed by the sympathetic provision of accurate information that addresses these. Cognitive therapy This therapy is based on the observation that some psychiatric disorders are associated with systematic errors in the patient’s conscious thinking, such as a tendency to interpret events in a negative way or see them as unduly threatening. A triad of ‘cognitive errors’ has been described in depression (Box 28.17). Cognitive therapy aims to help patients to identify such cognitive errors and to learn how to challenge them. It is widely used for depression, anxiety and eating and somatoform disorders, and also increasingly in psychoses. Behaviour therapy This is a practically orientated form of treatment, in which patients are assisted in changing unhelpful behaviour, such as helping patients to implement carefully graded exposure to the feared stimulus in phobias. Cognitive behaviour therapy Cognitive behaviour therapy (CBT) combines the methods of behaviour therapy and cognitive therapy. It is the most widely available and extensively researched psychological treatment. Action Main groups Clinical use Antipsychotic Phenothiazines Butyrophenones Second-generation antipsychotics Schizophrenia Bipolar mania Delirium Antidepressant Tricyclics and related drugs Serotonin and noradrenergic re-uptake inhibitors Depression/anxiety Obsessive–compulsive disorder Monoamine oxidase inhibitors Depression/anxiety Mood-stabilising Lithium Valproate Lamotrigine Treatment and prophylaxis of bipolar disorder Adjunctive therapy in depression Anti-anxiety Benzodiazepines Anxiety/insomnia (short term) Alcohol withdrawal (short term) β-adrenoceptor antagonists Anxiety (somatic symptoms) } } } } 28.16 Classification of commonly used psychotropic drugs

Psychiatric disorders • 1191

Interpersonal psychotherapy Interpersonal psychotherapy (IPT) is a specific form of brief psychotherapy that focuses on patients’ current interpersonal relationships and is an effective treatment for mild to moderate depression. Social interventions Some adverse social factors, such as unemployment, may not be readily amenable to intervention but others, such as access to benefits and poor housing, may be. Patients can be helped to address these problems themselves by being taught problem-solving. Befrienders and day centres can reduce social isolation, benefits advisers can ensure appropriate financial assistance, and medical recommendations can be made to local housing departments to help patients obtain more appropriate accommodation. Psychiatric disorders Dementia Dementia is a clinical syndrome characterised by a loss of previously acquired intellectual function in the absence of impairment of arousal. It affects 5% of those over 65 and 20% of those over 85. It is defined as a global impairment of cognitive function and is typically progressive and non-reversible. There are many subtypes (Box 28.19) but Alzheimer’s disease and diffuse vascular dementia are the most common. Rarer causes of dementia should be actively sought in younger patients and those with short histories. Problem-solving therapy This is a simplified brief form of CBT, which helps patients actively tackle problems in a structured way (Box 28.18). It can be delivered by non-psychiatric doctors and nurses after appropriate training and is commonly used to help patients who self-harm in response to a situational crisis. Psychodynamic psychotherapy This treatment, also known as ‘interpretive psychotherapy’, was pioneered by Freud, Jung and Klein, among others. It is based on the theory that early life experience generates powerful but unconscious motivations. Psychotherapy aims to help the patient to become aware of these unconscious factors on the assumption that, once identified, their negative effects are reduced. The relationship between therapist and patient is used as a therapeutic tool to identify issues in patients’ relationships with others, particularly parents, which may be replicated or transferred to their relationship with the therapist. Explicit discussion of this relationship (transference) is the basis for the treatment, which traditionally requires frequent sessions over a period of months or even years. 28.18 Stages of problem-solving therapy • Define and list problems • Choose one to work on • List possible solutions • Evaluate these and choose the best • Try it out • Evaluate the result • Repeat until problems are resolved 28.19 Subtypes and causes of dementia Type Common Less common Rare Vascular Diffuse small-vessel disease Amyloid angiopathy Multiple emboli Cerebral vasculitis Systemic lupus erythematosus Inherited Alzheimer’s disease Fronto-temporal dementia Leukodystrophies Huntington’s disease Wilson’s disease Dystrophia myotonica Lewy body dementia Progressive supranuclear palsy Mitochondrial encephalopathies Cortico-basal degeneration Neoplastic (p. 1110) Secondary deposits Primary cerebral tumour Paraneoplastic syndrome (limbic encephalitis) Inflammatory – Multiple sclerosis Sarcoidosis Traumatic Chronic subdural haematoma Post-head injury Punch-drunk syndrome – Hydrocephalus (p. 1132) Communicating/non-communicating ‘normal pressure’ hydrocephalus – Toxic/nutritional Alcohol Thiamin deficiency Vitamin B12 deficiency Anoxia/carbon monoxide poisoning Heavy metal poisoning Infective – Syphilis HIV Post-encephalitis Whipple’s disease Subacute sclerosing panencephalitis Prion diseases (p. 1126) – Sporadic Creutzfeldt–Jakob disease (CJD) Variant CJD Kuru Gerstmann–Sträussler–Scheinker disease

1192 • MEDICAL PSYCHIATRY invasive investigations, such as lumbar puncture or, very rarely, brain biopsy, may be indicated. Management This is mainly directed at addressing treatable causes and providing support for patients and carers. Tackling risk factors may slow deterioration, e.g. effective management of hypertension in vascular dementia, or abstinence and vitamin replacement in toxic/nutritional dementias. Psychotropic drugs may have a role in alleviating symptoms, such as disturbance of sleep, perception or mood, but should be used with care because of an increased mortality in patients who have been treated long-term with these agents. Sedation is not a substitute for good care of patients and carers or, in the later stages, attentive residential nursing care. In the UK, incapacity and mental health legislation may be required to manage patients’ financial and domestic affairs, as well as to determine their safe placement. If the diagnosis is Alzheimer-type dementia, cholinesterase inhibitors and memantine may slow progression for a time. Alzheimer’s disease Alzheimer’s disease is the most common form of dementia. It increases in prevalence with age and is rare in people under 45 years. Pathogenesis Genetic factors play an important role and about 15% of cases are familial. These cases fall into two main groups: early-onset disease with autosomal dominant inheritance and a later-onset group where the inheritance is polygenic. Mutations in several genes have been described but most are rare and/or of small effect. The inheritance of one of the alleles of apolipoprotein ε (apo ε4) is associated with an increased risk of developing the disease (2–4 times higher in heterozygotes and 6–8 times higher in homozygotes). Its presence is, however, neither necessary nor sufficient for the development of the disease and so genetic testing for ApoE4 is not clinically useful. The brain in Alzheimer’s disease is macroscopically atrophic, particularly the cerebral cortex and hippocampus. Histologically, the disease is characterised by the presence of senile plaques and neurofibrillary tangles in the cerebral cortex. Histochemical staining demonstrates significant quantities of amyloid in the plaques (Fig. 28.4); these typically stain positive for the protein ubiquitin, which normally is involved in targeting unwanted or damaged proteins for degradation. This has led to the suggestion that the disease may be due to defects in the ability of neuronal cells to degrade unwanted proteins. Many different neurotransmitter abnormalities have also been described. In particular, there is impairment of cholinergic transmission, although abnormalities of noradrenaline (norepinephrine), 5-HT, glutamate and substance P have also been described. Clinical features The key clinical feature is impairment of the ability to remember new information. Hence, patients present with gradual impairment of memory, usually in association with disorders of other cortical functions. Short- and long-term memory are both affected but defects in the former are usually more obvious. Later in the course of the disease, typical features include apraxia, visuo-spatial impairment and aphasia. In the early stages of the disease, patients may notice these problems, but as the disease progresses it is common for patients to deny that there is anything wrong (anosognosia). In this situation, patients are Pathogenesis Dementia may be divided into ‘cortical’ and ‘subcortical’ types, depending on the clinical features. Clinical features The usual presentation is with a disturbance of personality or memory dysfunction. A careful history is essential and it is important to interview both the patient and a close family member. Simple bedside tests, such as the MoCA (p. 1182), are useful in assessing the nature and severity of the cognitive deficit, although a more intensive neuropsychological assessment may sometimes be required, especially if there is diagnostic uncertainty. It is important to exclude a focal brain lesion. This is done by determining that there is cognitive disturbance in more than one area. Mental state assessment is important to seek evidence of depression, which may coexist with or occasionally cause apparent cognitive impairment. Many of the primary degenerative diseases that cause dementia have characteristic features that may allow a specific diagnosis during life. Creutzfeldt–Jakob disease, for example, is usually quickly progressive (over months) and is associated with myoclonus. The more slowly progressive dementias are more difficult to distinguish during life, but fronto-temporal dementia typically presents with signs of temporal or frontal lobe dysfunction, whereas Lewy body dementia may present with visual hallucinations. The course may also help to distinguish types of dementia. Gradual worsening suggests Alzheimer’s disease, whereas stepwise deterioration is typical of vascular dementia. Investigations The aim is to seek treatable causes and to estimate prognosis. This is done using a standard set of investigations (Box 28.20). Imaging of the brain can exclude potentially treatable structural lesions, such as hydrocephalus, cerebral tumour or chronic subdural haematoma, though the only abnormality usually seen is that of generalised atrophy. An electroencephalogram (EEG) may be helpful if Creutzfeldt–Jakob disease is suspected, as characteristic abnormalities of generalised periodic sharp wave pattern are usually observed. If the initial tests are negative, more 28.20 Initial investigation of dementia In most patients • Imaging of head (computed tomography and/or magnetic resonance imaging) • Blood tests: Full blood count, erythrocyte sedimentation rate Urea and electrolytes, glucose Calcium, liver function tests Thyroid function tests Vitamin B12 Syphilis serology ANA, anti-dsDNA • Chest X-ray • Electroencephalography In selected patients • Lumbar puncture • HIV serology • Brain biopsy (ANA = antinuclear antibody; anti-dsDNA = anti-double-stranded DNA)

Psychiatric disorders • 1193

Many patients are depressed, and if this is confirmed, treatment with antidepressant medication may be helpful. Fronto-temporal dementia Fronto-temporal dementia encompasses a number of different syndromes characterised by behaviour abnormalities and impairment of language. Symptoms usually occur before the age of 60 and the prevalence has been estimated at 15 per 100 000 in the population aged between 45 and 65 years. The three major clinical subtypes are behavioural-variant fronto-temporal dementia, primary progressive aphasia and semantic dementia. Pick’s disease is a common cause of the first two in particular. Genetic factors play an important role and familial cases have been described caused by mutations in several genes, including MAPT, which encodes microtubule-associated protein tau, GRN, TPD43, FUS, VCP and C9orf72. The causal mutations trigger abnormal accumulation of tau and other proteins in brain tissue, which are seen as cytoplasmic inclusion bodies on histological examination (Fig. 28.5). It is of interest that many of the gene mutations that cause fronto-temporal dementia are also associated with amyotrophic lateral sclerosis (p. 1116), suggesting that these disorders share a similar pathogenic basis in which neuronal degeneration is caused by accumulation of abnormal proteins. The clinical presentation may be with personality change due to frontal lobe involvement or with language disturbance due to temporal lobe involvement. In contrast to Alzheimer’s disease, memory is relatively preserved in the early stages. There is no specific treatment. Disinhibition and compulsive behaviours can often brought to medical attention by their carers. Depression is commonly present. Occasionally, patients become aggressive, and the clinical features can be made acutely worse by intercurrent physical disease. Patients typically present with subjective memory loss, sometimes getting lost in familiar locations. A history of progressive memory loss and associated functional impairment, corroborated by an informant, is the key to making the diagnosis. Cognitive testing and neuroimaging can be helpful but in themselves are not diagnostic. Investigations Investigation is aimed at excluding treatable causes of dementia (see Box 28.19), as histological confirmation of the diagnosis usually occurs only after death. Management Treatment with anticholinesterases, such as donepezil, rivastigmine and galantamine, has been shown to be of some benefit at slowing progression of cognitive impairment in the early stages of the disease while post-synaptic cholinergic receptors are still available. The N-methyl-D-aspartate (NMDA) receptor antagonist memantine slightly enhances learning and memory in early disease and can also be useful in selected patients with more advanced disease. Novel treatments are under development to block amyloid plaque formation directly, by inhibiting the enzyme γ-secretase. Non-pharmacological approaches include the provision of a familiar environment for the patient and support for the carers. Fig. 28.4 Alzheimer’s disease. Section of neocortex stained with polyclonal antibody against βA4 peptide showing amyloid deposits in plaques in brain substance (arrow A) and in blood-vessel walls (arrow B). Courtesy of Dr J. Xuereb. A B Fig. 28.5 Fronto-temporal dementia. A Lateral view of formalin-fixed brain from a patient who died of Pick’s disease, showing gyral atrophy of frontal and parietal lobes and a more severe degree of atrophy affecting the anterior half of the temporal lobe (arrow). B High power (× 200) view of hippocampal pyramidal layer, prepared with monoclonal anti-tau antibody. Many neuronal cell bodies contain sharply circumscribed, spherical cytoplasmic inclusion bodies (Pick bodies, arrows). A and B, Courtesy of Dr J. Xuereb. A B

1194 • MEDICAL PSYCHIATRY Anxiety People who are anxious may use alcohol as a means of relieving anxiety in the short term and this can develop into dependence. Conversely, alcohol withdrawal increases anxiety. Alcohol withdrawal syndrome The features are described in Box 28.22. Symptoms usually become maximal about 2–3 days after the last drink and can include seizures. The term ‘delirium tremens’ is used to describe severe alcohol withdrawal syndrome characterised by both delirium (characteristically, agitation and visual hallucinations) and physiological hyper-arousal (tremor, sweating and tachycardia). It has a significant mortality and morbidity (Box 28.22). Hallucinations Hallucinations (characteristically visual but sometimes in other modalities) are common in delirium tremens. Less common is the phenomenon called ‘alcoholic hallucinosis’, where a patient with alcohol dependence experiences auditory hallucination in clear consciousness at a time when they are not withdrawing from alcohol. be helped by selective serotonin re-uptake inhibitors (SSRIs). Although Alzheimer’s and fronto-temporal dementia share certain symptoms, they cannot be treated with the same pharmacological agents because the cholinergic systems are not affected in the latter. Lewy body dementia This neurodegenerative disorder is clinically characterised by dementia and signs of Parkinson’s disease. It is often inherited and mutations in the α-synuclein and β-synuclein genes have been identified in affected patients. These mutations result in accumulation of abnormal protein aggregates in neurons that contain the protein α-synuclein in association with other proteins, including ubiquitin (see Fig. 25.31, p. 1112). The cognitive state often fluctuates and there is a high incidence of visual hallucinations. Affected individuals are particularly sensitive to the side-effects of anti-parkinsonian medication and also to antipsychotic drugs. There is no curative treatment but anticholinesterase drugs can be helpful in slowing progression of cognitive impairment. Alcohol misuse and dependence Alcohol consumption associated with social, psychological and physical problems constitutes misuse. The criteria for alcohol dependence, a more restricted term, are shown in Box 28.21. Approximately one-quarter of male patients in general hospital medical wards in the UK have a current or previous alcohol problem. Pathogenesis Availability of alcohol and social patterns of use appear to be the most important factors. Genetic factors predispose to dependence. The majority of people who misuse alcohol do not have an associated psychiatric disorder, but a few drink heavily in an attempt to relieve anxiety or depression. Clinical features The modes of presentation of alcohol misuse and complications are summarised below. Social problems Common features include absenteeism from work, unemployment, marital tensions, child abuse, financial difficulties and problems with the law, such as violence and traffic offences. Low mood Low mood is common since alcohol has a direct depressant effect and heavy drinking creates numerous social problems. Attempted and completed suicide are associated with alcohol misuse. 28.22 Presentation and consequences of chronic alcohol misuse Acute intoxication • Emotional and behavioural disturbance • Medical problems: hypoglycaemia, ketoacidosis, aspiration of vomit, respiratory depression • Accidents, injuries sustained in fights Withdrawal phenomena • Psychological symptoms: restlessness, anxiety, panic attacks • Autonomic symptoms: tachycardia, sweating, pupil dilatation, nausea, vomiting • Delirium: agitation, hallucinations (classically ‘Lilliputian’), illusions, delusions • Seizures Consequences of harmful use Medical • Neurological: peripheral neuropathy, cerebellar degeneration, cerebral haemorrhage, dementia • Hepatic: fatty change and cirrhosis, liver cancer • Gastrointestinal: oesophagitis, gastritis, pancreatitis, oesophageal cancer, Mallory–Weiss syndrome, malabsorption, oesophageal varices • Respiratory: pulmonary tuberculosis, pneumonia • Skin: spider naevi, palmar erythema, Dupuytren’s contractures, telangiectasias • Cardiac: cardiomyopathy, hypertension • Musculoskeletal: myopathy, fractures • Endocrine and metabolic: pseudo-Cushing’s syndrome, hypoglycaemia, gout • Reproductive: hypogonadism, fetal alcohol syndrome, infertility Psychiatric and cerebral • Depression • Alcoholic hallucinosis • Alcoholic ‘blackouts’ • Wernicke’s encephalopathy: nystagmus or ophthalmoplegia with ataxia and delirium • Korsakoff’s syndrome: short-term memory deficits leading to confabulation 28.21 Criteria for alcohol dependence • Narrowing of the drinking repertoire • Priority of drinking over other activities (salience) • Tolerance of effects of alcohol • Repeated withdrawal symptoms • Relief of withdrawal symptoms by further drinking • Subjective compulsion to drink • Reinstatement of drinking behaviour after abstinence

Psychiatric disorders • 1195

arisen. The risk of side-effects, such as respiratory depression with benzodiazepines and anaphylaxis with Pabrinex, is small when weighed against the potential benefits of treatment. Acamprosate (666 mg 3 times daily) may help to maintain abstinence by reducing the craving for alcohol. Disulfiram (200–400 mg daily) can be given as a deterrent to patients who have difficulty resisting the impulse to drink after becoming abstinent. It blocks the metabolism of alcohol, causing acetaldehyde to accumulate. When alcohol is consumed, an unpleasant reaction follows, with headache, flushing and nausea. Disulfiram is always an adjunct to other treatments, especially supportive psychotherapy. Treatment with antidepressants may be required if depression is severe or does not resolve with abstinence. Antipsychotics, such as chlorpromazine (100 mg 3 times daily), are needed for alcoholic hallucinosis. Although such treatment may be successful, there is a high relapse rate. Prognosis Between 80% and 90% of patients with established alcohol dependence syndrome who embark on medically supervised detoxification will successfully complete detoxification without encountering significant complications. Sustaining abstinence is more challenging than achieving it, however. Studies indicate that 1 year after successful detoxification, only 20% of patients will remain abstinent. This figure rises to approximately 30% for patients who are engaged with alcohol services, and to over 40% if such specialist support is combined with supervised disulfiram treatment. Substance misuse disorder Dependence on and misuse of both illegal and prescribed drugs is a major problem worldwide. Drugs of misuse are described in detail in Chapter 7. They can be grouped as follows. Sedatives These commonly give rise to physical dependence, the manifestations of which are tolerance and a withdrawal syndrome. Drugs include benzodiazepines, opiates (including morphine, heroin, methadone and dihydrocodeine) and barbiturates (now rarely prescribed). Overdosage with sedatives can be fatal, primarily as a result of respiratory depression (Ch. 7). Withdrawal from opiates is notoriously unpleasant, and withdrawal from benzodiazepines and barbiturates can cause prolonged anxiety and even hallucinations and/or seizures. Intravenous opiate users are prone to bacterial infections, hepatitis B (p. 873), hepatitis C (p. 877) and HIV infection (Ch. 12) through needle contamination. Accidental overdose is common, mainly because of the varied and uncertain potency of illicit supplies of the drug. The withdrawal syndrome, which can start within 12 hours of last use, presents with intense craving, rhinorrhoea, lacrimation, yawning, perspiration, shivering, piloerection, vomiting, diarrhoea and abdominal cramps. Examination reveals tachycardia, hypertension, mydriasis and facial flushing. Stimulants Stimulant drugs include amphetamines and cocaine. They are less dangerous than the sedatives in overdose, although they can cause cardiac and cerebrovascular problems through their pressor effects. Physical dependence syndromes do not arise, but withdrawal causes a rebound lowering in mood and can give rise to an intense craving for further use, especially in any form Wernicke–Korsakoff syndrome This is a rare but important indirect complication of chronic alcohol misuse. It is an organic brain disorder resulting from damage to the mamillary bodies, dorsomedial nuclei of the thalamus and adjacent areas of periventricular grey matter caused by a deficiency of thiamin (vitamin B1). The syndrome most commonly results from long-standing heavy drinking and an inadequate diet but can also arise from malabsorption or even protracted vomiting. Wernicke’s encephalopathy (nystagmus or ophthalmoplegia with ataxia and delirium) often presents acutely and, without prompt treatment (see below), can progress and become irreversible. Korsakoff’s syndrome (severe short-term memory deficits and confabulation) can develop chronically or acutely (with Wernicke’s). Alcohol-related brain damage The term alcohol-related brain damage (ARBD) is often used as a collective description of the many brain pathologies associated with alcohol excess, which often coexist in the same patient. Acute alcohol intoxication causes ataxia, slurred speech, emotional incontinence and aggression. Very heavy drinkers may experience periods of amnesia for events that occurred during bouts of intoxication, termed ‘alcoholic blackouts’. Established alcohol dependence may lead to ‘alcoholic dementia’, a global cognitive impairment resembling Alzheimer’s disease, but which does not progress and may even improve if the patient becomes abstinent. Heavy alcohol use can damage the brain indirectly through Wernicke–Korsakoff syndrome (see above), head injury, hypoglycaemia and encephalopathy (p. 864). Effects on other organs These are protean and virtually any organ can be involved (Box 28.22). These effects are discussed in detail in other chapters in this book. Diagnosis The diagnosis of alcohol excess may emerge while taking the patient’s history, but many patients do not tell the truth about their alcohol intake. Alcohol misuse may also present through its effects on one or more aspects of the patient’s life, as listed above. Alcohol dependence commonly presents with withdrawal in those admitted to hospital, as they can no longer maintain their high alcohol intake in this setting. Management For the person misusing alcohol, provision of clear information from a doctor about the harmful effects of alcohol and safe levels of consumption is often all that is needed. In more serious cases, patients may have to be advised to alter leisure activities or change jobs to help them to reduce their consumption. Psychological treatment is used for people who have recurrent relapses and is usually available at specialised centres. Support to stop drinking is also provided by voluntary organisations, such as Alcoholics Anonymous (AA) in the UK. Alcohol withdrawal syndromes can be prevented, or treated once established, with long-acting benzodiazepines. Large doses may be required (such as diazepam 20 mg 4 times daily), tailed off over a period of 5–7 days as symptoms subside. Prevention of the Wernicke–Korsakoff syndrome requires the immediate use of high doses of thiamin, which is initially given parenterally in the form of Pabrinex (two vials 3 times daily for 48 hrs, longer if symptoms persist) and then orally (100 mg 3 times daily). There is no treatment for Wernicke–Korsakoff syndrome once it has

1196 • MEDICAL PSYCHIATRY In some cases, complete opiate withdrawal is not successful and the patient functions better if maintained on regular doses of oral methadone as an outpatient. This decision to prescribe long-term methadone should be taken only by a specialist, and carried out under long-term supervision at a specialist drug treatment centre. Substitute prescribing is neither necessary nor possible for the hallucinogens and stimulants, but the principles of management are the same as those that should accompany prescribing for the sedatives. These include identifying problems associated with the drug misuse that may serve to maintain it, and intervening where possible. Intervention may be directed at physical illness, psychiatric comorbidity, social problems or family disharmony. Relapsing patients and those with complications should be referred to specialist drug misuse services. Support can also be provided by self-help groups and voluntary bodies, such as Narcotics Anonymous (NA) in the UK. Schizophrenia Schizophrenia is characterised by delusions, hallucinations and lack of insight. Acute schizophrenia may also present with disturbed behaviour, disordered thinking, or with insidious social withdrawal and other so-called negative symptoms and less obvious delusions and hallucinations. Schizophrenia occurs worldwide in all ethnic groups with a prevalence of about 0.5%. It is more common in men (1.4 to 1). Children of an affected parent have an approximate 10% risk of developing the illness, but this rises to 50% if an identical twin is affected. The usual age of onset is the mid-twenties but can be older, particularly in women. Pathogenesis There is a strong genetic contribution, usually involving many susceptibility genes, each of small effect, but 2–3% of cases can be attributed to increased or decreased copies of genes (so-called ‘copy number variations’, p. 44). Environmental risk factors include a history of obstetric complications at the time of the patient’s birth and urban upbringing. Brain imaging techniques have identified subtle structural abnormalities in groups of people with schizophrenia, including an overall decrease in brain size (by about 3% on average), with a relatively greater reduction in temporal lobe volume (5–10%). Episodes of acute schizophrenia may be precipitated by social stress and also by cannabis, which increases dopamine turnover. Consequently, schizophrenia is now viewed as a neurodevelopmental disorder, caused by abnormalities of brain development associated with genetic predisposition and early environmental influences, but precipitated by later triggers. Clinical features Acute schizophrenia should be suspected in any individual with bizarre behaviour accompanied by delusions and hallucinations that are not due to organic brain disease or substance misuse. The characteristic clinical features are listed in Box 28.23. Hallucinations are typically auditory but can occur in any sensory modality. They commonly involve voices from outside the head that talk to or about the person. Sometimes the voices repeat the person’s thoughts. Patients may also describe ‘passivity of thought’, experienced as disturbances in the normal privacy of thinking, such as the delusional belief that their thoughts are being ‘withdrawn’ from them and perhaps ‘broadcast’ to others, and/or that alien thoughts are being ‘inserted’ into their mind. of drug with a rapid onset and offset of effect, such as crack cocaine. Chronic ingestion can cause a paranoid psychosis similar to schizophrenia. A ‘toxic psychosis’ (delirium) can occur with high levels of consumption. Unpleasant tactile hallucinations described as ‘like ants crawling under the skin’ (formication) may be prominent in either acute intoxication or withdrawal. Hallucinogens The hallucinogens are a disparate group of drugs that cause prominent sensory disturbances. They include cannabis, ecstasy, lysergic acid diethylamide (LSD), Psilocybin (magic mushrooms) and a variety of synthetic cannabinoids (as one of the so-called ‘legal highs’ or ‘novel psychoactive substances’). A toxic confusional state can occur after heavy cannabis consumption. Acute psychotic episodes are well recognised, especially in those with a family or personal history of psychosis, and there is evidence that prolonged heavy use increases the risk of developing schizophrenia. Paranoid psychoses have been reported in association with ecstasy. A chronic psychosis has also been documented after regular LSD use. Organic solvents Solvent inhalation (glue sniffing) is popular in some adolescent groups. Solvents produce acute intoxication characterised by euphoria, excitement, dizziness and a floating sensation. Further inhalation leads to loss of consciousness; death can occur from the direct toxic effect of the solvent, or from asphyxiation if the substance is inhaled from a plastic bag. Pathogenesis Many of the causal factors for alcohol misuse also apply to substance misuse. The main factors are the psychological and behavioural vulnerabilities described above, cultural pressures, particularly within a peer group, and availability of a drug. In the case of some drugs such as opiates, medical over-prescribing has increased their availability, but there has also been a relative decline in the price of illegal drugs. Most drug users take a range of drugs – so-called polydrug misuse. Diagnosis As with alcohol, the diagnosis either may be apparent from the history and examination, or may be made only once the patient presents with a complication. Drug screening of samples of urine or blood can be valuable in confirming the diagnosis, especially if the patient persists in denial. Management The first step is to determine whether patients wish to stop using the drug. If they do not, they can still benefit from advice about how to minimise harm from their habit, such as how to obtain and use clean needles for those who inject. For those who are physically dependent on sedative drugs, substitute prescribing (using methadone, for example, in opiate dependence) may help stabilise their lives sufficiently to allow a gradual reduction in dosage until they reach abstinence. Some specialist units offer inpatient detoxification. For details of the medical management of overdose, see page 135. The drug lofexidine, a centrally acting α-agonist, can be useful in treating the autonomic symptoms of opiate withdrawal, as can clonidine, although this carries a risk of hypotension and is best used by specialists. Long-acting opiate antagonists, such as naltrexone, may also have a place, again in specialist hands, in blocking the euphoriant effects of the opiate, thereby reducing addiction.

Psychiatric disorders • 1197

Management First-episode schizophrenia usually requires admission to hospital because patients lack the insight that they are ill and are unwilling to accept treatment. In some cases, they may be at risk of harming themselves or others. Subsequent acute relapses and chronic schizophrenia are now usually managed in the community. Drug treatment Antipsychotic agents are effective against the positive symptoms of schizophrenia in the majority of cases. They take 2–4 weeks to be maximally effective but have some beneficial effects shortly after administration. Treatment is then ideally continued to prevent relapse. In a patient with a first episode of schizophrenia this will usually be for 1 or 2 years, but in patients with multiple episodes treatment may be required for many years. The benefits of prolonged treatment must be weighed against the adverse effects, which include extrapyramidal side-effects (EPSE) like acute dystonic reactions (which may require treatment with parenteral anticholinergics), akathisia and parkinsonism. For long-term use, antipsychotic agents are often given by slow-release (depot) injections to improve adherence. A number of antipsychotic agents are available (Box 28.25). These may be divided into conventional (first-generation) drugs such as chlorpromazine and haloperidol, and novel or secondgeneration drugs such as olanzapine and clozapine. All work by blocking D2 dopamine receptors in the brain. Patients who have not responded to conventional drugs may respond to newer agents, which are also less likely to produce unwanted EPSE but do tend to cause greater weight gain and metabolic disturbances, such as dyslipidaemia. Clozapine can be remarkably effective in those who do not respond to other antipsychotics but can cause agranulocytosis in about 1% of patients in the first few months. Prescription therefore requires regular monitoring of white blood cell count, initially on a weekly basis, then fortnightly and monthly thereafter. Clozapine should not be stopped suddenly because of the likelihood of relapse. Adverse effects of antipsychotic drugs are listed in Box 28.26. Two serious adverse effects deserve special mention. Neuroleptic malignant syndrome This is a rare but serious condition characterised by fever, tremor and rigidity, autonomic instability Other characteristic symptoms are delusions of control: believing that one’s emotions, impulses or acts are controlled by others. Another phenomenon is delusional perception, a delusion that arises suddenly alongside a normal perception, such as ‘I saw the moon and I immediately knew he was evil.’ Other, less common, symptoms may occur, including thought disorder, as manifest by incomprehensible speech, and abnormalities of movement, such as those in which the patient can become immobile or adopt awkward postures for prolonged periods (catatonia). Diagnosis The diagnosis is made primarily on clinical grounds but investigations may be required to rule out organic brain disease. The main differential diagnosis of schizophrenia (Box 28.24) includes: • Other functional psychoses, particularly psychotic depression and mania, in which delusions and hallucinations are congruent with a marked mood disturbance (negative in depression and grandiose in mania). Schizophrenia must also be differentiated from specific delusional disorders that are not associated with the other typical features of schizophrenia. • Organic psychoses, including delirium, in which there is impairment of consciousness and loss of orientation (not found in schizophrenia), typically with visual hallucinations; drug misuse, particularly in young people; and temporal lobe epilepsy with psychotic symptoms, in which olfactory and gustatory hallucinations may occur. Many of those who experience acute schizophrenia go on to develop a chronic state in which the acute, so-called positive symptoms resolve, or at least do not dominate the clinical picture, leaving so-called negative symptoms that include blunt affect, apathy, social isolation, poverty of speech and poor self-care. Patients with chronic schizophrenia may also manifest positive symptoms, particularly when under stress, and it can be difficult for those who do not know the patient to judge whether or not these are signs of an acute relapse. Investigations As in dementia, investigations are focused on excluding a treatable cause, such as a slow-growing brain tumour, temporal lobe epilepsy, neurosyphilis or various autoimmune conditions. These are required only in patients with neurological or other organic symptoms or signs. 28.23 Symptoms of schizophrenia First-rank symptoms of acute schizophrenia • A = Auditory hallucinations – second- or third-person/écho de la pensée • B = Broadcasting, insertion/withdrawal of thoughts • C = Controlled feelings, impulses or acts (‘passivity’ experiences/ phenomena) • D = Delusional perception (a particular experience is bizarrely interpreted) Symptoms of chronic schizophrenia (negative symptoms) • Flattened (blunted) affect • Apathy and loss of drive (avolition) • Social isolation/withdrawal (autism) • Poverty of speech (alogia) • Poor self-care 28.24 Differential diagnosis of schizophrenia Alternative diagnosis Distinguishing features Other functional psychoses Delusional disorders Absence of specific features of schizophrenia Psychotic depression Prominent depressive symptoms Manic episode Prominent manic symptoms Schizoaffective disorder Mood and schizophrenia symptoms both prominent Puerperal psychosis Acute onset after childbirth Organic disorders Drug-induced psychosis Evidence of drug or alcohol misuse Side-effects of prescribed drugs Levodopa, methyldopa, glucocorticoids, antimalarial drugs Temporal lobe epilepsy Other evidence of seizures Delirium Visual hallucinations, impaired consciousness Dementia Age, established cognitive impairment Huntington’s disease Family history, choreiform movements, dementia

1198 • MEDICAL PSYCHIATRY given as part of an integrated treatment package, reduces the rate of relapse. Social treatment After an acute episode of schizophrenia has been controlled by drug therapy, social rehabilitation may be required. Recurrent illness is likely to cause disruption to patients’ relationships and their ability to manage their accommodation and occupation; consequently, patients with schizophrenia often need help to obtain housing and employment. A graded return to employment and sometimes a period of supported accommodation are required. Patients with chronic schizophrenia have particular difficulties and may need long-term, supervised accommodation. This now tends to be in supported accommodation in the community. Patients may also benefit from sheltered employment if they are unable to participate effectively in the labour market. Ongoing contact with a health worker allows monitoring for signs of relapse, sometimes as part of a multidisciplinary team working to agreed plans (the ‘care programme approach’). Partly because of a tendency to inactivity, smoking and a poor diet, patients with chronic schizophrenia are at increased risk of cardiovascular disease, diabetes and stroke, and require proactive medical as well as psychiatric care. Prognosis About one-third of those who develop an acute schizophrenic episode have a good outcome. One-third develop chronic, incapacitating schizophrenia, and the remainder largely recover after each episode but suffer relapses. Most affected patients cannot work or live independently. Schizophrenia is associated with suicide and up to 10% of patients take their own lives. Mood disorders Mood or affective disorders include: • unipolar depression: one or more episodes of low mood and associated symptoms • bipolar disorder: episodes of elevated mood interspersed with episodes of depression • dysthymia: chronic low-grade depressed mood without sufficient other symptoms to count as ‘clinically significant’ or ‘major’ depression. Depression Major depressive disorder has a prevalence of 5% in the general population and approximately 10–20% in chronically ill medical outpatients. It is a major cause of disability and suicide. If comorbid with a medical condition, depression magnifies disability, diminishes adherence to medical treatment and rehabilitation, and may even shorten life expectancy. Pathogenesis There is a genetic predisposition to depression, especially when of early onset. The genetic predisposition is mediated by variants in a large number of genes and loci of small effect rather than mutations in single genes. Adversity and emotional deprivation early in life also predispose to depression. Depressive episodes are often, but not always, triggered by stressful life events (especially those that involve loss or imposed change), including medical illnesses. Associated biological factors include and delirium. Characteristic laboratory findings are an elevated creatinine phosphokinase and leucocytosis. Antipsychotic medication must be stopped immediately and supportive therapy provided, often in an intensive care unit. Treatment includes ensuring hydration and reducing hyperthermia. Dantrolene sodium and bromocriptine may be helpful. Mortality is 20% untreated and 5% with treatment. Cardiac arrhythmias Antipsychotic medications cause prolongation of the QTc interval, which may be associated with ventricular tachycardia, torsades de pointes and sudden death. If this occurs, treatment should be stopped, with careful electrocardiographic monitoring and treatment of serious arrhythmias if necessary (p. 479). Psychological treatment Psychological treatment, including general support for the patient and family, is now seen as an essential component of management. CBT may help patients to cope with symptoms. There is evidence that personal and/or family education, when 28.26 Adverse effects of antipsychotic drugs Weight gain due to increased appetite Effects due to dopamine blockade* • Acute dystonia • Akathisia (motor restlessness) • Parkinsonism • Tardive dyskinesia • Gynaecomastia • Galactorrhoea Effects due to cholinergic blockade • Dry mouth • Blurred vision • Impotence • Constipation • Urinary retention Hypersensitivity reactions • Blood dyscrasias (neutropenia with clozapine) • Cholestatic jaundice • Photosensitive dermatitis Ocular complications • Corneal and lens opacities (long-term use) *Less severe with clozapine, quetiapine and olanzapine, possibly because of strong 5-hydroxytrytamine-blocking effect and relatively weak dopamine blockade. 28.25 Antipsychotic drugs Group Drug Usual adult dose1 Phenothiazines Chlorpromazine 400–600 mg daily Butyrophenones Haloperidol 8–12 mg daily Thioxanthenes Flupentixol decanoate 40 mg fortnightly (depot injection) Diphenylbutylpiperidines Pimozide 8–10 mg daily Substituted benzamides Sulpiride 800–1200 mg daily Dibenzodiazepines2 Clozapine 300–600 mg daily Benzisoxazole2 Risperidone 4–6 mg daily Thienobenzodiazepines2 Olanzapine 10–15 mg daily Dibenzothiazepines2 Quetiapine 300–600 mg daily 1Lower or higher doses may be required in some patients. 2Second-generation antipsychotics.

Psychiatric disorders • 1199

an effective drug for an adequate period. For those who do not respond, a proportion will do so if changed to another class of antidepressant. The patient’s progress must be monitored and, after recovery, treatment should be continued for at least 6–12 months to reduce the high risk of relapse. The dose should then be tapered off over several weeks to avoid discontinuation symptoms. The Scottish Intercollegiate Guidelines Network (SIGN) and National Institute for Health and Clinical Excellence (NICE) have published treatment guidelines. Tricyclic antidepressants Tricyclic antidepressant (TCA) agents inhibit re-uptake of the amines noradrenaline (norepinephrine) and 5-HT at synaptic clefts. The therapeutic effect is noticeable within a week or two. Adverse effects, such as sedation, anticholinergic effects, postural hypotension, lowering of the seizure threshold and cardiotoxicity, can be troublesome during this period. TCAs may be dangerous in overdose and should be used with caution in people who have coexisting heart disease, glaucoma and prostatism. Selective serotonin re-uptake inhibitors Selective serotonin reuptake inhibitors (SSRIs) are less cardiotoxic and less sedative than TCAs, and have fewer anticholinergic effects. They are safer in overdose but can still cause QTc prolongation, headache, nausea, anorexia and sexual dysfunction. They can also interact with other drugs increasing serotonin (5-HT), to produce ‘serotonin syndrome’. This is a rare syndrome of neuromuscular hyperactivity, autonomic hyperactivity and agitation, and potentially seizures, hyperthermia, delirium and even death. Noradrenaline (norepinephrine) re-uptake inhibitors These agents inhibit noradrenaline uptake at the synaptic cleft but have additional pharmacological effects. Venlafaxine and duloxetine also act as serotonin re-uptake inhibitors, whereas mirtazapine also acts as an antagonist at 5-HT2a, 5-HT2c and 5-HT3 receptors. These drugs have similar efficacy to the agents listed above but a different adverse-effect profile. Monoamine oxidase inhibitors Monoamine oxidase inhibitors (MAOIs) increase the availability of neurotransmitters at synaptic clefts by inhibiting metabolism of noradrenaline (norepinephrine) and 5-HT. They are now rarely prescribed in the UK, since they can cause potentially dangerous interactions with drugs such as amphetamines and certain anaesthetic agents, and with foods rich in tyramine (such as cheese and red wine). This is due to accumulation of amines in the systemic circulation, causing a potentially fatal hypertensive crisis. Psychological treatment Both CBT and interpersonal therapy are as effective as antidepressants for mild to moderate depression. Antidepressant drugs are, however, preferred for severe depression. Drug and psychological treatments can be used in combination. Prognosis Over 50% of people who have had one depressive episode and over 90% of people who have had three or more episodes will have another. The risk of suicide in an individual who has had a depressive disorder is 10 times greater than in the general population. Bipolar disorder Bipolar disorder is an episodic disturbance with interspersed periods of depressed and elevated mood; the latter is known hypofunction of monoamine neurotransmitter systems, including 5-HT and noradrenaline (norepinephrine), and abnormalities of the hypothalamic–pituitary–adrenal (HPA) axis, which results in elevated cortisol levels that do not suppress with dexamethasone. Diagnosis The symptoms are listed in Box 28.6. Depression may be mild, moderate or severe. It may also be recurrent or chronic. It can be both a complication of a medical condition and a cause of MUS (see below), so physical examination is essential; an associated medical condition should always be considered, particularly where there is no past history of depression and no apparent psychological precipitant. Investigations Investigations are not usually required unless there are clinical grounds for suspicion of an underlying medical disorder, such as Cushing’s syndrome or hypothyroidism. Management Pharmacological and psychological treatments both work in depression. In practice, the choice is determined by patient preference and local availability. Severe depression complicated by psychotic symptoms, dehydration or suicide risk may require ECT. Drug treatment Antidepressant drugs are effective in moderate and severe depression, whether it is primary or secondary to a medical illness. The most suitable drug for an individual patient will depend on their previous response, likely side-effects, their concurrent illnesses and potential drug interactions. Commonly used antidepressants are shown in Box 28.27. The different classes of antidepressant have similar efficacy and about three-quarters of patients respond to treatment. Successful treatment requires the patient to take an appropriate dose of 28.27 Antidepressant drugs Group Drug Usual adult dose* Tricyclic antidepressants Amitriptyline 75–150 mg daily Imipramine 75–150 mg daily Dosulepin 75–150 mg daily Clomipramine 75–150 mg daily Selective serotonin re-uptake inhibitors (SSRIs) Citalopram 20–40 mg daily Escitalopram 10–20 mg daily Fluoxetine 20–60 mg daily Sertraline 50–100 mg daily Paroxetine 20–50 mg daily Monoamine oxidase inhibitors Phenelzine 45–90 mg daily Tranylcypromine 20–40 mg daily Moclobemide 300–600 mg daily Noradrenaline (norepinephrine) re-uptake inhibitors and SSRIs Venlafaxine 75–375 mg daily Duloxetine 60–120 mg daily Noradrenaline and specific serotonergic inhibitor Mirtazapine 15–45 mg daily *Higher doses may be required in some patients: see guidelines.

1200 • MEDICAL PSYCHIATRY Anxiety disorders These are characterised by the emotion of anxiety, worrisome thoughts, avoidance behaviours and the somatic symptoms of autonomic arousal. Anxiety disorders are divided into three main subtypes: phobic, paroxysmal (panic) and generalised (Box 28.28). The nature and prominence of the somatic symptoms often lead the patient to present initially to medical services. Anxiety may be stress-related and phobic anxiety may follow an unpleasant incident. Many patients with anxiety also have depression. Clinical features Phobic anxiety disorder A phobia is an abnormal or excessive fear of a specific object or situation, which leads to avoidance of it (such as excessive fear of dying in an air crash, leading to avoidance of flying). A generalised phobia of going out alone or being in crowded places is called ‘agoraphobia’. Phobic responses can develop to medical procedures such as venepuncture. Panic disorder Panic disorder describes repeated attacks of severe anxiety, which are not restricted to any particular situation or circumstances. Somatic symptoms, such as chest pain, palpitations and paraesthesia in lips and fingers, are common. The symptoms are in part due to involuntary over-breathing (hyperventilation). Patients with panic attacks often fear that they are suffering from a serious illness, such as a heart attack or stroke, and seek emergency medical attention. Panic disorder may coexist with agoraphobia. Generalised anxiety disorder This is a chronic anxiety state associated with uncontrollable worry. The associated somatic symptoms of muscle tension and bowel disturbance often lead to a medical presentation. Diagnosis The diagnosis is made on the basis of clinical history and typical symptoms, as described above. Where a diagnosis of panic disorder is suspected, it can be confirmed by asking the patient to hyperventilate deliberately for 1–2 minutes and observing whether the symptoms are reproduced. A finding of respiratory alkalosis on arterial blood gas measurement is indicative of chronic hyperventilation. Management Psychological treatment Explanation and reassurance are essential, especially when patients fear they have a serious medical condition. Specific as hypomania when mild or short-lived, or mania when severe or chronic. The lifetime risk of developing bipolar disorder is approximately 1–2%. Onset is usually in the twenties, and men and women are equally affected. Pathogenesis Bipolar disorder is strongly heritable (approximately 70%). Relatives of patients have an increased incidence of both bipolar and unipolar affective disorder. A number of genetic variants of small effect have been identified by genome-wide association studies. Life events, such as physical illness, sleep deprivation and medication, may also play a role in triggering episodes. Diagnosis The diagnosis is based on clear evidence of episodes of depression and mania. Isolated episodes of hypomania or mania do occur but they are usually preceded or followed by an episode of depression. Psychotic symptoms may occur in both the depressive and the manic phases, with delusions and hallucinations that are usually in keeping with the mood disturbance. This is described as an affective psychosis. Patients who present with symptoms of both bipolar disorder and schizophrenia in equal measure may be given a diagnosis of schizoaffective disorder. Management Depression should be treated as described above. If antidepressants are prescribed, however, they should be combined with a mood-stabilising drug (see below) to avoid ‘switching’ the patients into (hypo)mania. Manic episodes and psychotic symptoms usually respond well to antipsychotic drugs (see Box 28.25). Prophylaxis to prevent recurrent episodes of depression and mania with mood-stabilising agents is important. The main drugs used are lithium and sodium valproate but lamotrigine, olanzapine, quetiapine and risperidone are increasingly employed. Caution must be exercised when stopping these drugs, as a relapse may follow. Lithium carbonate is the drug of first choice. It is also used for acute mania, and in combination with a tricyclic as an adjuvant treatment for resistant depression. It has a narrow therapeutic range, so regular blood monitoring is required to maintain a serum level of 0.5–1.0 mmol/L. Toxic effects include nausea, vomiting, tremor and convulsions. With long-term treatment, weight gain, hypothyroidism, increased calcium and parathyroid hormone (PTH), nephrogenic diabetes insipidus (p. 687) and renal failure can occur. Thyroid and renal function should be checked before treatment is started and regularly thereafter. Lithium may be teratogenic and should not be prescribed during the first trimester of pregnancy. Anticonvulsants, such as sodium valproate and lamotrigine, and the antipsychotic drug olanzapine can all be used as prophylaxis in bipolar disorder, usually as a second-line alternative to lithium. Valproate conveys a high risk of birth defects and should not be used in women of child-bearing age. Olanzapine can cause significant weight gain. (For a list of the adverse effects of antipsychotic drugs, see Box 28.26.) Prognosis The relapse rate of bipolar disorder is high, although patients may be perfectly well between episodes. After one episode, the annual average risk of relapse is about 10–15%, which doubles after more than three episodes. There is a substantially increased lifetime risk of suicide of 5–10%. 28.28 Classification of anxiety disorders Phobic anxiety disorder Panic disorder Generalised anxiety disorder Occurrence Situational Paroxysmal Persistent Behaviour Avoidance Escape Agitation Cognitions Fear of situation Fear of symptoms Worry Symptoms On exposure Episodic Persistent

Psychiatric disorders • 1201

The symptoms are transient and usually resolve completely within a few days. The lay media often describes this as ‘shock’. Adjustment disorder A more common psychological response to a major stressor is a less severe but more prolonged emotional reaction. Clinical features The predominant symptom is usually depression and/or anxiety, which is insufficiently persistent or intense to merit a diagnosis of depressive or anxiety disorder. There may also be anger, aggressive behaviour and associated excessive alcohol use. Symptoms develop within a month of the onset of the stress, and their duration and severity reflect the course of the underlying stressor. Grief reactions following bereavement are a particular type of adjustment disorder. They manifest as a brief period of emotional numbing, followed by a period of distress lasting several weeks, during which sorrow, tearfulness, sleep disturbance, a sense of futility, anger and ‘bargaining’ are common. Perceptual distortions may occur, including misinterpreting sounds as the dead person’s voice or ‘seeing’ the dead person. ‘Pathological grief’ describes a grief reaction that is abnormally intense or persistent. Diagnosis The diagnosis is made on the basis of the typical history following a stressful life event, as described above. Management Ongoing contact with and support from a doctor or another person who can listen, reassure, explain and advise are often all that is needed. Most patients do not require psychotropic medication, although benzodiazepines reduce arousal in acute stress reactions and can aid sleep in adjustment disorders. Post-traumatic stress disorder Post-traumatic stress disorder (PTSD) is a delayed and/or protracted response to a stressful event of an exceptionally threatening or catastrophic nature. Examples of such events include natural disasters, terrorist activity, serious accidents and witnessing violent deaths. PTSD may also sometimes occur after distressing medical treatments or intensive care. Clinical features The development of PTSD is usually delayed from a few days to several months between the traumatic event and the onset of symptoms. Typical symptoms are recurrent intrusive memories (flashbacks) of the trauma; sleep disturbance, especially nightmares (usually of the traumatic event) from which the patient awakes in a state of anxiety; symptoms of autonomic arousal (anxiety, palpitations, enhanced startle); emotional blunting; and avoidance of situations that evoke memories of the trauma. Anxiety and depression are often associated and excessive use of alcohol or drugs frequently complicates the clinical picture. Diagnosis The diagnosis is made on the basis of the typical clinical features following a traumatic life event. Management In the immediate aftermath of a significant trauma, the main aim is to provide support, direct advice and the opportunity treatment may be needed. Treatments include relaxation, graded exposure (desensitisation) to feared situations for phobic disorders, and CBT. Drug treatment Antidepressants are the drugs of first choice (p. 1199). The therapeutic dose is usually higher for anxiety disorders than for depression and there is some evidence that, within their respective classes, paroxetine (SSRI) and clomipramine (TCA) have greatest efficacy against anxiety disorders. Early side-effects of antidepressants can lead to a worsening of anxiety symptoms in the first 2 weeks and patients should be warned of this. Benzodiazepines are useful in the short term but regular (> 3 doses per week) long-term use carries a very high risk of dependence. Regular prescriptions should therefore be limited to 3 weeks; beyond that, prescriptions should be restricted to occasional use as required, with periodic review to guard against dose escalation. Short-acting benzodiazepines, such as lorazepam, have a rapid onset and provide symptomatic relief for up to 2 hours but have the greatest potential for dependence. Longer-acting drugs, such as diazepam, can take an hour to take effect when given orally but provide symptomatic relief for up to 12 hours. A β-blocker, such as propranolol, can help when somatic symptoms are prominent. Obsessive–compulsive disorder Obsessive–compulsive disorder (OCD) is characterised by ‘obsessions’ – thoughts, images or impulses that are recurrent, unwanted and usually anxiety-provoking, but recognised as one’s own. In many cases, the obsessions give rise to ‘compulsions, which are repeated acts performed to relieve the anxiety. Unlike the anxiety disorders discussed above, which are more common in women, OCD is equally common in men and women. Clinical features Common examples include thoughts of contamination, giving rise to repeated and ritualised hand-washing, and thoughts of having forgotten something, giving rise to time-consuming repeated checking. The differential diagnoses include normal checking behaviour and delusional beliefs about thought possession. Diagnosis The diagnosis is made on the basis of the typical history, as described above. Management OCD usually responds to some degree to antidepressant drugs (high-dose clomipramine or SSRI; see Box 28.27) and to ‘exposure response prevention’ – a form of CBT in which patients are encouraged to expose themselves to the feared thought or situation without performing the anxiety-relieving compulsions. Relapses are common, however, and the condition often becomes chronic. Stress-related disorders Acute stress reaction Following a stressful event, such as a serious medical diagnosis or a major accident, some people develop a characteristic pattern of symptoms: an initial state of ‘daze’ or bewilderment is followed by altered activity (withdrawal or agitation), often with anxiety.

1202 • MEDICAL PSYCHIATRY Dissociative conversion disorders Dissociative conversion disorders are characterised by a loss or distortion of neurological functioning that is not fully explained by organic disease. These may be psychological functions such as memory (‘dissociative amnesia’), sensory functions such as vision (‘dissociative blindness’), or motor functions (‘functional gait disorder’) (Box 28.29). The cause is unknown but there is an association with recent stress and with adverse childhood experiences, including physical and sexual abuse. Organic disease may precipitate dissociation and provide a model for symptoms. For example, non-epileptic seizures often occur in those with epilepsy. Treatment with CBT may be of benefit. Somatisation disorder This is defined as the occurrence of multiple medically unexplained physical symptoms affecting several bodily systems. It is also known as Briquet’s syndrome after the physician who first described the presentation. Symptoms often start in early adult life but somatisation disorder can arise later, usually following an episode of physical illness. The disorder is much more common in women. Patients may undergo a multitude of negative investigations and unhelpful operations, particularly hysterectomy and cholecystectomy. There is no proven treatment except to try to ensure that unnecessary investigations and surgical procedures are avoided to minimise iatrogenic harm. Hypochondriacal disorder Patients with this condition have a strong fear or belief that they have a serious, often fatal, disease (such as cancer), and that fear persists despite appropriate medical reassurance. They are typically highly anxious and seek many medical opinions and investigations in futile but repeated attempts to relieve their fears. Hypochondriacal disorder often resembles OCD, but in a small proportion of cases the conviction that disease is present reaches delusional intensity. The best-known example is that of parasitic infestation (‘delusional parasitosis’), which leads patients to consult dermatologists. Treatment with CBT can be helpful. Patients who suffer delusions may benefit from antipsychotic medication. The condition may become chronic. Body dysmorphic disorder This is defined as a preoccupation with bodily shape or appearance, with the belief that one is disfigured in some way (previously known as ‘dysmorphophobia’). People with this condition may make inappropriate requests for cosmetic surgery. Treatment with CBT or antidepressants may be helpful. The belief in disfigurement may sometimes be delusional, in which case antipsychotic drugs can help. Management The management of the various syndromes of medically unexplained complaints described above is based on the general principles outlined in Box 28.30 and discussed in more detail below. for emotional catharsis (debriefing may actually be harmful). In established PTSD, structured psychological approaches (CBT, eye movement desensitisation and reprocessing (EMDR), and stress management) are effective. Antidepressant drugs are moderately effective. Prognosis The condition runs a fluctuating course, with most patients recovering within 2 years. In a small proportion, the symptoms become chronic. Somatoform disorders The essential feature of these disorders is that the somatic symptoms are not explained by a medical condition (medically unexplained symptoms), nor better diagnosed as part of a depressive or anxiety disorder. The derivation of the term ‘somatoform’ is ‘body-like’. Several syndromes are described within this category; there is considerable overlap between them, both in the underlying causes and in the clinical presentation. Pathogenesis The cause of somatoform disorders is incompletely understood but contributory factors include depression and anxiety, the erroneous interpretation of somatic symptoms as evidence of disease, excessive concern with physical illness and a tendency to seek medical care. A family history or previous history of a particular condition may have shaped the patient’s beliefs about illness. Doctors may exacerbate the problem, either by dismissing the complaints as non-existent or by over-emphasising and investigating the possibility of disease. Clinical features Somatoform disorders can present in several different ways, as described below. Somatoform autonomic dysfunction This describes somatic symptoms referable to bodily organs that are largely under the control of the autonomic nervous system. The most common examples involve the cardiovascular system (‘cardiac neurosis’), respiratory system (‘psychogenic hyperventilation’) and gut (‘psychogenic vomiting’ and ‘irritable bowel syndrome’). Antidepressant drugs and CBT may be helpful. Somatoform pain disorder This describes severe, persistent pain that cannot be adequately explained by a medical condition. Antidepressant drugs (especially tricyclics and dual action drugs such as duloxetine) are helpful, as are some of the anticonvulsant drugs, particularly carbamazepine, gabapentin and pregabalin. CBT and multidisciplinary pain management teams are also useful. Chronic fatigue syndrome Chronic fatigue syndrome (CFS) is characterised by excessive fatigue after minimal physical or mental exertion, poor concentration, dizziness, muscular aches and sleep disturbance. This pattern of symptoms may follow a viral infection such as infectious mononucleosis, influenza or hepatitis. Symptoms overlap with those of depression and anxiety. There is good evidence that many patients improve with carefully graded exercise and with CBT, as long as the benefits of such treatment are carefully explained. 28.29 Common presentations of dissociative (conversion) disorder • Gait disturbance • Loss of function in limbs • Aphonia • Non-epileptic seizures • Sensory loss • Blindness

Psychiatric disorders • 1203

re-referral for investigation, to ensure that treatable aspects of the patient’s problems, such as depression, are actively managed and to prevent the GP from becoming demoralised. Eating disorders There are two well-defined eating disorders, anorexia nervosa (AN) and bulimia nervosa (BN); they share some overlapping features. Ninety per cent of people affected are female. There is a much higher prevalence of abnormal eating behaviour in the population that does not meet diagnostic criteria for AN or BN but may attract a diagnostic label such as ‘binge eating disorder’. In developed societies, obesity is arguably a much greater problem but is usually considered to be more a disorder of lifestyle or physiology than a psychiatric disorder. Anorexia nervosa The lifetime risk of anorexia nervosa for women living in Europe is approximately 1–2% (for men it is < 0.5%) with a peak age of onset of 15–19 years. Predisposing factors include familiality (both genetic and shared environmental factors appear to play a role) and ‘neurotic’ personality traits. The illness is often precipitated by weight loss, whether due to non-pathological dieting/increased exercise or physical illness such as gastrointestinal disorders or diabetes mellitus. Many sufferers do not engage with specialist services and it is not uncommon for the first presentation to be with a medical problem (Box 28.31) rather than to psychiatric services. Clinical features There is marked weight loss, arising from food avoidance, often in combination with bingeing, purging, excessive exercise and/ or the use of diuretics and laxatives. Body image is profoundly disturbed so that, despite emaciation, patients still feel overweight and are terrified of weight gain. These preoccupations are intense and pervasive, and the false beliefs may be held with a conviction approaching the delusional. Anxiety and depressive symptoms are common accompaniments. Downy hair (lanugo) may develop on the back, forearms and cheeks. Extreme starvation is associated with a wide range of physiological and pathological bodily changes. All organ systems may be affected, although the most serious problems are cardiac and skeletal (Box 28.31). Pathogenesis The underlying cause is unclear but probably includes personality (high neuroticism), genetic (twin studies indicate heritability of 0.3–0.5) and environmental factors, including, in many societies, the social pressure on women to be thin. Diagnosis Diagnostic criteria are shown in Box 28.32. Differential diagnosis is from other causes of weight loss, including psychiatric disorders such as depression, and medical conditions such as inflammatory bowel disease, malabsorption, hypopituitarism and cancer, although it is important to remember that AN can coexist with any of these. The diagnosis is based on a pronounced fear of fatness despite being thin, and on the absence of an adequate alternative explanation for weight loss. Management The aims of management are to ensure patients’ physical wellbeing while helping them to gain weight by addressing the Reassurance Patients should be asked what they are most worried about. Clearly, it may be unwise to state categorically that the patient does not have any disease, as that is difficult to establish with certainty. However, it can be emphasised that the probability of having a disease is low and that doctors often see patients with physical symptoms but no physical disease. If patients repeatedly ask for reassurance about the same health concern despite reassurance, they may have hypochondriasis. Explanation Patients need a positive explanation for their symptoms. It is unhelpful to say that symptoms are psychological or ‘all in the mind’. Rather, a term such as ‘functional’ (meaning that the symptoms represent a reversible disturbance of bodily function) may be more acceptable. When possible, it is useful to describe a plausible physiological mechanism that is linked to psychological factors such as stress and implies that the symptoms are reversible. For example, in irritable bowel syndrome, psychological stress results in increased activation of the autonomic nervous system, which leads to constriction of smooth muscle in the gut wall, which in turn causes pain and bowel disturbance. Advice This should focus on how to overcome factors perpetuating the symptoms: for example, by resolving stressful social problems or by practising relaxation. The doctor can offer to review progress, to prescribe (for example) an antidepressant drug and, if appropriate, to refer for physiotherapy or psychological treatments such as CBT. The attitudes of relatives may need to be addressed if they have adopted an over-protective role, unwittingly reinforcing the patient’s disability. Drug treatment Antidepressant drugs are often helpful, even if the patient is not depressed. Psychological treatment There is evidence for the effectiveness of CBT. Other psychological treatments such as IPT may also have a role. Rehabilitation Where there is chronic disability, particularly in dissociative (conversion) disorder, conventional physical rehabilitation may be the best approach. Shared care Ongoing planned care is required for patients with chronic intractable symptoms, especially those of somatisation disorder. Review by the same specialist, interspersed with visits to the same GP, is probably the best way to avoid unnecessary multiple 28.30 General management principles for medically unexplained symptoms • Take a full sympathetic history • Exclude disease but avoid unnecessary investigation or referral • Seek specific treatable psychiatric syndromes • Demonstrate to patients that you believe their complaints • Establish a collaborative relationship • Give a positive explanation for the symptoms, including but not over-emphasising psychological factors • Encourage a return to normal functioning

1204 • MEDICAL PSYCHIATRY that minimum lifetime BMI is the strongest prognostic indicator (BMI < 11.5 is associated with an standardised mortality ratio of 4–5). Other indicators of poor prognosis are comorbid BN and atypical demographics (very early or relatively late onset, male gender). Forty per cent of additional deaths are due to suicide, the remainder being due to complications of starvation. Bulimia nervosa The prevalence of BN is difficult to determine with precision, as only a small proportion of sufferers come to medical attention. It is believed to be more common than AN, with a similar gender ratio. Peak age of onset is slightly later than for AN, typically late adolescence or early adult life. Clinical features Patients with BN are usually at or near normal weight (unlike in AN), but display a morbid fear of fatness associated with disordered eating behaviour. They recurrently embark on eating binges, often followed by corrective measures such as self-induced vomiting. Diagnosis Diagnostic criteria are shown in Box 28.32. Physical signs of repeated self-induced vomiting include pitted teeth (from gastric acid), calluses on knuckles (‘Russell’s sign’) and parotid gland enlargement. There are many associated physical complications, including the dental and oesophageal consequences of repeated vomiting, as well as electrolyte abnormalities, cardiac arrhythmias and renal problems (see Box 28.31). Investigations Self-induced vomiting and/or abuse of laxatives and diuretics can lead to clinically significant electrolyte disturbances, including hypokalaemia leading to cardiac arrhythmias. Hence it is good practice to measure urea and electrolytes and obtain an ECG whenever these behaviours are prominent in any patient and when BN is suspected in any medical inpatient. Repeated vomiting can also give rise to Mallory–Weiss tears and even oesophageal rupture; if symptoms are suggestive of these, an endoscopy should be performed. Management Treatment of bulimia with CBT achieves both short-term and long-term improvements. Guided self-help and IPT may also be of value. There is also evidence for benefit from the SSRI fluoxetine, but high doses of up to 60 mg daily may be required for a prolonged period of up to 1 year; this appears to be independent of the antidepressant effect. Prognosis Bulimia is not associated with increased mortality but a proportion of sufferers go on to develop anorexia. At 10-year follow-up, approximately 10% are still unwell, 20% have a subclinical degree of bulimia, and the remainder have recovered. Personality disorders Personality refers to the set of characteristics and behavioural traits that best describes an individual’s patterns of interaction with the world. The intensity of particular traits varies from person to person, although certain ones, such as shyness or irritability, are displayed to some degree by most people. A personality disorder (PD) is diagnosed when an individual’s personality causes persistent and severe problems for the person or for others. beliefs and behaviours that maintain the low weight. Treatment is usually given on an outpatient basis. Inpatient treatment should be reserved for those at risk of death from medical complications or from suicide. There is a limited evidence base for CBT-based psychological treatments. Family behaviour therapy (FBT) has efficacy among adolescent but not adult patients. Psychotropic drugs are of no proven benefit in AN but antidepressant medication may be indicated in those with clear-cut comorbid depressive disorder. Weight gain is best achieved in a collaborative fashion. Compulsory admission and refeeding (including tube feeding) are very occasionally resorted to when patients are at risk of death and other measures have failed. While this may produce a short-term improvement in weight, it rarely changes long-term prognosis. Prognosis Two-thirds of patients with AN no longer meet diagnostic criteria at 5-year follow-up. However, long-term follow-up studies suggest that many sufferers continue to have a relatively low body mass index (BMI), suggesting that the symptoms do not completely resolve. Approximately 20% of patients develop a chronic, intractable disorder. Long-term follow-up studies demonstrate 28.32 Diagnostic criteria for eating disorders Anorexia nervosa • Weight loss of at least 15% of total body weight (or body mass index ≤ 17.5) • Avoidance of high-calorie foods • Distortion of body image so that patients regard themselves as fat even when grossly underweight • Amenorrhoea for at least 3 months Bulimia nervosa • Recurrent bouts of binge eating • Lack of self-control over eating during binges • Self-induced vomiting, purgation or dieting after binges • Weight maintained within normal limits 28.31 Medical consequences of eating disorders Cardiac • ECG abnormalities: T-wave inversion, ST depression and prolonged QTc interval • Arrhythmias, including profound sinus bradycardia and ventricular tachycardia Haematological • Anaemia, thrombocytopenia and leucopenia Endocrine • Pubertal delay or arrest • Growth retardation and short stature • Amenorrhoea • Sick euthyroid state Metabolic • Uraemia • Renal calculi • Osteoporosis Gastrointestinal • Constipation • Abnormal liver function tests

Psychiatric disorders • 1205

Management PDs usually persist throughout life and are not readily treated. They typically become less extreme with age but can re-emerge in the context of cognitive decline. Treatment options are limited but there is some evidence that emotionally unstable PD may respond to dialectical behavioural therapy (DBT). Anxious (avoidant) and obsessional (anankastic) PD may benefit from prescription of anxiolytic drugs, while paranoid/schizotypal PD may be improved by treatment with low doses of antipsychotic agents. The problematic and inflexible patterns of interaction that characterise a PD are often apparent in the patient’s interaction with health services and can present a challenge to both the service and the patient. Clear clinical communication supported by robust documentation can help to minimise any potential disruption. Factitious disorder and malingering Factitious disorder describes the repeated and deliberate production of the signs or symptoms of disease to obtain medical care. Pathogenesis It is difficult to understand what motivates a person to act in this way. Several theories have been proposed but the deception that lies at the heart of the condition makes it impossible to gather accurate data from which to draw reliable conclusions. Clinical features The disorder feigned is usually medical but can be a psychiatric illness (for example false reports of hallucinations or symptoms of depression). An example of a medical factitious disorder is dipping of a thermometer into a hot drink to fake a fever. Factitious disorder is uncommon and is important to distinguish from somatoform disorders. A suggested diagnostic algorithm is shown in Figure 28.6. Pathogenesis Some PDs appear to have an inherited aspect (especially schizotypal and paranoid subtypes) but most are more clearly related to an unsatisfactory upbringing and adverse childhood experiences. Clinical features PD can present in various ways. For example, anxiety may be so pronounced that the individual rarely ventures into any situation where they fear scrutiny. Dissocial traits, such as disregard for the well-being of others and a lack of guilt concerning the adverse effects of one’s actions on others, may occur. If pronounced, they may lead to damage to others, to criminal acts or to successful careers, such as in politics. Diagnosis It is possible to classify PD into several subtypes (such as emotionally unstable, antisocial or dependent), depending on the particular behavioural traits in question. A patient who meets diagnostic criteria for one subtype may also meet criteria for others. As allocation to one particular subtype gives little guidance to management or prognosis, classification is of limited value. Diagnosis requires a longitudinal perspective, with clear evidence that the patient’s behavioural traits and pattern of interaction with the world have been present throughout their adult life, have been evident across a range of settings and have caused repeated and persistent problems. It can be difficult to achieve this during a single interview, and most psychiatrists warn against making a diagnosis of personality disorder until the patient has been seen several times and corroborative accounts have been obtained. It is common for PD to accompany other psychiatric conditions, making treatment of the latter more difficult and therefore affecting their prognosis. Fig. 28.6 Diagnosis of medically unexplained symptoms (MUS). Are symptoms fully explained by organic disease? Organic disease Yes ‘Medically unexplained’ Is patient consciously feigning? No ‘Factitious disorder’ No ‘Malingering’ Yes ‘Functional somatic syndrome’ (see Box 28.11) No ‘Somatisation disorder’ Yes Is there a preoccupation with symptoms or diagnosis? No Is there an identifiable gain? Yes Diagnosis ‘Hypochondriasis’ Symptoms ‘Somatisation’ Multiple presentations to various departments?

1206 • MEDICAL PSYCHIATRY mother and to remain vigilant for development of post-partum depression. Post-partum depression This occurs in 10–15% of women, with onset typically within a month of delivery (although women often suffer for some time before presenting). It can usually be differentiated from postpartum blues by the duration and severity of the symptoms, in particular anhedonia (loss of capacity for pleasure) and negative thoughts. Risk factors include a previous history of depression, a previous history of post-partum depression, antenatal depression and antenatal anxiety. Unlike depression arising at other times, post-partum depression is not more common in lower socioeconomic groups; the prevalence is similar across all social backgrounds. Diagnosis, explanation and reassurance are important. The usual psychological and drug treatments for depression should be considered (p. 1199) to minimise the impact on the mother and child at what is a very important time for both. A number of helpful guidelines are available to inform prescribing decisions. The potential risks to both mother and child should be considered and, if hospital admission is required, it should ideally be to a mother and baby unit. Puerperal psychosis This has its peak onset in the first 2 weeks after childbirth but can arise several weeks later. It is a rare but serious complication affecting approximately 1 in 500 women. There is a strong association with a personal or familial history of bipolar disorder. It usually takes the form of a manic or depressive psychosis but with sudden onset and fluctuation in severity. Delirium is rare with modern obstetric management but should still be considered in the differential diagnosis. Suspiciousness, concealment and impulsivity are common features of puerperal psychosis; hence the risks to both mother and baby are considerable. The clinical priority is to ensure the safety of both mother and baby and so psychiatric admission, ideally to a psychiatric mother and baby unit, is usually necessary. Pharmacological treatment reflects the clinical picture; antipsychotic medication is almost always indicated, augmented by antidepressants if the picture is of psychotic depression and/or by mood stabilisers if the picture is bipolar. Most women recover but the risk of recurrence following subsequent deliveries is 50% and some women will progress to psychotic episodes not associated with childbirth, usually bipolar disorder. Psychiatric disorders during pregnancy Pregnancy can affect the course of psychiatric illnesses and of bipolar affective disorder in particular. Mood-stabilising drugs such as lithium and valproate, which are prescribed for prophylaxis in bipolar disorder (p. 1200), are teratogenic and should be avoided whenever possible. Most guidelines recommend deferring conception until mood-stabilising medication is not required, or replacing the mood stabiliser with an antipsychotic such as chlorpromazine. Furthermore, the immediate post-partum period is associated with a dramatically increased risk of relapse in bipolar disorder: studies report relapse rates of up to 60% in the first 3 months after delivery in the absence of prophylactic medication. When relapse occurs following childbirth, not only are the stakes higher than at other times but also the onset of illness is more rapid, the symptoms more severe and concealment more pronounced. Post-partum relapse of bipolar affective Münchausen’s syndrome This refers to a severe chronic form of factitious disorder. Patients characteristically travel widely, sometimes visiting several hospitals in one day. Although the condition is rare, such patients are memorable because they present so dramatically. The history can be convincing enough to persuade doctors to undertake investigations or initiate treatment, including exploratory surgery. It may be possible to trace the patient’s history and show that they have presented similarly elsewhere, often changing name several times. Some emergency departments hold lists of such patients. Malingering Malingering is a description of behaviour, not a psychiatric diagnosis. It refers to the deliberate and conscious simulation of signs of disease and disability for an identifiable gain (patients have motives that are clear to them but which they initially conceal from doctors). Examples include the avoidance of burdensome responsibilities (such as work or court appearances) or the pursuit of financial gain (fraudulent claims for benefits or compensation). Malingering can be hard to detect at clinical assessment but is suggested by evasion or inconsistency in the history. Management Management is by gentle but firm confrontation with clear evidence of the fabrication of illness, together with an offer of psychological support. Treatment is usually declined but recognition of the condition may help to avoid further iatrogenic harm. Puerperal psychiatric disorders There are three important psychiatric presentations following childbirth. When managing these conditions, it is important always to consider both the mother and the baby, and their relationship (Box 28.33). Post-partum blues This is characterised by irritability, labile mood and tearfulness. About 80% of women are affected to some degree. Symptoms begin soon after childbirth, typically peak on about the fourth day and then resolve spontaneously within a few weeks. While the aetiology of baby blues is not fully understood, it is likely to be related to hormonal or physiological changes associated with childbirth. No treatment is required, other than to reassure the 28.33 Psychiatric illness and pregnancy • Psychiatric disorder and pregnancy: always consider effects on mother, fetus and child. • Bipolar disorder: women should have pre-conceptual advice because there is a very high risk of relapse following delivery and some mood stabilisers are teratogenic. • Psychiatric treatments and pregnancy: always make an individual assessment of the risks and benefits taking into consideration effects on mother, fetus and child. • Post-partum low mood (‘blues’): weeks 1–3; most cases are transient. • Persistent low mood and anhedonia: may indicate depressive illness. • Puerperal psychosis: progresses rapidly and is an indication for psychiatric admission.

Further information • 1207

that balances the restrictions imposed. There should also be provisions for appeals and oversight. Further information Books and journal articles Hofer H, Pozzi A, Joray M, et al. Safe refeeding management of anorexia nervosa inpatients: an evidence-based protocol. Nutrition 2014; 30:524–30. Steel RM. Factitious disorder (Munchausen’s syndrome). J R Coll Physicians Edinb 2009; 39:343–7. Taylor D, Meader N, Bird V, et al. Pharmacological interventions for people with depression and chronic physical health problems: systematic review and meta-analyses of safety and efficacy. Br J Psychiatry 2011; 198:179–88. Whiteford HA, Degenhardt L, Rehm J, et al. Global burden of disease attributable to mental and substance use disorders: findings from the Global Burden of Disease Study 2010. Lancet 2013; 382: 1575–86. Websites cebmh.com Centre for Evidence-based Mental Health. dementia.ie/images/uploads/site-images/ACE-III_Scoring_(UK).pdf Addenbrooke’s Cognitive Examination – 3rd edn (ACE-III): administration and scoring guide. mind.org.uk Information on depression. mocatest.org Montreal Cognitive Assessment. neurosymptoms.org A guide to medically unexplained neurological symptoms. niaaa.nih.gov/ Information on alcoholism. nice.org.uk National Institute for Health and Care Excellence: treatment guidelines for depression. ocdaction.org.uk Useful information about obsessive–compulsive disorder. rcpsych.ac.uk/info/index.htm Royal College of Psychiatrists: mental health information. sign.ac.uk Scottish Intercollegiate Guidelines Network: treatment guidelines for depression, including Guideline 127 – Management of perinatal mood disorders. who.int/mental_health/ World Health Organisation: mental health and brain disorders. www4.parinc.com/ Mini-Mental State Examination. disorder requires urgent specialist treatment, usually comprising admission to a psychiatric mother and baby unit. Ideally, women with major mental disorders such as bipolar affective disorder should be offered expert pre-conception advice to help them make informed decisions about medication and other aspects of their psychiatric care. A comprehensive post-partum risk management plan should be agreed during pregnancy. Psychiatry and the law Medicine takes place in a legal framework, made up of legislation (statute law) drafted by parliament or other governing bodies, precedent built up from court judgements over time (case law), and established tradition (common law). Psychiatry is similar to other branches of medicine in the applicability of common and case law but differs in that patients with psychiatric disorders can also be subject to legislative requirements to remain in hospital or to undergo treatments they refuse, such as the administration of antipsychotic drugs to a patient with acute schizophrenia who lacks insight and whose symptoms and/or behaviour pose a risk to himself/herself or to others. The UK has three different Mental Health Acts, covering England and Wales, Scotland, and Northern Ireland, and all of these have recently been revised. Other countries may have very different provisions. It is important for practitioners to be familiar with the relevant provisions that apply in their jurisdictions and are likely to arise in the clinical settings in which they work. All the countries that make up the UK have also introduced Incapacity Acts in recent years, with detailed provisions covering medical treatments for patients incapable of consenting, whether this incapacity arises from physical or mental illness. In general, the guiding principle in British law is that people should be free to make their own decision about any proposed medical treatment, except where their ability to make and/or communicate that decision is demonstrably impaired (by mental illness or physical incapacity). Any restrictions or compulsions applied should be the minimum necessary, they should be applied only for as long as is necessary, and there should be a benefit to the patient

7KLVSDJHLQWHQWLRQDOO\OHIWEODQN

Ch04-3 Clinical Medicine

19-29 Dermatology

29 Dermatology

Dermatology SH Ibbotson Clinical examination in skin disease 1210 Functional anatomy and physiology 1212 Investigation of skin disease 1214 Presenting problems in skin disease 1216 Lumps and lesions 1216 Rash 1216 Blisters 1218 Itch 1219 Photosensitivity 1220 Leg ulcers 1223 Abnormal pigmentation 1224 Hair and nail abnormalities 1224 Acute skin failure 1224 Principles of management of skin disease 1225 General measures 1225 Topical treatments 1225 Phototherapy and photochemotherapy 1227 Systemic therapies 1227 Dermatological surgery 1228 Non-surgical treatments 1228 Skin tumours 1229 Malignant tumours 1229 Benign skin lesions 1234 Common skin infections and infestations 1235 Bacterial infections 1235 Viral infections 1238 Fungal infections 1239 Infestations 1241 Acne and rosacea 1241 Eczemas 1244 Psoriasis and other erythematous scaly eruptions 1247 Lichenoid eruptions 1252 Urticaria 1252 Bullous diseases 1254 Toxic epidermal necrolysis 1254 Immunobullous diseases 1255 Pigmentation disorders 1257 Decreased pigmentation 1257 Increased pigmentation 1258 Hair disorders 1258 Nail disorders 1260 Skin disease in general medicine 1261 Conditions involving cutaneous vasculature 1261 Connective tissue disease 1262 Granulomatous disease 1263 Porphyrias 1263 Abnormal deposition disorders 1264 Genetic disorders 1264 Reactive disorders 1264 Drug eruptions 1265

1210 • DERMATOLOGY Involvement of face Central Hairline Cheeks and nasal bridge: ‘butterfly’ distribution Sparing of light-protected sites, e.g. behind ears, under chin Overall description of individual lesions Discrete, grouped, confluent, reticulate (lace-like), linear Observation If symmetrical Extensor, e.g. psoriasis Flexor, e.g. eczema Involvement of hands, including nail folds and finger webs The patient must be undressed, with make-up and dressings removed, and examined in good lighting. Consider the following: • Age • General health • Distress • Scratching Distribution of rash Symmetrical vs asymmetrical Proximal vs distal vs facial Localised vs widespread Eye involvement e.g. Conjunctivitis/blepharitis in rosacea or eyelash loss in alopecia areata General medical examination Including lymph nodes and other systems as indicated Involvement of axillae/groins e.g. hidradenitis suppurativa Oral and genital involvement Nail involvement Psoriatic changes in nails and peri-ungual involvement Palmoplantar pustulosis Magnifying lens image of benign naevus Morphology of rash Monomorphic or polymorphic Detailed morphology of individual lesions Use a magnifying lens in good lighting to assist Use correct terminology (see definitions throughout text) Reticulate (lacy) network on buccal mucosa in lichen planus. May also be genital involvement Joint involvement e.g. Psoriatic arthritis Examination of scalp Hair loss Scalp changes Alopecia areata Arthritis, plaque psoriasis and psoriatic nail dystrophy

Clinical examination in skin disease

Clinical examination in skin disease • 1211

B A C To find the PASI score, add together: (A) Sum for each part × (B) % of that part involved × (C) % weighting of that body part Minimum = 0; maximum = 72 Four body parts are each scored individually Each of the four body parts is scored: Redness (erythema) 0–4 Thickness (induration) 0–4 Scaling (desquamation) 0–4 The area of each involved body part is scored: 10% 20% 30% 40% 0 0% 1 < 10% 2 10–29% 3 30–49% 4 50–69% 5 70–89% 6 90–100% Plaque Blisters/bullae Pustule Macule/patch Papule Nodule • Onset and course • Exacerbating/relieving factors • Past history of skin disease, atopy or autoimmune disease • Social history, occupation, recreation • Psychological impact, gauged by health- related life quality indices • Always take a detailed drug and allergy history • Include all systemic and topical drugs, and over-the-counter preparations It is tempting to examine the skin first. This is a mistake; take a history, then examine the skin and the rest of the patient.

  1. History-taking
  2. Drug/allergy history • General examination, incl. peripheral lymph nodes, may be indicated/important • Skin diseases may have systemic features (e.g. cardiovascular disease in psoriasis); many systemic diseases have dermatological features (e.g. diabetes)
  3. General examination
  4. Examination of skin • Examine skin, hair, nails and mucous membranes • Is it a rash or a lesion? • Distribution and morphology important for rash • Use of a magnifying lens and/or dermatoscope may be invaluable • Site, size and detailed morphology of a lesion are essential factors to elicit
  5. Closer inspection
  6. Define type of lesion using correct terminology Helps in differential diagnosis and allows colleagues to visualise the process. Other definitions are provided in the chapter. Macule: circumscribed flat area of colour change ≤ 1 cm diameter; patch: > 1 cm Discrete elevation ≤ 1 cm diameter Like papule but deeper (into dermis or subcutaneous layer),

1 cm diameter Raised area > 1 cm diameter with flat top Large (> 1 cm diameter) fluidfilled blister Vesicle Small (≤ 1 cm diameter) fluidfilled blister Visible accumulation of pus in blister Petechiae/purpura Petechiae: tiny macules due to extravascular blood in dermis; purpura: larger, may be palpable

  1. Score activity Tools for objective assessment of disease severity (e.g. Psoriasis Area and Severity Index, PASI) are important in assessing severity and treatment responses. Include:

1212 • DERMATOLOGY The remaining 10% of epidermal cells are: • Langerhans’ cells: these are dendritic, bone marrowderived cells that circulate between the epidermis and local lymph nodes. Their prime function is antigen presentation to lymphocytes. Other dermal antigenpresenting dendritic cells are also present. • Melanocytes: these occur predominantly in the basal layer and are of neural crest origin. They synthesise the pigment melanin from tyrosine, package it in melanosomes and transfer it to surrounding keratinocytes via their dendritic processes. • Merkel cells: these occur in the basal layer and are thought to play a role in signal transduction of fine touch. Their embryological derivation is unclear. Basement membrane The basement membrane (Fig. 29.1) is an anchor for the epidermis and allows movement of cells and nutrients between dermis and epidermis. The cell membrane of the epidermal basal cell is attached to the basement membrane via hemi-desmosomes. The lamina lucida lies immediately below the basal cell membrane and is composed predominantly of laminin. Anchoring filaments extend through the lamina lucida to attach to the lamina densa. This electron-dense layer consists mostly of type IV collagen; from it extend loops of type VII collagen, forming anchoring fibrils that fasten the basement membrane to the dermis. Dermis The dermis is vascular and supports the epidermis structurally and nutritionally. It varies in thickness from just over 1 mm on the inner forearm to 4 mm on the back. Fibroblasts are the predominant cells but others include mast cells, mononuclear phagocytes, T lymphocytes, dendritic cells, neurons and endothelial cells. The acellular part of the dermis consists mainly of collagen I and III, elastin and reticulin, synthesised by fibroblasts. Support is provided by an amorphous ground substance (mostly glycosaminoglycans, hyaluronic acid and dermatan sulphate), whose production and catabolism are altered by hormonal changes and ultraviolet radiation (UVR). Based on the pattern of collagen fibrils, the superficial dermis is termed the ‘papillary dermis’, and the deeper, coarser part is the ‘reticular dermis’. Epidermal appendages Hair follicles There are 3–5 million hair follicles, epidermal invaginations that develop during the second trimester. They occur throughout the skin, with the exception of palms, soles and parts of the genitalia (glabrous skin). The highest density of hair follicles is on the scalp (500–1000/cm2). Newborns are covered with fine ‘lanugo’ hairs, which are usually non-pigmented and lack a central medulla; these are subsequently replaced by vellus hair, which is similar but more likely to be pigmented. By contrast, scalp hair becomes terminal hair, which is thicker with a central medulla, is usually pigmented and grows longer. At puberty, vellus hairs in hormonally sensitive regions, such as the axillary and genital areas, become terminal hairs. Human hairs grow in a cycle with three phases: anagen (active hair growth), catagen (transitional phase) and telogen (resting phase). The duration of each phase varies by site. On the scalp, anagen lasts several years, catagen a few days and Diseases affecting the skin are common, and important because the absence of normal skin function, as well as sometimes being life-threatening, can severely impair quality of life. This may be exacerbated by the fact that people with skin disease can suffer the effects of stigma, often brought about by the ill-informed understanding of others with respect to skin diseases, particularly as regards visually disfiguring skin changes or the belief that they are contagious. Skin diseases affect all ages and there are more than 2000 different types and presentations. Assessment of the skin is valuable in the management of anyone presenting with a medical problem and, conversely, assessment of the other body systems is important when managing primary skin diseases. This chapter concentrates on common skin diseases and those that are important components of general medical conditions. Skin infections, including those related to the human immunodeficiency virus (HIV), tuberculosis, leprosy (Hansen’s disease) and syphilis are also discussed in Chapters 12, 17, 11 and 13, respectively. Functional anatomy and physiology The skin covers just under 2 m2 in the average adult. The outer layer is the epidermis, a stratified squamous epithelium consisting mainly of keratinocytes. The epidermis is attached to, but separated from, the underlying dermis by the basement membrane. The dermis is less cellular and supports blood vessels, nerves and epidermal-derived appendages (hair follicles and sweat glands). Below it is the subcutis, consisting of adipose tissue. Epidermis In most sites, the epidermis is only 0.1–0.2 mm thick, except on the palms or soles, where it can extend to several millimetres. Keratinocytes make up approximately 90% of epidermal cells (Fig. 29.1). The main proliferative compartment is the basal layer. Keratinocytes synthesise a range of structural proteins, such as keratins, loricrin and filaggrin (filament aggregating protein), which play key roles in maintaining the skin’s barrier function. Keratinocytes are also responsible for synthesis of vitamin D under the influence of ultraviolet B (UVB) light (p. 1049). There are more than 50 types of keratin and their expression varies by body site, site within the epidermis and disease state. Mutations of certain keratin genes can result in blistering disorders (p. 1254) and ichthyosis (characterised by scale without major inflammation). As keratinocytes migrate from the basal layer, they differentiate, producing a variety of protein and lipid products. Keratinocytes undergo apoptosis in the granular layer before losing their nuclei and becoming the flattened corneocytes of the stratum corneum (keratin layer). The epidermis is a site of lipid production, and the ability of the stratum corneum to act as a hydrophobic barrier is the result of its ‘bricks and mortar’ design; dead corneocytes with highly cross-linked protein membranes (‘bricks’) lie within a metabolically active lipid layer synthesised by keratinocytes (‘mortar’). Terminal differentiation of keratinocytes relies on the keratin filaments being aggregated and this is, in part, mediated by filaggrin. Mutations of the filaggrin gene are found in icthyosis vulgaris and in some patients with atopic eczema (p. 1245). The skin is a barrier against physical stresses. Cell-to-cell attachments must be able to transmit and dissipate stress, a function performed by desmosomes. Diseases that affect desmosomes, such as pemphigus (p. 1256), result in blistering due to keratinocyte separation.

Functional anatomy and physiology • 1213

oestrogens reducing it. In animals, sebum is important for hair waterproofing but its role in humans is unclear. Sweat glands Eccrine sweat glands develop in the second trimester and are also epidermal invaginations found all over the body. Their coiled ducts open directly on to the skin surface. They play a major role in thermoregulation and, unusually, are innervated by cholinergic fibres of the sympathetic nervous system. Eccrine glands of the palms and soles are innervated differently and are activated in the telogen around 3 months. The length of hair at different sites reflects the differing lengths of anagen. Sebaceous glands Sebaceous glands are epidermal downgrowths, usually associated with hair follicles and composed of modified keratinocytes. The cells of the sebaceous gland (sebocytes) produce a range of lipids, discharging the contents into the duct around the hair follicle. Sebum excretion is under hormonal control, with androgens increasing it (as do progesterones, to a lesser degree) and Fig. 29.1 Structure of normal skin. Anchoring filament (laminin 332) Basement membrane Epidermis Desmosome (desmoglein-1 and 3, desmoplakin) Tonofilaments (keratins 5 and 14) Hemi-desmosome (BP230, type XVII collagen, α6β4 integrin, plectin) Anchoring fibrils (collagen VII) Basal keratinocyte Basal cell membrane Lamina lucida (laminin-1) Lamina densa (type IV collagen) Sublamina densa Epidermis Dermis Stratum corneum (keratin layer) Granular layer Prickle cell layer Basal layer Hair shaft Langerhans' cell Melanocyte Keratinocytes containing keratins 1 and 10 Keratinocytes containing keratins 5 and 14 Epidermis Dermis Subcutis Eccrine sweat duct Superficial vascular plexus Sebaceous gland Hair sheath Eccrine sweat gland Deep vascular plexus Hair matrix Dermal papilla Subcutaneous vessel

1214 • DERMATOLOGY of the lesion clearer. Granulomatous skin diseases may have a characteristic appearance under diascopy, such as in lupus vulgaris (cutaneous tuberculosis), in which ‘apple jelly nodules’ are typically seen on diascopy. Skin biopsy Skin biopsy is a mainstay investigation in dermatology and can be used in a range of dermatological presentations. In the most common scenario, a skin biopsy is undertaken in order to obtain tissue on which to perform standard histopathology. However, tissue may also be subjected to a variety of staining and culture techniques, including immunostaining. Histopathological examination of skin biopsies is especially ‘fight or flight’ response. Apocrine sweat glands are restricted to the axillae and the mammary and genital areas, are connected to hair follicles and are not involved in thermoregulation. Nails Fingernail growth commences at approximately 8 weeks of gestation and is complete by 32 weeks. Toenails develop slightly later. The anatomy of the nail apparatus is covered later in the chapter (p. 1260). Blood vessels and nerves Human skin has a plentiful blood supply, arranged in superficial and deep plexuses consisting of arterioles, arterial and venous capillaries, and venules. The upper plexus in the papillary dermis communicates with the lower plexus at the junction between the dermis and the subcutis. Capillary loops arise from terminal arterioles in the horizontal papillary plexus. Blood vessels are supplied by sympathetic and parasympathetic nerves, with the relative contributions of the pathways differing by site. Sympathetic signals are important in mediating autonomic-induced vasoconstriction. The blood supply of skin is far greater than that required for normal skin physiology and reflects the importance of skin in thermoregulation. Functions of the skin The skin has many functions, all of which can be affected by disease (Box 29.1). Skin changes associated with ageing are shown in Box 29.2. Investigation of skin disease Magnifying glass A hand-held or freestanding magnifying lens used under good lighting conditions (ideally daylight) is valuable for examination of the skin. Wood’s light Wood’s light is a long-wavelength UVA/short-wavelength visible (violet) light source that can be used in various ways. In hypopigmentation, such as in vitiligo, it can help in appreciating the extent of disease. In pigmented conditions, such as melasma, it can determine whether pigmentation is mainly epidermal (sharp cut-off under Wood’s lamp) or mixed epidermal and dermal (ill-defined cut-off). Wood’s lamp can also be used to help with the diagnosis of some fungal infections because of their characteristic fluorescence. Dermatoscopy and diascopy Dermatoscopy (also known as dermoscopy and epiluminescence microscopy) is increasingly performed with hand-held dermatoscopes. What makes dermatoscopy unique is the fact that it allows visualisation through contact of a glass plate on the instrument with a liquid film applied to the skin, or through special optics to allow non-contact dermatoscopy, enabling deeper structures to be seen without interference from reflection and refraction of light in the epidermis. Diascopy is simply pressing on the lesion with a glass slide. This provides some of the effect of dermatoscopy, but is mainly used to remove blood from vascular lesions to make the appearance 29.1 Functions of the skin Function Structure/cell involved Protection against: Chemicals, particles, desiccation Stratum corneum Ultraviolet radiation Melanin produced by melanocytes and transferred to keratinocytes Stratum corneum hyperproliferation Antigens, haptens Langerhans’ cells, lymphocytes, mononuclear phagocytes, mast cells, dermal dendritic cells Microorganisms Stratum corneum, Langerhans’ cells, mononuclear phagocytes, mast cells, dermal dendritic cells Maintenance of fluid balance Prevents loss of water, electrolytes and macromolecules Stratum corneum Shock absorber Strong, elastic and compliant covering Dermis and subcutaneous fat Sensation Specialised nerve endings mediating pain and withdrawal Itch leading to scratch and removal of a parasite Metabolism Detoxification of xenobiotics, retinoid metabolism, isomerisation of urocanic acid Predominantly keratinocytes Temperature regulation Eccrine sweat glands and blood vessels Protection, and fine manipulation of small objects Nails Hormonal Steroidogenesis, testosterone synthesis and conversion to other androgenic steroids Hair follicles, sebaceous glands Conversion of thyroxine (T4) to triiodothyronine (T3) Keratinocytes Conversion of 7-dehydrocholesterol to vitamin D Keratinocytes Pheromonal Importance unknown in humans Apocrine sweat glands, possibly sebaceous glands Psychosocial, grooming and sexual behaviour Appearance, tactile quality of skin, hair, nails

Investigation of skin disease • 1215

point being at 96 hours. When interpreting patch test readings, it is important to determine the clinical relevance of any allergic reactions before giving avoidance advice. Photopatch testing is similar to patch testing but investigates delayed hypersensitivity to an agent (usually a sunscreen or a non-steroidal anti-inflammatory drug (NSAID)) after the absorption of UVR. It involves applying substances in duplicate and irradiating one set with UVR (typically UVA, 5 J/cm2), readings then being conducted in a similar manner to patch testing. Prick tests and specific immunoglobulin E testing Prick tests are used to investigate cutaneous type I (immediate) hypersensitivity to various antigens such as pollen, house dust mite or dander. The skin is pricked with commercially available stylets through a dilution of the appropriate antigen solution (p. 86). Alternatively, specific immunoglobulin E (IgE) levels to antigens can be measured in serum. If challenge tests are undertaken for patients with suspected allergy, these must be performed under controlled conditions due to the potential risk of triggering a severe reaction (p. 86). Phototesting Phototesting is extremely valuable in the assessment of suspected photosensitivity. The mainstay investigation is monochromator phototesting, which involves exposing the patient’s back to increasing doses of irradiation using narrow wavebands across the solar spectrum and then assessing responses, using the minimal erythema dose (MED) at each waveband. This is the dose required to cause just perceptible skin reddening and is compared with values for the normal population. If a patient has reduced MED (develops erythema at lower doses than healthy subjects), this indicates abnormal photosensitivity. Thus, monochromator phototesting can be used to determine whether a patient is abnormally photosensitive, which wavebands are involved and how sensitive the patient is (p. 1220). Provocation testing can be performed with a broadband (usually UVA) source to induce rash at a test site (most useful for polymorphic light eruption) and can be helpful for diagnosis. Provocation testing to a variety of light sources, including artificial compact fluorescent lamps, may also be indicated, the latter being most relevant in patients with severe photosensitivity. Patients who are referred for phototherapy will also commonly undergo an MED test, in which they are exposed to a series of test doses of the light source that will be used therapeutically (often narrowband UVB); the MED is determined 24 hours later (or 72–96 hours for the psoralen–ultraviolet A (PUVA) minimal phototoxic dose; p. 1227). This allows treatment regimens to be individualised, based on a patient’s erythemal responses, and may detect abnormal photosensitivity. Blood tests Although most patients presenting with a skin problem do not need blood tests as part of their investigations, there are many systemic diseases that can present with skin features and, indeed, blood tests may also be indicated in the investigation of primary skin disease. A wide range of possible investigations may be required and some examples include haemoglobin, iron studies and thyroid function tests in pruritus or hair loss; autoantibody screening if lupus is suspected; porphyrin plasma scan for skin fragility and hypertrichosis; and hepatitis screening in lichen useful for tumour diagnosis. When a dermatologist or pathologist with dermatopathology expertise is involved, it can also assist in the diagnosis of inflammatory skin diseases. It is rare for histopathology of a previously undiagnosed inflammatory skin disease to provide a diagnosis on its own; clinico-pathological correlation is critical. Most biopsies are stained with haematoxylin and eosin but other stains may be useful in special situations, such as for fungal hyphae, iron or mucin. Direct immunofluorescence can also be undertaken on a fresh skin biopsy, allowing antigen visualisation using fluorescein-labelled antibodies; this is especially important in the diagnosis of autoimmune bullous disorders or connective tissue disease, such as cutaneous lupus. Microbiology Bacteriology Bacterial swabs may identify a causative infective agent. However, organisms identified from the skin surface may not be the cause of the skin disease but instead may simply reflect colonisation of skin that has already been damaged by a primary skin disease. Virology A number of techniques, including immunofluorescence and polymerase chain reaction (PCR), are available to diagnose herpes simplex or herpes zoster viruses from vesicle fluid (p. 106). Mycology Scale, nail clippings (or scrapings of crumbly subungual hyperkeratosis) and plucked hairs can be examined by light microscopy. If potassium hydroxide and a simple light microscope are available, this can be performed in any outpatient clinic. Microbiology laboratories will also routinely undertake microscopy and culture for fungi and yeasts. Patch testing Patch testing is the investigation of choice for delayed, cellmediated, type IV hypersensitivity, which clinically manifests as dermatitis. Potential allergens (see Box 29.22, p. 1247) are applied as patches to the back under occlusion for 48 hours, in vehicles and at concentrations that minimise false-positive and false-negative reactions. After 48 hours the patches are removed and patch-test readings are undertaken at time points of up to 7 days after patch-test application, with the most typical time 29.2 Skin changes in old age • Chronological ageing: due to the intrinsic ageing process. • Photo-ageing: due to cumulative ultraviolet radiation (UVR) exposure and superimposed on intrinsic ageing. • Typical changes: include atrophy, laxity, yellow discoloration, wrinkling, dryness, irregular pigmentation, and thinning and greying of hair. • Causes: age-related alterations in structure and function of the skin, cumulative effects of environmental insults, especially UVR and smoking, cutaneous consequences of disease in other organ systems. • Consequences: reduction in immune and inflammatory responses, reduction in absorption and clearance of topical medications, reduced healing, increased susceptibility to irritants, dermatitis, adverse drug effects (including topical glucocorticoid-induced atrophy and purpura) and diseases such as skin cancer.

1216 • DERMATOLOGY Is it a melanocytic naevus or a malignant melanoma? This is a common clinical scenario and one that it is critical to resolve correctly. • The precise nature of the change should be determined (as above). Listen to the patient and pay attention to subtle changes, as people know their skin well. • If the patient has other pigmented lesions, then these should be examined too, as they may be informative. For example, if the presenting lesion looks different from the others, then suspicion of melanoma is increased; conversely, if the patient has multiple basal cell papillomas, this may be reassuring – although do not be falsely reassured. • Is there a positive family history of melanoma? A suspicious naevus in a patient with a first-degree relative with melanoma probably warrants excision. The ABCDE ‘rule’ is a guide to the characteristic features of melanoma (Box 29.3 and see Figs 29.2 and 29.15), although melanomas should ideally be diagnosed before the diameter is greater than 0.5 cm. Loss of normal skin markings in a pigmented lesion may be suggestive of melanoma. Conversely, normal skin markings and fine hairs dispersed evenly over a lesion are reassuring but do not exclude melanoma. The Glasgow seven-point checklist is another useful guide: • major features: change in size, shape and colour • minor features: diameter > 0.5 cm, inflammation, oozing, bleeding, itch or altered sensation. Patients with one major or one minor feature should be referred for further evaluation. Investigations and management If a benign diagnosis, such as basal cell papilloma, is made on clinical grounds, then the patient can be reassured and the lesion either left or treated: for example, with cryotherapy. If there are concerns about the diagnosis or malignancy is suspected on clinical grounds, then skin biopsy in order to obtain a tissue diagnosis is the usual approach. An incisional biopsy may be indicated, although if the lesion is small, excision may be most appropriate. If significant concern exists about the possibility of malignant melanoma, initial excision with a 2 mm margin would usually be undertaken prior to more definitive management once histology was confirmed. Further management of a changed lesion would, of course, depend on the histology of the diagnostic biopsy. Rash A rash is the other common presentation in dermatology. The main categories of scaly rashes are listed in Box 29.4. The most common type of rash presentation is maculopapular. Diagnosis can often be made on clinical grounds, although a biopsy may be required. planus. These diverse examples emphasise the importance of considering an underlying systemic disease when assessing a patient with a dermatological presentation. Imaging Imaging techniques are not typically required but X-rays, ultrasound, magnetic resonance imaging (MRI) or computed tomography (CT) may occasionally be indicated in specific situations, such as in metastatic melanoma or in a patient presenting with a diagnosis of cutaneous sarcoid. Presenting problems in skin disease The major presentations in dermatology are outlined below. Detail of the underlying disorders is mostly provided in the disease-specific sections further on in the chapter. Lumps and lesions The term lump or lesion is typically used to describe a papule or nodule, although sometimes may refer to a macule or plaque (p. 1211). A new or changing lump is one of the key dermatology presentations. Clinical assessment Detailed history-taking and examination are essential: • Change: Is the lump new or has there been a change in a pre-existing lesion? What is the nature of the change – size, colour, shape or surface change? Has change been rapid or slow? Are there other features – pain, itch, inflammation, bleeding or ulceration (definition of ‘ulcer’: an area from which the epidermis and at least the upper part of the dermis have been lost – see Fig. 29.9, p. 1223)? • Patient: What is the patient’s age? Are they fair-skinned and freckled? Has there been much sun exposure? Have they used sunbeds or lived in sunny climates? Have they used photoprotection? • Site: Is it on a sun-exposed or covered site? The scalp, face, upper limbs and back in men, and face, hands and lower legs in women, are the most chronically sunexposed sites. • Are there other similar lesions? These might include actinic keratoses (see Fig. 29.13, p. 1231) or basal cell papillomas (see Fig. 29.17, p. 1234). • Morphology: Tenderness, size, symmetry, regularity of border, colour, surface characteristics and the presence of features such as crust (definition: dried exudate of blood or serous fluid – see Fig. 29.19, p. 1235), scale (definition: a flake arising from the stratum corneum; any condition with a thickened stratum corneum can cause scaling – see Fig. 29.13, p. 1231) and ulceration must be assessed. Stretching the skin and using a magnifying lens can be helpful, such as for detecting the raised, pearled edge of a basal cell carcinoma (see Fig. 29.11, p. 1229). • Dermatoscopy: This can be used to detect the presence of abnormal vessels, such as in basal cell carcinoma or the characteristic keratin cysts in basal cell papillomas. It is invaluable for assessing pigmented and vascular lesions (Fig. 29.2). 29.3 ABCDE features of malignant melanoma • Asymmetry • Border irregular • Colour irregular • Diameter > 0.5 cm • Elevation irregular (+ Loss of skin markings)

Presenting problems in skin disease • 1217

Fig. 29.2 Dermatoscopy. A A changing lesion. B Dermatoscopy highlights the abnormal pigment network and other features suggestive of melanoma. Excision biopsy confirmed the diagnosis of superficial spreading malignant melanoma (Breslow thickness 0.8 mm). C Another changing lesion. D Dermatoscopy highlights the vascular lacunae of this benign angioma and the patient was reassured. A D C B 29.4 Causes and clinical features of common scaly rashes Diagnosis Distribution Morphology Associated signs Atopic eczema (p. 1245) Face and flexures Poorly defined erythema, scaling Vesicles Lichenification if chronic Shiny nails Infra-orbital crease ‘Dirty neck’ (grey–brown discoloration) Psoriasis (p. 1247) Extensor surfaces Lower back Well-defined Erythematous plaques Silvery scale Nail pitting, onycholysis Scalp involvement Axillae and genital areas often affected Joint involvement Köbner phenomenon (p. 1252) Pityriasis rosea (p. 1251) ‘Fir tree’ pattern on trunk Well-defined Small, erythematous plaques Collarette of scale Herald patch Drug eruption (p. 1265) Widespread Macules and papules Erythema and scale Exfoliation Possible mucosal involvement or erythroderma Pityriasis versicolor (p. 1240) Upper trunk and shoulders Hypo- and hyper-pigmented scaly patches Lichen planus (p. 1252) Distal limbs Flexural aspect of wrists Lower back Shiny, flat-topped, violaceous papules Wickham’s striae White, lacy network on buccal mucosa Nail changes Scarring alopecia Köbner phenomenon Tinea corporis (p. 1240) Asymmetrical Often isolated lesions Erythematous, often annular plaques Peripheral scale (sometimes pustules) Expansion with central clearing Possible nail, scalp, groin involvement Secondary syphilis (p. 337) Trunk and proximal limbs Palms and soles Red macules and papules, which become ‘gun-metal’ grey History of chancre Systemic symptoms, e.g. malaise and fever

1218 • DERMATOLOGY Blisters A blister is a fluid-filled collection in the skin. The term vesicle is used for small lesions and bulla for larger lesions (p. 1211). Blistering occurs due to loss of cell adhesion within the epidermis or subepidermal region (see Fig. 29.1). The clinical presentation depends on the site or level of blistering within the skin, which in turn reflects the underlying cause (p. 1254). There are a limited number of conditions that present with blisters (Box 29.5): • Intact blisters are not often seen if the split is high in the epidermis (below the stratum corneum), as the blister roof is so fragile that it ruptures easily, leaving erosions (definition: an area of skin denuded by complete or partial loss of the epidermis). This occurs in pemphigus foliaceus, staphylococcal scalded skin syndrome (see Fig. 29.20, p. 1236) and bullous impetigo. • If the split is lower in the epidermis, then intact flaccid blisters and erosions may be seen, as occurs in pemphigus vulgaris and toxic epidermal necrolysis (see Fig. 29.41, p. 1254). • If the split is subepidermal, then tense-roofed blisters are seen. This occurs in bullous pemphigoid (see Fig. 29.42, p. 1256), epidermolysis bullosa acquisita and porphyria cutanea tarda (see Fig. 29.52, p. 1264). • If there are foci of separation at different levels of the epidermis, as in dermatitis (p. 1244), then multilocular bullae made up of coalescing vesicles can occur. Clinical assessment Important aspects of the history include: • Age at onset and duration of rash. Atopic eczema often starts in early childhood and psoriasis between 15 and 40 years, and both may be chronic. Infective or druginduced rashes are more likely to be of short duration and the latter to occur in relation to drug ingestion. Duration of individual lesions is also important, as in urticaria, for example. • Body site at onset and distribution. Flexural sites are more typically involved in atopic eczema, and extensor surfaces and scalp in psoriasis. Symmetry is often indicative of an endogenous disease, such as psoriasis, whereas asymmetry is more common with exogenous causes, such as contact dermatitis or infections like herpes zoster. • Itch. Eczema is usually extremely itchy and psoriasis may be less so. • Preceding illness and systemic symptoms. Guttate psoriasis may be precipitated by a β-haemolytic streptococcal throat infection; almost all patients with infectious mononucleosis (p. 241) treated with amoxicillin will develop an erythematous maculopapular eruption; a history of chancre at the site of inoculation may be elicited in a presentation of secondary syphilis; malaise and arthralgia are common in drug eruptions and vasculitis. The morphology of the rash and the characteristics of individual lesions are important (Box 29.4). Investigations and management It is important to have a short differential diagnosis based on clinical assessment in order to direct investigations. For example, in psoriasis, no investigations may be needed and initial management with patient counselling and topical therapies may suffice. If the diagnosis is unclear, then a diagnostic skin biopsy and other targeted investigations based on the clinical picture may be required. An initial management plan should also be implemented. For example, in a child presenting with a rash that has features suggestive of impetigo, skin and nasal swabs should be performed and, once these have been taken, topical or systemic antibiotics should be introduced, depending on clinical extent of disease, and management should be adjusted accordingly, dependent on investigation findings and clinical course. In contrast, if a patient presents with a maculopapular rash shortly after introduction of a new drug, then drug withdrawal, diagnostic biopsy, full blood count, including eosinophil count, and liver and renal function tests, in parallel with topical emollients and glucocorticoids, may be indicated. Fig. 29.3 A systematic approach to the diagnosis of blistering diseases. (TEN = toxic epidermal necrolysis) Think of immunobullous causes Bullous pemphigoid, pemphigus, linear IgA disease, bullous lupus Systematic approach to the diagnosis of blistering diseases Exclude infection Herpes simplex, varicella zoster, Staphylococcus aureus Consider common diseases in which blisters are uncommon Peripheral oedema, cellulitis, allergic contact dermatitis, other eczemas Remember blisters in drug eruptions Fixed drug eruptions, erythema multiforme, vasculitis, TEN 29.5 Causes of acquired blisters Localised Generalised Vesicular Herpes simplex Herpes zoster Impetigo Pompholyx Eczema herpeticum* Dermatitis herpetiformis Acute eczema Bullous Impetigo Cellulitis Stasis oedema Acute eczema Insect bites Fixed drug eruption Toxic epidermal necrolysis* Erythema multiforme Stevens–Johnson syndrome* Bullous pemphigoid Pemphigus* Epidermolysis bullosa acquisita Lupus erythematosus Porphyria cutanea tarda Pseudoporphyria Drug eruptions *Usually with mucosal involvement too.

Presenting problems in skin disease • 1219

Medical condition Cause of pruritus Treatment* Liver disease Central opioid effect Elevation in bile salts may contribute Naltrexone Colestyramine Rifampicin Sedative antihistamines UVB Renal failure Unknown; uraemia contributes UVB Oral activated charcoal Haematological disease Anaemia Polycythaemia rubra vera Lymphoma Laukaemia Myeloma Iron deficiency Unknown (often aquagenic pruritus) Unknown Iron replacement Endocrine disease Diabetes mellitus Increased infection risk, e.g. candidiasis, tinea Treatment of infection Medical condition Cause of pruritus Treatment* Thyrotoxicosis Hypothyroidism Carcinoid syndrome (p. 678) Unknown Unknown 5-HT-mediated HIV infection Infection, infestation Treatment of infection Eosinophilic folliculitis Local corticosteroids, UVB Seborrhoeic dermatitis Anti-pityrosporal treatment Unknown UVB Malignancy Unknown Psychogenic Unknown Psychotherapy, anxiolytics, antidepressants *In addition to specific treatment of the primary condition and symptomatic treatments, such as emollients. (5-HT = 5-hydroxytryptamine, serotonin; UVB = ultraviolet B) 29.7 Secondary causes of pruritus synonymous; however, ‘pruritus’ is often used when itch is generalised. Itch can arise from primary cutaneous disease or be secondary to systemic disease, which may cause itch by central or peripheral mechanisms. Even when the mechanism is peripheral, there are not always signs of primary skin disease. The nerve endings that signal itch are in the epidermis or near the dermo-epidermal junction. The underlying mechanisms of itch are not fully understood. Transmission is by unmyelinated slow-conducting C fibres through the spinothalamic tract to the thalamus and then the cortex. Aδ fibres also seem to be involved in transmitting signals to the spinal cord, and the heat-sensitive transient receptor potential (TRP) channels 1–4 are important. There is an inhibitory relationship between pain and itch. Scratching may relieve the symptom of itch after the sensation has ceased and this is either by stimulation of ascending sensory pathways that inhibit itch-transmitting neurons at the spinal cord (Wall’s ‘gate’ mechanism), or by direct damage to cutaneous sensory nerves. The mechanisms of itch in most systemic diseases remain unclear. The itch of kidney disease, for example, may be mediated by circulating endogenous opioids. The clinical observation that peritoneal dialysis helps reduce itch more frequently than haemodialysis is consistent with this, with smaller molecules generally being dialysed more readily if the peritoneal membrane is used rather than a dialysis machine membrane. Clinical assessment It is important to determine whether skin changes are primary (a process in the skin causing itch) or secondary (skin changes caused by rubbing and scratching because of itch). This requires a thorough history and examination, sometimes with investigations, to exclude systemic disease. Many common primary skin disorders are associated with itch (Box 29.6). If itch is not connected with primary skin disease, other causes should be considered (Box 29.7). These include liver diseases (mainly cholestatic diseases, such as primary biliary cirrhosis), malignancies (generalised itch may be the presenting feature Clinical assessment Detailed history-taking and examination are critical. A history of onset, progression, mucosal involvement, drugs and systemic symptoms should be sought. Clinical assessment of the distribution, extent and morphology of the rash should be made. The Nikolsky sign is useful: sliding lateral pressure from a finger on normal-looking epidermis can dislodge and detach the epidermis in conditions with intra-epidermal defects, such as pemphigus and toxic epidermal necrolysis. A systematic approach to diagnosis is required (Fig. 29.3). Investigations and management Investigations and initial management will be guided by the clinical presentation and differential diagnosis, and are described in more detail under the specific diseases. For example, an initial approach may include directed investigations, such as incisional diagnostic skin biopsy for histology and direct immunofluorescence, indirect immunofluorescence and other targeted blood tests or skin swabs. Management should be based on the likely diagnosis and begin in parallel with investigations, until the diagnosis is confirmed. Itch Itch describes the unpleasant sensation that leads to scratching or rubbing. The terms ‘itch’ and ‘pruritus’ are 29.6 Primary skin diseases causing pruritus Generalised pruritus • Scabies • Eczemas • Pre-bullous pemphigoid • Urticarias • Xeroderma of old age • Psoriasis Localised pruritus • Eczemas • Lichen planus • Dermatitis herpetiformis • Pediculosis • Tinea infections

1220 • DERMATOLOGY Photosensitivity Cutaneous photosensitivity is an abnormal response of the skin to UVR or visible radiation. The sun is the natural source but patients may also be exposed to artificial sources of UVR through the use of sunbeds and/or phototherapy (p. 1227). Chronic UVR exposure increases skin cancer risk and photo-ageing (p. 1215). Acute exposure can induce erythema (redness) as a normal response (Fig. 29.5). However, abnormal photosensitivity occurs when a patient reacts to lower doses than would normally cause a response, either with a heightened erythemal reaction or the development of a rash. Photo-aggravated skin diseases are exacerbated by sunlight but not caused by it. The main photosensitive and photo-aggravated diseases are listed in Box 29.9. Fig. 29.4 An overall approach to the investigation and management of itch (pruritus). Investigate for underlying causes of itch (Box 29.7) Itch (pruritus) Itch plus rash Primary skin disease Diagnose and manage underlying skin disease (Box 29.6) Only secondary changes of excoriation due to itch Itch, no rash of lymphoma), haematological conditions (generalised itch in chronic iron deficiency or water contact-provoked (aquagenic) intense itch in polycythaemia), endocrine diseases (including hypo- and hyperthyroidism), chronic kidney disease (in which severity of itch is not always clearly associated with plasma creatinine concentration) and psychogenic causes (such as in ‘delusions of infestation’). Itch is common in pregnancy and may be due to one of the pregnancy-specific dermatoses. Making a correct diagnosis is particularly important in pregnancy, as some disorders can be associated with increased fetal risk (Box 29.8). Investigations and management Investigations should be directed towards finding an underlying cause and there will be a different approach for itch with rash, as opposed to itch with no signs of primary skin disease (Fig. 29.4). If there are no signs of primary skin disease, investigations should be undertaken to exclude systemic disease or iatrogenic causes. Psychogenic itch should be considered only if organic disease has been ruled out. There are no consistently effective therapies to suppress itch, and so establishing the underlying cause is critical. If a clear-cut diagnosis cannot be made, non-specific approaches can be used for symptom relief. These include sedation, often with H1 receptor antihistamines, along with emollients and counter-irritants (such as topical menthol-containing preparations). UVB phototherapy is useful for generalised itch due to a variety of causes but the only randomised controlled study of efficacy is in chronic kidney disease. Other treatments include low-dose tricyclic antidepressants (probably through similar mechanisms to those involved when these drugs are used for chronic pain) and opiate antagonists. If a psychogenic itch is considered likely, antidepressants and/or cognitive behavioural therapy may be effective. Itch of any cause can be severe and its potentially major adverse effects on quality of life are not always fully appreciated. Assessments of impact on quality of life, such as Dermatology Life Quality Index (DLQI) scores, are essential. 29.8 Causes of pruritus in pregnancy Diagnosis Pregnancy, gestation and features Treatment Polymorphic eruption of pregnancy (pruritic urticarial papules and plaques, PUPP) Typically first pregnancy and uncommonly recurs 3rd trimester, after delivery Polymorphic urticated papules and plaques, start in striae Chlorphenamine, emollients Topical glucocorticoids Acute cholestasis of pregnancy (p. 1284) 3rd trimester and commonly recurs in subsequent pregnancies Abnormal liver function tests Increased fetal and maternal risk Emollients Chlorphenamine Colestyramine UVB Early delivery Pemphigoid gestationis Any stage, often 2nd trimester and commonly recurs in subsequent pregnancies Urticated erythema, blistering initially periumbilical Characteristic histology and immunofluorescence Topical or oral glucocorticoids Prurigo gestationis 2nd trimester Excoriated papules Emollients Topical glucocorticoids Chlorphenamine UVB Pruritic folliculitis 3rd trimester Sterile pustules on trunk Topical glucocorticoids UVB (UVB = ultraviolet B)

Presenting problems in skin disease • 1221

and UVA1 (340–400 nm). UVA2 behaves biologically more like UVB, and UVA1 can be used therapeutically for several skin conditions, such as morphoea and eczema. Patients with photosensitivity diseases can be abnormally sensitive to UVB, UVA, visible light (over 400 nm) or, commonly, a combination of wavebands. UVB is absorbed by window glass, whereas UVA and visible light are transmitted through glass. Clinical assessment Taking a careful history is essential, as the patient may not have the rash when assessed. Seasonal pattern and distribution of rash are important. Key sites are the face (particularly nose, cheeks and forehead), top of ears, neck (Fig. 29.7), bald scalp, back of hands and forearms. Sparing is often seen under the chin and nose, behind the ears, on the upper eyelids and the distal digits – as we normally walk about with our eyes open and fingers flexed! It can be misleading if there is covered site involvement. Patients who are sensitive to UVA and visible light may be affected through clothing. These patients commonly experience perennial symptoms and may not be aware of the association with daylight exposure. Other photosensitive conditions, such as actinic prurigo or chronic actinic dermatitis, may also involve covered sites. Sparing of habitually exposed sites, such as the face and back of hands, occurs most commonly in polymorphic light eruption (PLE) and is called the ‘hardening phenomenon’. Importantly, some conditions, such as solar urticaria, develop rapidly after sunlight exposure, whereas others, such as cutaneous lupus, can take several days to evolve. Investigations and management If photosensitivity is suspected, the patient should be referred to a specialist centre for monochromator phototesting (p. 1215), if feasible. Other investigations will often include provocation, Sunlight consists mainly of visible light, and the UVR component is divided into three wavebands (Fig. 29.6), according to the Commission Internationale de l’Eclairage (CIE): • UVC (200–280 nm), which is absorbed by ozone and does not reach the Earth’s surface. • UVB (280–315 nm), which constitutes less than 10% of UVR exposure but is around 1000-fold more potent than UVA and so accounts for the erythemal ‘sunburning’ effects of sunlight. • UVA (315–400 nm), which is the most abundant UVR component reaching the Earth’s surface. The arbitrary division between UVB and UVA regions is more often considered to be at 320 nm by photobiologists, and the UVA region can be further subdivided into UVA2 (320–340 nm) Fig. 29.5 Sunburn. Acute exposure to ultraviolet radiation results in an erythemal response that peaks 12–24 hours later. Sensitivity depends on the individual’s constitutive skin phototype. 29.9 The photosensitivity and photo-aggravated diseases Cause Condition Clinical features Immunological (previously known as idiopathic) Polymorphic light eruption (PLE) Seasonal, itchy, papulovesicular rash on photo-exposed sites; face and back of hands often spared. Often hours of UVR exposure needed to provoke; lasts a few days; affects about 20% in Northern Europe, more common in young women Chronic actinic dermatitis (CAD) Chronic dermatitis on sun-exposed sites. Most common in elderly males. Predominantly UVB, but also often UVA and visible light photosensitivity. Most also have contact allergies Solar urticaria Immediate-onset urticaria on photo-exposed sites. Usually UVA and visible light photosensitivity. Can occur at any age Actinic prurigo Uncommon, presents in childhood. Often familial, with strong HLA association. Some similarities to PLE, although scarring occurs Hydroa vacciniforme Rare childhood photodermatosis. Varioliform scarring Drugs (variety of mechanisms) Phototoxicity Usually UVA (and visible light) photosensitivity Most common. Exaggerated sunburn and exfoliation. Many drugs such as thiazides, tetracyclines, fluoroquinolones, quinine, NSAIDs Pseudoporphyria NSAIDs, retinoids, tetracyclines, furosemide are examples Photoallergy Usually to topical agents, particularly sunscreens and NSAIDs Metabolic Porphyrias Pellagra Mainly porphyria cutanea tarda and erythropoietic protoporphyria (p. 378). Photo-exposed site dermatitis due to tryptophan deficiency (see Fig. 14.15, p. 378) Photogenodermatoses Xeroderma pigmentosum Rare. Defect in DNA excision repair, abnormal photosensitivity, photo-ageing and skin cancer. There may be neurological features Photo-aggravation of pre-existing conditions Lupus erythematosus Can also be drug-induced (see Box 29.35, p. 1266) Erythema multiforme p. 1264 Rosacea p. 1243 (HLA = human leucocyte antigen; NSAID = non-steroidal anti-inflammatory drug; UVA/UVB = ultraviolet A/B; UVR = ultraviolet radiation)

1222 • DERMATOLOGY mechanism of desensitisation is uncertain. Other approaches may be necessary, depending on disease and severity, and may include antihistamines (useful in two-thirds of patients with solar urticaria) and systemic immunosuppression (sometimes required in the immunological photodermatoses). Patients with photosensitivity are at risk of vitamin D deficiency because of reduced synthesis in the skin and should be advised to optimise dietary vitamin D intake or take supplements (p. 1052). Sunscreens Sunscreens can be divided into two categories: chemical sunscreens, which absorb specific wavelengths of UVR, and physical sunscreens, which reflect UVR and the shorter visible wavelengths (see Fig. 29.6). Sunscreens are now highly sophisticated and most offer protection against UVB and most UVA wavelengths. If a patient is abnormally photosensitive to the longer wavelengths of UVA and the visible part of the spectrum (for example, in cutaneous porphyrias and solar urticaria), then conventional sunscreens are not beneficial and specific reflectant sunscreens are required. Historically, these agents were less cosmetically acceptable due to visible light reflection, but current formulations, some of which are tinted, have reduced this problem. Sunscreen protection levels are described by sun protection factor (SPF). This is the ratio of the dose of UVR required to produce skin erythema in the presence and absence of the sunscreen. A sunscreen of SPF20 means that it would take 20 times as long for a person to develop sunburn in the presence of the sunscreen, as compared to not using it. Therefore, SPF is really a sunburn protection factor and is not a good guide to how well a sunscreen will perform in protecting against other reactions (such as skin pain in erythropoietic protoporphyria or UVR-induced immunosuppression). SPF values are determined under experimental conditions whereas, in practice, people tend to use 25–33% of the amount of sunscreen required to achieve patch or photopatch testing and screening for lupus and the porphyrias (p. 1263). Rarely, investigations such as human leucocyte antigen (HLA) typing in suspected actinic prurigo, or DNA excision repair functional activity or genotyping in suspected xeroderma pigmentosum, may be required. Management depends on the cause. If there is a phototoxic drug or chemical cause, this must be addressed: for instance, by stopping the drug or treating the porphyria. Counselling in regard to sun avoidance is essential: keeping out of direct sun in the middle of the day, covering up with clothing, wearing hats with a wide brim and careful use of high-factor sunscreens. Paradoxically, in some conditions, particularly PLE and solar urticaria, phototherapy can be used to induce ‘hardening’; the Fig. 29.7 Chronic actinic dermatitis. Note the sharp cut-off and sparing behind the ear in the shadow cast by the earlobe (Wilkinson’s triangle). Fig. 29.6 The electromagnetic spectrum. The action spectrum is not well defined for many conditions and, for some, is approximate and may vary between patients. The action spectrum for non-melanoma skin cancer mirrors that for erythema. The action spectrum for melanoma is not known but includes ultraviolet (UV) B. Photoprotection measures vary, depending on condition, although the mainstay always includes behavioural modification, clothing cover and appropriate sunscreen choices. (UVR = ultraviolet radiation) 200 nm 290 nm 320 nm 400 nm Atmospheric ozone Window glass Behavioural avoidance, shelter, clothing Sunscreens γ-rays X-rays UVC UVB UVA Visible Infrared Sunburn (erythema) Pigmentation Skin cancer Skin ageing Porphyria Most photodermatoses Most drug photosensitivity Skin disorders and the main wavelengths involved UVR absorbers or reflectors Wavelength 760 nm UVA2 Grenz rays UVA1

Presenting problems in skin disease • 1223

and subcutis, which may produce the well-known ‘inverted champagne bottle’ appearance. Ulceration, often precipitated by trauma or infection, follows. Venous ulcers typically occur on the medial lower leg (Fig. 29.9). Complications of venous leg ulceration include bacterial colonisation and infection, and contact allergic dermatitis to topical medicaments, dressings and bandages. Lipodermatosclerosis may cause lymphoedema and hyperkeratosis; rarely, a squamous cell carcinoma (SCC) may develop in a long-standing venous ulcer (Marjolin’s ulcer). Leg ulceration due to arterial disease Deep, painful, punched-out ulcers on the lower leg, especially the shin and foot and in the context of intermittent claudication, are the stated SPF. Patient counselling is therefore important with regard to adequate application of sunscreen. All sunscreens offer, at best, partial protection only and are no substitute for modifying behaviour and covering up. Leg ulcers Leg ulcer is not a diagnosis, but a symptom of an underlying disease in which there is complete loss of the epidermis, leaving dermal layers exposed. Ulcers on the lower leg are frequently caused by vascular disease but there are other causes, as summarised in Box 29.10. Clinical assessment A detailed history of the onset and course of leg ulceration and predisposing conditions should be elicited. The site and surrounding skin should be assessed. Varicose veins are often present, although not inevitably. Assessment of the venous and arterial vasculature and neurological examination are critical. The site of ulceration may also help to indicate the underlying primary cause (Fig. 29.8). Full clinical examination is essential as the ulcer may be arising in the context of systemic disease, such as vasculitis. Leg ulceration due to venous disease Varicose veins, a history of deep venous thrombosis and obesity are predisposing factors. Incompetent valves in the deep and perforating veins of the lower leg result in retrograde flow of blood to the superficial system, and a rise in capillary pressure (‘venous hypertension’). Pericapillary fibrin cuffing occurs, leading to impairment of local tissue oxygenation and homeostasis. The first symptom in venous ulceration is often heaviness of the legs, followed by oedema. Haemosiderin pigmentation, pallor and firmness of surrounding skin, and sometimes venous/gravitational eczema (p. 1247) subsequently develop. This progresses to lipodermatosclerosis – firm induration due to fibrosis of the dermis Fig. 29.8 Causes of lower limb ulceration. The main types of leg ulcer tend to affect particular sites. Anterior Posterior Venous Vasculitis Arterial Neuropathic Fig. 29.9 A chronic venous ulcer on the medial lower leg, with surrounding lipodermatosclerosis. 29.10 Causes of leg ulceration Venous hypertension • Sometimes following deep vein thrombosis Arterial disease • Atherosclerosis • Vasculitis • Buerger’s disease Small-vessel disease • Diabetes mellitus • Vasculitis Haematological disorders • Sickle-cell disease • Cryoglobulinaemia • Spherocytosis • Polycythaemia • Myeloma • Waldenström’s macroglobulinaemia • Immune complex disease Neuropathy • Diabetes mellitus • Leprosy (Hansen’s disease) • Syphilis Tumour • Squamous cell carcinoma • Basal cell carcinoma • Malignant melanoma • Kaposi’s sarcoma Trauma • Injury • Factitious

1224 • DERMATOLOGY grafting (such as pinch and mince grafts) may hasten healing of clean ulcers but do not reduce recurrence risk. Leg ulcers can be very persistent. Symptomatic relief, including oral analgesics and sometimes chronic pain management, is important. Once the ulcer has healed, ongoing use of compression hosiery may limit the risk of recurrence. Abnormal pigmentation Loss of skin pigmentation (depigmentation), reduction in pigmentation (hypopigmentation) and increased pigment (hyperpigmentation) are features of a variety of disorders. A detailed history and examination, including use of a Wood’s light, are required to establish the diagnosis. Investigations will depend on the presentation. For example, microscopy of skin scrapings should be undertaken if hypopigmentation is associated with inflammation and scaling; screening for autoimmune disease may be required if vitiligo is suspected; and investigation for endocrine disease or the porphyrias may be appropriate in hyperpigmentation. Further details of the specific conditions are included on page 1257. Hair and nail abnormalities Many conditions affect the skin appendages, particularly hair and nails. Conditions causing hair loss (alopecia) are listed in Box 29.30 (p. 1259). Nail changes may be a marker for systemic disease (e.g. iron deficiency) or be a feature of certain skin conditions (e.g. psoriasis). Acute skin failure Acute skin failure is a medical emergency. Several conditions can cause widespread and acute failure of many skin functions (see Box 29.1, p. 1214), including thermoregulation, fluid balance control and barrier to infection. Many of these conditions involve widespread dilatation of the dermal vasculature and can provoke high-output cardiac failure; they are also associated with increased protein loss from the skin and often from the gut. Many lead to acute skin failure by causing erythroderma (erythema affecting at least 90% of the body surface area), although severe autoimmune blistering diseases and the spectrum of Stevens–Johnson syndrome/toxic epidermal necrolysis (TEN) disease can produce acute skin failure without erythroderma (p. 1254). Clinical assessment Detailed history-taking and full examination are required. Particular attention should be paid to drug history, chronology and history of any preceding skin disease. Eczema, psoriasis, drug eruptions and cutaneous T-cell lymphoma (Sézary’s syndrome, p. 1232) are among the diseases that can either present with, or progress to, erythroderma. Other causes include the psoriasis-like condition, pityriasis rubra pilaris, and rare types of ichthyosis. Erythroderma may occur at any age and is associated with severe morbidity and significant mortality (see Fig. 29.35D, p. 1249). Older people are at greatest risk, especially if they have comorbidities. Erythroderma may appear suddenly or evolve slowly. In dark skin, the presence of pigmentation may mask erythema, giving a purplish hue. Erythrodermic patients are usually systemically unwell with shivering and hypothermia, secondary to excess heat loss. They may also be pyrexial, however, and unable to lose heat due to damage to sweat gland function and sweat duct occlusion. likely to be due to arterial disease. Risk factors include smoking, hypertension, diabetes and hyperlipidaemia. The foot is cold and dusky, and the skin atrophic and hairless. Peripheral pulses are absent or reduced. A vascular surgical assessment should be sought urgently (p. 502). Leg ulceration due to vasculitis Vasculitis can cause leg ulceration either directly through epidermal necrosis due to damage to the underlying vasculature, or indirectly due to neuropathy. Leg ulceration due to neuropathy The most common causes of neuropathic ulcers are diabetes and leprosy. Microangiopathy also contributes to ulceration in diabetes (p. 758). The ulcers occur over weight-bearing areas, such as the heel. In the presence of neuropathy, protection of skin from trauma is essential to prevent ulceration. Investigations Appropriate investigations include: • Full blood count to detect anaemia and blood dyscrasias. • Urea and electrolytes to assess renal function. • Urinalysis for glycosuria. • Bacterial swab if there is a purulent discharge, rapid extension, cellulitis, lymphangitis or sepsis. This can guide antibiotic therapy for secondary infection but pathogenic bacteria are not always the same as those identified from the ulcer surface. • Doppler ultrasound to assess arterial circulation. An ankle systolic pressure to brachial systolic pressure index (ABPI) of below 0.8 suggests significant arterial disease and a vascular surgery opinion should be sought. However, arterial calcification, such as in diabetes, can produce a spuriously high ABPI. Pulse oximetry may also be useful, although ABPI is the preferred investigation if feasible. Management General advice on exercise, weight loss and smoking cessation is important in all cases. Specific management depends on making the correct diagnosis to identify the cause(s) of ulceration. Underlying factors, such as diabetes or anaemia, must be treated. Oedema must be reduced by leg elevation and, if there is no arterial compromise, graduated compression bandaging from toes to knees to enhance venous return and improve healing. Compression bandaging is effective for individuals with an ABPI of more than 0.8 but should be avoided if the ABPI is less than 0.8. If the ulcer is purulent, weak potassium permanganate soaks may help, and exudate and slough can be removed with normal saline or clean water. Dressings do not themselves heal leg ulcers, but can reduce discomfort and odour and, by reducing colonisation by potential pathogens, may reduce the frequency of secondary infection. A variety of dressings may be used, including non-adherent and absorbent (alginates, hydrogels, hydrocolloids) types. The frequency of dressing changes varies; heavily exudative ulcers may need daily dressings, whereas changes once weekly may suffice for drier ulcers. Occasionally, leeches may be used topically for ulcers with heavy adherent exudate. Surrounding eczema should be suppressed with a topical glucocorticoid. Commonly, this is venous eczema, but there should be a low threshold for referral for patch testing, as contact allergy to topical applications is common (p. 1215). Systemic antibiotics are indicated only if there is evidence of infection, as opposed to colonisation. Various techniques of split-thickness

Principles of management of skin disease • 1225

impact of the disease on quality of life and the person’s support network. The psychological impact of chronic skin diseases should not be under-estimated and it is important to remember that psychiatric illness can also manifest as a skin disease, such as in delusions of infestation or trichotillomania. Careful clinical assessment, taking psychological factors into account, is essential and any management strategy must include approaches to address the psychological well-being of the patient. Topical treatments Topical treatments are first-line therapy for most skin diseases and many can be treated effectively by topical therapies alone. Selection of the appropriate active drug/ingredient and vehicle is essential. Ointments are preferred to creams for dry skin conditions, such as chronic eczemas, as they are more hydrating and contain fewer preservatives than creams, and so allergy risk is reduced. However, patients find creams easier to apply and so adherence may be better. Gels and lotions can be easier to use on hair-bearing sites. The molecular weight and lipid–water coefficient of a drug determine its skin penetration, with larger, water-soluble, polar molecules penetrating poorly. In skin disease, if the stratum corneum is impaired – as in eczema – increased drug absorption occurs. Occlusion under dressings also increases absorption. Drugs can be used in different potencies or concentrations, or in combination with other active ingredients, and many are available in more than one formulation. The properties of different vehicles are listed in Box 29.11. Overall, adherence to topical treatments can be problematic, so it is essential for patients to know exactly what is required of them and for regimens to be kept as simple as possible. Emollients, topical glucocorticoids and other selected key topical therapies that are widely used in a diverse range of skin conditions are detailed below. For the more diseasespecific therapies, detailed descriptions are included in the disease sections. Tachycardia and hypotension may be present because of volume depletion. Peripheral oedema is common in erythroderma, owing to low albumin and high-output cardiac failure. Lymph nodes may be enlarged, either as a reaction to skin inflammation or, rarely, due to lymphomatous infiltration. Investigations and management Investigations are required to establish the underlying cause and to identify any systemic impact, such as hypoalbuminaemia and electrolyte disturbances. Skin biopsy may be necessary if the cause is unclear. Regardless of the cause, important aspects of the management of erythroderma include supportive measures to ensure adequate hydration, maintenance of core temperature and adequate nutrition. Insensible fluid loss can be many litres above normal losses. Protein may be lost directly from the skin and through the gut because of the protein-losing enteropathy that often accompanies conditions such as erythrodermic psoriasis. To reduce the risks of infection, any intravenous cannulae should be sited in peripheral veins, if possible. In the initial management of acute erythroderma, urinary catheterisation is often required (for patient comfort and accurate fluid balance monitoring) but catheters should be removed as soon as possible. Frequent application of a simple ointment emollient (such as white soft paraffin/liquid paraffin mix) is usually appropriate. Principles of management of skin disease General measures General measures that apply in all skin diseases include establishment of the correct diagnosis, removal of precipitating or aggravating factors, use of safe, effective treatments and consideration of the patient holistically, taking into account the 29.11 Characteristics of vehicles used in topical treatments Vehicle Definition Use Site Cosmetic acceptability Risk of contact sensitisation Creams Emulsions of oil and water (aqueous cream) Acute presentations Cooling, soothing Well absorbed Mild emollients All sites, including mucous membranes and flexures, but not hair-bearing areas Very good Helps adherence Significant, due to preservatives, antimicrobials and often lanolin Ointments Greasy preparations Insoluble in water (white soft paraffin) Soluble (emulsifying ointment) Chronic dry skin conditions Occlusive and emollient Hydrating Mildly anti-inflammatory Avoid hair-bearing areas and flexures Moderate Low Lotions Water-based Liquid formulations Often antiseptic and astringent (potassium permanganate) Cooling effect Cleans the skin and removes exudates Large areas of the skin and the scalp Good, but can sting if in an alcoholic base Rare Gels Thickened lotions Hydrophilic and hydrophobic bases For specific sites Hair-bearing areas and the face Good Low Pastes Semi-solid preparations consisting of finely powdered solids suspended in an ointment Occlusive, protective Hydrating Circumscribed skin lesions, (psoriasis, lichen simplex chronicus) Any area of skin Often used in medicated bandages Moderate Moderate

1226 • DERMATOLOGY cessation of use. Nevertheless, glucocorticoids are invaluable for many sites, particularly the flexures. Topical glucocorticoids are often formulated in combination with antiseptics, antibiotics or antifungals, and their controlled use may be appropriate in infected eczema or flexural psoriasis. Intralesional injections of glucocorticoids can be used in a variety of indications, including nodular prurigo, keloid scar (definition of ‘scar’: replacement of normal structures by fibrous tissue at the site of an injury, although keloid scar describes a pathological process extending beyond the site of injury), acne cysts and alopecia areata. Anti-infective agents Antiseptics should be considered before antibiotics, as they cover a wide range of organisms and help to reduce the risk of antibiotic resistance. Antibiotics can be used either for their anti-infective properties (p. 1236) or for their anti-inflammatory properties (pp. 1242 and 1244). Topical antiviral and antifungal agents are also widely used for a range of mild skin infections (p. 1239). Calcineurin inhibitors The topical calcineurin inhibitors, tacrolimus and pimecrolimus, can be used to treat eczema and a variety of other conditions, through local cutaneous immunosuppression (p. 1244). Immune response modifiers Topical imiquimod was introduced for the treatment of anogenital warts but can be used for a diverse range of other skin diseases, including actinic keratosis, Bowen’s disease, basal cell carcinoma, lentigo maligna, cutaneous lupus and common and planar warts. Its mechanism of action is via stimulation of endogenous Th2 immune responses and release of cytokines, including interferon-gamma (IFN-γ). It can cause significant inflammation, requiring dose adjustments, but subclinical disease may respond to treatment. Dressings A ‘wound’ covering is called a dressing. Box 29.13 shows the indications for their use. The active agent, vehicle and ‘wound’ type should be considered. Wet lesions should be treated with Emollients These are mainstays in the treatment of eczema, psoriasis and many other conditions, and are used to moisturise, lubricate, protect and ‘soften’ skin. They are essentially vehicles without active drug and are available in many formulations: creams, ointments, gels and bath, shower and soap substitutes. White soft paraffin is the most effective and is widely used. Topical glucocorticoids Glucocorticoids are available in a variety of formulations, potencies and strengths, most commonly as creams and ointments (Box 29.12). Selection of the correct product depends on the condition being treated, body site and duration of expected use. Mild topical glucocorticoids are used in delicate areas, such as the face or genitals, and close supervision of glucocorticoid use at these sites is required. In contrast, very potent glucocorticoids may be required under occlusion for chronic resistant disease such as nodular prurigo. Adverse cutaneous effects of chronic glucocorticoid use include atrophy (definition: an area of thin, translucent skin caused by loss of epidermis, dermis or subcutaneous fat – Fig. 29.10), striae (definition: linear, atrophic, pink, purple or white bands caused by connective tissue changes – Fig. 29.10), petechiae and purpura (definition: haemorrhagic macules or papules caused by extravasated blood – see p. 1211) and telangiectasiae (definition: visible dilatations of small cutaneous blood vessels – see Fig. 29.11A), increased risk of infection and systemic absorption, causing Cushingoid features and suppression of the hypothalamic–pituitary–adrenal axis. However, under-treatment with glucocorticoids is more common than over-treatment in routine clinical practice. In general, the lowest potency of glucocorticoid should be used for the shortest period to gain control of the disease; this can be achieved by initial use of a more potent glucocorticoid, with reduction in potency or frequency of application as control is gained. Tolerance or tachyphylaxis can develop with chronic use, so intermittent courses of treatment are advised. Caution is required with glucocorticoids in psoriasis, as rebound, unstable or pustular psoriasis can occur with sudden Fig. 29.10 Striae and atrophy induced by excess prolonged potent topical glucocorticoid use. UK trade names are given in brackets. 29.12 Potencies and strengths of commonly used topical glucocorticoid preparations Mild • Hydrocortisone 0.5%, 1%, 2.5% • Hydrocortisone 1% and fusidic acid 2% (Fucidin H) Moderate • Clobetasone butyrate 0.05% (Eumovate) • Betamethasone valerate 0.025% (Betnovate-RD) • Fluocinolone acetonide 0.00625% (Synalar 1 : 4) Potent • Betamethasone valerate 0.1% (Betnovate) • Betamethasone valerate 0.1% and clioquinol 3% (Betnovate-C) • Fluocinolone acetonide 0.025% (Synalar) • Hydrocortisone butyrate 0.1% (Locoid) • Mometasone furoate 0.1% (Elocon) Very potent • Clobetasol propionate 0.05% (Dermovate)

Principles of management of skin disease • 1227

on local antimicrobial prescribing guidelines. Several antibiotics, such as tetracyclines, erythromycin and co-trimoxazole are used predominantly for their anti-inflammatory effects in indications such as acne vulgaris, bullous pemphigoid and pyoderma gangrenosum. Antihistamines A range of H1 and H2 receptor antagonists are used in dermatology. For diseases in which histamine in the skin is relevant (such as urticaria), non-sedating antihistamines should be given: for example, fexofenadine or cetirizine. For pruritic conditions such as eczema, the sedating effect of antihistamines like hydroxyzine or chlorphenamine is important. However, antihistamines are widely used in older patients for the symptom of pruritus due to a variety of causes such as xeroderma, metabolic impairment, malignancy or concomitant drugs. Sedating antihistamines should be used with caution in older patients, as they may increase the risk of falls and accidents in the home, with disastrous consequences. Careful choice of drug and dose is therefore essential. Leukotriene receptor antagonists, such as montelukast, may be added to antihistamine regimes. Retinoids Oral retinoids are used in a range of conditions, including acne, psoriasis and other keratinisation disorders. They promote differentiation of skin cells and have anti-inflammatory effects. Isotretinoin (13-cis-retinoic acid) is widely used for moderate to severe acne (p. 1243). Acitretin can be effective in psoriasis and other keratinisation disorders, such as ichthyosis, as can alitretinoin (9-cis-retinoic acid) in hand and foot eczema and bexarotene in cutaneous T-cell lymphoma. Adverse effects of retinoids include dryness of the skin and mucous membranes, abnormalities in liver function or hepatitis, increase in serum triglycerides (levels should be checked before and during therapy) and mood disturbances. Alitretinoin and bexarotene can cause hypothyroidism. Systemic retinoids are teratogenic and must be prescribed along with a robust form of contraception. Females must have a negative pregnancy test before, during and after therapy, and pregnancy must be avoided for 2 months after stopping isotretinoin and 2 years after stopping acitretin. Immunosuppressants Systemic glucocorticoids, particularly prednisolone, are widely used in inflammatory skin diseases, such as eczema, immunobullous disease and connective tissue disorders. Methotrexate, azathioprine and mycophenolate mofetil are effective in eczema and psoriasis either alone or as glucocorticoid-sparing agents. Further details on the mechanism of action, adverse effects and monitoring requirements for these agents are provided on page 1004, although it is important to be aware that there may be different approaches to treatment regimens and doses between specialties for some drugs. For example, in dermatology, methotrexate is used in a once-weekly regimen, with doses of up to 25 mg per week, depending on the response (p. 1004). Hydroxycarbamide is an alternative immunosuppressant to methotrexate in psoriasis, but appears to be less effective and the risk of myelosuppression is greater. Ciclosporin (p. 1005) has a rapid onset of action and is effective in inducing clearance of psoriasis and eczema. Monitoring of blood pressure and renal function is required. Ciclosporin should be used only with caution after phototherapy, particularly PUVA, because of the wet dressings. Paste bandages can be used in conjunction with topical emollients and glucocorticoids to soothe and cool, ease pruritus and scratching, and reduce inflammation. Dressings for venous leg ulcers are described on page 1224. Phototherapy and photochemotherapy Ultraviolet radiation (UVR) treatments (most commonly, narrowband ultraviolet B and psoralen–ultraviolet A (PUVA)) are used in the management of many different diseases. The best evidence for their efficacy is in psoriasis, atopic eczema, vitiligo and chronic urticaria, although there is also evidence that UVB is helpful in treating generalised itch associated with chronic kidney disease and a range of other diverse skin conditions. Psoralens are natural photosensitisers found in a number of plants. They intercalate between the strands of DNA and, on excitation with UVA, cross-link the DNA strands. Psoralens are therefore prodrugs that are activated only in skin that is exposed to UVA. Psoralens can also be applied topically in a bath before irradiation with UVA (bath PUVA) or can be applied in creams or gels for localised topical PUVA. PUVA is a more complex treatment than UVB and has more adverse effects; in particular, cumulative exposure to PUVA increases the risk of skin cancer, particularly squamous cell carcinoma. Therefore, PUVA is generally used for poor responders to UVB, or in diseases such as plaque-stage cutaneous T-cell lymphoma or pityriasis rubra pilaris, where it is the phototherapy of first choice. Phototherapy or PUVA may be offered as a whole-body or localised treatment. Longer-wavelength UVA1 (340–400 nm) is also used for several conditions, particularly the fibrosing skin diseases such as morphoea, where efficacy has been shown and there is a lack of other well-proven therapies. The evidence base for its place in the management of several diseases, such as eczema, is not fully proven and availability of UVA1 is mainly through centres of specialist expertise. Systemic therapies General information is provided here for drugs used in a range of skin diseases; details of other drugs are provided in diseasespecific sections. Antibiotics Antibiotics are generally used for their anti-infective properties, particularly for staphylococcal and streptococcal skin infections. In these indications, the correct antibiotic should be selected, based on bacterial sensitivity and patient factors. As examples, oral flucloxacillin may be indicated for clinically infected eczema, intravenous flucloxacillin for cellulitis, and clarithromycin for a patient with a staphylococcal carbuncle who is penicillin-allergic. Optimal therapeutic doses and courses must be chosen, based 29.13 Indications for dressings • Protection • Symptomatic relief from pain or itch • Maintenance of direct application of topical treatment • Possible improvement in healing time • Reduction of exudate • Reduction of odour

1228 • DERMATOLOGY affecting epidermis and upper dermis, such as benign naevi and skin tags. Mohs’ micrographic surgery Mohs’ micrographic surgery is employed to ensure adequate tumour excision margins, while conserving unaffected tissue. It is most commonly used for basal cell carcinoma (p. 1229). Non-surgical treatments Cryotherapy Cryotherapy is a destructive treatment using liquid nitrogen to cause cell-wall and membrane destruction and cell death. Liquid nitrogen can be applied either with a cotton bud or, more effectively, with a spray gun. A wide variety of conditions can be treated but it is essential for the correct diagnosis to be made first, if necessary by diagnostic biopsy. Cryotherapy should not be used to treat melanocytic naevi. Benign lesions, such as viral warts and basal cell papillomas, respond well, and cryotherapy can also be effective for actinic keratoses, Bowen’s disease or superficial non-melanoma skin cancer. Malignant indications require more vigorous treatment, usually with two cycles, and this is normally carried out in secondary care. Considerable inflammation, blistering and pigmentary change, particularly hypopigmentation, can occur. Caution is required to avoid damage to tendons and nerves, especially when using cryotherapy on digits. Laser therapy Laser therapy involves treatment with monochromatic light. Skin components (chromophores), such as haemoglobin and melanin, absorb specific wavelengths of electromagnetic radiation, and these wavelengths can therefore be used to destroy these targets selectively and to treat certain skin disorders. Lasers targeting haemoglobin are employed for vascular abnormalities, such as spider naevi, telangiectasiae and port-wine stains, and lasers targeting melanin can treat benign pigmentary disorders or pigment in tattoos or drug-induced hyperpigmentation (for example, secondary to minocycline). Melanin lasers can also be used for hair removal if the hair is pigmented. Light delivery in short pulses restricts damage to the treated site. The carbon dioxide laser emits infrared light that is absorbed by water in tissues and can therefore be used for destructive purposes. The depth of effect can be controlled, such that the carbon dioxide laser is widely employed for resurfacing in photorejuvenation or acne scarring. Significant morbidity is associated with this destructive laser, although this may be minimised with fractionated regimens, and general anaesthesia is usually required. Photodynamic therapy Photodynamic therapy (PDT) is widely used in dermatology, predominantly for actinic keratoses, Bowen’s disease and superficial basal cell carcinoma (p. 1229). Radiotherapy and grenz (Bucky) ray therapy Radiotherapy can be employed for several skin conditions, including non-melanoma skin cancer or lentigo maligna that is not suitable for surgical treatment, but its use in dermatology has declined. Scarring and poikiloderma can occur at treated increased risk of skin cancer. Long-term use of ciclosporin is not advised. Dapsone is an immunomodulator and may be used in diseases in which neutrophils are implicated, such as dermatitis herpetiformis (p. 1256). Haemolysis, methaemoglobinaemia and hypersensitivity can occur, and monitoring is required (pp. 123 and 269). Hydroxychloroquine is of particular value in cutaneous lupus. More details on the mechanism of action, adverse effects and monitoring requirements are provided on page 1005. Biological therapies Biological inhibitors of pro-inflammatory cytokines, including tumour necrosis factor alpha (TNF-α) inhibitors, ustekinumab (an antibody to the p40 component of interleukin (IL)-12 and IL-23), guselkumab (an antibody to IL-23), secukinumab and ixekizumab (antibodies to IL-17A) and brodalumab (an antibody to the IL-17 receptor) are effective treatments for psoriasis. Rituximab, which causes depletion of B cells, may be used in pemphigus vulgaris. More details on the dosages, mechanism of action and adverse effects of these agents are provided on page 1006. Omalizumab, a monoclonal antibody directed against immunoglobulin E (IgE), was introduced for allergic asthma but may also have a role in non-allergic diseases, such as treatment-resistant urticaria (pp. 86 and 572). Intravenous immunoglobulin, pooled from donor plasma, may be used in the treatment of dermatomyositis (p. 1039) and occasionally may be indicated in other dermatological diseases. Dermatological surgery Most dermatological surgical procedures are performed under local anaesthetic. Knowledge of local anatomy is essential, particularly the locations of vessels and nerves. In certain sites, such as the fingers, soles of the feet and nose, local cutaneous nerve blocks are useful. Some sites are associated with particular risks, such as keloidal scarring on the upper trunk of young patients, unsightly scars over the scapulae, and poor healing and risk of ulceration following procedures on the lower legs. Excision biopsy This involves surgical removal of the lesion followed by histological examination. The most common indication is suspicion of malignancy. The lesion and line of excision should be marked out and the margin of excision decided before the procedure. It is important to excise down to the appropriate anatomical plane. Depending on body site, a range of procedures can minimise the resulting defect. Healing by secondary intention may also achieve good cosmetic results. Curettage Curettage involves using a small, spoon-shaped implement (curette), not only as a definitive treatment but also to obtain histology. Curettage does not preserve tissue architecture very well, however, and it may be difficult to distinguish between dysplasia and invasive malignancy. It can be an effective treatment for basal cell papillomas, actinic keratoses, intra-epidermal carcinoma and superficial basal cell carcinoma. Shave excision Shave excision using local anaesthetic may be used for simple and effective treatment of raised superficial benign skin lesions

Skin tumours • 1229

(more than 150), which is immunosuppressive, are also at increased risk of skin cancer, particularly SCC. Despite UVB being a complete carcinogen, there is no evidence at present that UVB phototherapy significantly increases skin cancer risk, although ongoing vigilance is required. Ionising radiation, notably radiotherapy, thermal radiation and chemical carcinogens, such as arsenic or coal tar, can increase NMSC risk, particularly SCC. A role for oncogenic human papillomaviruses in SCC development is also implicated, particularly in immunosuppressed patients, where viral DNA is detected in more than 80% of tumours. Chronic inflammation is a risk factor for SCC, which may arise in chronic skin ulcers (p. 1223), discoid lupus erythematosus or vulgaris, and the scarring genetic skin disease dystrophic epidermolysis bullosa (see Box 29.25, p. 1254), in which up to 50% of patients develop SCC. Malignant tumours Basal cell carcinoma The incidence of NMSC has increased dramatically in recent decades and basal cell carcinoma (BCC) accounts for more than 70% of cases. In Europe, the ratio of BCC to SCC is 4–5 : 1 in immunocompetent patients. It is a malignant tumour that rarely metastasises; it is thought to derive from immature pluripotent epidermal cells and is composed of cells with similarities to basal layer epidermis and appendages. Lesions typically occur at sites of moderate sun exposure, particularly the face, and are slow-growing. The incidence increases with age and males are more commonly affected. Lesions may ulcerate and invade locally; hence the term ‘rodent ulcer’. Clinical features Early BCCs usually present as pale, translucent papules or nodules, with overlying superficial telangiectatic vessels (nodular BCC). If untreated, they increase in size and ulcerate, to form a crater with a rolled, pearled edge and ectatic vessels (Fig. 29.11). There may be some pigmentation or a cystic component. A superficial multifocal type can occur, frequently on the trunk, and may be large (up to 10 cm in diameter); often there are multiple lesions. Superficial BCC usually presents as a red/ brown plaque or patch with a raised, thread-like edge, which is sites, although these are minimised if fractionated regimens are chosen. Superficial radiotherapy is now rarely employed to treat benign dermatoses. Even more superficial ionising radiation (grenz, or Bucky, rays) can be useful for localised dermatoses that are having severe effects on quality of life, if conventional treatments have been inadequate; for example, it may avoid the need for systemic immunosuppression in a patient with severe recalcitrant localised scalp psoriasis. Skin tumours Pathogenesis Skin cancer is the most common malignancy in fair-skinned populations. It is subdivided into non-melanoma skin cancer (NMSC) and melanoma. NMSC is further subdivided into the most common skin cancer, basal cell carcinoma (BCC), and squamous cell carcinoma (SCC). The latter has precursor noninvasive states of intra-epithelial carcinoma (Bowen’s disease, BD) and dysplasia (actinic keratosis, AK). Melanoma is much less common than NMSC, but because of its metastatic risk it is the cause of most skin cancer deaths. UVR is a complete carcinogen and is the main environmental risk factor for skin cancer, which is much more common in countries with high ambient sun exposure, such as Australia. Skin cancer risk also increases if an individual migrates to such a country when young, particularly if less than 10 years of age. Epidemiological evidence supports a close link between chronic UVR exposure and risk of SCC and AK, and a modest link between sun exposure and BCC risk. Melanoma usually arises on sites that are intermittently exposed to UVR, and episodes of sunburn have been implicated as a risk factor for melanoma. There is good evidence to show that sunbed exposure is also a risk for both melanoma and NMSC, particularly when exposure starts in adolescence and early adult life. Strategies to reduce sun exposure are therefore important for skin cancer prevention, with reliance mainly on behavioural modification, covering up and judicious sunscreen use. Indeed, there is evidence to show that sunscreen use reduces naevi development in children, and in adults regular sunscreen use reduces the risk of AK and SCC and is likely also to have preventative roles in melanoma and BCC development. There are identifiable genetic predispositions for some skin cancers, such as in xeroderma pigmentosum, an autosomal recessive condition caused by an inherited defect in DNA excision repair (pp. 1221 and 1321), or basal cell naevus (Gorlin’s) syndrome, an autosomal dominant disorder caused by lossof-function mutations affecting the PTCH1 tumour suppressor genes, with consequent activation of the Hedgehog pathway (p. 1321). Interestingly, the Hedgehog pathway is also almost invariably activated in sporadic BCC, which usually contain somatic mutations in PTCH1 and less commonly in the SMO gene, which lies in the same signalling pathway. The genetics of SCC are heterogeneous and less clearly defined, with several mutations and pathways implicated, including TP53, CDKN2A/p16, NOTCH, EGFR and the MAPK signalling pathways. Interestingly, many of the mutations seen in SCC also occur in the pre-cancers AK and BD. The genetics of melanoma are discussed on page 1232. Cutaneous immune surveillance is also critical and immunosuppressed organ transplant recipients have a greatly increased risk of skin cancer, particularly SCC. Interestingly, patients who have received high treatment numbers of PUVA Fig. 29.11 Basal cell carcinoma. A A nodular BCC showing the translucent nature of the tumour and the abnormal arborising vessels. B An ulcerated BCC showing the raised, rolled edge. A B

1230 • DERMATOLOGY be required, although follow-up may be appropriate as not all tumours that are incompletely excised recur. However, this is not recommended for tumours at high-risk sites or for infiltrative morphoeic BCC, where complete excision is advisable. Cryotherapy may be effective for BCC but can cause blistering and scarring, so is best suited to small, superficial lesions at low-risk sites. Radiotherapy can be invaluable for large BCC lesions in frail patients but is less commonly used because of the risk of scarring. Medical therapies can be used to treat low-risk BCC, particularly when surgery is not appropriate for a patient. Topical immunomodulators, such as imiquimod, are effective for low-risk BCC and may be particularly useful for patients who are not able to attend a hospital clinic setting but are able to apply a topical preparation at home over a 6-week period. Imiquimod usually induces a prominent inflammatory reaction and patients should be advised that dose adjustments may be required. Topical 5-fluorouracil can also be effective for low-risk small lesions of superficial BCC, but is rarely used since it usually provokes an intense inflammatory reaction. Intralesional interferon-alpha2b has been used for BCC but multiple treatments and high cost preclude its regular use. PDT is an effective treatment for low-risk, predominantly superficial BCC, as well as AK and BD. Usually, topical porphyrin PDT is employed, which involves application of a porphyrin prodrug to the lesion to be treated. The prodrug is taken up and converted by the cell’s haem cycle to protoporphyrin IX, a photosensitiser. This is photochemically activated by visible (normally red) light, usually delivered by a light-emitting diode (LED), in the presence of oxygen, causing the production of reactive oxygen species, which cause destruction of treated tissue. The photosensitiser is taken up preferentially by diseased skin, and adverse effects in normal skin are minimised. PDT is at least as effective as cryotherapy and surgery for superficial BCC and may be preferred at sites of poor healing, such as the lower leg, or where cosmetic outcome is important. PDT is not as effective as surgery for long-term clearance of nodular BCC but can be considered if surgery is not appropriate. Pain during irradiation may occur during PDT, although adjustments to the irradiation regime can reduce discomfort. PDT is usually undertaken in the outpatient clinic setting and is well suited to frail elderly patients who are not able to undertake treatment with topical agents at home. Rarely, advanced BCC may be locally invasive or even metastasise. Major advances have been made in targeted drug development, and Hedgehog pathway inhibitors, such as vismodegib and sonidegib, can be used effectively for disease control and palliation in this setting, although there may be significant associated drug-induced toxicity. Squamous cell carcinoma Squamous cell carcinoma (SCC) is a malignancy that arises from epidermal keratinocytes and is the second most common skin cancer, occurring most frequently in elderly males and smokers. There is a close association between cumulative UVR exposure and SCC risk, with most SCC lesions occurring on chronically sun-exposed sites in white populations and often arising at sites of field-change carcinogenesis, with coexistent precursors of AK and BD commonly evident. In the immunosuppressed patient population, such as organ transplant recipients, SCC is the most common skin cancer and its incidence is dramatically increased, particularly in association with the duration of immunosuppression often best seen by stretching the skin; this helps to distinguish it from Bowen’s disease. Less commonly, a morphoeic, infiltrative BCC presents as a poorly defined, slowly enlarging, sclerotic yellow/grey plaque. Diagnosis and management The diagnosis is often obvious clinically, based on the features mentioned above, although a diagnostic confirmatory biopsy may be required prior to definitive treatment. Management depends on the characteristics of the tumour and on patient factors, including comorbidities and patient wishes. Essentially, treatment will be either surgical or, in some cases, medical (Box 29.14). Surgical excision, ideally with a 4–5 mm margin, is the treatment of choice, with a cure rate of approximately 95%. Curettage and cautery may also be effective for selected lesions. Management of infiltrative morphoeic BCC and/or lesions at difficult sites, such as around the eye, may require more complex techniques such as Mohs’ micrographic surgery to ensure adequate tumour excision margins, while conserving unaffected tissue. This involves processing of frozen sections of all margins in stages (usually on the same day) until all the tumour is removed. The procedure is time-consuming (so can be difficult for elderly, frail patients) and requires particular surgical and pathology skills, but is associated with the highest long-term cure rates, with 98–99% clear at 5-year follow-up. If a surgical approach is used for management of BCC and the primary tumour is not completely excised, re-excision may 29.14 Management of non-melanoma skin cancer and pre-cancer Basal cell carcinoma • Excision results in the lowest recurrence rates • Mohs’ micrographic surgery is effective for high-risk BCC • Medical treatments are often appropriate for low-risk superficial tumours in patients with comorbidities • Cryotherapy and topical 5-fluorouracil can be used for superficial BCC • Topical photodynamic therapy and topical imiquimod are both effective in superficial BCC • BCC in patients with Gorlin’s syndrome should not be treated with radiotherapy • Hedgehog pathway inhibitors can induce clinical response in patients with advanced inoperable BCC Squamous cell carcinoma • Excision is the treatment of choice for invasive SCC • Most recurrences or metastases occur within 5 years • Medical management is not usually considered for invasive SCC Carcinoma in situ (Bowen’s disease) • For single/few lesions on good healing sites, cryotherapy, curettage, photodynamic therapy, topical imiquimod and 5-fluorouracil are options • For multiple lesions and/or poor healing sites such as the lower leg, photodynamic therapy, where feasible, is the treatment of choice, although topical 5-fluorouracil or imiquimod is an alternative Actinic keratosis • For single/few lesions on good healing sites, cryotherapy, curettage, 5-fluorouracil/salicylic acid and ingenol mebutate are options. especially if hyperkeratotic • For multiple lesions/field change, conventional or daylight photodynamic therapy, topical 5-fluorouracil, imiquimod or diclofenac in hyaluronic acid gel may be effective

Skin tumours • 1231

Actinic keratosis Actinic keratoses (AK) are scaly, erythematous lesions arising on chronically sun-exposed sites. Histology shows dysplasia, although the diagnosis of typical AK is usually made on clinical grounds (Fig. 29.13). They are common in fair-skinned people who have had significant sun exposure, are often multiple and increase with age. The prevalence is much higher in Australia than in the UK and some surveys have shown a prevalence of more than 50% in those over 40 years old. The rate of progression to SCC is less than 0.1% and spontaneous resolution is possible. However, SCC can also arise de novo and without progression from AK. Increase in size, ulceration, bleeding, pain or tenderness can be indicative of transformation into SCC. Management Several treatments are available for AK (see Box 29.14). Emollients and photoprotection, including high-factor sunscreens, may suffice for mild disease. Single or low numbers of lesions of AK can be effectively treated with cryotherapy. Hyperkeratotic lesions may be treated with the antimetabolite 5-fluorouracil, combined with salicylic acid, or may require curettage and cautery. Multiple lesions require field-directed therapy; 5-fluorouracil is widely used in this setting and is effective but topical imiquimod is an alternative. Diclofenac in a hyaluronic acid gel base can also be used topically for low-grade maintenance control of AK, the rationale for its use being the over-expression of cyclooxygenase (COX)-2 in AK lesions. Topical ingenol mebutate can also be used and has the advantage of a short treatment regime, although severe inflammation may be induced. PDT is widely used for field-change multiple AK, with high efficacy rates; it is at least as effective as cryotherapy or 5-fluorouracil. The relative selectivity of treatment allows subclinical disease to be treated, while sparing normal skin. A regimen using daylight to activate the photosensitiser is increasingly used worldwide for extensive mild AK, with high efficacy rates, comparable to hospital-based PDT but without the need for specialised equipment and allowing patients to be treated at home. and the degree of sun exposure and damage accrued pretransplant. The risk of SCC is also increased in HIV infection. Furthermore, SCC arising in the immunosuppressed is more likely to behave aggressively or to metastasise. Clinical features The tumours usually occur on chronically sun-exposed sites, such as bald scalp, tops of ears, face and back of hands. The clinical presentation may be diverse, ranging from rapid development of a painful keratotic nodule in a pre-existing area of dysplasia (Fig. 29.12) to the de novo presentation of an erythematous, infiltrated, often-warty nodule or plaque that may ulcerate. The clinical appearance depends on histological grading; well-differentiated tumours more often present as defined keratotic nodules (Fig. 29.12), whereas poorly differentiated tumours tend to be ill defined and infiltrative, and may ulcerate. SCC has metastatic potential; some tumours, such as those on lips and ears and in immunosuppressed patients, behave more aggressively and are more likely to metastasise to draining lymph nodes. Management Early diagnosis is important and complete surgical excision is the usual treatment of choice (see Box 29.14). Standard excision with a 4–6 mm margin is advised and the cure rate is approximately 90–95%. Mohs’ surgery is an option but is used less frequently for SCC than for BCC. High-risk SCC should be treated aggressively, with a wider margin of excision of at least 6 mm where feasible. This may include larger, thicker lesions, tumours at sites where metastases are more likely, such as the ear, lip or non-sun-exposed sites, and those occurring in the immunosuppressed and/or with histology showing the tumour to be poorly differentiated, with evidence of lymphatic, vascular or perineural involvement or a high mitotic index. Such patients and those with metastatic disease require management via a multidisciplinary team. In patients who are at high risk for further SCC, systemic retinoids may have a role in reducing the rate of SCC development, but rapid appearance of tumours occurs on drug cessation. Occasionally, curettage and cautery may be appropriate if the tumour is small and low-risk and either surgical excision is contraindicated or the patient is unwilling to proceed. Radiotherapy may be indicated if surgical excision is not feasible. Cryotherapy and topical non-surgical therapies are not usually used in invasive SCC because of risk of recurrence and metastasis. Fig. 29.12 Squamous cell carcinoma. A A centrally keratinous, symmetrical, well-differentiated SCC. Clinically, this could be confused with keratoacanthoma. B An SCC arising from an area of epidermal dysplasia. A B Fig. 29.13 Actinic keratosis. Close-up of a hyperkeratotic AK on the ear.

1232 • DERMATOLOGY radiation, the synthetic retinoid bexarotene, interferon-alpha, extracorporeal photopheresis and systemic anti-lymphoma chemotherapy regimens may be needed. Management of advanced disease invariably requires a multidisciplinary team approach, with collaboration between dermatologists, pathologists and haematological oncologists. Melanoma Melanoma is a malignant tumour of epidermal melanocytes. While only 4% of skin cancers are melanomas, they account for 80% of skin cancer deaths. There has been a steady rise in the incidence of melanoma in fair-skinned populations over recent decades, with the highest figures in Australasia. Primary prevention and early detection are essential, as therapy for advanced and metastatic disease remains unsatisfactory. Pathophysiology Risk factors for melanoma include fair skin, freckles, red hair, number of naevi and sunlight exposure. The type of sunlight exposure is under debate but intermittent exposure, such as recreational time in the sun, sunburn and sunbed use, is implicated. Patients with multiple atypical naevi (dysplastic naevus syndrome) and fair-skinned people, often with variant alleles in the melanocortin-1 gene, are at increased risk of melanoma. A family history of melanoma increases the risk but a strong family history is unusual. Rarely, autosomal dominant inheritance of melanoma with incomplete penetrance can occur due to mutations in CDKN2A, which encodes the p16 tumour suppressor protein. In these patients, the lifetime risk of melanoma is more than 50%. Several other susceptibility genes and potential genetic targets for therapeutic intervention in advanced disease have also been identified. Clinical features Melanoma can occur at any age and site and in either sex, but typically affects the leg in females and back in males. It is rare before puberty. The classification of invasive malignant melanoma is shown in Box 29.15. Early lesions may be in situ and pre-invasive before becoming invasive melanoma with metastatic potential. Any change in naevi or development of new lesions should be assessed to exclude malignancy and, for this, the dermatoscope is invaluable (see Fig. 29.2, p. 1217). Real-time non-invasive imaging techniques are being investigated as tools to assist in diagnosis but are largely experimental. If there is any doubt, excision is advised. Superficial spreading melanoma Superficial spreading melanoma (SSM) is the most common type in Caucasians. It usually presents as a slowly enlarging, macular, pigmented lesion, with increasing irregularity in shape and pigment; this superficial, radial growth phase can last for Bowen’s disease Clinical features Bowen’s disease (BD) is the name given to an intra-epidermal carcinoma that usually presents as a slowly enlarging, erythematous, scaly plaque on the lower legs of fair-skinned elderly women (Fig. 29.14) but other sites can also be involved. It can be confused with eczema or psoriasis, but is usually asymptomatic and does not respond to topical glucocorticoids. It may also be hard to distinguish from superficial BCC. Transformation into SCC occurs in 3% or less. Diagnosis Incisional biopsy is usually undertaken to confirm the diagnosis. This shows an intra-epidermal carcinoma with no invasion through the basement membrane. Histology may also be obtained by curettage but this does not allow distinction from invasive SCC to be made, due to loss of tissue orientation and architecture. Management While curettage or excision may be appropriate in some settings, non-surgical therapies are generally preferred (see Box 29.14), especially on the lower legs. PDT, in particular, may be advantageous for BD on the lower leg because of relative selectivity of treatment and sparing of normal tissue, thus reducing the risk of poor healing and ulceration at this vulnerable site. Given the low risk of malignant transformation, the option of no active treatment may also be appropriate for some elderly frail patients. Cutaneous lymphomas The most common form of cutaneous T-cell lymphoma is mycosis fungoides (MF). This can persist for years in patch and plaque stages, often resembling eczema or psoriasis. Only sometimes does it progress through to nodules and finally a systemic stage, Sézary’s syndrome. B-cell lymphomas, on the other hand, usually present as nodules or plaque-like tumours. The diagnosis of cutaneous T-cell lymphoma requires a high index of suspicion, particularly in patients thought to have unusual recalcitrant forms of eczema or psoriasis. Treatment is symptomatic and there is no evidence that it alters prognosis. In the early stages of cutaneous T-cell lymphoma, systemic or local glucocorticoids may be indicated; alternatively, narrowband UVB phototherapy (for patch-stage MF) or PUVA (for plaque-stage MF) may be used. Once lesions have moved beyond plaque stage, localised radiotherapy, electron beam Fig. 29.14 Intra-epidermal carcinoma (Bowen’s disease). The lower leg is a common site and lesions are often treated non-surgically. 29.15 Classification of cutaneous malignant melanoma Melanoma without metastatic potential • Melanoma in situ • Lentigo maligna Melanoma with metastatic potential • Superficial spreading melanoma • Nodular melanoma • Acral lentiginous melanoma • Subungual melanoma • Lentigo maligna melanoma

Skin tumours • 1233

tumour (the maximal depth from epidermal granular cell layer to deepest tumour cells) is critical for management and prognosis. The presence of ulceration may lead to under-estimation of the Breslow thickness. The mitotic rate and the presence or absence of any evidence of lymphovascular or perineural involvement should also be ascertained. The clinical staging of melanoma extent is essential, in order to establish whether disease is primary and localised, or if there is nodal or metastatic spread. Wide excision of melanoma with a low risk of metastasis (stage 1 disease, Breslow thickness < 1 mm) with a 1 cm clear margin is accepted practice. The margin of excision for more advanced disease is controversial, although a 2–3 cm margin for thicker tumours is generally advised as an attempt to reduce risk of local recurrence. There is no evidence that more radical surgery with 4–6 cm margins is beneficial. The majority of tumours can be excised without the need for grafting. For tumours with a Breslow thickness of 1 mm or more, a sentinel lymph node biopsy should be considered. This is usually performed at the time of wider excision and involves injection of radiolabelled blue dye at the site of the primary melanoma, allowing identification of the draining ‘sentinel’ node by radioscintigraphy; this sentinel node is then removed and examined in detail by histology, immunohistochemistry and/or PCR of melanocyte gene products to look for tumour deposits. If the biopsy is positive, local lymphadenectomy is usually offered. This procedure provides additional prognostic information but there is no evidence that it improves survival. Local recurrence of disease and palpable local node involvement should be treated surgically. Localised cutaneous metastases or in transit disease may be amenable to palliation with electrochemotherapy if there is no evidence of widespread metastatic disease. Despite the major advances in treatment options for advanced melanoma, the prognosis for metastatic disease remains poor and treatment options are palliative. Genetic developments have facilitated the introduction of tumour-targeted treatments for advanced, unresectable and/or metastatic disease, such as the B-Raf and c-Kit kinase inhibitors for patients expressing these gene mutations, notably dabrafenib and vemurafenib, with demonstrable clinical responses. Immunotherapy with ipilimumab, which blocks T-cell activation by inhibiting CTLA-4, alone or in combination with the programmed cell death (PD1) pathway blockers nivolumab or pembrolizumab, provides clinically meaningful improvements in quality of life and survival to patients with advanced disease. Standard chemotherapy may also be used in some cases of metastatic disease, although outcomes are poor. Other biological and gene therapies and vaccines are also being investigated. It is important for patients with advanced melanoma to be managed through a multidisciplinary team in order to optimise care and facilitate their inclusion in clinical trials. All patients should be advised regarding ongoing photoprotection, with sensible behaviour in the sun, covering up, wearing hats and high-factor sunscreen use. However, evidence has shown that despite patients with melanoma being advised to photoprotect, many follow this advice only for the first year following diagnosis, thus emphasising the need for ongoing reinforcement of guidance with regard to photoprotection. It is also prudent to advise patients who are photoprotecting to optimise oral vitamin D through diet and/or supplements. Prognosis Patients with a primary tumour of less than 1 mm Breslow thickness have more than a 95% chance of disease-free survival approximately 2 years. Subsequently, the lesion may become palpable and this is indicative of a vertical growth phase, with dermal invasion; when this occurs, the tumour has the potential to invade lymphatics and vessels and to become metastatic (Fig. 29.15A). Approximately 50% of melanomas arise from a pre-existing naevus. Nodular melanoma Nodular melanoma is most common in the fifth and sixth decades, particularly in men and on the trunk (Fig. 29.15B). This may account in part for the increased mortality rates from melanoma in men, as these are tumours with greater metastatic risk. They often present as a rapidly growing nodule that may bleed and ulcerate. Nodular melanomas may be heavily pigmented, or relatively amelanotic and erythematous, and be confused with benign vascular lesions. A rim of pigmentation may, however, be seen under the dermatoscope. Lesions may develop de novo or from a pre-existing naevus or SSM. Lentigo maligna melanoma This arises from a prolonged pre-invasive phase termed lentigo maligna. It occurs as a very slowly expanding, pigmented, macular lesion, usually on photo-exposed head and neck sites of elderly patients; histology shows in situ changes only. This phase may last for several years before a nodule of invasive melanoma develops in a proportion of cases (lentigo maligna melanoma). Acral lentiginous or palmoplantar melanoma This accounts for only approximately 10% of melanomas in fair-skinned races and is more common in dark-skinned people, in whom it is responsible for 50% of cases. This indicates that UVR exposure may not be implicated in acral melanoma risk. Subungual melanoma This form of melanoma is rare. It may present as a painless, proximally expanding streak of pigmentation arising from the nail matrix, and progresses to nail dystrophy and involvement of the adjacent nail fold (Hutchinson’s sign). Diagnosis and management The diagnosis is made by excision biopsy of a suspicious lesion. The initial biopsy should include a 2 mm margin, followed up where possible by wider excision if the diagnosis is confirmed. Occasionally, radiotherapy or imiquimod may be used for lentigo maligna, if surgery is not feasible. The Breslow thickness of the Fig. 29.15 Superficial spreading melanoma. A A superficial spreading malignant melanoma with a palpable area indicative of vertical growth phase (Breslow thickness 1.3 mm). B A nodular malignant melanoma arising de novo and with Breslow thickness of 3.5 mm. B A

1234 • DERMATOLOGY background skin changes in Fig. 29.12A), become more common with age, and are often referred to as ‘liver spots’ or ‘age spots’. They can vary in colour from light to very dark brown. Distinction from melanoma is essential and histology may be required. Haemangiomas Benign vascular tumours or hamartomas are common and include Campbell de Morgan spots (Fig. 29.17), which present as pink/ red papules on the upper half of the body. They can sometimes be difficult to distinguish from melanocytic lesions, particularly if they are thrombosed or occur on particular sites, such as the lip or genitalia. The dermatoscope is helpful for this (see Fig. 29.2, p. 1217). Basal cell papilloma Basal cell papillomas (also known as seborrhoeic warts or keratoses) are common, benign epidermal tumours (Fig. 29.17). They may be flat, raised, pedunculated or warty-surfaced, and can appear to be ‘stuck on’. They occur in both sexes and with increasing age, and are most common on the face and trunk. The colour may vary from yellow to almost black and the surface may seem ‘greasy’, with pinpoint keratin plugs visible, particularly with a magnifying lens. If there is no doubt about the diagnosis, they can be left alone or treated by cryotherapy or curettage if they are cosmetically troublesome. If there is a suspicion of melanoma, excision or diagnostic biopsy should be undertaken. Melanocytic naevi Melanocytic naevi (moles) are localised benign clonal proliferations of melanocytes. It is thought that they may arise as the result of abnormalities in the normal migration of melanocytes during development. It is quite normal to have 20–50, although, interestingly, individuals with red hair have fewer. Genetic and environmental factors are implicated. Monozygotic twins have higher concordance in naevi numbers than dizygotic twins. Individuals who have had greater sun exposure have higher numbers of naevi. Most melanocytic naevi appear in childhood and early adult life, or during pregnancy or oestrogen therapy. The onset of a new mole is less common after the age of 25 years. Congenital melanocytic naevi occur at or shortly after birth. at 10 years, but this figure drops to approximately 50% for a tumour of greater than 3.5 mm thickness. Survival rates fall to less than 10% for those with advanced nodal or metastatic disease. Benign skin lesions In practice, it is often difficult to distinguish between skin cancer and a benign lesion on clinical grounds; if there is any doubt, biopsy and histology are required. Benign melanocytic naevi and basal cell papillomas, in particular, can often be mistaken for melanoma, even by dermatologists. Keratoacanthoma, while benign, is also commonly considered to be invasive SCC on clinical grounds. Keratoacanthoma This benign tumour has a striking clinical presentation of rapid growth over weeks to months and subsequent spontaneous resolution. It is thought to be associated with chronic sun exposure and most commonly occurs on the central face. The classical appearance is of an isolated dome-shaped nodule often of 5 cm or more in diameter, with a central keratin plug (Fig. 29.16). Clinically and histologically, the lesion often resembles SCC (see Fig. 29.12A). Most are treated surgically, either by curettage and cautery or by excision, to rule out SCC and to avoid the unsightly scar after spontaneous resolution. Freckle Histologically, a freckle (ephelis) consists of normal numbers of melanocytes, but with focal increases in melanin in keratinocytes. They are most common on sun-exposed sites in fair-skinned individuals, particularly children and those with red hair, and on the face. There is a familial tendency. Clinically, freckles are brown macules that darken following UVR exposure. Lentigo A lentigo (plural lentigines) consists of increased numbers of melanocytes along the basement membrane, but without formation of the nests that occur in melanocytic naevi. These lesions usually occur at sites of chronic sun exposure (see the Fig. 29.16 Keratoacanthoma. Fig. 29.17 A typical basal cell papilloma. Note the neighbouring basal cell papillomas and the coincidental benign angiomas (Campbell de Morgan spots).

Common skin infections and infestations • 1235

Acrochordon Acrochordons, or skin tags, are benign pedunculated lesions; they are most common in skin flexures and usually have a very characteristic clinical appearance. However, they may sometimes be confused with melanocytic naevi. Treatment is not required unless there is diagnostic doubt or they are causing symptoms, such as irritation, or for cosmetic reasons. Cryotherapy or snip or shave excision may be appropriate in that situation. Lipoma Lipomas are benign tumours of adipocytes that are characteristically soft and lie more deeply in the skin than epidermal tumours; they are usually diagnosed easily on clinical grounds. A variant, angiolipoma, is typically painful. Treatment is not required unless there is diagnostic doubt or they are symptomatic or cosmetically troublesome, in which case a diagnostic biopsy or surgical excision may be required. Common skin infections and infestations Bacterial infections Impetigo Impetigo is a common and highly contagious superficial bacterial skin infection. There are two main presentations: bullous impetigo, caused by a staphylococcal epidermolytic toxin, and non-bullous impetigo (Fig. 29.19), which can be caused by either Staphylococcus aureus or streptococci, or both together. Staphylococcus spp. are the most common agents in temperate climates, whereas streptococcal impetigo is more often seen in hot, humid areas. All ages can be affected but non-bullous disease particularly affects young children, often in late summer. Outbreaks can arise in conditions of overcrowding Clinical features Acquired melanocytic naevi are classified according to the microscopic location of the melanocyte nests (Fig. 29.18). Junctional naevi are usually macular, circular or oval, and mid- to dark brown. Compound and intradermal naevi are nodules because of the dermal component, and may be hair-bearing. Intradermal naevi are usually less pigmented than compound naevi. Their surface may be smooth, cerebriform, hyperkeratotic or papillomatous. Some individuals have large numbers of naevi, often at unusual sites, such as the scalp, palms or soles, and these may frequently appear ‘atypical’ in terms of variability in pigmentation, size and shape. Some may be very dark or pink and may show a depigmented or inflamed halo. If these naevi are removed, then ‘dysplastic changes’ are often seen. Such naevi are known to occur in some rare families with an inherited melanoma predisposition. However, the significance of such changes in non-familial cases is unclear and there is no consensus on management and follow-up. Although approximately 50% of melanomas arise in pre-existing naevi, most naevi do not become malignant; although a changing naevus must be taken seriously, most will not be melanomas. Malignant change is most likely in large congenital melanocytic naevi (risk may correlate with the size of the lesion) and possibly in families who have been diagnosed as showing large numbers of atypical naevi with a history of melanoma. Diagnosis and management Melanocytic naevi are normal and do not require excision, unless malignancy is suspected or they become repeatedly inflamed or traumatised. Advice on photoprotection is important for fair-skinned individuals with multiple naevi. Blue naevi These are melanocytic naevi in which there is a proliferation of spindled melanocytes relatively deep within the dermis. Light scattering means that the pigment appears blue rather than brown. They may be difficult to distinguish from nodular melanoma and are therefore often excised. Dermatofibroma A dermatofibroma is a characteristically firm, often pigmented, raised lesion, most commonly found on the lower legs. Its aetiology is unclear, although a reactive process secondary to insect bites or trauma is one hypothesis. There is frequently a ring of pigment around the lesion and dimpling when the skin is pinched, reflecting epidermal tethering. Fig. 29.18 Classification of melanocytic naevi. Classification is based on microscopic location of the nests of naevus cells. Junctional Compound Intradermal Fig. 29.19 Non-bullous impetigo.

1236 • DERMATOLOGY Ecthyma Ecthyma is caused by either staphylococci or streptococci, or both together, and is characterised by adherent crusts overlying ulceration. It occurs worldwide but is more common in the tropics. In Europe, it occurs more frequently in children. Predisposing factors include poor hygiene, malnutrition and underlying skin disease, such as scabies. It is commonly seen in drug abusers, and minor trauma can predispose to lesion development. Folliculitis, furuncles and carbuncles Hair follicle inflammation can be superficial, involving just the ostium of the follicle (folliculitis), or deep (furuncles and carbuncles). Superficial folliculitis The primary lesions are follicular pustules and erythema. Superficial folliculitis is often infective, caused by Staph. aureus, but can also be sterile and caused by physical (for example, traumatic epilation) or chemical (for example, mineral oil) injury. Staphylococcal folliculitis is most common in children and often occurs on the scalp or limbs. Pustules usually resolve without scarring in 7–10 days but can become chronic. In older children and adults, they may progress to a deeper form of folliculitis. The condition and poor hygiene or in institutions. A widespread form can occur in neonates. Predisposing factors are minor skin abrasions and the existence of other skin conditions, such as infestations or eczema. In non-bullous impetigo, a thin-walled vesicle develops; it rapidly ruptures and is rarely seen intact. Dried exudate, forming golden crusting, arises on an erythematous base. In bullous disease, the toxins cleave desmoglein-1, causing a superficial epidermal split and the occurrence of intact blisters with clear to cloudy fluid, which last for 2–3 days. The face, scalp and limbs are commonly affected but other sites can also be involved, particularly if there are predisposing factors such as eczema. Lesions may be single or multiple and coalesce. Constitutional symptoms are uncommon. A bacterial swab should be taken from blister fluid or an active lesion before treatment commences. Around one-third of the population is a nasal carrier of Staphylococcus, so swabs from the nostrils should also be obtained. In mild, localised disease, topical treatment with mupirocin or fusidic acid is usually effective and limits the spread of infection. The use of topical antiseptics and soap and water to remove infected crusts is also helpful. Staphylococcal carriage should be treated, with mupirocin topically to the nostrils, if swabs are positive. In severe cases, an oral antibiotic, such as flucloxacillin or clarithromycin, is indicated. If nephritogenic streptococci are isolated then systemic antibiotics should be considered to reduce the risk of streptococcal glomerulonephritis (p. 401). Underlying disease, such as infestations, must be treated and cross-infection minimised. Scarring does not occur but there may be temporary dyspigmentation. Staphylococcal scalded skin syndrome Staphylococcal scalded skin syndrome (SSSS) is a potentially serious exfoliating condition occurring predominantly in children, particularly neonates (Fig. 29.20). It is caused by systemic circulation of epidermolytic toxins from a Staph. aureus infection. The same toxins are implicated in bullous impetigo, which is a localised form of SSSS. The focus of infection may be minor skin trauma, the umbilicus, urinary tract or nasopharynx. The child presents with fever, irritability and skin tenderness. Erythema usually begins in the groin and axillae, and around the mouth. Blisters and superficial erosions develop over 1–2 days and can rapidly involve large areas, with severe systemic upset. Bacterial swabs should be obtained from possible primary sites of infection. A skin snip should also be taken for urgent histology. This is a sample of the superficial peeling skin removed by ‘snipping with scissors’, without the need for local anaesthetic. It shows a split beneath the stratum corneum, and differentiates SSSS from toxic epidermal necrolysis, in which the whole epidermis is affected (see Fig. 29.41, p. 1254). Systemic antibiotics and intensive supportive measures should be commenced immediately. Bacterial swabs from nostrils, axillae and groins should be taken from family members to exclude staphylococcal carriage. Although the acute presentation of SSSS is often severe, rapid recovery and absence of scarring are usual, as the epidermal split is superficial. Toxic shock syndrome This condition is characterised by fever, desquamating rash, circulatory collapse and multi-organ involvement (p. 252). It is caused by staphylococcal toxins and early cases were thought to arise with tampon use. Intensive supportive care and systemic antibiotics are required. Fig. 29.20 Staphylococcal scalded skin syndrome. A Extensive erythema and superficial peeling of the skin. B The condition was rapidly diagnosed by examination of a frozen section of skin snip. A, From Savin JA, Dahl M, Hunter JAA. Clinical dermatology, 3rd edn. Oxford: Blackwell; 2002. A B

Common skin infections and infestations • 1237

has malaise, fever and leucocytosis, and streptococcal serology will often be positive. The face (erysipelas) and legs (cellulitis) are most often affected and the site is hot, painful, erythematous and oedematous. Blistering often occurs and may be haemorrhagic. Regional lymphadenopathy is common. Erysipelas typically has a well-defined edge due to its more superficial level of involvement, whereas cellulitis is typically ill defined. Treatment is usually with intravenous flucloxacillin, with clarithromycin, clindomycin and vancomycin as alternatives for penicillin-allergic patients. Milder cases may be treated with oral antibiotics. If cases are untreated, sequelae include lymphoedema, cavernous sinus thrombosis, sepsis and glomerulonephritis. Mycobacterial infections Mycobacterium leprae infection may involve the skin and its manifestations will be influenced by host immunity, patients with high levels of immunity presenting with paucibacillary Fig. 29.21 Staphylococcal carbuncle. Fig. 29.22 Acute cellulitis of the leg. Note the chronic lymphoedema and the haemorrhagic blistering. Blister fluid was positive for group G streptococci. Fig. 29.23 Erysipelas. Note the blistering and the crusted rash with raised, erythematous edge. The yellow discoloration is due to topical iodine treatment. is often self-limiting and may respond to irritant removal and antiseptics. More severe cases may require topical or systemic antibiotics and treatment of Staph. aureus carrier sites. Deep folliculitis (furuncles and carbuncles) A furuncle (boil) is an acute Staph. aureus infection of the hair follicle, usually with necrosis. It is most common in young adults and males. It is usually sporadic but epidemics occasionally occur. Malnutrition, diabetes and HIV predispose, although most cases arise in otherwise healthy people. Any body site can be involved but neck, buttocks and anogenital areas are common. Infection is often associated with chronic Staph. aureus carriage in the nostrils and perineum, and may be due to resistant strains, such as meticillin-resistant organisms (MRSA). Friction caused by tight clothing may be contributory. Initially, an inflammatory follicular nodule develops and becomes pustular, fluctuant and tender. Crops of lesions sometimes occur. There may be fever and mild constitutional upset. Lesions rupture over days to weeks, discharge pus, become necrotic and leave a scar. If a deep Staph. aureus infection of a group of contiguous hair follicles occurs, this is termed a carbuncle and is associated with intense deep inflammation (Fig. 29.21). This usually occurs in middle-aged men, often with predisposing conditions such as diabetes or immunosuppression. A carbuncle is an exquisitely tender nodule, usually on the neck, shoulders or hips, associated with severe constitutional symptoms. Discharge, necrosis and scarring are usual. Bacterial swabs must be taken and treatment is with anti-staphylococcal antibiotics, e.g. flucloxacillin, and sometimes incision and drainage. Other staphylococcal toxins may also be pathogenic. For example, Panton–Valentine leukocidin-producing Staph. aureus can cause recurrent abscesses (definition: localised collections of pus in cavities) and may be difficult to eradicate. Cellulitis and erysipelas Cellulitis is inflammation of subcutaneous tissue, due to bacterial infection (Fig. 29.22). In contrast, erysipelas is bacterial infection of the dermis and upper subcutaneous tissue (Fig. 29.23), although in practice it may be difficult to distinguish between them. These conditions are most commonly caused by group A streptococci but culture of swabs from affected sites is often negative. There is frequently a source of organism entry, such as an ear infection, varicose eczema/ulcer or tinea pedis, and swabs should also be taken from these sites. Diabetes and immunosuppression are predisposing factors. The patient usually

1238 • DERMATOLOGY characteristic circular erosions (‘pits’) on the soles. It is usually asymptomatic. The bacterium can be identified in skin scrapings and typically occurs in association with hyperhidrosis, which must be treated to prevent recurrence. Treatment is as for erythrasma. Other bacterial skin infections Syphilis and the non-venereal treponematoses are described on pages 337 and 253. There has been a marked increase in incidence of syphilis. Skin signs may be subtle; for example, secondary syphilis may be misdiagnosed as pityriasis rosea. Lesions on palms, soles and mucosae should raise suspicion. Microscopic identification of the spirochaete may be possible and syphilitic serology should be undertaken using enzyme immunoassay or PCR-based techniques, depending on availability. Lyme disease is described on page 255. Viral infections Herpesvirus infections The cutaneous manifestations of the human herpesviruses are described on page 247. Topical antivirals may suffice for prophylaxis or treatment of mild viral disease, such as herpes simplex cold sore virus infection. Systemic antivirals are indicated for significant viral skin disease. For example, systemic aciclovir should be prescribed for eczema herpeticum (see Fig. 11.14, p. 247). Papillomaviruses and viral warts Viral warts are extremely common and are caused by the DNA human papillomavirus (HPV). There are over 90 subtypes, based on DNA sequence analysis, causing different clinical presentations. Transmission is by direct virus contact, in living or shed skin, and is encouraged by trauma and moisture such as in swimming pools. Genital warts are spread by sexual activity and show a clear relationship with cervical and intra-epithelial cancers of the genital area. HPV-16 and 18 appear to inactivate tumour suppressor gene pathways and lead to squamous cell carcinoma of the cervix or intra-epithelial carcinoma of the genital skin (p. 242). Vaccinations are available against HPV-16 and 18 and are recommended for adolescent females before they become sexually active. The relationship between skin HPV and skin cancer is unclear. Individuals who are systemically immunosuppressed – after organ transplantation, for example – have greatly increased risks of skin cancer and HPV infection but a causal link is not certain. Clinical features Common warts are initially smooth, skin-coloured papules, which become hyperkeratotic and ‘warty’. They are most common on the hands (Fig. 29.24) but can occur on the face, genitalia and limbs, and are often multiple. Plantar warts (verrucae) have a slightly protruding rough surface and horny rim, and are often painful on walking. Paring reveals capillary loops that distinguish plantar warts from corns. Other varieties of wart include: • mosaic warts: mosaic-like sheets of warts • plane warts: smooth, flat-topped papules, usually on the face and backs of hands, which may be pigmented and therefore misdiagnosed • facial warts: often filiform • genital warts: may be papillomatous and exuberant. tuberculoid leprosy and those with low immune resistance developing multibacillary lepromatous leprosy. Hypopigmented or erythematous patches, with associated altered or lost sensation, or skin thickening, nodules and infiltration should raise suspicion of a diagnosis of leprosy (p. 267). The skin may also be an extrapulmonary site of involvement in tuberculosis, usually due to infection with Mycobacterium tuberculosis. Skin manifestations depend on the route of infection, previous sensitisation and host immunity. There may be a variety of cutaneous features, including the red–brown scarring inflammatory plaques seen in lupus vulgaris due to direct skin inoculation; scrofuloderma, which describes the skin changes overlying lymph nodes or joints infected with tuberculosis; and the reactive nodular and ulcerated changes seen in patients with high levels of immune response, notably the tuberculids and erythema induratum (Bazin’s disease). On diascopy, an ‘apple jelly’ appearance is typically seen, indicating the granulomatous nature of skin involvement. Granulomas evident on skin biopsy should certainly raise suspicion of a diagnosis of mycobacterial infection. Culture of organisms may be tricky but PCR can assist with diagnosis. Patients should be thoroughly investigated for signs of tuberculosis at pulmonary or other extrapulmonary sites (p. 588). Reactivation of latent tuberculosis is a particular concern for patients receiving treatment with immunosuppressants and biological agents, particularly TNF-α antagonists for conditions such as psoriasis. Vigilance is required in screening and workup of such patients prior to consideration of these therapeutic agents. Other mycobacterial skin infections may occur, such as Mycobacterium marinum, typically seen in those who clean tropical fish tanks. Sporotrichoid spread of granulomatous nodules from the site of inoculation along lymphatics is typical; granulomatous changes are seen on histology and resolution usually occurs with a prolonged course of antibiotics such as doxycycline or minocycline. Resolution may also take place spontaneously or after destructive therapies, such as cryotherapy. Leishmaniasis This protozoan infection may be restricted to the skin or there may be may be systemic features depending on the species, which occur in different geographical areas (p. 281). Necrotising soft tissue infections and anthrax See pages 226 and 266, respectively. Erythrasma Erythrasma is a mild, chronic, localised, superficial skin infection caused by Corynebacterium minutissimum, which is part of the normal skin flora. Warmth and humidity predispose to this infection, which usually occurs in flexures and toe clefts. It is asymptomatic or mildly itchy and lesions are well defined, red–brown and scaly. C. minutissimum has characteristic coralpink fluorescence under Wood’s light. Microscopy and culture of skin scrapings can confirm the diagnosis but are not usually needed if Wood’s light examination is positive. A topical azole (clotrimazole or miconazole) or fusidic acid is usually effective. Oral erythromycin can be used for extensive or resistant disease. Antiseptics can be used to prevent disease recurrence. Pitted keratolysis This is another superficial skin infection caused by Corynebacterium and Streptomyces spp., and possibly other organisms, producing

Common skin infections and infestations • 1239

Orf Orf is a parapoxvirus skin infection and is an occupational risk for those who work with sheep and goats. Inoculation of virus, usually into finger skin, causes significant inflammation and necrosis, which typically resolves within 2–6 weeks. No specific treatment is required, unless there is secondary infection. Erythema multiforme (p. 1264) can be provoked by orf. Other viral exanthems See page 236. Fungal infections Fungal skin infections can be superficial (dermatophytes and yeasts) or, less commonly, deep (chromomycosis or sporotrichosis); the latter are seen more often in tropical climates or in the immunocompromised. Dermatophyte infections (ringworm) are extremely common and usually caused by fungi of the Microsporum, Trichophyton and Epidermophyton species. The fungi can originate from soil (geophilic) or animals (zoophilic), or be confined to human skin (anthropophilic). Dermatophyte infections usually present with skin (tinea corporis), scalp (tinea capitis), groin (tinea cruris), foot (tinea pedis) and/or nail (onychomycosis) involvement (Fig. 29.26). Diagnosis Skin scrapings, hair pluckings or nail clippings must be taken from areas of disease activity – typically, the advancing lesion edge for skin involvement, the crumbling dystrophic nail and subungual hyperkeratosis for nail involvement, and plucked hair from scalp or other affected hair-bearing sites – in order to confirm the diagnosis by microscopy and culture (p. 1215). Management The azoles (ketoconazole, miconazole), triazoles (itraconazole, fluconazole) and triallylamines (terbinafine) are used most widely in fungal skin disease. Topical antifungals such as terbinafine or miconazole may suffice, although systemic treatment (terbinafine, itraconazole or griseofulvin) may be required for stubborn or extensive disease and scalp or nail involvement. Indeed, prolonged courses of systemic treatment may be needed for nail involvement. The fungistatic agent griseofulvin, given orally, is usually used for fungal infection of scalp or nails in children in the UK, as it is the only drug licensed in children for this indication; outside the UK, and in adults, terbinafine is usually the treatment of Management Most viral warts resolve spontaneously, although this may take years and active treatment is therefore often sought. However, asymptomatic warts generally should not be treated. Viral warts are particularly problematic and more recalcitrant to treatment in immunosuppressed patients following organ transplantation. Treatments are destructive. Salicylic acid or salicylic/lactic acid combinations and regular wart paring for several months are the most consistently effective treatments. For certain types of warts, such as filiform facial warts, cryotherapy is generally the treatment of choice, but for common hand and foot warts salicylic acid wart paint should be used first. Cryotherapy is usually the next step and is repeated 2–4-weekly. However, caution is required, particularly on the hands, as over-vigorous cryotherapy can lead to scarring, nail dystrophy and even tendon rupture. Periungual and subungual warts can be problematic and nail cutting and subsequent electrodessication may help. Several other therapies have been used for recalcitrant warts, including topical formaldehyde, podophyllotoxin, trichloroacetic acid, cantharidin, topical or systemic retinoids, intralesional bleomycin or interferon injections, and contact sensitisation with, for example, diphencyprone. Imiquimod and PDT may also be beneficial, particularly for multiple warts in immunosuppressed patients, and laser therapy can have a role in some cases. Molluscum contagiosum Molluscum contagiosum is caused by a DNA poxvirus skin infection. It is most common in children over the age of 1 year, particularly those with atopic dermatitis. It also occurs frequently in immunosuppressed patients, including those with HIV (p. 306). Lesions are dome-shaped, ‘umbilicated’, skin-coloured papules with central punctum (Fig. 29.25). They are often multiple and found at sites of apposition, such as the side of the chest and the inner arm. Spontaneous resolution occurs but can take months. Prior to resolution, they often become inflamed and may leave small, atrophic scars. Destructive therapies may be painful and risk scarring, and the decision not to treat is often sensible. Gentle squeezing with forceps after bathing can hasten resolution. Topical salicylic acid, podophyllin, cantharidin, trichloroacetic acid, cryotherapy and curettage are alternatives. Efficacy with imiquimod has also been reported. Fig. 29.24 Viral wart on the finger. The capillary loops are evident within the warty hyperkeratosis. Periungual sites are common and more difficult to treat. Fig. 29.25 Molluscum contagiosum. Note the central umbilication.

1240 • DERMATOLOGY audouinii (anthropophilic)) shows minimal inflammation; M. canis (from dogs and cats) infections are more inflammatory and can be identified by green fluorescence with Wood’s light. Kerion is a boggy, inflammatory area of tinea capitis, usually caused by zoophilic fungi such as cattle ringworm (T. verrucosum). Onychomycosis This is a fungal infection of the nail plate and the species involved are generally those that cause tinea capitis or tinea pedis. Onychomycosis usually presents with yellow/brown nail discoloration, crumbling, thickening and subungual hyperkeratosis. Usually, some nails are spared, there is asymmetry and toenails are more commonly involved. Candidiasis This is a superficial skin or mucosal infection caused by a yeast-like fungus, Candida albicans (p. 300). Infections are usually not serious, unless the patient is immunocompromised, in which case deeper tissues can be involved (p. 316). The organism has a predilection for warm, moist environments and typical presentations are napkin candidiasis in babies, genital and perineal candidiasis, intertrigo and oral candidiasis. The diagnosis can be confirmed by microscopy and culture of skin swabs, and treatment is with topical or systemic antifungals, such as azoles. Pityriasis versicolor Pityriasis versicolor is a persistent, superficial skin condition caused by various species of the commensal yeast Malassezia, most commonly Malassezia globosa, but sometimes M. sympadialis or M. furfur, It occurs in men and women and in different races. It is found more frequently in warmer, humid climates, and is usually more severe and persistent in the immunocompromised. It is characterised by scaly, oval macules on the upper trunk, usually hypopigmented but occasionally hyperpigmented. Hypopigmentation is more obvious after sun exposure and tanning. The diagnosis can be confirmed by microscopy of skin scrapings, showing ‘spaghetti and meatballs’ hyphae. Treatment with selenium sulphide or ketoconazole shampoos and topical or systemic azole antifungal agents is usually effective, although recurrence is common because these yeasts are skin commensals, and maintenance topical therapy may be required. Altered pigmentation can persist for months after treatment. choice. In addition to systemic antifungals, short courses of systemic or topical glucocorticoid are often used in kerion on the basis of reducing inflammation and possible hair loss. However, glucocorticoid use is controversial, with no good evidence of benefit. Tinea corporis Tinea corporis should feature in the differential diagnosis of a red, scaly rash (p. 1217). Typically, lesions are erythematous, annular and scaly, with a well-defined edge and central clearing. There may also be pustules at the active edge. Lesions are usually asymmetrical and may be single or multiple. The degree of inflammation is dependent on the organism involved and the host immune response. Microsporum canis (from dogs) and Trichophyton verrucosum (from cats) are common culprits. Ill-advised use of topical glucocorticoids can modify the clinical presentation and increase disease extension (tinea incognito). Tinea cruris This is extremely common worldwide and is usually caused by Trichophyton rubrum. Itchy, erythematous plaques develop in the groins and extend on to the thighs, with a raised active edge (Fig. 29.26A). Tinea pedis Tinea pedis or ‘athlete’s foot’ is the most common fungal infection in the UK and USA, and is usually caused by anthropophilic fungi, such as T. rubrum, T. interdigitale and Epidermophyton floccosum. It typically presents as an itchy rash between the toes, with peeling, fissuring and maceration. Involvement of one sole or palm (tinea manuum) with fine scaling is characteristic of T. rubrum infection. Vesiculation or blistering is more often seen with T. mentagrophytes. Tinea capitis This is a dermatophyte infection of scalp hair shafts and is most common in children. It typically presents as an area of scalp inflammation and scaling, often with pustules and partial hair loss (Fig. 29.26B). Infection may be within the shaft (endothrix, most commonly caused by T. tonsurans), causing patchy hair loss with broken hairs at the surface (‘black dot’), little inflammation and no fluorescence with Wood’s light. Infection outside the hair shaft (ectothrix, most commonly caused by Microsporum Fig. 29.26 Dermatophyte infections. A Trichophyton rubrum infection of the groin (tinea cruris). B Microsporum canis infection of the scalp (tinea capitis). A B

Acne and rosacea • 1241

and cervical lymphadenopathy. The diagnosis is confirmed by identifying the living louse or nymph on the scalp or on a black sheet of paper after careful fine-toothed combing of wet hair following conditioner application. The empty egg cases (‘nits’) are easily seen on the hair shaft (p. 1210) and are hard to dislodge. Treatment is recommended for the affected individual and any infected household/school contacts. Eradication in school populations is difficult because of poor adherence and treatment resistance. Topical treatment with dimeticone, permethrin, carbaryl or, less often, malathion in lotion or aqueous formulations may be effective and should be applied twice at an interval of 7–10 days. Rotational treatments within a community may avoid resistance. ‘Wet-combing’ (physical removal of live lice by regular combing of conditioned wet hair – ‘bug busting’) can suffice but may be less effective than pharmacological treatments. Vaseline should be applied to eyelashes/brows twice daily for at least a fortnight. High-temperature washing of clothing and bedding is required. Treatment resistance and recurrence can be problematic. Body lice These are similar to head lice but live on clothing, particularly in seams, and feed on the skin. Poor hygiene and overcrowded conditions predispose. Itch, excoriation (definition: a linear ulcer or erosion resulting from scratching) and secondary infection occur. Dry-cleaning and high-temperature washing or insecticide treatment of clothes are required. Treatment options are as for head lice. For heavy infestation, oral ivermectin may be indicated. Pubic (crab) lice Usually, these are sexually acquired and very itchy. Management is as for head and body lice and whole-body treatment should be undertaken. Pubic hair may need to be shaved. Sexual and other close contacts should also be treated and patients should also be screened for sexually transmitted diseases. Acne and rosacea Acne vulgaris Acne is chronic inflammation of the pilosebaceous units. It is extremely common, generally starts during puberty and has been estimated to affect over 90% of adolescents. It is usually most severe in the late teenage years but can persist into the thirties and forties, particularly in females (Box 29.16). Infestations Scabies Scabies is caused by the mite Sarcoptes scabiei. It spreads in households and environments where there is intimate personal contact. The diagnosis is made by identifying the scabietic burrow (definition: a linear or curvilinear papule, caused by a burrowing scabies mite; p. 234 and Fig. 29.27) and visualising the mite (by extracting with a needle or using a dermatoscope). In small children, the palms and soles can be involved, with pustules. Pruritus is prominent. The clinical features include secondary eczematisation elsewhere on the body; the face and scalp are rarely affected, except in infants. Involvement of the genitals in males and of the nipples commonly occurs. Even after successful treatment, itch can continue and occasionally nodular lesions persist. Topical treatment of the affected individual and all asymptomatic family members/physical contacts is required to ensure eradication. Two applications 1 week apart of an aqueous solution of permethrin or malathion to the whole body, excluding the head, are usually successful. If there is poor adherence, immunosuppression or heavy infestation (crusted ‘Norwegian’ scabies), systemic treatment with a single oral dose of ivermectin is sometimes appropriate. Head lice Infestation with the head louse, Pediculus humanus capitis, is common. It is highly contagious and spread by direct head-tohead contact. Scalp itch leads to scratching, secondary infection Fig. 29.27 Scabies. A Burrows evident on the palm of the hand. B A mite still in its egg, seen on light microscopy of scrapings over a burrow. Note that the mite has only six legs, unlike adult mites, which have eight. A B 29.16 Acne in adolescence • Epidemiology: acne vulgaris is most common between the ages of 12 and 20. It often begins around 10–13 years of age, lasts 5–10 years and usually resolves by age 20–25. • Emotional effects: at all ages acne can have negative effects on self-esteem, but it is especially important to assess how it affects an adolescent. Depression and suicideal ideation may occur. The consequences (whether acne is objectively severe or not) can be devastating, leading to embarrassment, school avoidance, and life-long effects on ability to form friendships, attract partners, and acquire and keep employment. • Treatment: effective treatments aim to improve the condition, prevent worsening (including later scarring) and restore emotional well-being and self-esteem.

1242 • DERMATOLOGY • Acne excoriée: self-inflicted excoriations due to compulsive picking of pre-existing or imagined acne lesions. It usually affects teenage girls, and underlying psychological problems are common. • Secondary acne: comedonal acne can be caused by greasy cosmetics or occupational exposure to oils, tars or chlorinated aromatic hydrocarbons. Predominantly pustular acne can occur in patients using systemic or topical glucocorticoids, oral contraceptives, anticonvulsants, lithium or antineoplastic drugs, such as the epidermal growth factor receptor (EGFR) inhibitors. Most patients with acne do not have an underlying endocrine disorder but acne is a common feature of polycystic ovary syndrome (p. 658), which should be suspected if acne is moderate to severe and associated with hirsutism and menstrual irregularities. Virilisation should also raise suspicion of an androgen-secreting tumour. Investigations Investigations are not required in typical acne vulgaris. Secondary causes and suspected underlying endocrine disease or virilisation should be investigated (p. 657). Management Mild to moderate disease Mild disease is usually managed with topical therapy (p. 1225). If comedones predominate, then topical benzoyl peroxide or retinoids should be used. Benzoyl peroxide has both anticomedogenic and antiseptic effects. It is an irritant, which may contribute to the therapeutic response, but this can be minimised by adjusting treatment regimes. Azelaic acid may Pathogenesis The key components are increased sebum production; colonisation of pilosebaceous ducts by Propionibacterium acnes, which in turn causes inflammation; and hypercornification and occlusion of pilosebaceous ducts (Fig. 29.28). Severity of acne is associated with sebum excretion rate, which increases at puberty. Both androgens and progestogens increase sebum excretion and oestrogens reduce it, but most patients with acne have normal hormone profiles. There may be a positive family history and there is high concordance in monozygotic twins, indicating that genetic factors are important, but the candidate genes are poorly defined. Clinical features Acne usually affects the face and often the trunk. Greasiness of the skin may be obvious (seborrhoea). The hallmark is the comedone (definition: open comedones (blackheads) are dilated keratin-filled follicles, which appear as black papules due to the keratin debris; closed comedones (whiteheads) usually have no visible follicular opening and are caused by accumulation of sebum and keratin deeper in the pilosebaceous ducts – Fig. 29.28). Inflammatory papules, nodules and cysts occur and may arise from comedones (Fig. 29.29). Scarring may follow deep-seated or superficial acne and may be keloidal. There are also distinct clinical variants: • Acne conglobata: characterised by comedones, nodules, abscesses, sinuses (definition: cavities or channels that permit the escape of pus or fluid) and cysts, usually with marked scarring. It is rare, usually affecting adult males, and most commonly occurs on trunk and upper limbs. It may be associated with hidradenitis suppurativa (a chronic, inflammatory disorder of apocrine glands, predominantly affecting axillae and groins), scalp folliculitis and pilonidal sinus. • Acne fulminans: a rare but severe presentation of acne, associated with fever, arthralgias and systemic inflammation, with raised neutrophil count and plasma viscosity. It is usually found on the trunk in adolescent males. Costochondritis can occur. Fig. 29.28 Pathogenesis of acne. Rupture of obstructed sebaceous gland, with release of contents into dermis Increased sebum secretion rate Bacterial colonisation of duct and release of inflammatory mediators Occlusion of pilosebaceous duct Epidermis Sebaceous gland Hair follicle Fig. 29.29 Cystic acne in a teenager. A Before treatment. B After prolonged systemic antibiotic treatment. A B

Acne and rosacea • 1243

be prevented by adequate treatment of active acne. Keloid scars may respond to intralesional glucocorticoid and/or silicone dressings. Carbon dioxide laser, microdermabrasion, chemical peeling or localised excision can also be considered for scarring. UVB phototherapy or PDT can occasionally be used in patients with inflammatory acne who are unable to use conventional therapy, such as isotretinoin. There is no convincing evidence to support a causal association between diet and acne. The psychological impact of acne must not be under-estimated and should be considered in management decisions (Box 29.16). Rosacea This chronic inflammatory condition affects the central face and consists of flushing, erythema, papules, pustules and telangiectasiae. The cause is unknown. Rosacea is distinct from acne vulgaris; sebum excretion is normal and comedones are absent. The relative contribution of Demodex mite and cutaneous vasomotor instability to the pathogenesis of rosacea remains poorly defined. Clinical features Rosacea most commonly affects fair-skinned, middle-aged females and can be exacerbated by heat, sunlight and alcohol. The convexities of nose, forehead, cheeks and chin are typically involved (Fig. 29.30). The condition is heterogeneous and intermittent flushing, followed by fixed erythema and telangiectasiae, predominates in some; in others, papules and pustules are prominent. Sebaceous gland hyperplasia and soft tissue overgrowth of the nose (rhinophyma) can occur, particularly in males. Conjunctivitis and blepharitis may also occur. Facial lymphoedema can be an added complication. Investigations Usually, no investigations are required and the diagnosis is obvious clinically. However, rosacea must be distinguished from acne vulgaris, systemic lupus erythematosus, photosensitivity disorders and seborrhoeic dermatitis (the latter may coexist with rosacea). also be used for mild acne and has both antimicrobial and anti-comedogenic action. Topical retinoids, in particular all-trans retinoic acid and adapalene, are widely employed for mild to moderate comedonal acne vulgaris. Treatment should be initially applied at low concentrations for short duration and increased as tolerated. Patients with mild inflammatory acne should respond to topical antibiotics, such as erythromycin or clindamycin, which can be used in combination with other treatments. For moderate inflammatory acne, a systemic tetracycline should be used at adequate dose for 3–6 months in the first instance (p. 1227; Fig. 29.29B). Oxytetracycline must be taken on an empty stomach, in a dose of up to 1.5 g a day. It has a good safety profile, even with long-term use, but adherence may be a challenge. Lymecycline is an alternative and is taken once daily, with or without food, thereby improving adherence. Doxycycline is another option but commonly causes photosensitivity. Minocycline is used less frequently, as it can cause hyperpigmentation, autoimmune hepatitis and drug-induced lupus, and monitoring is required. If the patient fails to respond, then alternatives include erythromycin or trimethoprim. In women with acne, oestrogen-containing oral contraceptives can be a useful adjunct, as they are associated with a small reduction in sebum production. Combined oestrogen and antiandrogen (such as cyproterone acetate) contraceptives may provide additional efficacy, particularly in women with acne and hirsutism, as seen in polycystic ovary syndrome (p. 658). Patients should be referred for consideration of isotretinoin (13-cis-retinoic acid) if there is a failure to respond adequately to 6 months of therapy with these combined systemic and topical approaches (p. 1227). Moderate to severe disease Isotretinoin (13-cis-retinoic acid) has revolutionised the treatment of moderate to severe acne that has not responded adequately to other therapies. It has multifactorial mechanisms of action, with reduction in sebum excretion by over 90%, follicular hypercornification, P. acnes colonisation and inflammation. Oral isotretinoin is usually used at a dose of 0.5–1 mg/kg over 4 months. Sebum excretion typically returns to baseline within a year after treatment cessation, although clinical benefit is usually longer-lasting. Many patients will not require further treatment, although a second or third course of isotretinoin may be needed. A low-dose continuous or intermittent-dose regimen may occasionally be considered for a longer duration in patients who relapse after a higher-dose regimen, and may also be beneficial for older females with persistent acne. Combination with systemic glucocorticoid may be required in the short term for severe acne, in order to minimise the risk of disease flare early in the treatment course. Thorough screening and monitoring are required, given the side-effect profile of isotretinoin, particularly with respect to teratogenicity and possible mood disturbance (p. 1227). Pregnancy must be avoided during treatment and for a minimum of 2 months after drug cessation, and a strict pregnancy prevention programme and regular pregnancy testing are required. Depression and suicide have been reported in association with isotretinoin, although a causal role has not been established. However, pre-drug screening for depressive symptoms should be undertaken and mood monitored during therapy. Other treatments and physical measures Intralesional injections of triamcinolone acetonide may be required for inflamed acne nodules or cysts, which can also be incised and drained, or excised under local anaesthetic. Scarring may Fig. 29.30 Rosacea. Typical erythematous papulopustular rosacea affecting the mid-face.

1244 • DERMATOLOGY are commonly positive, particularly for staphylococci, although clinical assessment is required in order to ascertain whether swab results are of clinical significance and whether antibiotic treatment is required. Individuals with atopic eczema have an increased susceptibility to herpes simplex virus (HSV) and are at risk of developing a widespread infection, eczema herpeticum. The presence of small, punched-out lesions on a background of worsening eczema suggests the possibility of secondary HSV infection. Skin scrapings to rule out secondary fungal infection should also be considered. Total IgE and specific IgE tests and skin prick tests are not routinely undertaken in atopic eczema as they are not usually helpful, although they may occasionally be indicated in some cases as directed by the history. Patch tests should be performed if contact allergic dermatitis is suspected (see Box 29.22 below). Skin biopsy is not usually required unless there is diagnostic doubt. Management A general approach to the management of eczema includes advice, education and support, required for patients with eczema of any type (Fig. 29.31). Input from patient support groups, such as the National Eczema Society in the UK, can be very helpful. Intensive and prolonged treatments are often required and chronic eczema can have a major and devastating adverse impact on personal and family lives. Emollients and topical glucocorticoids are mainstays of treatment for all eczema types, in order to improve skin barrier function, limit transepidermal water loss and reduce inflammation. Emollients can be used as bath additives and soap substitutes, and applied directly to the skin, often combined with antiseptics. Sedative antihistamines are useful if sleep is interrupted but non-sedating antihistamines are ineffective, as the itch of eczema is not primarily mediated by histamine. Ointments are preferred for chronic eczema, whereas cream- or lotion-based treatment may be more appropriate for acute eczema (see Box 29.11). Treatment is once to twice daily (p. 1225). Hydrocortisone (1%) or clobetasone butyrate is generally used on the face, with more potent glucocorticoids restricted to trunk and limbs (see Box 29.12). A good strategy is to employ an intensive regimen with more potent glucocorticoids initially and then taper use according to response. A key principle is to use the least potent glucocorticoid that is effective for the shortest possible time. The patient should be given instructions on how much to apply, using the fingertip unit for guidance (a strip of glucocorticoid cream on distal phalanx pulp should cover two palm-size areas). It is also important to monitor glucocorticoid use and the easiest way to do this is ask how long it takes to use a specific size of glucocorticoid tube. The side-effects of topical glucocorticoid therapy need to be considered but glucocorticoid phobia and under-treatment of eczema are often more of a problem than over-treatment. Particular care should be taken on certain sites, such as the face and flexures, and in children and the elderly (see Box 29.2 and Fig. 29.10, p. 1226). The clinical features of eczema influence the choice of topical treatment. For example, appropriate treatment of acute exudative eczema could be with potassium permanganate soaks, emollients and topical glucocorticoids under wet wraps. Chronic eczema may be best treated with a potent topical glucocorticoid in an ointment formulation and occlusion with a paste bandage to ease itching and scratching. The topical calcineurin inhibitors tacrolimus and pimecrolimus may be useful glucocorticoid-sparing agents for eczema, particularly on the face; they cause local cutaneous immunosuppression. 29.18 The clinical morphology of eczema Acute • Erythema, oedema, usually typically ill defined • Papules, vesicles and occasionally bullae • Exudation, fissuring • Scaling Chronic • May be as above but less oedema, vesiculation and exudate • Lichenification: skin thickening with pronounced skin markings, secondary to chronic rubbing and scratching • Fissures (definition: slit-shaped deep ulcers), excoriations • Dyspigmentation: hyper- and hypopigmentation can occur 29.17 Classification of eczema Endogenous • Atopic, seborrhoeic Exogenous • Irritant, allergic, photo-allergic, chronic actinic dermatitis Characteristic patterns and morphology • Asteatotic, discoid, gravitational, lichen simplex, pompholyx Management Mild disease may respond to topical antimicrobials, such as metronidazole or azelaic acid. Topical ivermectin may be beneficial in some cases, supporting a contributory role of Demodex in pathogenesis. Tetracycline or erythromycin for 3–6 months is usually effective in inflammatory pustular disease resistant to topical therapy (p. 1227). Relapse may require intermittent or chronic antibiotic use. Erythema and telangiectasiae do not usually respond well to antibiotics but vascular laser therapy may be effective. Topical vasoconstrictors, such as the α2-adrenoceptor agonist brimonidine, may be of benefit in some cases where erythema and telangiectasiae predominate. Systemic isotretinoin may be helpful in severe resistant disease and rhinophyma may require laser therapy or surgery. Eczemas The term ‘eczema’ derives from the Greek word ‘to boil’ and is synonymous with the other descriptive term, ‘dermatitis’. Eczema describes a clinical and histological pattern, which can be acute or chronic and has several causes. Acutely, epidermal oedema (spongiosis) and intra-epidermal vesiculation (producing multilocular blisters) predominate, whereas with chronicity there is more epidermal thickening (acanthosis). Vasodilatation and T-cell lymphocytic infiltration of the upper dermis also occur. Clinical features There are several patterns of eczema (Box 29.17) but the clinical features are similar, irrespective of the cause (Box 29.18). Some subtypes of eczema have specific distinguishing features and these are discussed in more detail below. Investigations Bacterial and viral swabs for microscopy and culture are important in suspected secondary infection. Bacterial swabs

Eczemas • 1245

Fig. 29.31 General management approaches: atopic eczema. (PDE = phosphodiesterase; PUVA = psoralen-ultraviolet A; UVA1 = ultraviolet A1; UVB = narrowband ultraviolet B) Next steps Narrowband UVB, PUVA/UVA1 (depending on availability, patient age etc.) Initial steps Accurate diagnosis Establishing severity and impact Removal of triggers and treatable causes, such as infection, and allergens Education and support of patient and family Psychological support General treatment approach Emollients, topical glucocorticoids, topical calcineurin inhibitors, sedating antihistamines Consider bandages, wet wraps Inpatient admission If feasible, for intensive inpatient care ± Phototherapy ± Systemic treatment Immunosuppression Prednisolone, azathioprine, ciclosporin, methotrexate Systemic retinoids Acitretin or alitretinoin for hand eczema For severe resistant disease Dupilumab (Trials in progress with other biologics and PDE inhibitors) Consider Initial burning and stinging may limit use but are usually transient side-effects. Bacterial and viral skin infection risk may be increased due to immunosuppression. Caution should be employed with sun exposure and these agents should not be used in combination with phototherapy because of their immunosuppressive effects. Atopic eczema This is the most common subtype of eczema. The prevalence has increased dramatically since the early 1980s, and the disease now affects at least 20% of schoolchildren and 5–10% of adults in the UK. Pathogenesis Generalised prolonged hypersensitivity to common environmental antigens, such as pollen and house-dust mite, is the hallmark of atopy, in which there is a genetic predisposition to produce excess IgE. Atopic individuals manifest one or more of a group of diseases that includes asthma, hay fever, food and other allergies, and atopic eczema. Genetic factors play an important role in all of these conditions, supported by higher concordance of atopic disease in monozygotic twins compared with dizygotic twins. Filaggrin gene mutations increase the risk of developing atopic eczema by more than threefold, emphasising the importance of epidermal barrier impairment in this disease. Other genes are also likely to be implicated, with many other susceptibility loci identified, although these studies require further replication. Decreased skin barrier function may also allow greater penetration of allergens through the epidermis, and thus cause immune stimulation and subsequent inflammation. The interaction between genes and environment is important; it has been estimated that 60–80% of individuals are genetically susceptible to the induction of IgE-mediated sensitisation to environmental allergens such as food and animal hair. Eczema is characterised by infiltration of Th2 cells, which are known to play a role in activating mast cells and eosinophils, as well as stimulating IgE production by IgE-producing B cells. The contributing roles of the microbiome are also being explored. Thus, the pathogenesis of atopic eczema is complex and multifactorial, involving an interplay of contributing factors. Clinical features Atopic eczema is extremely itchy and scratching accounts for many of the signs (Fig. 29.32). Widespread cutaneous dryness (also known as xeroderma or xerosis) is another feature. The distribution and character of the rash vary with age (Box 29.19). Complications are listed in Box 29.20. Investigations The diagnosis of atopic eczema is made using clinical criteria (Box 29.21). Interestingly, while most patients with atopic eczema have raised total IgE levels and IgE-specific antibodies, this is not a prerequisite for the diagnosis, as a significant minority have normal levels of IgE.

1246 • DERMATOLOGY Management The general principles of management are as described in Figure 29.31. Emollients and topical glucocorticoids, tar and ichthammol paste bandages, or wet wraps in children, are often required. Topical calcineurin inhibitors may be used as glucocorticoid-sparing agents but should not be used in infected eczema. Secondary infection should be treated but positive skin swabs in isolation, without clinical evidence of infection, do not necessarily require treatment with antibiotics, although antiseptics would be appropriate. Sedating antihistamines may help to break the itch/scratch cycle. Identification and avoidance of allergens are important. Phototherapy is generally the next step, if topical therapies are insufficient (see Fig. 29.31). Narrowband UVB is usually the initial phototherapy of choice and can also be used in children. PUVA or UVA1 can also be chosen if UVB is ineffective, although mainly in adults as PUVA is generally avoided in children. Localised phototherapy may be used for eczema on hands and feet and PUVA may be more effective in that situation. Systemic immunosuppression with, for example, oral glucocorticoids, intermittent ciclosporin, azathioprine or methotrexate may be needed if the response to topical therapies and phototherapy is inadequate. Systemic retinoids, such as acitretin or alitretinoin, may be indicated: for example, in hand and foot eczema. Encouraging early trial data are emerging to support the use of dupilumab, which blocks IL-4Rα, and the anti-IL-13 agents lebrikizumab and tralokinumab in atopic eczema. Phosphodiesterase 4 inhibitors are also being investigated. Seborrhoeic eczema This is an erythematous scaly rash affecting the scalp (dandruff), central face, nasolabial folds, eyebrows, central chest and upper back. It is associated with, and may be due to, overgrowth of Malassezia yeasts. When severe, it may resemble psoriasis. Severe or recalcitrant seborrhoeic eczema can be a marker of immunodeficiency, including HIV infection (p. 314). Topical azoles, such as ketoconazole shampoo and cream, often combined with mild glucocorticoid, are mainstays. Treatment often needs to be repeated due to disease recurrence. Discoid eczema Discoid eczema, which is also known as nummular eczema, is common and characteristically consists of discrete, coin-shaped eczematous lesions, which are often impetiginised and most commonly occur on the limbs of men. It is an eczema type that can be due to any chronic itchy condition, whether primarily of the skin or secondary to an underlying disease. Initial management should include topical antiseptics, in addition to emollients and topical glucocorticoids. Judicious antibiotic use may also be required for acute flares. 29.21 Diagnostic criteria for atopic eczema Itchy skin rash (or history of itch or rubbing from parent) and at least three of the following: • History of involvement of skin creases (or cheeks if < 4 years) • History of atopic disease (asthma, hay fever) (or in a first-degree relative if < 4 years) • Dry skin (xeroderma) • Visible flexural eczema (cheeks, forehead, outer limbs if < 4 years) • Onset in first 2 years of life 29.20 Complications of atopic eczema Secondary infection Bacterial • Staphylococcus aureus most common Viral • Herpes simplex virus can cause a widespread severe eruption – eczema herpeticum • Papillomavirus and molluscum contagiosum are more common in atopic eczema, especially if treated with topical glucocorticoids Increased susceptibility to irritants • Defective barrier function Increased susceptibility to allergy • Food allergy – mainly relevant in infants; eggs, cow’s milk protein, nuts, fish, wheat and soya may cause an immediate reaction with angioedema and/or urticaria rather than exacerbation of eczema • Anaphylaxis in severe allergy • Increased risk of sensitisation to type IV allergens because of impaired barrier function Impact on life and health • Poor sleep, loss of schooling, behavioural difficulties, failure to thrive in children • Impact on sleep, work, relationships, hobbies, psychology and quality of life in adults 29.19 Atopic eczema: distribution and character of rash Babies and infants • Often acute and facial involvement prominent • Trunk involved but nappy area usually spared Children • Flexures: behind knees, antecubital fossae, wrists and ankles Adults • Face and trunk usually involved, limb involvement not restricted to flexures • Lichenification common Fig. 29.32 Atopic eczema. A This patient had life-long chronic atopic eczema and experienced a generalised flare of disease triggered by infection. B Lichenification of chronic flexural eczema secondary to rubbing and scratching. B A

Psoriasis and other erythematous scaly eruptions • 1247

in combination with topical glucocorticoids. Patients must be advised to use caution with flammable emollients and to avoid bathroom slippages related to emollients on floor and feet, and this is particularly relevant for the elderly. Gravitational eczema Gravitational or stasis eczema occurs on the lower legs and is often associated with signs of venous insufficiency: oedema, loss of hair, induration, lipodermatosclerosis and ulceration. Emollients should be used and topical glucocorticoids should be applied to eczematous areas but not to ulcers. There is a high risk of sensitisation to topical preservatives (such as chlorocresol), antibiotics (such as neomycin) and bandages (such as rubber additives). Oedema and ulceration are treated by leg elevation and compression bandages (p. 1224). Lichen simplex Lichenification of eczema occurs secondary to chronic rubbing and scratching, and lichen simplex is a localised form. Common sites include the neck, lower legs and anogenital region. Treatment with emollients and very potent topical glucocorticoids may be required, often impregnated in tape or with occlusion. Pompholyx Intensely itchy vesicles and bullae occur on the palms, palmar surface and sides of the fingers and soles. Pompholyx may have several causes, which include atopic eczema, irritant and contact allergic dermatitis and fungal infection. The underlying cause must be treated or removed. Psoriasis and other erythematous scaly eruptions Psoriasis Psoriasis is a chronic inflammatory, hyperproliferative skin disease. It is characterised by well-defined, erythematous scaly plaques, Irritant eczema Detergents, alkalis, acids, solvents and abrasives are common irritants. Strong irritants have acute effects, whereas weaker irritants commonly cause chronic eczema, especially of the hands, after prolonged exposure. Individual susceptibility varies and the elderly, atopic and fair-skinned are predisposed. Irritant eczema accounts for most occupational cases of eczema and is a significant cause of time off work. Irritant avoidance, including protective clothing (such as gloves), is essential. Emollients and topical glucocorticoids are indicated. Allergic contact eczema This occurs due to a delayed hypersensitivity reaction following contact with antigens or haptens. Previous allergen exposure is required for sensitisation and the reaction is specific to the allergen or closely related chemicals. Common allergens are listed in Box 29.22. Allergy persists indefinitely and eczema occurs at sites of allergen contact and can secondarily spread beyond this. The distribution of eczema can be very informative with regard to possible culprits. There are many recognisable patterns of sites of eczema involvement, such as earlobes, wrists and umbilicus due to contact with nickel in earrings, watches and jeans studs; hands and wrists due to rubber gloves; and upper eyelids due to colophony from rubbing of the eyes in nail varnish wearers. Oedema may also be a feature (Fig. 29.33). Allergen avoidance is key and may involve a change of occupation, recreational activities or hobbies. It is important to ensure that patients are fully informed as to the nature and likely occurrence of allergens and good detective work is required to scrutinise lifestyle and daily activities. Treatment with emollients and topical glucocorticoids helps but will not suffice if there is continued allergen exposure. Asteatotic eczema This occurs in dry skin and is common in the elderly. Low humidity caused by central heating, over-washing, diuretics and cholesterol-lowering drugs predispose. The most common site is the lower legs, and a ‘crazy paving’ pattern of fine fissuring on an erythematous background is seen. Emollients are a mainstay, Fig. 29.33 Allergic contact eczema. This was caused by the application of an antihistamine cream. The acute eczematous reaction and bilateral periorbital oedema are typical. 29.22 Common type IV delayed hypersensitivity allergens Allergen Source Nickel Jewellery, jean studs, bra clips, watches Dichromate Cement, leather, matches Rubber chemicals Clothing, shoes, rubber gloves, tyres Colophony Sticking plaster, collodion, nail varnish Paraphenylenediamine Hair dye, clothing, tattoos Balsam of Peru Perfumes, citrus fruits, shower/bath products Neomycin, benzocaine Topical medications Parabens Preservative in cosmetics and creams Wool alcohols Lanolin, cosmetics, creams Epoxy resin Resin adhesives, glues Methyl- and chloromethylisothiazolinone Preservatives, with increasing numbers of cases of allergy reported

1248 • DERMATOLOGY and IL-23), TNF-α, IFN-γ and intercellular adhesion molecule (ICAM)-1 • vascular changes, with tortuosity of dermal capillary loop vessels and release of mediators, such as vascular endothelial growth factor (VEGF). The initiating event for psoriasis is unknown. Disordered cell proliferation is a key feature; this was previously thought to be the primary event but is now considered to be secondary to inflammatory change. The transit time for keratinocyte migration, from basal layer to shedding from stratum corneum, is shortened from approximately 28 to 5 days, so that immature cells reach the stratum corneum prematurely. Proliferation rate is also increased in non-lesional skin but to a lesser extent. Similarly, even the clinically unaffected nails of patients with psoriasis grow more quickly than those of controls. While immunological factors clearly play a key role in psoriasis, the precise mechanisms of disease initiation and the sequence of events that lead to psoriasis are not fully defined. particularly affecting extensor surfaces, scalp and nails, and usually follows a relapsing and remitting course. Psoriasis affects approximately 1.5–3% of Caucasians but is less common in Asian, South American and African populations. It occurs equally in both sexes and at any age; although it is uncommon under the age of 5 years, more than 50% of patients present before the age of 30 years. The age of onset follows a bimodal distribution, with an early-onset type in the teenage or early adult years, often with a family history of psoriasis, a more severe disease course and strong HLA association. The later-onset type is typically seen between 50 and 60 years, usually without a family history and with a less severe disease course. Pathogenesis Both genetic and environmental factors are important. Twin studies show concordance rates of 60–75% and 15–20% for psoriasis arising in monozygotic and dizygotic twins, respectively. The age at onset and severity of disease are often similar in familial cases. If one parent has psoriasis, the chance of a child being affected is about 15–20%; if both parents have the disease, this rises to 50% and the risk is increased further if a sibling also has the disease. Variants of the HLA-C region within the major histocompatibility complex (MHC) on chromosome 6 account for almost half of the heritability of psoriasis. However, at least 70 other loci are implicated, with susceptibility variants that lie within or close to genes involved in regulating epidermal barrier function, antigen presentation, cytokine production, notably IL-13 and IL-23, T-cell differentiation (especially Th-1 and Th-17 subsets) and nuclear factor kappa B (NFκB) signalling. Some of the loci that predispose to psoriasis overlap with those implicated in Crohn’s disease, ankylosing spondylitis and psoriatic arthritis. Environmental triggers for psoriasis are shown in (Box 29.23). Although the theory is controversial, stress may exacerbate psoriasis in susceptible individuals and psoriasis is itself a cause of psychological stress. Likewise, there is a higher incidence of smoking and heavy alcohol consumption in patients with psoriasis but it is unclear whether this is cause or effect. There is also an association between psoriasis and metabolic syndrome (p. 730). The histological changes of psoriasis are shown in Figure 29.34. The main features are: • keratinocyte hyperproliferation and abnormal differentiation, leading to retention of nuclei in the stratum corneum • inflammation, with a T-cell (mainly activated Th-1 and Th-17) lymphocytic infiltrate and release of cytokines and adhesion molecules, such as interleukins (including IL-17 Fig. 29.34 The histology of psoriasis. Upper dermal T-lymphocyte infiltrate Irregular thickening of epidermis Dilated and tortuous capillary loops Micro-abscess Supra-papillary plate thinning Hyperkeratosis Parakeratosis Keratin layer Epidermis Dermis Psoriasis Normal 29.23 Exacerbating factors in psoriasis Trauma • Lesions can appear at sites of skin trauma, such as scratches or surgical wounds (Köbner isomorphic phenomenon) Infection • β-haemolytic streptococcal throat infections often precede guttate psoriasis (see Fig. 29.35C) • Severe psoriasis may be the initial presentation of HIV infection Sunlight • Psoriasis may occur or worsen after sun exposure, mainly due to Köbnerisation at sites of sunburn or polymorphic light eruption Drugs • Antimalarials, β-adrenoceptor antagonists (β-blockers), lithium, NSAIDs and TNF-α inhibitors can exacerbate psoriasis • ‘Rebound’ flare of psoriasis may occur after withdrawal of systemic glucocorticoids or potent topical glucocorticoids. Rebound psoriasis is often unstable and may be pustular Psychological factors • Anxiety and stress may exacerbate psoriasis in predisposed individuals (NSAID = non-steroidal anti-inflammatory drug; TNF-α = tumour necrosis factor alpha)

Psoriasis and other erythematous scaly eruptions • 1249

a streptococcal throat infection and evolves rapidly. Individual lesions are droplet-shaped, small (usually less than 1 cm in diameter), erythematous, scaly and numerous. An episode of guttate psoriasis may clear spontaneously or with topical treatment within a few months, but UVB phototherapy is often required and is highly effective. Guttate psoriasis often heralds the onset of plaque psoriasis in adulthood. Erythrodermic psoriasis Generalised erythrodermic psoriasis is a medical emergency (Fig. 29.35D). Pustular psoriasis Pustular psoriasis may be generalised or localised. Generalised pustular psoriasis is uncommon, unstable and life-threatening. It will often emerge in the context of plaque disease and the onset is usually sudden, with large numbers of small, sterile pustules on an erythematous background, often merging into sheets, with waves of new pustules in subsequent days. The patient is usually febrile and systemically unwell, and this must be dealt with as a medical emergency (p. 1224). Unstable pustular psoriasis may be precipitated as a rebound phenomenon following either topical or systemic glucocorticoid use in a patient with psoriasis. Localised pustular psoriasis of the palms and soles (palmoplantar pustulosis) is more common, chronic and closely associated with smoking; small, sterile pustules and erythema develop and resolve with pigmentation and scaling (p. 1210). A localised form of sterile pustulosis of a few digits (acropustulosis) can also occur. It is unclear whether these localised forms of pustulosis are truly psoriatic. Arthropathy Between 5% and 10% of individuals with psoriasis develop an inflammatory arthropathy, which can take on a number of patterns (p. 1035). Joint involvement is more likely in patients with psoriatic nail disease. Clinical features Psoriasis has several different presentations (Fig. 29.35). Plaque psoriasis This is the most common presentation and usually represents more stable disease. The typical lesion is a raised, well-demarcated erythematous plaque of variable size (Fig. 29.35A). In untreated disease, silver/white scale is evident and more obvious on scraping the surface, which reveals bleeding points (Auspitz sign). The most common sites are the extensor surfaces, notably elbows and knees, and the lower back. Others include: • Scalp: involvement is seen in approximately 60% of patients. Typically, easily palpable, erythematous scaly plaques are evident within hair-bearing scalp and there is clear demarcation at or beyond the hair margin. Occipital involvement is common and difficult to treat. Less often, fine diffuse scaling may be present and difficult to distinguish from seborrhoeic dermatitis. Involvement of other ‘seborrhoeic sites’, such as eyebrows, nasolabial folds and the pre-sternal area, is not uncommon and again may be confused with seborrhoeic dermatitis. Temporary hair loss can occur but permanent loss is unusual. • Nails: involvement is common, with ‘thimble pitting’, onycholysis (separation of the nail from the nail bed, Fig. 29.35B), subungual hyperkeratosis and periungual involvement (p. 1210). • Flexures: psoriasis of the natal cleft and submammary and axillary folds is usually symmetrical, erythematous and smooth, without scale. • Palms: psoriasis of the palms can be difficult to distinguish from eczema. Guttate psoriasis This is most common in children and adolescents and is often the initial presentation (Fig. 29.35C). It may present shortly after Fig. 29.35 Psoriasis. A Chronic plaque psoriasis, most prominent on extensor surfaces. B Nail involvement, with coarse pitting and separation from the nail plate (onycholysis). C Guttate psoriasis following a streptococcal throat infection. D Erythrodermic psoriasis. A C D B

1250 • DERMATOLOGY If topical treatment is insufficient, then UVB phototherapy or PUVA should usually be the next step. If the patient continues to have active disease or early recurrence, then the addition of systemic retinoid such as acitretin to UVB or PUVA can be effective. Alternatively, immunosuppressants, such as methotrexate or ciclosporin, may be required. For difficult treatment-resistant disease, fumaric acid esters, apremilast and biologics should be considered (p. 1005 and Fig. 29.37). The active component of fumaric acid ester therapy is dimethyl fumarate and efficacy in psoriasis has been confirmed. Common adverse effects are flushing and diarrhoea. Lymphopenia is also expected at effective doses. Apremilast is indicated for moderate to severe psoriasis resistant to standard measures. Of the biological agents, the anti-TNF-α agents (etanercept, infliximab, adalimumab or golimumab), ustekinumab (an inhibitor Investigations Skin biopsy is not usually required but may be performed if there is diagnostic doubt. An infection screen, particularly throat swab and/or serology for recent streptococcal infection, may be informative in guttate psoriasis. Assessment of impact on life using the DLQI and disease extent using PASI (Psoriasis Area and Severity Index, p. 1211) is essential. Due to the association of psoriasis with metabolic syndrome, comorbidities and cardiovascular risk factors should be assessed and managed (p. 730). HIV testing should be considered in severe or recalcitrant psoriasis. Management Counselling about diagnosis and management of skin involvement and other comorbidities is paramount. Information and services must be available for patients. Psoriasis can have a major impact on all aspects of life and this must not be under-estimated. Reassurance is also needed, as the condition is generally not life-threatening. Advice regarding reduction in risk factors for cardiovascular disease should be given (smoking cessation, reduction of alcohol intake, adequate exercise and a normal body mass index). Associated diseases, such as hypertension and diabetes, should be treated. Patients need to be involved in their own management, as the disease is usually chronic and the benefit/risk profile of treatments must be discussed and tailored to individuals. The endpoint for treatment also needs to be discussed because complete disease clearance may not be practical or appropriate and patients vary considerably in their treatment requirements. Extent of disease and impact on quality of life must be taken into account. Patient adherence to topical and systemic therapies is essential and dependent on the treatment practicalities. The treatment approach generally follows a stepwise progression, with treatment categories broadly summarised (Fig. 29.36). Topical treatments, including emollients, are the first-line approach. Vitamin D receptor agonists, such as calcipotriol, calcitriol and tacalcitol, are often used as first-line topical treatment. The mechanism of action includes increased differentiation and reduction of proliferation, reducing plaque scale and thickness. Calcipotriol is most widely used and can be applied once to twice daily; if less than 100 g of ointment is used each week, there is no risk of hypercalcaemia. Vitamin D analogues can cause irritation but this is often temporary. Topical glucocorticoids may be required in the management of psoriasis, particularly at flexural or facial sites, and may be alternated or combined with vitamin D analogues. However, safe, appropriately supervised and judicious use is necessary, with awareness of the potential risk of rebound unstable or pustular psoriasis with glucocorticoid over-use or sudden cessation. Dithranol and coal tar are effective and, like vitamin D analogues, work by increasing differentiation and inhibiting proliferation. Although often effective, they are messy and time-consuming. Modified versions of Goeckerman’s regimen (the combination of coal tar and UVB) are still used, but coal tar has a characteristic odour and can be irritant. Short-contact dithranol therapy at relatively high concentrations applied for 15–30 minutes can be used but causes brown staining of skin and purple discoloration of light hair. In recent years, efforts have been made to improve the tolerance of tar and dithranol preparations, but at reduced efficacy. Overall, the use of tar and dithranol has reduced in recent years but they can be highly effective in selected patients. Fig. 29.36 General management approaches: psoriasis. (IL = interleukin; PUVA = psoralen–ultraviolet A; TNF-α = tumour necrosis factor alpha; UVB = ultraviolet B) Consider Anti-IL-17 Secukinumab Ixekizumab Brodalumab Initial steps Accurate diagnosis Establishing severity and impact Removal or treatment of triggers Identification of comorbidities (especially in severe disease) Education, support, psychological input General treatment approach Emollients, topical vitamin D analogues, tars, dithranol, retinoids ± Topical glucocorticoids, e.g. flexural sites Next steps Narrow-band UVB (or excimer laser, if available, for localised disease), PUVA Inpatient admission If feasible, for intensive inpatient care ± Phototherapy/PUVA ± Systemic treatment Systemic agents Methotrexate, ciclosporin, acitretin (can add to phototherapy or PUVA) May consider Fumaric acid esters/apremilast For resistant disease Biologics Anti-TNF-α Infliximab Etanercept Adalimumab Anti-IL-12/23 Ustekinumab Anti-IL-23 Guselkumab

Psoriasis and other erythematous scaly eruptions • 1251

Mucosal involvement is rare. There is a small risk of recurrence. Symptomatic relief can be achieved with emollients and mild topical glucocorticoids. Post-inflammatory hyperpigmentation can supervene, particularly in darker skin types. Pityriasis lichenoides chronica This is rare but typically presents within the first three decades of life. The aetiology is unclear but the condition is part of a spectrum and remits spontaneously. The more acute variety (pityriasis lichenoides et varioliformis acuta, PLEVA) presents as crops of papules that rapidly evolve with central necrosis, each attack lasting up to 3 months. The more chronic variety presents as a persistent, widespread, scaly eruption. Characteristically, lesions are brown papules with a mica-like scale (‘cornflake’). The condition fluctuates but can persist for months or years. Emollients, topical glucocorticoids and long-term oral erythromycin can occasionally be helpful. UVB phototherapy or PUVA is usually effective, although recurrences are high. Drug eruptions It is essential to consider a drug cause in anyone presenting with an erythematous maculopapular or papulosquamous eruption, and a careful drug history is critical (p. 1265). Exfoliation (‘peeling’) and post-inflammatory hyper- or, less commonly, hypopigmentation can occur. Other causes Secondary syphilis (p. 337), pityriasis versicolor (p. 1240) and fungal infection with Tinea corporis (p. 1240) can all cause an of IL-12 and IL-23), guselkumab (an IL-23 inhibitor) and secukinumab or ixekizumab (an IL-17 inhibitor) may all be effective and this is a rapidly evolving field. More details of the mechanisms of action and adverse effects of these agents are provided on page 1006. Individualised management is essential. For example, a patient with localised plaque psoriasis on elbows, knees and sacrum should respond to topical treatment only, whereas someone with guttate psoriasis is likely to need phototherapy as a first-line approach because of difficulties in topical drug application in extensive disease. A patient with extensive chronic plaque psoriasis and significant arthropathy would be better suited to a systemic drug, such as methotrexate, than phototherapy, which would be unlikely to improve joint symptoms. Thus, whilst a stepwise general approach to management (see Fig. 29.36) may offer guidance, the correct choice for any given patient must be determined on an individual basis. Pityriasis rosea This is an acute, self-limiting exanthem that particularly affects young adults and occurs worldwide, with a slight female predominance. It usually presents in spring and summer, although no infective agent has been identified and its aetiology is unknown. It is characterised by the appearance of a ‘herald patch’, an oval lesion (1–2 cm) with a central pinkish (salmon-coloured) centre, a darker periphery and a characteristic collarette of scale. It is followed 1–2 weeks later by a widespread papulosquamous eruption, which is typically arranged in a symmetrical ‘fir tree’ pattern on the trunk. Individual lesions also have a collarette of scale. An inverse variant with flexural involvement can occur. Fig. 29.37 Developments in understanding of key pathways and drug targets in psoriasis. Other drug targets are also under development, such as Janus kinase (JAK) inhibitors (tofacitinib and baricitinib) and sphingosine-1-phosphate receptor (S1PR1) antagonists (ponesimod). This diagrammatic image is illustrative of key pathways and drug targets but is not comprehensive. (AMP = adenosine monophosphate; cAMP = cyclic adenosine monophosphate; GM-CSF = granulocyte macrophage colony-stimulating factor; IL = interleukin; TNF-α = tumour necrosis factor alpha) Infliximab Etanercept Adalimumab Golimumab Dendritic cell Neutrophil GM-CSF T cell IL-12 IL-23 IL-23 Secukinumab Ixekizumab Infliximab Etanercept Adalimumab Golimumab Ustekinumab Guselkumab Brodalumab Phosphodiesterase 4 Adenylyl cyclase Keratinocyte ↑Inflammatory cytokines TNF-α IFN-γ IL-17A IL-17R IL-17A TNF-α Apremilast cAMP AMP Gene activation AC AC

1252 • DERMATOLOGY presents as an inflammatory scarring alopecia, often with tufting of residual hairs. The classical presentation of lichen planus is unmistakable, but less common atypical variants, which include annular, atrophic, actinic, linear, bullous, follicular, pigmented and ulcerative types, can be a diagnostic challenge. Investigations A skin biopsy should be performed if there is diagnostic doubt. A careful drug history must be taken, as, although the classical presentation of lichen planus is usually ‘idiopathic’, the main differential is a drug-induced lichenoid reaction (see below). Other differential diagnoses include psoriasis, pityriasis rosea, pityriasis lichenoides chronica and secondary syphilis. Screening for underlying disease, such as hepatitis, must be considered. Management The condition is usually self-limiting, although rarely it may persist for years, particularly oral lichen planus. Treatment is symptomatic and potent local glucocorticoids (topical, with occlusion or by injection for hypertrophic disease, or as oral rinse for oral involvement) may help the intense itch; short courses of systemic glucocorticoids are sometimes required for extensive disease. UVB, PUVA or UVA1 can be beneficial and, for recalcitrant disease, retinoids or immunosuppressants, such as ciclosporin or methotrexate, may be needed. A low but significant risk of malignant transformation exists with persistent oral and genital disease, so active treatment, surveillance and smoking cessation are important. Drug-induced lichenoid eruptions Drug-induced lichenoid reactions that are clinically and histologically difficult to distinguish from idiopathic lichen planus are important to identify. The likely culprits are gold, quinine, proton pump inhibitors, sulphonamides, penicillamine, antimalarials, antituberculous drugs, thiazide diuretics, β-blockers, angiotensinconverting enzyme (ACE) inhibitors, NSAIDs, sulphonylureas, lithium and dyes in colour developers (see Box 29.35, p. 1266). Graft-versus-host disease In the acute stage of graft-versus-host disease (GVHD, p. 937), there is a distinctive dermatitis associated with hepatitis. After about 3 months, chronic GVHD can present with a lichenoid eruption on the palms, soles, face and upper trunk. Progressive sclerodermatous skin thickening, associated with pigmentary changes, may lead to contractures and limited mobility. Urticaria Urticaria (‘hives’) is caused by localised dermal oedema secondary to a temporary increase in capillary permeability. If oedema involves subcutaneous or submucosal layers, the term angioedema is used. Clinical features Acute urticaria may be associated with angioedema of the lips, face, tongue, throat and, rarely, wheezing, abdominal pain, headaches and even anaphylaxis (p. 75). Urticaria present for less than 6 weeks is considered to be acute, and chronic if it continues for more than 6 weeks. Individual weals (definition: evanescent discrete areas of dermal oedema, often centrally white due to masking of local blood supply by fluid; weals can erythematous papulosquamous rash and must be considered in the differential diagnosis of erythematous papulosquamous rashes. Lichenoid eruptions Lichen planus Lichen planus occurs worldwide. It typically presents as a pruritic rash; the mucosae, hair and nails may also be involved. Pathogenesis The disease probably has an autoimmune basis since there is an association with inflammatory bowel disease, primary biliary cirrhosis, autoimmune hepatitis, hepatitis B and C, alopecia areata, myasthenia gravis (p. 1141) and thymoma. There are also similarities with graft-versus-host disease (GVHD, p. 937). Lichen planus can occasionally occur in families and possible HLA associations have been reported but there is no clear inheritance pattern. On skin biopsy, characteristic histological changes include hyperkeratosis, basal cell degeneration and a heavy, band-like T-lymphocyte infiltrate in the papillary dermis, with affinity for the epidermis (epidermotropism). The dermo-epidermal junction has a ‘sawtooth’ appearance. Clinical features Lichen planus occurs in both sexes and at any age, although usually between 30 and 60 years. It generally presents on the distal limbs, most commonly on the flexural aspects of the wrists and forearms (Fig. 29.38), and on the lower back. It is intensely itchy and lesions are violaceous, shiny, flat-topped, polygonal papules, with a characteristic fine lacy, white network on the surface (Wickham’s striae). New lesions may appear at sites of skin trauma (Köbner phenomenon) and the rash may become generalised. Individual lesions may last for many months and can become hypertrophic and modified by scratching, particularly on the lower legs. The eruption usually remits over months but can become chronic, particularly with hypertrophic disease. Post-inflammatory pigmentary change is common, particularly in darker skin types. Mucous membrane involvement occurs in 30–70% of patients, usually as a network of white, lacy striae on the buccal mucosae (p. 1210) and tongue. These oral changes are often asymptomatic and should be sought on examination. Genital and other mucosal surfaces can also be affected (pp. 334 and 336). Nail involvement occurs in about 10% and can range from longitudinal ridging to a destructive nail dystrophy, scarring (pterygium) and nail loss (p. 1261). Scalp involvement usually Fig. 29.38 Lichen planus. Violaceous papules on the flexural aspect of forearm, arising at a site of minor linear trauma (Köbner phenomenon).

Urticaria • 1253

Investigations Investigations should be guided by the history and possible causes but are often negative, particularly in acute urticaria. Some or all of the following may be appropriate: • Full blood count: eosinophilia in parasitic infection or drug cause. • Erythrocyte sedimentation rate (ESR) or plasma viscosity: elevated in vasculitis. • Urea and electrolytes, thyroid and liver function tests, iron studies: may reveal an underlying systemic disorder. • Total IgE and specific IgE to possible allergens: shellfish, peanut, house-dust mite. Particularly relevant if there is angioedema. • Autoantibodies, particularly antinuclear factor: positive in systemic lupus erythematosus (SLE) and often positive in urticarial vasculitis. Other autoimmune diseases, such as Fig. 29.39 Urticaria. Erythema, reflecting dilated dermal vessels, and oedema (with upper dermal oedema obscuring the erythema centrally) are evident. Note the absence of epidermal changes. Fig. 29.40 Pathogenesis of urticaria. Mast cell degranulation occurs in a variety of ways. (1) Type I hypersensitivity causes degranulation. (2) Spontaneous mast cell degranulation in chronic urticaria. (3) Chemical mast cell degranulation. (4) Autoimmunity, with IgE antibodies directed against IgE receptors or IgE itself. Histamine and the leukotrienes are especially relevant mediators in urticaria. Heparin release is probably not a major factor in urticaria but plays a role in the osteoporosis that can occur in systemic mastocytosis. (IgE = immunoglobulin E; NSAID = non-steroidal anti-inflammatory drug) Histamine Inflammatory mediators

• prostaglandins

• leukotrienes

• chemotactic cytokines

for eosinophils and

neutrophils Heparin 5-hydroxytryptamine Proteases Aspirin NSAIDs Morphine Codeine Benzoic acid Mast cell Granules High-affinity IgE receptor (FcεRI) Antigen Autoantibody to FcεRI and IgE Increased capillary permeability Key IgE

29.24 Causes of urticaria Acute and chronic urticaria • Autoimmune: due to antibodies that cross-link the IgE receptor on mast cells • Allergens in foods and inhalants • Contact allergens: latex, animal saliva • Drugs: see Box 29.35 (p. 1266) • Physical stimuli: heat, cold, pressure, sun, sweat, water • Infections: intestinal parasites, hepatitis • Others: SLE, pregnancy, thyroid disease • Idiopathic: chronic spontaneous urticaria and angioedema Urticarial vasculitis • Hepatitis B, SLE, idiopathic (IgE = immunoglobulin E; SLE = systemic lupus erythematosus) be papules, macules, patches and plaques – Fig. 29.39) last for less than 24 hours; if they persist, urticarial vasculitis needs to be considered. Clarification of the duration of urticaria can be achieved by drawing around the weal and re-assessing 24 hours later. History-taking should probe for possible causes, including medications (Box 29.24). Physical triggers can also be assessed in challenge testing, such as eliciting dermographism or pressure testing. Enquiry about family history and medication, particularly ACE inhibitors, is important in angioedema. Examination may be unremarkable or weals may be evident (Fig. 29.39). The skin should be stroked firmly with an orange stick in order to ascertain whether dermographism is present or not. Mast cell degranulation and release of histamine and other vasoactive mediators is the basis of urticaria (Fig. 29.40). Chronic spontaneous urticaria (previously called ‘chronic idiopathic’ or ‘chronic ordinary’ urticaria) is the most common chronic urticaria and has an autoimmune pathogenesis in some cases.

1254 • DERMATOLOGY Toxic epidermal necrolysis Toxic epidermal necrolysis (TEN) is a medical emergency, as the extensive mucocutaneous blistering is associated with a high mortality rate. It is usually drug-induced (see Box 29.35, p. 1266), with anticonvulsants, sulphonamides, sulphonylureas, NSAIDs, allopurinol and antiretroviral therapy often implicated. Usually 1–4 weeks after drug commencement, the patient becomes systemically unwell and often pyrexial. Erythema and blistering develop, initially on the trunk but rapidly involving all skin; an early warning sign is cutaneous pain. Sheets of blisters coalesce and denude, and the underlying skin is painful and erythematous (Fig. 29.41). Gentle lateral pressure on stroking the skin results in epidermal detachment (Nikolsky sign), demonstrating the severity of skin fragility. Mucous membrane involvement and blistering are usual. Blistering of skin and mucosae may be haemorrhagic. A disease severity score (Box 29.26) is used to predict outcome. The main differential diagnosis is staphylococcal scalded skin syndrome (p. 1236), although the diagnosis is usually obvious in an adult patient with a culprit drug. There is often overlap with Stevens–Johnson syndrome and targetoid lesions, especially on palms and soles, may be evident. Skin rheumatoid arthritis and autoimmune hepatitis or thyroid disease, may be associated. • Complement C3 and C4 levels: if these are low due to complement consumption, C1 esterase inhibitor activity should be measured. • Infection screen: hepatitis screen and HIV may be indicated. • Skin biopsy: if urticarial vasculitis is suspected. • Challenge tests: to confirm physical urticarias, such as dermographism, pressure, heat, cold. Management Removal or treatment of any trigger is essential, although this may not be identified in the majority of cases. Urticaria may be precipitated by aspirin, NSAIDs, codeine and opioids, and it is advisable to suggest alternatives such as paracetamol. In chronic urticaria, non-sedating antihistamines, such as fexofenadine, loratadine or cetirizine, are usually beneficial. If there is lack of response after 2 weeks, an alternative non-sedating antihistamine should be used and an H2-blocker, such as cimetidine or ranitidine, can be added. Mast cell stabilisers or leukotriene receptor antagonists, such as montelukast, can be used for more recalcitrant disease. For chronic urticaria, narrowband UVB phototherapy is valuable and has proven efficacy. Systemic glucocorticoids are widely prescribed for urticaria but are not indicated in the majority of cases. If systemic glucocorticoids are used, efficacy may be seen only at relatively high doses and they are appropriate only for occasional short courses in the acute setting, usually in association with angioedema. Patients with a history of life-threatening anaphylaxis, as in peanut or wasp sting allergy, should carry a self-administered adrenaline (epinephrine) injection kit. The management of anaphylaxis and hereditary angioedema is discussed on pages 76 and 87. The IgE monoclonal antibody omalizumab may be effective in patients with severe recalcitrant urticaria. Bullous diseases Blistering can occur at any level in the skin and there are a variety of different presentations, depending on the underlying defect and level of involvement. Knowledge of the molecular basis of many blistering disorders has advanced considerably through understanding of the basic processes of cell adhesion and studies of rare genetic blistering disorders, particularly epidermolysis bullosa (Box 29.25). This section concentrates on primary blistering skin diseases. Fig. 29.41 Toxic epidermal necrolysis. Note the extensive erythema, oedema and epidermal loss secondary to carbamazepine. 29.25 Classification of epidermolysis bullosa Type Mode of inheritance Level of blister* Abnormality Simple Autosomal dominant Epidermal basal cell Keratins 5 and 14 Junctional Autosomal recessive Lamina lucida Laminin-5 and α6β4 integrin Dystrophic Autosomal dominant and recessive Dermis below lamina densa Collagen VII *See Figure 29.1 (p. 1213). 29.26 Disease severity score for toxic epidermal necrolysis: SCORTEN Factor • Age > 40 years • Heart rate > 120 beats/min • Cancer or haematological malignancy • Involved body surface area > 10% • Blood urea > 10 mmol/L (28 mg/dL) • Serum bicarbonate < 20 mmol/L • Blood glucose ≥ 14 mmol/L (252 mg/dL) Mortality rates • 0–1 factor present = 3% • 2 factors = 12% • 3 factors = 35% • 4 factors = 58% • ≥ 5 factors = 90% From Bastuji-Garin S, Fouchard N, Bertocchi M, et al. SCORTEN: a severity-ofillness score for toxic epidermal necrolysis. J Invest Dermatol 2000; 115:149–153.

Bullous diseases • 1255

Pathogenesis The disease is caused by autoantibodies (BP-230 and BP-180) directed against the hemi-desmosomal BP antigens, BPAg-1 (intracellular) and BPAg-2 (transmembranous type XVII collagen), respectively. Antibody–antigen binding initiates complement activation and inflammation, with hemi-desmosomal damage and subepidermal blistering. Clinical features There is often a lengthy prodrome of an itchy, urticated, erythematous rash prior to the development of tense bullae (Fig. 29.42A). Milia (definition: small epidermal keratin cysts) may develop due to basement membrane disruption. Mucosal involvement is uncommon. 29.27 Age of onset in immunobullous skin disorders Disease Age Pemphigus vulgaris 40–60 years Pemphigus foliaceus Any age (endemic form in parts of Brazil and South Africa, from teenage years on) Bullous pemphigoid Sixties and over Dermatitis herpetiformis Young, associated with coeliac disease Linear IgA disease Any age Pemphigoid gestationis Pregnant females Epidermolysis bullosa acquisita Any age Bullous lupus erythematosus Young black females 29.28 Clinical and investigation findings in the immunobullous disorders Disease Site of blisters Nature of blisters Mucous membrane involvement Antigen Circulating antibody (indirect IF) Fixed antibody (direct IF) Pemphigus vulgaris Trunk, head Flaccid, fragile, many erosions 100% Desmoglein-1 and 3 (120 kD) IgG IgG, C3 intercellular (epidermal) Pemphigus foliaceus Trunk Often not present, multiple erosions, may mimic dermatitis No Desmoglein-1 IgG IgG, C3 intercellular (epidermal) Bullous pemphigoid Trunk, flexures and limbs Tense, milia as blisters resolve Occasional BP-230 and 180 IgG (70%) IgG, C3 at BMZ Dermatitis herpetiformis Elbows, lower back, buttocks Excoriated and often not present No Unknown Anti-endomysial and tissue transglutaminase Granular IgA in papillary dermis Linear IgA disease Widespread Tense, often annular configuration, ‘string of beads’ Frequent Unknown 50% have low titres of circulating antibody Linear IgA at BMZ Pemphigoid gestationis Periumbilical and limbs Tense, milia as blisters resolve Rare Collagen XVII (part of hemi-desmosome, BP-180) Circulating antibodies to BP-180 (type XVII collagen) (and BP-230) C3 at BMZ Epidermolysis bullosa acquisita Widespread Tense, scarring, milia Common (50%) Type VII collagen IgG (anti-type VII collagen) IgG at BMZ Bullous lupus erythematosus Widespread Tense Rare Type VII collagen Anti-type VII collagen IgG, IgA, IgM at BMZ (BMZ = basement membrane zone; IF = immunofluorescence; Ig = immunoglobulin) snip may allow early diagnosis. If there is diagnostic doubt, then full-thickness skin biopsy should be undertaken for histology and direct immunofluorescence in order to exclude immunobullous or other diagnoses. Identification and discontinuation of the causative drug are essential. Sepsis and multi-organ failure are major risks. Intensive care in a dedicated dermatology ward or intensive care or burns unit is of paramount importance. Treatment is supportive, with regular sterile dressings and emollients, careful attention to fluid balance and treatment of infection if it develops. Urethral and ocular involvement is common and must be looked for and treated symptomatically. Ocular and urethral scarring can be problematic in survivors. There is no conclusive evidence that intravenous immunoglobulins, systemic glucocorticoids or ciclosporin improve outcomes and survival. Immunobullous diseases There are various subtypes of immunobullous disease that affect patients of different ages and have clinical characteristics (Box 29.27). The key investigation is an elliptical biopsy taken from the edge of a recent blister (Box 29.28). The sample is halved: one half is put in formalin for subsequent histology, while the other is sent fresh for direct immunofluorescence. Serum should also be sent for indirect immunofluorescence in suspected immunobullous disease (p. 1215). Bullous pemphigoid Bullous pemphigoid (BP) is the most common immunobullous disease and occurs worldwide. It is a disease of the elderly, with an average age of onset of 65 years; males and females are equally affected.

1256 • DERMATOLOGY Pathogenesis The cause is IgG1 and IgG4 autoantibodies, directed against desmogleins-1 and 3, resulting in intra-epidermal blistering. The syndrome may occur spontaneously or be secondary to drugs such as penicillamine or captopril and underlying malignancy (paraneoplastic pemphigus). Pemphigus foliaceus is a very superficial form, in which antibodies are directed against desmoglein-1 only and affect just the most superficial epidermis. Clinical features Skin and mucosae are usually involved, although disease may be restricted to mucosae only, which may be severely affected. Due to the higher level of split within the epidermis, the blisters are flaccid, easily ruptured and often not seen intact. Erosions are common and the Nikolsky sign is positive. The trunk is usually affected. The condition is associated with significant morbidity and mortality. Investigations The diagnosis can be made by skin biopsy, which shows intra-epidermal blistering and acantholysis, with positive direct immunofluorescence for IgG (usually IgG1 or IgG4) and C3 at the periphery of keratinocytes, giving a ‘chicken wire’ appearance within the epidermis. The titres of circulating epidermal autoantibodies can also be used to monitor disease activity. Investigations should screen for associated autoimmune disease or malignancy if paraneoplastic pemphigus is suspected. Management Pemphigus is more difficult to treat than BP and high-dose systemic glucocorticoids such as prednisolone (0.5–1.0 mg/kg/ day) are usually required. Azathioprine and cyclophosphamide are most often used as glucocorticoid-sparing agents but a range of other immunosuppressants may be considered for severe recalcitrant disease, including methotrexate, ciclosporin, mycophenolate mofetil, intravenous immunoglobulins, plasma exchange, extracorporeal photopheresis and rituximab. Often, long-term treatment is required to prevent relapse. Dermatitis herpetiformis Dermatitis herpetiformis (DH) is an autoimmune blistering disorder that is strongly associated with coeliac disease (CD). While fewer than 10% of individuals with CD develop DH, almost all patients with DH have evidence of partial villous atrophy on intestinal biopsy, even if they have no gastrointestinal symptoms (p. 806). It is unclear why some CD patients develop DH and others do not. Although DH is a bullous disease, intact vesicles and blisters are seldom seen, as the condition is so pruritic that excoriations on extensor surfaces of arms, knees, buttocks, shoulders and scalp may be the only signs. The diagnosis can be made by skin biopsy, which shows subepidermal vesiculation in the dermal papillae and a neutrophil- and eosinophil-rich infiltrate. Direct immunofluorescence shows granular IgA in the papillary dermis. Anti-endomysial antibodies and tissue transglutaminase should be assessed and jejunal biopsy undertaken if indicated. The condition usually responds to a gluten-free diet but, if not, dapsone can also be used. Linear IgA disease This occurs in children (chronic bullous disease of childhood) and adults, and is usually self-limiting, although it can be active for a few years. Drugs, notably vancomycin, can be a secondary cause. Blisters Investigations The diagnosis can be made by skin biopsy, which shows subepidermal blistering with an eosinophil-rich inflammatory infiltrate. Direct immunofluorescence demonstrates the presence of IgG and C3 at the basement membrane (Fig. 29.42B). Indirect immunofluorescence may show positive titres of circulating anti-epidermal antibodies. Distinction from epidermolysis bullosa acquisita requires immunofluorescence studies using the patient’s serum on salt-split skin. In BP, the immunoreactants localise to the epidermal side (hemi-desmosome) of split skin, whereas in epidermolysis bullosa acquisita they localise to the base of the split (type VII collagen/anchoring fibrils). Management Very potent topical glucocorticoids are effective and may be sufficient in frail elderly patients; they need to be applied to all sites, however, and not just lesional skin. Tetracyclines, such as doxycycline, have an important role and may limit the use of systemic glucocorticoids. However, most patients with extensive disease require systemic glucocorticoids (0.75 mg/ kg/day or less), often combined with immunosuppressants as glucocorticoid-sparing agents. In severe refractory disease, other therapies, such as intravenous immunoglobulin or rituximab, are sometimes used but are of unproven efficacy. The condition often burns out over a few years. Pemphigus Pemphigus is less common than BP and patients tend to be younger. Fig. 29.42 Bullous pemphigoid. A Large, tense, unilocular blisters. B Immunofluorescence on salt-split skin, showing a subepidermal blister and linear IgG and C3 deposition at the basement membrane zone. A B Epidermis Split Dermis

Pigmentation disorders • 1257

of patches of hypopigmentation. A positive family history of vitiligo is relatively common in those with extensive disease, and this type is also associated with other autoimmune diseases. Trauma and sunburn may (through the Köbner phenomenon) precipitate the appearance of vitiligo. It is thought to be the result of cell-mediated autoimmune destruction of melanocytes but why some areas are targeted and others are spared is unclear. Clinical features Generalised vitiligo is often symmetrical and involves hands, wrists, feet, knees and neck, as well as areas around body orifices (Fig. 29.43). The hair of the scalp, beard, eyebrows and lashes may also depigment. Segmental vitiligo is restricted to one part of the body but not necessarily a dermatome. The patches of depigmentation are sharply defined, and in Caucasians may be surrounded by hyperpigmentation. Spotty perifollicular pigment may be seen within the depigmentation and is often the first sign of repigmentation. There is no history or evidence of inflammation within the patches, which may be helpful in distinguishing vitiligo from post-inflammatory hypopigmentation. Sensation in the depigmented patches is normal (unlike in tuberculoid leprosy, p. 267). Wood’s light examination enhances the contrast between pigmented and non-pigmented skin. The course is unpredictable but most patches remain static or enlarge; a few repigment spontaneously. Management Protecting the patches from excessive sun exposure with clothing or sunscreen may be helpful to avoid sunburn. Camouflage cosmetics may be beneficial, particularly in those with dark skin. In fair skin, photoprotection and cosmetic cover may be all that is required. Very potent or potent topical glucocorticoids have limited efficacy with respect to repigmentation. Topical pimecrolimus or tacrolimus may also have a role as a glucocorticoid-sparing agent. Phototherapy with narrowband UVB or PUVA can also be used. Narrowband UVB is the most effective repigmentary treatment available for generalised vitiligo, but even very prolonged courses often do not produce a satisfactory outcome. The absence of leucotrichia (white hairs in the area of vitiligo) and the presence of a trichrome pattern (three colours – normal skin colour, hypopigmentation and depigmentation) are good prognostic features. Vitiligo on the face, trunk and proximal limbs is more likely to respond than that on hands and feet. can arise on erythematous, urticated or otherwise normal-looking skin and often form an annular configuration at the edge of the lesion: ‘clusters of jewels’ (herpetiform) and ‘string of beads’ (annular/ polycyclic). Mucosal involvement is common and ophthalmology input important, as corneal scarring is a risk with longstanding disease. Linear IgA is seen at the basement membrane on direct immunofluorescence and localises to either roof or floor of salt-split skin. Dapsone, sulfapyridine, prednisolone, colchicine or intravenous immunoglobulin may be effective. Epidermolysis bullosa acquisita This chronic blistering disease affects skin and mucosae, and scarring, hair loss and nail dystrophy may be problematic. Blisters often follow trauma and milia develop. It can be very difficult to distinguish from other immunobullous diseases, such as bullous pemphigoid. It is caused by an IgG antibody to type VII collagen, which provokes subepidermal blistering and a mixed inflammatory infiltrate, although the latter may not be prominent. Direct immunofluorescence on perilesional skin shows IgG and C3 at the dermo-epidermal junction and pattern analysis may be helpful in distinction from bullous pemphigoid. Indirect immunofluorescence microscopy on salt-split normal human skin typically shows IgG and IgA in the floor of the artificially induced blister, whereas in BP antibody localisation would be to the roof of the blister. Epidermolysis bullosa acquisita is very difficult to treat, as it often does not respond well to immunosuppressants. Mainstays of treatment include systemic glucocorticoids in combination with dapsone or colchicine. Other immunosuppressive approaches may be required and include ciclosporin, azathioprine, immunoglobulins, plasmapheresis and rituximab. The condition may be associated with inflammatory bowel disease, rheumatoid arthritis, multiple myeloma and lymphoma, and thus associated comorbidities should be sought. Porphyria cutanea tarda and pseudoporphyria These conditions may also cause blistering (see Boxes 29.9 and 29.35, pp. 1221 and 1266). Porphyria is discussed in more detail on page 378. Pigmentation disorders Decreased pigmentation Disorders causing hypopigmentation and/or depigmentation include: • vitiligo • albinism • pityriasis alba: depigmented areas on the face, particularly in children, with or without scale and usually considered to be eczematous • pityriasis versicolor (p. 1240): hypopigmentation or, less commonly, hyperpigmentation can occur • idiopathic guttate hypomelanosis: multiple small areas of depigmentation arising in chronically sun-exposed skin • rarely, phenylketonuria (p. 369) and hypopituitarism. Vitiligo Vitiligo is an acquired condition affecting 1% of the population worldwide. Focal loss of melanocytes results in the development Fig. 29.43 Vitiligo. Symmetrical localised patches of depigmented skin.

1258 • DERMATOLOGY • Photo-exposed site hyperpigmentation: occurs in some of the porphyrias but can also be drug-induced. • Drug-induced pigmentation (Box 29.29): may be diffuse or localised. It is not always due to hypermelanosis but sometimes is caused by deposition of the drug or a metabolite. • Focal hypermelanosis: seen in lesions such as freckles and lentigines, characterised by focal areas of increased pigmentation. Establishing the cause is important. Photoprotection may minimise the risk of increasing pigmentation. Topical hydroquinone preparations can be used for skin lightening in some types of hyperpigmentation, although caution is required, particularly in darker skin types. Hair disorders These can be subdivided into disorders that cause loss of hair (alopecia) or excessive hair growth (hypertrichosis and hirsutism). Alopecia Alopecia is characterised by loss of hair. It can be further subdivided into localised and diffuse, and into scarring and non-scarring subtypes (Box 29.30). Pathogenesis Alopecia can be observed in association with inflammatory disorders that cause scarring (lichen planus, discoid lupus) and others that do not cause scarring (tinea capitis, psoriasis, seborrhoeic eczema). These conditions are discussed elsewhere. Alopecia areata has an autoimmune basis and there is a strong genetic component, with a family history in approximately 20% of cases. In addition to atopy, it is associated with other autoimmune diseases, particularly thyroid disease, and with Down’s syndrome. The cause of androgenetic alopecia is unclear but likely to be multifactorial, with genetic, hormonal and end-organ receptor sensitivity to the factors implicated. Clinical features Alopecia areata This usually presents with well-defined, localised, noninflammatory, non-scarring patches of alopecia, usually on the Exceptionally, depigmentation of normal non-lesional skin or a surgical approach with autologous melanocyte transfer, using a range of techniques including split-skin grafts and blister roof grafts, is sometimes used on dermabraded recipient skin in specific severe cases. The impact of vitiligo differs markedly between populations. In the Indian subcontinent, the effects are more readily discernible than in pale-skinned individuals in northern Europe. Depigmentation is also seen in leprosy, which means that individuals with vitiligo are often stigmatised. The emotional impact of vitiligo may be immense; psychological support is essential and is important in conveying realistic expectations of possible treatment approaches. Oculocutaneous albinism Albinism results from a range of genetic abnormalities that lead to reduced melanin biosynthesis in the skin and eyes; the number of melanocytes is normal (in contrast to vitiligo). Albinism is usually inherited as an autosomal recessive trait and there are several different types and presentations. Type 1 albinism is due to a defect in the tyrosinase gene, whose product is rate-limiting in the production of melanin. Affected individuals have an almost complete absence of pigment in the skin and hair at birth, with consequent pale skin and white hair, and failure of melanin production in the iris and retina. Patients have photophobia, poor vision not correctable with refraction, rotatory nystagmus, and an alternating strabismus associated with abnormalities in the decussation of nerve fibres in the optic tract. A second form of albinism is due to a defect in the P gene, which encodes an ion channel protein in the melanosome. Patients may have gross reduction of melanin in the skin and in the eyes, but may be more mildly affected than type 1 albinos. Establishing the subtype of albinism requires genetic analysis, as there is considerable phenotypic heterogeneity. Oculocutaneous albinos are at grossly increased risk of sunburn and skin cancer. In equatorial regions, many die from squamous cell carcinoma or, more rarely, melanoma in early adult life. Interestingly, they may develop pigmented melanocytic naevi and freckle in response to sun exposure. Management Strict photoprotection (p. 1221), with sun avoidance (including occupational exposure), clothing, hats and sunscreens, is important. Early diagnosis and treatment of skin tumours is essential. Increased pigmentation • Diffuse hyperpigmentation: most commonly due to hypermelanosis but other pigments may be deposited in the skin, such as orange discoloration with carotenaemia and bronze with haemochromatosis (p. 895). • Endocrine pigmentation: may occur in several conditions. Melasma (chloasma) describes discrete patches of facial pigmentation that occur in pregnancy and in some women taking oral contraceptives. The mechanism for this localised increased hormonal sensitivity is unknown. Diffuse pigmentation, sometimes worse in the skin creases and mucosae, may be a feature of Addison’s disease (p. 671), Cushing’s syndrome (p. 666), Nelson’s syndrome (p. 669) and chronic renal failure due to increased levels of pituitary melanotrophic peptides, including adrenocorticotrophic hormone (ACTH; p. 669). 29.29 Drug-induced pigmentation Drug Appearance Amiodarone Photo-exposed sites, slate-grey Arsenic Diffuse bronze pigmentation Raindrop depigmentation Bleomycin Usually flexural, brown Busulfan Diffuse brown Chloroquine Photo-exposed sites, blue-grey Clofazimine Red Mepacrine Yellow Minocycline Temples, shins, gingiva, sclera, scar sites, slate-grey Phenothiazines Photo-exposed sites, slate-grey Psoralens Photo-exposed sites, brown

Hair disorders • 1259

Androgenetic alopecia Male-pattern baldness is physiological in men over 20 years old, although it can also occur in teenagers. It is also found in women, particularly post-menopausal ones. Characteristically, this involves bitemporal recession initially and subsequent involvement of the crown (‘male pattern’), although it is often diffuse in women. Investigations Important investigations include full blood count, renal and liver function tests, iron studies, thyroid function, autoantibody screen and syphilis serology, as several systemic diseases, particularly iron deficiency and hypothyroidism, can cause diffuse non-scarring alopecia. Hair pull tests may help to establish the ratio of anagen to telogen hairs but require expertise for interpretation. Scrapings and pluckings should be sent for mycology if there is localised inflammation. Scalp biopsy and direct immunofluorescence of scarring alopecia may confirm a diagnosis of lichen planus or discoid lupus erythematosus but expert interpretation is needed. Management Any underlying condition, such as iron deficiency, should be treated and may result in clinical improvement. Alopecia can have a major impact on quality of life and psychological support is usually required. It is particularly important to establish realistic expectations. Hair may spontaneously regrow in alopecia areata and it may be appropriate to offer no active intervention as, while some treatments may induce some hair regrowth, there is no evidence that any treatment fundamentally alters the course of the disease. There may be some response to topical or intralesional glucocorticoids. PUVA or immunotherapy with diphencyprone may be effective, with evidence of hair regrowth, but there is a risk of relapse on discontinuation of treatment. Short courses of systemic glucocorticoids are occasionally used in an attempt to limit acutely progressive extensive alopecia areata but should not be used in the long term; the risk of relapse on discontinuation is high. Ongoing trials of Janus kinase (JAK) inhibitors may provide future hope for patients with this difficult disease. Some males with androgenetic alopecia may be helped by systemic finasteride. Topical minoxidil can be used in males and females with androgenetic alopecia but, if an effect is obtained, treatment must be continued and is expensive. In females, anti-androgen therapy, such as cyproterone acetate, can be used. Wigs are often appropriate for extensive alopecia. Scalp surgery and autologous hair transplants are expensive but can be used for androgenetic alopecia. Hypertrichosis Hypertrichosis is a generalised or localised increase in hair and may be congenital or acquired. It can be primary or secondary: for example, to drugs such as ciclosporin, minoxidil or diazoxide, malignancy or eating disorders. Laser therapy or eflornithine, which inhibits ornithine decarboxylase and arrests hair growth while it is being used, may be helpful. When the hypertrichosis follows a male pattern, it is called hirsutism. Hirsutism Hirsutism is the growth of terminal hair in a male pattern in a female (p. 657). The cause of most cases is unknown and, while it may occur in hyperandrogenism, Cushing’s syndrome and polycystic ovary syndrome, only a small minority of patients have scalp (Fig. 29.44). Pathognomonic ‘exclamation mark’ hairs are seen (broken hairs, tapering towards the scalp) during active hair loss. A diffuse pattern can uncommonly occur on the scalp. Eyebrows, eyelashes, beard and body hair can be affected. Alopecia totalis describes complete loss of scalp hair, and alopecia universalis is complete loss of all hair. Nail pitting may occur (p. 1261). Spontaneous regrowth is usual for small patches of alopecia but the prognosis is less good for larger patches, more extensive involvement, early onset and an association with atopy. Fig. 29.44 Alopecia areata. The relatively extensive involvement and encroachment on posterior hairline are poor prognostic features. 29.30 Classification and causes of alopecia Localised Diffuse Non-scarring Tinea capitis Alopecia areata Androgenetic alopecia Traumatic (trichotillomania, traction, cosmetic) Syphilis Androgenetic alopecia Telogen effluvium Hypothyroidism Hyperthyroidism Hypopituitarism Diabetes mellitus HIV disease Nutritional (especially iron) deficiency Liver disease Post-partum Alopecia areata Syphilis Drug-induced: chemotherapy, retinoids Scarring Discoid lupus erythematosus Lichen planopilaris Herpes zoster Pseudopelade Tinea capitis/kerion Morphoea (en coup de sabre) Idiopathic Developmental defects Discoid lupus erythematosus Radiotherapy Folliculitis decalvans Lichen planopilaris

1260 • DERMATOLOGY differential is subungual melanoma, although rapid onset, lack of nail-fold involvement and proximal clearing as the nail grows are clues to the diagnosis of haematoma. If there is diagnostic doubt, a biopsy may be needed. Nail involvement in skin diseases • Dermatophyte infection/onychomycosis: this is described on page 1240. • Psoriasis: nail involvement is common (see Fig. 29.35B, p. 1249). a demonstrable hormonal abnormality. Psychological distress is often significant and oral contraceptives containing an antiandrogen such as cyproterone acetate, laser therapy or topical eflornithine may be beneficial. Nail disorders The nails can be affected by both local and systemic disease. The nail apparatus consists of the nail matrix and the nail plate, which arises from the matrix and lies on the nail bed (Fig. 29.45). The cells of the matrix and, to a lesser extent the bed, produce the keratinous plate. Important information may be obtained from nail-fold examination, including dilated capillaries and ragged cuticles in connective tissue disease (Fig. 29.46) and the boggy inflammation of paronychia. The latter commonly occurs chronically in individuals undertaking wet work, in those with diabetes or poor peripheral circulation, and subsequent to increased cosmetic nail procedures and vigorous manicuring. Normal variants Longitudinal ridging and beading of the nail plate occur with age. White transverse patches (striate leuconychia) are often caused by airspaces within the plate. Nail trauma • Nail biting/picking is a very common habit. Repetitive proximal nail-fold trauma (often involving the thumb nail) results in transverse ridging and central furrowing of the nail. • Chronic trauma from poorly-fitting shoes and sport can cause thickening and disordered growth of the nail (onychogryphosis) and subsequent ingrowing toenails. • Splinter haemorrhages are fine, linear, dark brown longitudinal streaks in the plate (see Fig. 16.89, p. 529). They are usually caused by trauma, especially if distal. Uncommonly, they can occur in nail psoriasis and are also a hallmark of infective endocarditis. • Subungual haematoma is red, purple or grey–brown discoloration of the nail plate, usually of the big toe (Fig. 29.47). These haematomas are usually due to trauma, although a history of this may not be clear. The main Fig. 29.45 The nail plate and bed. Arrows indicate the direction of nail growth. Fig. 29.46 Dermatomyositis. A Photo-aggravation. B Note the prominent periungual involvement. Erythema, dilated and tortuous capillaries in the proximal nail fold, and ragged cuticles are features of connective tissue disease. A B Fig. 29.47 Subungual haematoma. Hyponychium Nail bed Nail plate Matrix Proximal nail fold Cuticle Distal phalanx

Skin disease in general medicine • 1261

Skin disease in general medicine Many skin conditions present to other medical specialties. These are listed in Box 29.31 and the most common ones that are not discussed elsewhere are detailed below. Conditions involving cutaneous vasculature Vasculitis Vasculitic involvement of the skin usually presents as palpable purpura (see Fig. 24.53, p. 1042). The diagnosis is confirmed by skin biopsy, along with histology and immunofluorescence examination. Underlying causes and their treatment are discussed on page 1040. Pyoderma gangrenosum The initial lesion of pyoderma gangrenosum (PG) is usually a painful, tender, inflamed nodule or pustule, which breaks down centrally and rapidly progresses to an ulcer with an indurated, undermined purplish or pustular edge (Fig. 29.49). Lesions may be single or multiple and are classified as ulcerative, pustular, bullous or vegetative. PG usually occurs in adults and, although it may occur in isolation, is usually associated with underlying disease, particularly inflammatory bowel disease, inflammatory arthritis, blood dyscrasias, immunodeficiencies and HIV infection. Investigation should be made with these associations in mind. The diagnosis is largely clinical, as histology is not specific. Analgesia, treatment of secondary bacterial infection and supportive • Eczema: nails may be shiny due to rubbing skin. Fine pitting can occur. If there is periungual eczema, the nail may become dystrophic, with thickening and transverse ridging. Paronychia is common. • Lichen planus: there may be longitudinal ridging and thinning of the nail, giving a sandpaper texture (trachyonychia), erythematous streaks (erythronychia), subungual hyperkeratosis, pigmentation and, in severe cases, pterygium (splitting of nail due to central fibrosis and scarring, giving a winged appearance) and a destructive nail dystrophy. • Alopecia areata: nail-plate pitting and trachyonychia can occur. Nail involvement in systemic disease The nails may be affected in many systemic diseases and important examples are detailed below: • Beau’s lines: horizontal ridges/indentations in nail plate occur simultaneously in all nails (Fig. 29.48B). They typically follow a systemic illness and are thought to be due to temporary growth arrest of cells in the nail matrix; they subsequently migrate out as the nail grows. Normal nail growth is approximately 0.1 mm/day for fingers and 0.05 mm/day for toes, so the timing of the systemic upset can usually be estimated by the position of the Beau’s lines. • Koilonychia: this concave or spoon-shaped nail-plate deformity is caused by iron deficiency (Fig. 29.48C). • Clubbing: in the early stages, the angle between the proximal nail and nail fold is lost. In its more established form, there may be swelling of the distal digits (Figs 29.48D and E) or toes. Causes include bronchogenic carcinoma, asbestosis (especially with mesothelioma), suppurative or fibrosing lung disease, cyanotic congenital heart disease, infective endocarditis, inflammatory bowel disease, biliary cirrhosis and thyrotoxicosis; rarely, clubbing can be familial or idiopathic. • Nail discoloration: whitening may occur in hypoalbuminaemia. ‘Half-and-half’ nails (white proximally and red/brown distally) may be found in renal failure. Antimalarials and some other drugs occasionally discolour nails. Nail involvement in congenital disease Nails can be affected in congenital diseases, such as pachyonychia congenita, a rare, usually autosomal dominant, condition caused by mutations in differentiation-specific keratin genes 6A, 6B, 16 and 17. This results in palmoplantar keratoderma and gross nail discoloration and thickening, due to subungual hyperkeratosis, from birth. Fig. 29.48 The nail in systemic disease. A Normal nail. B Beau’s line. C Koilonychia. D and E Digital clubbing. A B C D E 29.31 Skin problems in general medicine Primary skin problems • Cellulitis • Vasculitis • Leg ulcers • Pressure sores Skin involvement in multisystem disease • Genetic: neurofibromatosis, tuberous sclerosis • Xanthomas • Amyloidosis • Porphyria • Sarcoidosis • Systemic lupus erythematosus • Systemic sclerosis Non-specific and variable skin reactions to systemic disease • Urticaria • Erythema multiforme • Annular erythemas • Erythema nodosum • Pyoderma gangrenosum • Sweet’s syndrome • Generalised pruritus Skin conditions associated with malignancy • Dermatomyositis • Generalised pruritus • Acanthosis nigricans • Superficial thrombophlebitis Skin problems associated with specific medical disorders • Liver: generalised pruritus, pigmentation, spider naevi, palmar erythema, nail clubbing • Kidney: generalised pruritus, uraemic frost, pigmentation • Diabetes mellitus: necrobiosis lipoidica, diabetic dermopathy • Cutaneous Crohn’s disease Skin problems secondary to treatment of systemic disease • Drug eruptions Miscellaneous • Granuloma annulare • Morphoea

1262 • DERMATOLOGY Connective tissue disease Lupus erythematosus This autoimmune disorder can be subdivided into systemic lupus erythematosus (SLE) and cutaneous lupus, which includes discoid lupus erythematosus (DLE) and subacute cutaneous lupus erythematosus (SCLE). The features of SLE are discussed on page 1035. Drug-induced DLE and SCLE should always be considered (see Box 24.78, p. 1057, and Boxes 29.34 and 29.35 below). DLE typically presents as scaly red plaques with follicular plugging, usually on photo-exposed sites of the face, head and neck, which resolve with scarring and pigmentary change. If the scalp is involved, scarring alopecia usually occurs (Fig. 29.50). Most patients with DLE do not develop SLE. Patients with SCLE may have extensive cutaneous involvement, usually aggravated by sun exposure, with an annular, polycyclic or papulosquamous eruption. Systemic involvement is uncommon and the prognosis usually good. There is a strong association with antibodies to Ro/SS-A antigen. A diagnosis of cutaneous lupus is confirmed by histopathology and direct immunofluorescence. Cutaneous lupus may respond to topical glucocorticoids, antimalarials or immunosuppressants. Antimalarials and photoprotection are important mainstays in the management of cutaneous lupus, and systemic immunosuppression may be required for resistant disease. Paradoxically, low-dose UVA1 phototherapy can be effective for lupus. Systemic sclerosis This autoimmune multisystem disease presents with severe Raynaud’s syndrome, digital ulcers and skin fibrosis. Dilated nail-fold capillaries and ragged cuticles are frequent. The clinical features and management are described on page 1037. Morphoea Morphoea is a localised cutaneous form of scleroderma that can affect any site at any age. It usually presents as a thickened dressings are important. Systemic treatment with glucocorticoids, dapsone, ciclosporin or other immunosuppressants is often required. Tetracyclines may be added for their anti-inflammatory effects. Treatment with TNF-α inhibitors and ustekinumab may be effective in severe recalcitrant PG. Once healing has taken place, recurrences are typically only intermittent. Other neutrophilic dermatoses These include Sweet’s acute febrile neutrophilic dermatosis and the neutrophilic dermatosis of rheumatoid disease, which are characterised by intense inflammation, mainly consisting of neutrophils, around dermal blood vessels. There can be damage to vessels (‘vasculopathy’) but usually no frank vasculitis. Pressure sores Localised, prolonged, pressure-induced ischaemia can lead to the development of pressure sores, which can occur in up to 30% of the hospitalised elderly. They are associated with considerable morbidity, mortality and expense to health services. The main risk factors are immobility, poor nutrition, local tissue hypoxia – for example, with anaemia, peripheral vascular disease, diabetes, sepsis and skin atrophy – or barrier impairment, such as in eczema. A localised area of erythema develops at sites of bony prominences (particularly sacrum, greater trochanter, ischial and calcaneal tuberosities, and lateral malleolus). This progresses to a blister and then erosion, which will develop into a deep necrotic ulcer, usually colonised by Pseudomonas aeruginosa if pressure is not alleviated. Prevention is key and involves identification of at-risk patients and regular repositioning and use of pressure-relieving mattresses. Predisposing factors, such as anaemia and poor nutrition, should be corrected. Once established, significant infection must be treated and necrotic tissue debrided. Dressings encourage granulation, although surgical intervention may sometimes be needed. Fig. 29.50 Scarring inflammatory alopecia. This patient had systemic lupus erythematosus and additional cutaneous features of scarring inflammatory discoid lupus erythematosus. Fig. 29.49 Pyoderma gangrenosum. This young patient had Crohn’s disease. Note the cribriform pattern of re-epithelialisation, which is characteristic of this condition.

Skin disease in general medicine • 1263

and plaques, infiltrative changes in scars and erythema nodosum (see Fig. 17.59, p. 609). It has been reported more commonly and may be more severe in those of African, African American or Indian ancestry. Investigation is described on page 609. Cutaneous disease may respond to topical or intralesional glucocorticoids, cryotherapy, UVA1, laser or PDT (pp. 1226–1228). Clinical features and management of systemic disease are discussed on pages 608 and 610. Cutaneous Crohn’s disease Cutaneous Crohn’s disease (p. 813) is rare but may present as perianal and peristomal infiltrative plaques, lymphoedema, sinuses or fistulae, and oral granulomatous disease. These changes are termed ‘metastatic’ Crohn’s and histology shows non-caseating granulomas. Reactive skin changes can also occur in the form of erythema nodosum and pyoderma gangrenosum (pp. 1265 and 1261). Treatment is of the underlying disease (p. 820). Porphyrias The porphyrias (described on p. 378) are a diverse group of diseases, caused by reduced or absent activity of specific enzymes in the porphyrin–haem biosynthetic pathway. Due to this loss of enzyme activity, porphyrin precursors proximal to the implicated enzyme step accumulate. If the accumulated porphyrins absorb visible light, then there will be skin features and photosensitivity, which explains why some porphyrias have skin features (porphyria cutanea tarda) and others do not (acute intermittent porphyria; p. 379). The most common skin presentations are photo-exposed site blistering, skin fragility and pain on daylight exposure. Cutaneous porphyrias: fragility and blisters Although porphyria cutanea tarda (PCT) may be genetically inherited, this is uncommon and acquired PCT is the most common porphyria worldwide. It is caused by an underlying chronic liver disease, in association with hepatic iron overload. The liver disease is often only diagnosed through investigation of the violaceous plaque, which may become hyper- or hypopigmented. Plaques can become generalised. Linear forms exist and, if in the scalp, are associated with scarring hair loss (en coup de sabre). There is usually no systemic involvement. Topical glucocorticoids or immunosuppressants or phototherapy, particularly PUVA or UVA1, can be effective, and systemic immunosuppression may be used for resistant extensive disease. Dermatomyositis Dermatomyositis is a multisystem disease, predominantly affecting skin, muscles and blood vessels. Typical cutaneous features include a violaceous ‘heliotrope’ erythema periorbitally and involving the upper eyelids, but this can sometimes affect the upper trunk, shoulders (‘shawl sign’) and limbs. Linear erythematous streaks may also be observed on the back of hands and fingers, and papules over the knuckles (Gottron’s papules). Tortuous dilated nail-fold capillaries, often best seen with a dermatoscope, and ragged cuticles are usually evident. Photo-aggravation of the cutaneous features is often prominent (see Fig. 29.46A, p. 1260). The clinical features and management are described on page 1039. Granulomatous disease Granuloma annulare This is common and may be reactive, although a trigger is usually not apparent. The hallmark is the presence of dermal granulomas, which are usually palisading and associated with alteration of dermal collagen (necrobiosis). The condition is generally asymptomatic and may present as an isolated dermal lesion with a raised papular annular edge, or may be more generalised. An association between generalised disease and diabetes has been proposed but not confirmed. Lesions often resolve spontaneously. Intralesional glucocorticoids or cryotherapy can be used for localised disease, and UVB or UVA1 phototherapy or PUVA for generalised disease. Necrobiosis lipoidica This condition has some histological features in common with granuloma annulare, although necrobiosis predominates. The lesion has a characteristic yellow, waxy, atrophic appearance, often with violaceous edge (Fig. 29.51). Underlying blood vessels are easily seen because of tissue atrophy. Necrobiosis lipoidica typically appears on the shins and is prone to ulceration after trauma. There is a strong association with diabetes: most patients with necrobiosis lipoidica have or develop diabetes, although less than 1% of diabetic patients develop necrobiosis lipoidica. Treatment is difficult and includes very potent topical or intralesional glucocorticoids, topical calcineurin inhibitors, PUVA or UVA1 phototherapy and systemic immunosuppression. Sarcoidosis This condition is characterised by the presence of non-caseating granulomas. The cause is unknown, although infectious and genetic factors have been proposed. It is usually a multisystem disease (p. 608), with skin lesions in about one-third of patients. Cutaneous features can occur in isolation and include violaceous infiltrated dermal plaques and nodules, which can affect any site but particularly digits and nose (lupus pernio), more generalised hyper- or hypopigmented or annular papules Fig. 29.51 Necrobiosis lipoidica. Atrophic yellow plaques with violaceous edges, on the shins of a patient with diabetes mellitus.

1264 • DERMATOLOGY Amyloidosis Cutaneous amyloid may present as periocular plaques in primary systemic amyloidosis (p. 81) and amyloid associated with multiple myeloma, but is uncommon in systemic amyloidosis secondary to rheumatoid arthritis or other chronic inflammatory diseases. Amyloid infiltration of blood vessels may manifest as ‘pinch purpura’ following skin trauma. Macular amyloid is more common in darker skin types and appears as pruritic grey/brown macules or patches, usually on the back. Potent topical glucocorticoids can be beneficial, although it is often treatment-resistant. Genetic disorders Neurofibromatosis This is described in detail on page 1131. Tuberous sclerosis This is an autosomal dominant condition and two genetic loci have been identified: TSC-1 (chromosome 9) encoding hamartin, and TSC-2 (chromosome 16) encoding tuberin. The hallmark is hamartomas in many systems. The classic triad of clinical features comprises learning disability, epilepsy and skin lesions but there is marked heterogeneity in clinical features. Skin changes include pale oval (ash leaf) macules that occur in early childhood; yellowish/pink papules in the mid-face (angiofibromas, ‘adenoma sebaceum’), occurring in adolescence; periungual and subungual fibromas; and connective tissue naevi (shagreen patches, often on lower back). Gum hyperplasia, retinal phakomas (fibrous overgrowths), renal, lung and heart tumours, cerebral gliomas and calcified basal ganglia may also occur. Reactive disorders Erythema multiforme Erythema multiforme has characteristic clinical and histological features and can be triggered by a variety of factors (Box 29.32) but a cause is not always identified. The disease is likely to have an immunological basis. Lesions are multiple, erythematous, annular, targetoid ‘bull’s eyes’ (Fig. 29.53) and may blister. Stevens–Johnson syndrome (pp. 1224 and 1254) is a severe form of erythema multiforme with marked blistering, mucosal involvement (mouth, eyes and genitals) and systemic upset. Identification and removal/treatment of any trigger are essential. Analgesia and topical glucocorticoids may provide symptomatic relief. Supportive care is required in Stevens–Johnson syndrome, including ophthalmology input. skin presentation and it is thus an important diagnosis not to miss. Typical features are increased skin fragility, blistering, erosions, hypertrichosis, scarring and milia occurring on light-exposed areas, particularly the backs of the hands (Fig. 29.52). Less common features include facial hypertrichosis, hyperpigmentation and morphoea-like changes. Variegate porphyria (VP) and hereditary coproporphyria (HCP) may be indistinguishable on skin features and it is important to make the correct diagnosis, as acute neurovisceral attacks, which may be drug-induced (p. 1265), can occur in VP and HCP but not in PCT. Pseudoporphyria may also be impossible to distinguish from PCT on clinical grounds but is most frequently caused by a drug (commonly naproxen; see Box 29.35) or by sunbed use; on investigation, porphyrins are normal. A PCT-like presentation may also be seen in uraemia due to renal failure, but is caused by raised porphyrins due to impaired elimination rather than an enzyme defect. Management of PCT requires removal or treatment of any underlying cause, which may involve venesection, iron chelation, very low-dose hydroxychloroquine once or twice per week and photoprotection. Cutaneous porphyria: pain on sun exposure Erythropoietic protoporphyria is caused by a genetic defect in the ferrochelatase gene that leads to ferrochelatase enzyme deficiency. It is an important diagnosis to consider. The presentation is usually in early childhood, although the diagnosis is often delayed. In part this is because, although the baby or child cries due to immediate pain on sunlight exposure, physical signs are often absent or minimal and thus a link with sunlight may not always be considered. The deficient ferrochelatase activity leads to accumulation of lipid-soluble protoporphyrins in the skin, explaining the photosensitivity manifest as pain on daylight exposure. Multiple pigment gallstones, anaemia (usually only problematic if considered to be due to iron deficiency) and, rarely, severe liver disease can occur, which may be fatal and requires liver transplantation. In addition to photoprotection, UVB phototherapy may be effective for the symptoms of photosensitivity and, more recently, the use of alpha-melanocyte-stimulating hormone (α-MSH) analogues has been explored. Abnormal deposition disorders Xanthomas Deposits of fatty material in the skin, subcutaneous fat and tendons may be the first clue to primary or secondary hyperlipidaemia (pp. 346 and p. 373). Fig. 29.52 Porphyria cutanea tarda. Skin fragility, blistering, scarring, milia and hypertrichosis on the back of hands and fingers in hepatitis C. 29.32 Provoking factors in erythema multiforme Infections • Viral: herpes simplex, orf, infectious mononucleosis, hepatitis B, HIV • Mycoplasma and other bacterial infections Drugs • Sulphonamides, penicillins, barbiturates and carbamazepine Systemic disease • Sarcoidosis, malignancy, systemic lupus erythematosus Other • Radiotherapy, pregnancy

Skin disease in general medicine • 1265

Annular erythemas This group of chronic, poorly defined, annular, erythematous and often scaly eruptions can be further subdivided and may be secondary to an identifiable cause. Erythema chronicum migrans can be associated with Lyme disease (Borrelia burgdorferi, p. 255). Erythema marginatum can occur in rheumatic fever (p. 515) or Still’s disease (p. 1040). Erythema gyratum repens typically presents as concentric circles of erythema and scale with an advancing edge and is usually associated with underlying malignancy. Erythema annulare centrifugum presents with expanding, scaly, erythematous rings, with central fading. A trigger may not be apparent but possible associations include fungal infection, drugs, autoimmune or endocrine diseases, such as lupus or thyroid disease, and malignancy, particularly haematological. An underlying trigger must be sought and removed or treated. Topical glucocorticoids or phototherapy may be helpful for chronic disease. Acanthosis nigricans Hyperkeratosis and pigmentation are typical and affected sites have a velvety texture. The flexures, especially axillae and, in dark-skinned people, sides of neck, are involved (pp. 1325, 1326 and 720). There are several types, mainly associated with insulin resistance. Most often, acanthosis nigricans is found in conjunction with obesity and regresses with weight loss. It can be associated with malignancy, usually adenocarcinoma (particularly gastric), when it is usually more extensive and pruritic, and can involve mucous membranes. Drug eruptions Virtually all drugs may have cutaneous adverse effects (Fig. 29.54) and this should be considered in the differential diagnosis of most presentations of skin disease. Drugs can exert their adverse effects via several mechanisms, which can be broadly subdivided into non-immunological and immunological (Box 29.34). Fig. 29.53 Erythema multiforme in a young woman. Herpes simplex virus infection was the trigger. 29.33 Provoking factors in erythema nodosum Infections • Bacteria: streptococci, mycobacteria, Brucella, Mycoplasma, Rickettsia, Chlamydia • Viruses: hepatitis B and infectious mononucleosis • Fungi Drugs • Sulphonamides, sulphonylureas, oral contraceptives Systemic disease • Sarcoidosis, inflammatory bowel disease, malignancy Other • Pregnancy 29.34 Types of drug eruption Non-immunological Predictable • Striae due to glucocorticoids (see Fig. 29.10, p. 1226) • Asteatosis with statins • Candidal infections with antibiotics • Worsening of psoriasis with lithium, β-blockers, antimalarials, NSAIDs • Urticaria with aspirin due to mast cell degranulation • Bradykinin-mediated angioedema due to ACE inhibitors • Doxycycline photosensitivity • Dapsone haemolysis Immunological Unpredictable • Immediate IgE-mediated hypersensitivity (type I): penicillin-induced urticaria and anaphylaxis • Antibody-mediated (type II): penicillin-induced haemolysis • Immune complex-mediated (type III): drug-induced serum sickness or vasculitis • Delayed hypersensitivity (type IV): drug-induced erythema multiforme, lichenoid or pemphigus-like reaction; drug-induced lupus (ACE = angiotensin-converting enzyme; IgE = immunoglobulin E; NSAIDs = non-steroidal anti-inflammatory drugs) Erythema nodosum This is characterised histologically by a septal panniculitis of subcutaneous fat (see Fig. 17.59, p. 609). An identified trigger is often present (Box 29.33). Lesions are typically painful, indurated violaceous nodules on the shins and lower legs. Systemic upset, arthralgias and fever are common. Spontaneous resolution occurs over a month or so, leaving bruise-like marks. Any underlying cause should be identified and removed or treated. Bed rest, leg elevation and an oral NSAID frequently offer symptomatic relief. Systemic glucocorticoids are effective but seldom required, and must be avoided when there is a possibility of infection. Potassium iodide, dapsone or hydroxychloroquine may be effective for resistant disease but these are rarely required. Acquired reactive perforating dermatosis The hallmark of this condition is transepidermal elimination of dermal material, particularly collagen and elastic tissue. It presents as keratotic papules, particularly in patients with diabetes and chronic renal disease. Treatment with topical glucocorticoids, retinoids, PUVA or UVA1 therapy may help. There are other related perforating dermopathies, with characteristic histology.

1266 • DERMATOLOGY 29.35 Clinical patterns of drug eruptions Reaction pattern Clinical features Examples of causative drugs Exanthematous Erythema, maculopapular Antibiotics (especially ampicillin), anticonvulsants, gold, penicillamine, NSAIDs, carbimazole, anti-TNF drugs and other biological therapies Urticaria and angioedema Sometimes accompanied by angioedema Salicylates, opiates, NSAIDs, antibiotics, dextran, ACE inhibitors Angioedema alone Lichenoid Violaceous, lichen planus-like, dyspigmentation Gold, penicillamine, antimalarials, thiazides, NSAIDs, β-blockers, ACE inhibitors, sulphonamides, lithium, sulphonylureas, proton pump inhibitors, quinine, antituberculous, dyes in colour developers Purpura and vasculitis Palpable purpura and necrosis Allopurinol, antibiotics, ACE inhibitors, NSAIDs, aspirin, anticonvulsants, diuretics, oral contraceptives Erythema multiforme Target-like lesions and bullae on extensor aspects of limbs See Box 29.32, p. 1264 Erythema nodosum Tender, painful, dusky, erythematous nodules on shins See Box 29.33, p. 1265 Exfoliative dermatitis There may be erythroderma Allopurinol, carbamazepine, barbiturates, penicillins, PAS, isoniazid, gold, lithium, penicillamine, ACE inhibitors Toxic epidermal necrolysis Rapid evolution, extensive blistering, erythema, necrolysis, mucosal involvement Anticonvulsants, antibiotics, especially sulphonamides, NSAIDs, terbinafine, sulphonylureas, antiretrovirals, allopurinol Photosensitivity (p. 1220) Photo-exposed site rash, may be sunburn-like, exfoliation, lichenoid Thiazides, amiodarone, quinine, NSAIDs, tetracyclines, fluoroquinolones, phenothiazines, sulphonamides, retinoids, psoralens Drug-induced lupus Photosensitivity, discoid lesions, urticarial or erythema multiforme-like. May have positive lupus serology and anti-histone antibodies Allopurinol, thiazides, ACE inhibitors, PAS, anticonvulsants, β-blockers, gold, hydralazine, minocycline, penicillamine, lithium, proton pump inhibitors Psoriasiform rash Rash resembles psoriasis See Box 29.23 (p. 1248) DRESS Facial oedema, fever, extensive rash, lymphadenopathy, eosinophilia and systemic involvement Anticonvulsants, trimethoprim, minocycline, allopurinol, dapsone, terbinafine AGEP/toxic pustuloderma Rapid onset of sterile, non-follicular pustules on erythematous base Ampicillin/amoxicillin, erythromycin, quinolones, sulphonamides, terbinafine, diltiazem, hydroxychloroquine Acneiform eruptions Rash resembles acne Lithium, anticonvulsants, oral contraceptives, androgens, glucocorticoids, antituberculous drugs, EGFR antagonists (cetuximab and erlotinib) Pigmentation See Box 29.29 (p. 1258) Bullous eruptions Often at pressure sites and there may be other features, such as purpura, milia Barbiturates, penicillamine, furosemide Pseudoporphyria May be indistinguishable from porphyria cutanea tarda clinically NSAIDs, tetracyclines, retinoids, furosemide, nalidixic acid Exacerbation of acute hepatic porphyrias See page 1263 Always check all drugs for safety of use in porphyrias against standard guidelines Drug-induced immunobullous disease May resemble pemphigoid, pemphigus, dermatomyositis, scleroderma, epidermolysis bullosa acquisita Penicillamine, ACE inhibitors, vancomycin Fixed drug eruptions Round/oval, erythema, oedema ± bullae Same site every time drug is given Pigmentation on resolution Tetracyclines, sulphonamides, penicillins, quinine, NSAIDs, barbiturates, anticonvulsants Hair loss Diffuse Cytotoxic agents, oral retinoids, anticoagulants, anticonvulsants, antithyroid drugs, lithium, oral contraceptives, infliximab Hypertrichosis Excessive hair growth in non-androgenic distribution Diazoxide, minoxidil, ciclosporin (ACE = angiotensin-converting enzyme; AGEP = acute generalised exanthematous pustulosis; DRESS = drug rash with eosinophilia and systemic symptoms; EGFR = epidermal growth factor receptor; NSAIDs = non-steroidal anti-inflammatory drugs; PAS = para-aminosalicylic acid; TNF = tumour necrosis factor)

Further information • 1267

Clinical features Cutaneous drug reactions typically present in specific patterns (Box 29.35). Non-immunologically mediated reactions can theoretically occur in anyone, given sufficient exposure to the drug, although idiosyncratic factors, such as genetic predisposition, may render some more susceptible. There is limited information on genetic determinants of drug responses and adverse effects, although advances have been made, e.g. with azathioprine (p. 1227), and provide exciting opportunities for therapeutic personalised medicine. Immunologically mediated cutaneous drug eruptions typically commence within days to weeks of starting the drug. Detailed history-taking relating to prescribed and non-prescribed medications is essential and there may be other clues (Box 29.36). Investigations and management The suspected drug must be stopped. If drug-induced photosensitivity is considered, the patient should be phototested while on the drug to confirm the diagnosis, and again after drug withdrawal to confirm resolution of photosensitivity (p. 1215). An eosinophilia and abnormalities in liver function tests may occur in adverse drug reactions and, for example, specific IgE to penicillin may be raised in penicillin-induced rash but, otherwise, specific investigations are not available. Rechallenge with drug is not usually undertaken unless the reaction is mild, as this can be risky. Drug withdrawal may not be straightforward and substitute drugs may be required. Antihistamines and/or topical or systemic glucocorticoids may provide supportive management, depending on the type of cutaneous reaction. The management of anaphylaxis is described on page 76. 29.36 Diagnostic clues to drug eruptions • Past history of reaction to suspected drug • Introduction of suspected drug a few days to weeks before onset of rash • Recent prescription of a drug commonly associated with rashes (penicillin, sulphonamide, thiazide, allopurinol) • Symmetrical eruption that fits with a well-recognised pattern, caused by a current drug • Resolution of rash following drug cessation Further information Websites bad.org.uk British Association of Dermatologists: guidelines and patient information for many skin diseases. cochrane.org/cochrane-reviews Many relevant skin reviews, including sun protection (CD011161), psoriasis (CD001976, CD007633, CD005028, CD001213, CD009481, CD010497, CD010017, CD009687, CD001433), eczema (CD009864, CD005205, CD004054, CD005500, CD005203, CD008642, CD008426, CD003871, CD004416, CD006135, CD007770), skin cancer (CD005413, CD008955, CD007281, CD003412, CD004415, CD007041, CD005414, CD007869, CD004835, CD010308, CD010307, CD011161), leg ulcers (CD010182, CD002303, CD003557, CD001737, CD008599, CD001733, CD000265, CD008394, CD001177, CD009432, CD001273, CD011354, CD001836), acne (CD004425, CD011946, CD002086, CD000194, CD007917), rosacea (CD003262), urticaria (CD007770, CD006137, CD008596), alopecia (CD007628, CD004413), skin infections (CD009992, CD003584, CD004685, CD004767, CD010095, CD003261), bullous pemphigoid (CD002292). nice.org.uk National Institute for Health and Care Excellence: guidance for skin cancer (NG14, NG34, PH32, CSG8, TA172, TA321, TA268, TA319, TA384, TA400, TA366, TA357, TA396, TA269, IPG446, IPG478, DG19), atopic eczema (QS44, CG57, TA81, TA82, TA177), psoriasis (CG153, TA146, TA372, TA368, TA103, TA134, TA350, TA180), sun exposure (NG34, PH32), vitamin D (PH56), urticaria (TA339, ESUOM31), rosacea (ESNM43, ESNM68), scabies (ESUOM29), photodynamic therapy (IPG155, MTG6) and Grenz rays (IPG236). sign.ac.uk Scottish Intercollegiate Guidelines Network: no. 120 – Management of chronic venous leg ulcers; 121 – Diagnosis and management of psoriasis and psoriatic arthritis in adults; 125 – Management of atopic eczema in primary care; 140 – Management of primary cutaneous squamous cell carcinoma. Fig. 29.54 Drug eruption. Possible drug causes of rash should always be considered. This was doxycycline-induced photosensitivity in a farmer.

7KLVSDJHLQWHQWLRQDOO\OHIWEODQN

Ch04-3 Clinical Medicine

20-30 Maternal medicine

30 Maternal medicine

Maternal medicine L Mackillop FEM Neuberger Clinical examination in pregnancy 1270 Clinical evaluation in maternal medicine 1271 Planning pregnancy in patients with medical conditions 1272 Functional anatomy and physiology 1272 Investigations 1274 Imaging 1274 Presenting problems in pregnancy 1274 Breathlessness 1274 Chest pain 1275 Circulatory collapse 1275 Headache 1275 Nausea and vomiting 1275 Oedema 1275 Seizures 1275 Medical disorders in pregnancy 1276 Hypertension 1276 Respiratory disease 1277 Gastrointestinal disease 1277 Diabetes 1278 Endocrine disease 1279 Human immunodeficiency virus infection 1280 Inflammatory rheumatic disease 1280 Cardiac disease 1282 Renal disease 1282 Liver disease 1283 Neurological disease 1284 Psychiatric disorders 1284 Haematological disease 1284

1270 • MATERNAL MEDICINE Insets: (Palmar erythema) From Fitzpatrick JE, Morelli JG. Dermatology secrets plus, 5th edn. Philadelphia: Elsevier Inc.; 2016; (Melasma) From Lawrence CM, Cox NH. Color atlas and text of physical signs in dermatology. London: Wolfe; 1993; (Jaundice) From Morse SA, Ballard RC, Holmes KK, et al. Atlas of sexually transmitted diseases and AIDS, 4th edn. Saunders, Elsevier Inc.; 2010; (Varicella pneumonia) From Voore N, Lai R. Varicella pneumonia in an immunocompetent adult. Can Med Assoc J 2012; 184(17):1924; (Linea nigra) From Bolognia JL, Schaffer JV, Duncan KO, et al. Dermatology essentials. Philadelphia: Elsevier Inc.; 2014; Courtesy of Jean L. Bolognia; (Striae gravidarum) From Buchanan K, Fletcher HM, Reid M. Prevention of striae gravidarum Increased risk of varicella pneumonia Striae gravidarum Linea nigra Striae albicans Peripheral oedema Jaundice in acute fatty liver of pregnancy Melasma Palmar erythema

Observation Plethoric Mood/affect Hands Pulse Pulse rate increased by 10–20 bpm Bounding pulse Blood pressure Lower in 2nd and 3rd trimesters Face Conjunctival pallor (physiological anaemia of pregnancy) Heart Ejection systolic murmur may be part of normal pregnancy Diastolic murmurs are always pathological Breasts Increase in size and vascularity

Respiratory system Mild breathlessness common Respiratory rate unchanged Abdomen Scars Excoriations Umbilicus eversion Obstetric examination Legs Varicose veins 10 Urine dipstick Mild oedema in normal pregnancy Rapid-onset oedema suggests pre-eclampsia Clinical examination in pregnancy

Clinical evaluation in maternal medicine • 1271

Clinical evaluation in maternal medicine Take a careful history Perform general examination Consider cardiovascular adaptations during pregnancy -40% Blood volume Cardiac output Heart rate Systolic blood pressure Diastolic blood pressure 1st trimester -20%

+20% +40% +60% Perform X-ray imaging if indicated • Anaemia • Altered thyroid function tests • Low creatinine/urea • Low CO2 • Raised alkaline phosphatase • Glycosuria Consider mother and fetus when prescribing Remember changes of pregnancy when interpreting laboratory results Perform urinalysis Perform further investigations if appropriate Palmar erythema Check for oedema and deep venous thrombosis Check blood pressure Check for anaemia and jaundice Take a careful drug history Stop fetotoxic drugs before conception • Methotrexate • Leflunomide • Mycophenolate • Valproate Ask specifically about: • Cardiac disease • Renal disease • Diabetes • Rheumatic disease • Inflammatory bowel disease • Epilepsy 2nd trimester 3rd trimester with cocoa butter cream. Int J Gynecol Obstet 2009; 108(2010):65–68; (Striae albicans) From Cantisano-Zilkha M. Aesthetic oculofacial rejuvenation. Philadelphia: Saunders, Elsevier Inc.; 2010; (Peripheral oedema) From Huang H-W, Wong L-S, Lee C-H. Sarcoidosis with bilateral leg lymphedema as the initial presentation: a review of the literature. Dermatologica Sinica 34(2016):29–32.

1272 • MATERNAL MEDICINE Major physiological changes occur during pregnancy, which impact on several organ systems. These are necessary to support the growing fetus, to prepare for delivery and to support lactation. These changes can adversely affect the activity and progression of many pre-existing medical conditions. Emphasising this fact, information from the UK Confidential Enquiry into Maternal Deaths has revealed that over recent years, two-thirds of maternal deaths occur as the result of pre-existing medical conditions, rather than from obstetric causes. The most common causes of death were cardiac conditions (23%), pneumonia and influenza (14%), and venous thromboembolism (11%). Although some diseases can undergo remission during pregnancy, others can worsen, potentially jeopardising the health and well-being of the mother and fetus. In this chapter, we review the physiological changes that occur during pregnancy and the impact of pregnancy on the diagnosis, clinical course and management of common medical conditions. In addition, we review the pathogenesis and management of several medical conditions specific to pregnancy. Planning pregnancy in patients with medical conditions Patients with pre-existing medical conditions require careful counselling when planning a pregnancy to make them aware of the risks that pregnancy might pose, as well as the changes in symptoms that might be expected to occur during pregnancy. Although each disease is different, as is discussed later in this chapter, the general principles are to ensure that drugs that may be fetotoxic are stopped before pregnancy is attempted; that high-risk patients are kept under close surveillance during their pregnancy; and that new symptoms that emerge during pregnancy are treated seriously and fully investigated where appropriate. Functional anatomy and physiology The most important changes that occur in the anatomy and physiology of major organ systems during pregnancy are discussed below. Bone metabolism Major changes in bone metabolism take place to meet the demands of the growing fetus. Intestinal calcium absorption increases, due in part to increased production of 1,25-dihydroxyvitamin D (1,25(OH)2D). Calcium is also released from the maternal skeleton due to increased bone resorption, stimulated by production of parathyroid hormone-related protein (PTHrP) by breast and placenta. This results in loss of bone from the maternal skeleton during pregnancy that continues until lactation ceases and then recovers. Serum concentrations of alkaline phosphatase (ALP) can increase by up to fourfold but this is due to release of ALP from the placenta rather than bone. Cardiovascular system Heart rate and stroke volume increase during pregnancy; when combined with peripheral vasodilatation and a reduction in systemic blood pressure, this causes a hyperdynamic circulatory state and an increase in cardiac output. Diaphragmatic elevation may affect the electrocardiogram (ECG), causing left axis deviation of up to 15°. Other changes include T-wave inversion in leads III and aVF, ST depression, small Q waves and a sinus tachycardia. Supraventricular and ventricular beats are common. Echocardiography shows a modest increase in the dimensions of the cardiac chambers. Endocrine system During early pregnancy there is secretion of human chorionic gonadotrophin (hCG) by trophoblast cells, which act on the corpus luteum in the ovary to stimulate oestradiol and progesterone production (Fig. 30.1). Levels of hCG rise rapidly during early pregnancy to reach a peak around 8 weeks, and then fall before stabilising at a lower level from 20 weeks until term. There is a progressive rise in oestradiol and progesterone levels; initially, these hormones are produced by the corpus luteum but placental production takes over after about 12 weeks. The high levels of gonadal hormones suppress pituitary gonadotrophin production but prolactin levels rise about 10-fold and there is an increase in volume of the anterior pituitary. Serum levels of free T4 increase during the first trimester but, paradoxically, thyroid-stimulating hormone (TSH) levels fall by almost 50%. This is because hCG is homologous to TSH and mimics the effect of TSH on the thyroid, stimulating both T3 and T4 production. The raised levels of T3 and T4 feed back to the pituitary and reduce TSH secretion. Later in pregnancy, there is increased degradation of thyroxine by the placenta and levels of thyroxine-binding globulin (TBG) rise, causing the normal range for free T4 and T3 to fall progressively during the course of pregnancy. Although TSH levels are difficult to interpret early in pregnancy, they provide the best measure of thyroid function after about 16 weeks’ gestation. Gastrointestinal system The high levels of progesterone during pregnancy lead to relaxation of smooth muscle in the gastrointestinal tract. This causes the lower oesophageal sphincter to relax, predisposing to gastro-oesophageal reflux and reduced gastrointestinal transit; this in turn leads to delayed gastric emptying and constipation. Genitourinary system Glomerular filtration rate (GFR) increases during pregnancy due to an increased cardiac output. By the second trimester, renal perfusion increases by up to 80% and GFR by 50%, leading to a fall in serum urea and creatinine. Mild glycosuria may be observed during normal pregnancy due mainly to an increase in filtered load of glucose. The ureters and renal pelvis are slightly dilated, most prominently on the left side, leading to the physiological hydronephrosis of pregnancy. Glucose metabolism Maternal glucose metabolism changes during pregnancy to optimise delivery of glucose and other nutrients to the fetus. During the second half of pregnancy in particular, there is maternal insulin resistance due largely to an increase in circulating levels of human placental lactogen (hPL) (Fig. 30.1). The net effect is to ensure that glucose is preferentially supplied to the fetus rather than the mother. Following delivery of the placenta, there is a rapid decline in hPL and reversal of insulin resistance. During pregnancy, fasting plasma glucose decreases slightly, while post-prandial blood glucose may increase. Glycosuria may occur, even in women who do not have diabetes, due to the

Functional anatomy and physiology • 1273

Fig. 30.1 Hormonal changes in pregnancy. In early pregnancy, oestradiol and progesterone are mainly derived from the corpus luteum in response to human chorionic gonadotrophin (hCG), secreted by the trophoblast. The raised levels of hCG also act on the thyroid to stimulate T3 (triiodothyronine) and T4 (thyroxine) production, which in turn suppresses thyroid-stimulating hormone (TSH) production by the pituitary. Later in pregnancy, oestradiol and progesterone are derived from the placenta, which also produces human placental lactogen (hPL), impairing glucose tolerance. There is a progressive reduction of free T3 and T4 during pregnancy as the result of T3 and T4 degradation by the placenta and increased secretion of thyroxine-binding globulin (TBG) by the liver. TSH-like effect Chorion Thyroid Early pregnancy Late pregnancy Pituitary Corpus luteum Ovary hCG hCG Progesterone Oestradiol hPL Prolactin Gestation (weeks) Hormone levels Oestradiol↑ Progesterone↑

TSH↓ T3 T4↑ Free T3, T4↓ T3 T4↓ TBG↑ Lactation Liver Placenta Insulin resistance Glucose↑ Pituitary Prolactin hPL TSH T3 T4 increased GFR. Insulin secretion in the fetus is driven by fetal glucose levels, which in turn are dependent on maternal glucose concentrations. Accordingly, in women with diabetes, maternal hyperglycaemia stimulates fetal insulin secretion, which increases fetal growth, resulting in increased birth weight or macrosomia. Haematological system Haemoglobin normally falls by about 20% during pregnancy since plasma volume increases more than red cell volume: the so-called physiological anaemia of pregnancy. The reduction in haematocrit lowers blood viscosity but this is offset by an elevation in levels of several clotting factors, resulting in a hypercoagulable state that increases the risk of venous and arterial thrombosis. Respiratory system Tidal volume (TV) increases during pregnancy due to an increased vital capacity and reduced residual volume, and by term the increase in TV is about 200 mL. These changes are required to meet the 20% increase in oxygen demand that occurs during pregnancy. The PCO2 level decreases but this is offset by an increase in renal excretion of bicarbonate, such that the blood pH remains relatively stable. Respiratory rate is unaffected by pregnancy.

1274 • MATERNAL MEDICINE Investigations The profound changes in physiology and anatomy that occur during pregnancy cause changes in the normal reference ranges for several hormones, electrolytes and other analytes, as summarised in Box 30.1. While many investigations can proceed as normal during pregnancy, invasive procedures should generally be avoided unless the potential benefit clearly outweighs the risk. Investigations that can be performed in pregnancy are shown in Box 30.2. Imaging Imaging during pregnancy should be undertaken only when the clinical benefit outweighs the potential risks to mother and fetus. In suspected pulmonary embolus, radionuclide ventilation/perfusion (Vࡆ/Qࡆ) scanning is preferred over computed tomographic pulmonary angiography (CTPA) in women with a normal chest X-ray since Vࡆ/Qࡆ scans expose the maternal breast and lungs to less radiation than CTPA. However, if the chest X-ray is abnormal, CTPA should be performed, since it is more likely to yield a definitive diagnosis. The radiation exposure for both investigations is well below the maximum recommended fetal radiation dose in pregnancy (5 rad). Chest X-rays may also be performed safely at any gestation during pregnancy if clinically indicated, since the radiation exposure is very low for the fetus. Magnetic resonance imaging (MRI) is safe in the second and third trimesters and is useful in the assessment of proximal deep vein thrombosis (DVT) and neurological disorders. However, gadolinium-containing contrast agents should be used only if absolutely necessary. If gadolinium contrast agents are used in women who are breastfeeding, the milk should be discarded for 24 hours. Ultrasound imaging is safe during pregnancy and useful in the assessment of patients with DVT or intra-abdominal pathology. Presenting problems in pregnancy Breathlessness The causes of breathlessness during pregnancy are summarised in Box 30.3. Many women experience mild breathlessness as part of normal pregnancy, which is known as physiological 30.2 Investigations in pregnancy* Investigation Use during pregnancy Comment Renal biopsy Can be performed during pregnancy < 22 weeks is safest; 23–28 weeks is period of highest risk Gastroscopy Safe during pregnancy Fetal monitoring should be offered pre- and post-procedure Left lateral position is recommended in the second half of pregnancy Low-dose sedation recommended Colonoscopy Safe during pregnancy Fetal monitoring should be offered pre- and post-procedure Low-dose sedation recommended Flexible sigmoidoscopy Safe during pregnancy Fetal monitoring should be offered pre- and post-procedure Low-dose sedation recommended Magnetic resonance imaging Not contraindicated at any gestation Theoretical risks to fetus in first trimester Computed tomography Can be performed at any gestation Radiation exposure to fetus and mother must be considered and addressed in counselling X-ray Safe at any gestation Ultrasound Safe at any gestation Echocardiogram Safe at any gestation Ambulatory electrocardiogram Safe at any gestation *For any investigation, the potential benefit must outweigh the risk. Laboratory test Change Cause Haematology Haematocrit Decrease Extracellular volume expansion Routine biochemistry GFR Increase Increased renal blood flow Urea and creatinine Decrease Increased GFR Alkaline phosphatase Increase Release by placenta Glucose Decrease (fasting) Increase (post-prandial) Insulin resistance Raised insulin Hormones T4 Increase (first trimester) Stimulation of thyroid by hCG Placental degradation due to TSH Increased T4 Prolactin Decrease (later pregnancy) Decrease (first trimester) Increase Increased production by pituitary Oestradiol Progressive increase Production by corpus luteum then placenta Progesterone hCG Increase then decrease Production by trophoblast hPL Progressive increase Production by placenta } stimulation of thyroid by hCG 30.1 Common laboratory changes during pregnancy (GFR = glomerular filtration rate; hCG = human chorionic gonadotrophin; hPL = human placental lactogen; TSH = thyroid-stimulating hormone)

Presenting problems in pregnancy • 1275

blood, intravenous fluids and oxygen. Patients with post-partum haemorrhage may also benefit from uterotonic agents such as oxytocin. If the bleeding fails to settle, surgical intervention or interventional radiology may be required. Headache Migraine and tension headache may occur during pregnancy and should be assessed along the usual lines, as described on page 1095. Important causes of headache that are specific to pregnancy are pre-eclampsia, which should be suspected in patients with hypertension, oedema and proteinuria, and cerebral venous thrombosis, which should be suspected when there is a neurological deficit or seizures. Nausea and vomiting Nausea and vomiting are common during the first trimester of pregnancy and do not usually require any specific investigation or treatment. Other causes of nausea and vomiting are summarised in Box 30.4. Severe vomiting with significant weight loss and/or electrolyte disturbance suggests hyperemesis gravidarum, which is discussed in more detail on page 1277. breathlessness of pregnancy. It is thought to be progesteronemediated and is classically of gradual onset and present at rest and on exercise. Physiological breathlessness does not require investigation but severe or persistent breathlessness should be investigated, especially if accompanied by chest pain. The diagnostic approach in pregnant patients with suspected pulmonary embolism differs from that in non-pregnant women. Measurement of D-dimer is not helpful since values normally increase progressively throughout pregnancy. Accordingly, the first-line investigation in suspected pulmonary embolism is a Vࡆ/Qࡆ scan in a patient with a normal chest X-ray and CTPA in a patient with an abnormal chest X-ray. Chest pain Chest pain does not occur during normal pregnancy but the incidences of acute coronary syndrome (ACS) and aortic dissection are both increased. Accordingly, if a pregnant woman develops acute severe chest pain suggestive of either of these conditions, she should be investigated and treated in the same way as a non-pregnant woman. Circulatory collapse The differential diagnosis of circulatory collapse is wide and causes unrelated to pregnancy are discussed on page 199. Obstetric causes include pulmonary embolism, haemorrhage and amniotic fluid embolism (AFE). AFE usually presents with collapse and profound shock during delivery or immediately afterwards, often with profound and early coagulopathy. It can be difficult to differentiate AFE from other causes of maternal collapse, and the diagnosis is clinical when other causes of collapse have been excluded. Management is supportive, with oxygenation, careful fluid balance and, in some cases, correction of coagulopathies, ventilatory support and vasopressors. Another important cause of circulatory collapse is obstetric haemorrhage, which can be divided into ante-partum and post-partum subtypes. Ante-partum haemorrhage is defined as bleeding from the vagina after 24 weeks’ gestation. Primary post-partum haemorrhage is defined as occurring in the first 24 hours after delivery, and secondary post-partum haemorrhage after 24 hours. Haemorrhage may be concealed, and physiological changes such as hypotension, tachycardia and tachypnoea may be late signs. Management is supportive with administration of 30.3 Breathlessness during pregnancy Cause Management Physiological breathlessness of pregnancy No treatment required Asthma Treatment as in non-pregnant women Pneumonia Treatment with antibiotic as in non-pregnant women Valvular heart disease Treatment as in non-pregnant women Heart failure Treatment as in non-pregnant women Peripartum cardiomyopathy (PPCM) Treatment as in non-pregnant women Early delivery if haemodynamic deterioration Pulmonary embolus Treatment as in non-pregnant women 30.4 Differential diagnosis of severe nausea and vomiting in pregnancy Gastrointestinal • Peptic ulcer disease • Gastroenteritis • Appendicitis • Pancreatitis Endocrine and metabolic • Thyrotoxicosis • Addison’s disease • Hyperparathyroidism • Diabetic ketoacidosis Neurological • Space-occupying lesion • Migraine Pregnancy-associated conditions • Molar pregnancy • Acute fatty liver of pregnancy • Hyperemesis gravidarum Genitourinary • Urinary tract infection Psychological • Bulimia nervosa Cardiovascular • Myocardial infarction Oedema A mild degree of ankle oedema can occur in normal pregnancy but significant oedema raises suspicion of pre-eclampsia. This should be considered in patients who are also hypertensive and those with proteinuria. Further details are on page 1276. Seizures The causes and management of seizures during pregnancy are summarised in Box 30.5. An important cause is eclampsia, which should be borne in mind in patients with no previous history of seizures and accompanying features such as hypertension,

1276 • MATERNAL MEDICINE Pre-eclampsia and eclampsia Pre-eclampsia is a disorder of vascular endothelial dysfunction that affects about 10% of all pregnancies worldwide. The risk factors for pre-eclampsia are shown in Box 30.8 and the clinical features illustrated in Figure 30.2. Management includes control of blood pressure, administration of magnesium sulphate as prophylaxis against seizures, correction of coagulation abnormalities and monitoring of fluid balance. If pre-eclampsia occurs early in pregnancy, medical management should be initiated with the aim of controlling the condition and maintaining the fetus in utero as long as possible. If these measures are ineffective and eclampsia supervenes (see below), then urgent delivery should be considered, provided the fetus is viable, since this results in an immediate cure. oedema and proteinuria. Seizures can also occur secondary to electrolyte disturbances associated with hyperemesis gravidarum or hypoglycaemia. Other disorders that are more common during pregnancy and can present with seizures include cerebral venous thrombosis and thrombotic thrombocytopenic purpura (TTP). Medical disorders in pregnancy Many disorders present specific management problems before pregnancy, during pregnancy and in the puerperium; the most important of these are discussed in more detail below. Hypertension Hypertension is one of the most common medical problems during pregnancy, occurring in about 10–15% of women. The causes and classification are summarised in Box 30.6. Pre-existing hypertension If hypertension is discovered during the first half of pregnancy, it usually indicates that there was pre-existing hypertension. This is most likely to be due to essential hypertension but secondary causes also need to be considered. Hypertension during pregnancy should be managed with vasodilators or methyldopa (Box 30.7), taking care to avoid hypotension, which can cause placental hypoperfusion and increase the risk of fetal growth restriction, stillbirth and miscarriage. Angiotensin-converting enzyme (ACE) inhibitors should be stopped in hypertensive women who are planning to become pregnant and should be avoided during pregnancy since they have fetotoxic effects. Diuretics should also be avoided unless there is heart failure, as they can reduce circulating volume and cause placental hypoperfusion. Gestational hypertension Gestational hypertension usually presents in the second half of pregnancy and most often resolves by 3 months post-partum. It should be managed actively with one of the drugs listed in Box 30.7, to reduce the risk of progression to pre-eclampsia. 30.5 Causes of seizures during pregnancy Cause Management Epilepsy Similar to that in non-pregnant women Avoid valproate Eclampsia Antihypertensives Magnesium sulphate Careful fluid balance Hypoglycaemia Glucose Hyponatraemia Saline infusion Alcohol withdrawal Supportive treatment Drugs Supportive treatment Stroke As in non-pregnant women Cerebral venous thrombosis Low-molecular-weight heparin Thrombotic thrombocytopenic purpura Plasma exchange Immunosuppressives 30.7 Drug treatment of hypertension during pregnancy Medication Mechanism of action Labetalol α- and β-receptor blocker Nifedipine Calcium channel blockers Amlodipine Methyldopa Central action Doxazosin α-receptor blocker 30.6 Classification of hypertension during pregnancy Hypertension Definition Hypertension in pregnancy Blood pressure ≥ 140/90 mmHg on two separate occasions, at least 4 hrs apart Pre-existing hypertension Hypertension prior to pregnancy or occurring before 20 weeks’ gestation Gestational hypertension Hypertension occurring after 20 weeks’ gestation without proteinuria or any other features of pre-eclampsia Pre-eclampsia Hypertension occurring after 20 weeks’ gestation with proteinuria, maternal organ dysfunction or uteroplacental dysfunction Eclampsia Generalised seizures in a pregnant woman previously diagnosed with pre-eclampsia White coat hypertension Hypertension that only occurs in a clinical environment Adapted from Tranquilli AL, Dekker G, Magee L, et al. The classification, diagnosis and management of the hypertensive disorders of pregnancy: a revised statement from the ISSHP. Pregnancy Hypertens 2014; 4:97–104. 30.8 Risk factors for pre-eclampsia • Previous history of pre-eclampsia • Multiple pregnancy • Primiparity • Genetic predisposition • Pre-existing medical conditions: Chronic kidney disease Hypertension Diabetes mellitus Systemic lupus erythematosus and connective tissue disease • Obesity • Increased maternal age Adapted from Duckitt K, Harrington D. Risk factors for pre-eclampsia at antenatal booking: systematic review of controlled studies. BMJ 2005; 330:565–567.

Medical disorders in pregnancy • 1277

of infections is important since mothers with pneumonia are more likely to deliver early and have low-birth-weight infants compared with healthy pregnant women. Bacterial infections Antibiotics should be given, depending on the causal organism and sensitivities, along with supplemental oxygen and fluids as required. Penicillins, cephalosporins and macrolides such as erythromycin are all safe during pregnancy but tetracyclines should be avoided because they may be embryotoxic and can cause staining of the teeth in the fetus (see Box 6.19, p. 120). Viral infections Viral pneumonia is more common and often more severe during pregnancy. Varicella zoster pneumonia in particular is associated with a high fetal and maternal mortality rate. It presents with cough, breathlessness and pyrexia, and is usually preceded by a vesicular rash up to 1 week before. Varicella infection can be diagnosed clinically, with laboratory confirmation by culture or polymerase chain reaction (PCR) of fluid from vesicles, or by serology. Varicella pneumonia causes an interstitial pneumonitis with a characteristic nodular appearance on chest X-ray (p. 1270). Women with confirmed varicella zoster pneumonia should be admitted to hospital for supportive care and treatment with intravenous aciclovir for 7–10 days. Tuberculosis Tuberculosis (TB) may occur during pregnancy and in the UK is more common among African and Asian women. Untreated TB is associated with premature delivery and low birth weight. Transmission to the fetus can occur but is unusual. If the diagnosis of TB is confirmed, then antituberculous chemotherapy should be given as normal, since the benefit of treating TB in pregnancy outweighs any potential risks from the medication. A proportion of pregnant women with TB have coexisting human immunodeficiency virus (HIV) infection, which confers a poorer prognosis and also requires treatment with antiretroviral therapy, as described on page 318. Gastrointestinal disease Hyperemesis gravidarum Hyperemesis gravidarum is a serious condition that affects about 0.5% of pregnant women. It typically presents during the first trimester with severe nausea, vomiting and other clinical features (Box 30.10). It is associated with significant morbidity and mortality, due to malnutrition and electrolyte imbalance. Wernicke’s encephalopathy may develop as the result of thiamin deficiency. Recurrence is common in successive pregnancies. Eclampsia occurs in about 1% of pregnancies and is associated with significant mortality. It usually presents with seizures on a background of pre-eclampsia but rarely can occur before the onset of hypertension and proteinuria. Treatment is with intravenous magnesium sulphate and delivery of the fetus as soon as possible. Women with pre-eclampsia are more likely to develop hypertension, chronic kidney disease, and cerebrovascular and ischaemic heart disease in later life. Respiratory disease Asthma Women with asthma should be managed aggressively during pregnancy, since poorly controlled asthma is associated with preeclampsia, fetal growth restriction, low birth weight and pre-term birth. The management is very similar to that in non-pregnant individuals. Short-acting and long-acting β-agonists, inhaled and oral glucocorticoids and theophylline can be used freely. There is less experience with leukotriene receptor agonists during pregnancy but they can be given if necessary. It is advisable to involve an anaesthetist or intensivist at an early stage in patients with severe exacerbations of asthma since airway management is more difficult in late pregnancy. Respiratory infection The most common causes of pneumonia during pregnancy are summarised in Box 30.9. Diagnosis and management are broadly the same as in non-pregnant patients. Prompt treatment Fig. 30.2 Symptoms and signs of pre-eclampsia. Flashing lights Oedema of face, hands, legs Nausea and vomiting Epigastric/right upper quadrant pain Constant abdominal pain (placental abruption) Headaches Delirium Seizures Hypertension Proteinuria Intrauterine death Fetal growth restriction 30.9 Causes of pneumonia during pregnancy Bacterial • Streptococcus pneumoniae • Mycoplasma pneumoniae • Legionella • Haemophilus influenzae • Staphylococcus aureus Viral • Influenza viruses • Varicella zoster Adapted from Lim W, Macfarlane J, Colthorpe C. Pneumonia in pregnancy. Thorax 2001; 56:398–405.

1278 • MATERNAL MEDICINE The diagnosis of gestational diabetes is based on maternal blood glucose measurements that are associated with increased fetal growth. An international consensus recommended that glucose values diagnostic of gestational diabetes should be lower than those for non-gestational diabetes (see Box 20.31, p. 753). Controversy remains about who should be screened, and the screening strategy depends, in part, on the population risk. It is widely accepted that women at high risk for gestational diabetes should have an oral glucose tolerance test at 24–28 weeks, and some guidelines recommend that all high-risk women should be screened by measuring HbA1c, fasting blood glucose or random blood glucose at the first booking visit. It should be noted that measurements of HbA1c cannot reliably be used to diagnose diabetes in early pregnancy and until 3 months post-partum, since HbA1c levels fall due to increased red cell turnover. Management The aim is to normalise maternal blood glucose concentrations and reduce the risk of excessive fetal growth. The first element of management is dietary modification, in particular by reducing consumption of refined carbohydrate. Women with gestational diabetes should undertake regular pre- and post-prandial selfmonitoring of blood glucose, aiming for pre-meal blood glucose levels of < 5.3 mmol/L (96 mg/dL) and a 1-hour post-prandial level of < 7.8 mmol/L (142 mg/dL) or a 2-hour post-prandial level of < 6.0 mmol/L (109 mg/dL). If pharmacological treatment is necessary, metformin, glibenclamide or insulin can all be used. Glibenclamide should be used rather than other sulphonylureas because it does not cross the placenta. Other oral therapies or injectable incretin-based therapies should not be given in pregnancy. After delivery, maternal glucose usually returns to pre-pregnancy levels. In the UK, it is currently recommended that women with gestational diabetes should have a fasting blood glucose measured at 6 weeks post-partum and have HbA1c concentrations measured annually to screen for the development of diabetes. This is because even those whose glucose tolerance returns to normal post-partum are at increased risk for developing type 2 diabetes, with a 5-year risk between 15 and 50%, depending on the population. Therefore, all women who have had gestational diabetes should be given diet and lifestyle advice to reduce their risk of developing type 2 diabetes (p. 743). Pregnancy in women with established diabetes Maternal hyperglycaemia early in pregnancy (during the first 6 weeks post conception) can adversely affect fetal development, causing cardiac, renal and skeletal malformations, of which the caudal regression syndrome (abnormal development of the lower The cause is unknown and the diagnosis is one of exclusion, since alternative causes of severe nausea and vomiting need to be ruled out, particularly if the onset of symptoms occurs after the first trimester. Management is with lifestyle advice and support, intravenous fluids, electrolyte replacement and antiemetics. Thiamin and glucocorticoids may be required in the most severe cases. Inflammatory bowel disease Women with inflammatory bowel disease (IBD) should be counselled prior to planning a pregnancy. Medications such as azathioprine, sulfasalazine, 5-aminosalicylic acid (5-ASA), glucocorticoids and tumour necrosis factor alpha (TNF-α) inhibitors can be continued as normal during pregnancy but methotrexate must be stopped at least 3 months before conception because of its teratogenic effects. Since poorly controlled IBD is associated with an increased risk of pre-term birth, low birth weight and miscarriage, it is important for the disease to be well controlled before conception. The activity of IBD can increase during pregnancy and ulcerative colitis is more likely to flare than Crohn’s disease. Women who experience disease flares should be managed by both medical and obstetric teams, and monitored closely. The TNF-α inhibitors infliximab and adalimumab are actively transported across the placenta in the third trimester and there is theoretical concern about immunosuppression in the neonate. Infants of mothers who have been treated with TNF-α inhibitors during the second and third trimesters should not be given live vaccines and should be monitored closely for any signs of infection. Most women with uncomplicated IBD can have a normal vaginal delivery and do not need a caesarean section, but the need for this should be assessed on an individual basis by obstetric and medical teams. Diabetes It is important to institute meticulous glucose control in pregnancy, as maternal diabetes is associated with increased risks of congenital malformations, stillbirth, pre-eclampsia, pre-term delivery, operative delivery, neonatal hypoglycaemia and admission to neonatal intensive care. Gestational diabetes Gestational diabetes is defined as diabetes with first onset or recognition during pregnancy. This definition will include a few patients who develop type 1 diabetes during pregnancy, where prompt action and early insulin treatment will be required, and some patients who develop type 2 diabetes, or had unknown pre-existing type 2 diabetes, in whom the diabetes does not remit after pregnancy. However, in most cases, gestational diabetes develops due to an inability to increase insulin secretion adequately to compensate for pregnancy-induced insulin resistance, and most women can expect to return to normal glucose tolerance immediately after pregnancy. Risk factors for gestational diabetes are shown in Box 30.11. 30.10 Clinical features of hyperemesis gravidarum • Weight loss of > 5% • Severe nausea and vomiting • Electrolyte imbalance: Hyponatraemia Hypokalaemia Hypomagnesaemia • Dehydration • Ketosis 30.11 Risk factors for gestational diabetes • Body mass index > 30 kg/m2 • Previous macrosomic baby weighing ≥ 4.5 kg • Previous gestational diabetes • Family history of diabetes (first-degree relative with diabetes) • Family origin with a high prevalence of diabetes: South Asian (specifically women whose country of family origin is India, Pakistan or Bangladesh) Black Caribbean Middle Eastern

Medical disorders in pregnancy • 1279

should be monitored closely if planning a pregnancy; they should be advised to have their thyroid function checked as soon as possible after conception and increase their daily levothyroxine dose if necessary. During pregnancy, serum TSH and free T4 should be measured during each trimester and the dose of levothyroxine adjusted to maintain a normal TSH level. Rarely, hypothyroidism may present during pregnancy with weight gain, constipation and lethargy. The diagnosis is easily missed since these symptoms are common in normal pregnancy. If suspected, the diagnosis can be confirmed by checking thyroid function tests, which show a raised TSH and low free T4. Hyperthyroidism The coexistence of pregnancy and thyrotoxicosis is unusual, since anovulatory cycles are common in thyrotoxic patients and autoimmune disease tends to remit during pregnancy, due to suppression of the maternal immune response. Thyroid function tests must be interpreted in the knowledge that thyroid-binding globulin, and hence total T4 and T3 levels, are increased in pregnancy and that the normal range for TSH is lower (see Box 18.18, p. 651). Despite this, a fully suppressed TSH is usually indicative of Graves’ disease. When thyroid disease during pregnancy is being dealt with, both mother and fetus must be considered, since maternal thyroid hormones, TSH receptor antibodies (TRAb) and antithyroid drugs can all cross the placenta to some degree, exposing the fetus to the risks of thyrotoxicosis, iatrogenic hypothyroidism and goitre. Moreover, poorly controlled thyrotoxicosis can result in fetal tachycardia, intrauterine growth retardation, prematurity, stillbirth and possibly even congenital malformations. Antithyroid drugs are the treatment of first choice for thyrotoxicosis in pregnancy. Newly diagnosed hyperthyroidism during pregnancy can be treated with β-adrenoceptor antagonists (β-blockers) in the short term, followed by antithyroid drugs. Propylthiouracil (PTU) is the preferred antithyroid drug because treatment with carbimazole during the first trimester has been associated with the occurrence of choanal atresia and aplasia cutis. Hyperthyroid women who become pregnant while taking carbimazole or PTU should be advised to continue their current drug in pregnancy, with close monitoring. Both carbimazole and PTU cross the placenta and are effective in treating thyrotoxicosis in the fetus caused by transplacental passage of TRAb. To avoid fetal hypothyroidism, which can affect brain development and cause goitre, it is important to use the smallest dose of antithyroid drug (typically < 150 mg PTU or 15 mg carbimazole per day) that will maintain maternal free T4, T3 and TSH concentrations within their respective reference ranges. Thyroid surgery is sometimes necessary because of poor drug adherence, drug hypersensitivity or failure of medical treatment and is most safely performed during the second trimester. Radioactive iodine is absolutely contraindicated throughout pregnancy, as it invariably induces fetal hypothyroidism. Frequent review of mother and fetus (monitoring heart rate and growth) is important during pregnancy and in the puerperium. Serum TRAb levels can be measured in the third trimester to predict the likelihood of neonatal thyrotoxicosis. PTU is the drug of choice in the breastfeeding mother, as it is excreted in the milk to a much lesser extent than carbimazole. Thyroid function should be monitored periodically in the breastfed child. Post-partum thyroiditis Post-partum thyroiditis typically presents 3–4 months after delivery. It is discussed in more detail on page 647. part of the spine) is the most characteristic. The risk of fetal abnormalities is about 2% for non-diabetic women and about 4% for women with well-controlled diabetes (HbA1c < 53 mmol/ mol) but more than 20% for those with poor glycaemic control (HbA1c > 97 mmol/mol). Therefore, it is important for women with diabetes to aim to achieve good glycaemic control before becoming pregnant. In addition, high-dose folic acid (5 mg daily, rather than the usual 400 μg) should be initiated before conception to reduce the risk of neural tube defects. As for gestational diabetes, mothers should attempt to maintain near-normal blood glucose levels while avoiding hypoglycaemia throughout their pregnancy, as this minimises excessive fetal growth and neonatal hypoglycaemia. This is often difficult to achieve, however. Pregnancy is also associated with an increased risk of ketosis, particularly, but not exclusively, in women with type 1 diabetes. Ketoacidosis during pregnancy is dangerous for the mother and is associated with a high rate (10–35%) of fetal mortality. Pregnancy is linked with a worsening of diabetic complications, most notably retinopathy and nephropathy, so careful monitoring of eyes and kidneys is required throughout pregnancy. If heavy proteinuria and/or renal dysfunction exist prior to pregnancy, there is a marked increase in the risk of pre-eclampsia, and renal function can deteriorate irreversibly during pregnancy. These risks need to be carefully discussed before a woman with diabetes is considering pregnancy. The outlook for mother and child has been vastly improved over recent years but pregnancy outcomes are still not equivalent to those of non-diabetic mothers. Perinatal mortality rates remain 3–4 times those of the non-diabetic population (at around 30–40 per 1000 pregnancies) and the rate of congenital malformation is increased 5–6-fold. Endocrine disease Thyroid disease Iodine deficiency Iodine deficiency is a major public health issue in many countries, particularly in South-east Asia, the Western Pacific and Central Africa. Severe iodine deficiency in pregnancy is associated with miscarriage, stillbirth and cretinism, with significant cognitive impairment, gait abnormalities and deafness in the affected child. More moderate iodine deficiency is associated with milder forms of cognitive impairment and affects millions of people. The World Health Organisation recommends a daily iodine intake of 250 μg/day for pregnant women. Treatment of iodine deficiency in the first and second trimesters can prevent impaired cognitive development but is less effective if started in the third trimester. Hypothyroidism Untreated hypothyroidism is associated with subfertility and so is uncommon in pregnancy. Subclinical hypothyroidism is more common, and is often due to poor adherence to levothyroxine in known primary hypothyroidism. Most pregnant women with primary hypothyroidism require an increase in the dose of levothyroxine of approximately 25–50 μg daily to maintain normal TSH levels because there is an increased requirement for thyroxine during pregnancy. Furthermore, inadequately treated maternal hypothyroidism may be associated with impaired brain development in the fetus. Because of this, hypothyroid women

1280 • MATERNAL MEDICINE serum calcium levels monitored during the first few days of life; if hypocalcaemia is detected, intravenous calcium should be given. Adrenal disease Women with known adrenal insufficiency can continue their glucocorticoid and mineralocorticoid replacement during pregnancy as normal. Rarely, adrenal insufficiency can present for the first time during pregnancy. If this occurs, the diagnosis is challenging because total cortisol normally increases during pregnancy, and short Synacthen tests (p. 672) can be falsely normal. Specialist assessment is required. In women with Conn’s syndrome who become pregnant, amiloride should be substituted for spironolactone to prevent anti-androgenic effects on a male fetus. Human immunodeficiency virus infection The course of HIV disease is not altered by pregnancy but treatment with antiretroviral therapy should be given during pregnancy to women that are HIV-positive, as outlined on page 326. In some societies, routine HIV testing is recommended at an early stage in pregnancy in all women. Inflammatory rheumatic disease Most women with inflammatory rheumatic disorders have successful pregnancies but it is critically important for them to be given pre-conception counselling and to review medication use, optimise disease control and make them aware of the risks that pregnancy might pose to their condition and vice versa. Rheumatoid arthritis Women with rheumatoid arthritis should have a medication review; methotrexate, leflunomide and mycophenolate should be stopped and, if necessary, an alternative substituted before conception (Box 30.12). Rheumatoid arthritis often improves during pregnancy, particularly in those who are negative for rheumatoid factor or anti-cyclic citrullinated peptide antibodies. There is an increased risk of pre-eclampsia, pre-term birth and small babies for women with active disease, emphasising the importance of maintaining disease control during pregnancy. Glucocorticoids, hydrochloroquine, azathioprine and sulfasalazine can all be continued as normal but non-steroidal anti-inflammatory drugs (NSAIDs) should be avoided after 20 weeks (Box 30.12). Inhibitors of TNF-α are safe during pregnancy and can be continued if necessary to maintain control of the disease. Most TNF-α inhibitors are actively transported across the placenta and this can lead to immunosuppression in the neonate if these drugs are used during the second and third trimesters. An exception is certolizumab, which is a pegylated antibody, and this is a good option for women who require TNF-α inhibition during pregnancy. Experience with other biological therapies during pregnancy is limited. Disease flares are common in the post-partum period, regardless of serology, and this can pose a problem for breastfeeding and care of the infant. Glucocorticoids are a good short-term option to control such flares, pending reintroduction of other disease-modifying antirheumatic drugs (DMARDs) that might have been stopped prior to pregnancy. Systemic sclerosis Pregnancy in women with diffuse systemic sclerosis (SSc), those with pulmonary hypertension or renal involvement and those with disease of recent onset (< 4 years) poses risks to mother and Pituitary disease Prolactinoma Prolactinomas are the most common pituitary tumours in young women. Although fertility is reduced in patients with prolactinoma, pregnancies can occur and if this happens the tumour may enlarge as part of the physiological pituitary enlargement that takes place during normal pregnancy. Macroprolactinomas (≥ 10 mm) are at greater risk of enlarging and may cause optic chiasm compression. If women known to have a prolactinoma become pregnant, they should have visual field testing each trimester, followed by pituitary imaging by MRI if enlargement is suspected from changes in visual fields or from symptoms. Measurement of serum prolactin is generally not helpful, since levels increase anyway as part of normal pregnancy. Dopamine receptor agonists such as cabergoline and bromocriptine should normally be stopped during pregnancy, but can be reintroduced if necessary in patients with an enlarging prolactinoma that is threatening the visual fields. Diabetes insipidus Women with pre-existing diabetes insipidus may find that their symptoms worsen in pregnancy due to placental production of vasopressinase, a protease that degrades vasopressin (antidiuretic hormone, ADH). Because of this, pregnant women with diabetes insipidus may need higher doses of desmopressin until delivery. The development of symptoms suggestive of diabetes insipidus, such as thirst and polyuria, during pregnancy should raise suspicion of acute fatty liver of pregnancy (AFLP), the syndrome of haemolysis, elevated liver enzymes and low platelets (HELLP) or pre-eclampsia, as all of these conditions are also associated with decreased breakdown of vasopressinase by the liver. Sheehan’s syndrome This is a form of post-partum hypopituitarism caused by infarction of the pituitary, usually associated with hypotension from major post-partum haemorrhage. It can present with failure to establish lactation after birth, amenorrhoea or other features of hypopituitarism. The diagnosis can be confirmed by tests of pituitary function and treated with hormone replacement, as described on page 682. Parathyroid disease Primary hyperparathyroidism Primary hyperparathyroidism (PHPT) is uncommon in women of child-bearing age, but if pregnancy does occur in a patient with pre-existing PHPT, careful monitoring is required. Women with mild disease can be managed conservatively but if serum calcium levels rise above 2.85 mmol/L (11.5 mg/dL), consideration should be given to parathyroidectomy, as fetal mortality is high (up to 40%) in patients with severe hypercalcaemia. If parathyroidectomy is required, it should ideally be performed during the second trimester. Anecdotal evidence suggests that the calcimimetic drug cinacalcet can be used for medical management of PHPT during pregnancy. Familial hypocalciuric hypercalcaemia Familial hypocalciuric hypercalcaemia (FHH) is a benign disorder caused by mutations in the calcium-sensing receptor, which is described on page 664. Although FHH poses no risk for pregnant women, the hypercalcemia can suppress PTH secretion in neonates that do not inherit the FHH mutation, resulting in severe hypocalcaemia. Infants of mothers with FHH should have their

Medical disorders in pregnancy • 1281

those who conceive when their disease has recently been active. It can be difficult to assess disease activity during pregnancy because symptoms such as oedema, hair loss, joint pain and fatigue, which occur in active SLE, are also common during normal pregnancies. The features in Box 30.14 can help differentiate between an SLE flare, normal pregnancy and pre-eclampsia. All women with SLE should be tested for anti-Ro and anti-La antibodies, since they can cross the placenta and cause neonatal complete heart block or cutaneous lupus, respectively. Medications should be reviewed prior to pregnancy, to ensure they are safe, and an alternative substituted if necessary (see Box 30.12). The management of patients with antiphospholipid antibodies (aPL) is described below. Anti-phospholipid syndrome Primary antiphospholipid syndrome (APS) is associated with an increased risk of adverse pregnancy outcomes, including thrombosis, miscarriage, fetal death and pre-eclampsia. This applies to primary APS and that associated with connective tissue diseases such as SLE. During pregnancy, women with APS should be managed with low-dose aspirin in combination with low-molecular-weight heparin (LMWH). fetus. In milder forms of the disease, however, the prognosis is better (Box 30.13). Raynaud’s phenomenon often improves during pregnancy due to vasodilatation but oesophageal symptoms may worsen. Renal crises are no more frequent during pregnancy, but if one occurs, ACE inhibitors should be given. Although these are normally contraindicated in pregnancy, the potential benefit in this situation outweighs the risk to the fetus. Glucocorticoids, which can be given to promote fetal lung maturation in premature babies, should be avoided in women with SSc where possible because they may provoke renal crisis. Systemic lupus erythematosus Pregnancy in women with systemic lupus erythematosus (SLE) poses several risks to both mother and fetus, especially if there is renal involvement. There is an increased risk of pre-eclampsia, thrombosis, fetal growth restriction, pre-term delivery, miscarriage and fetal death. There is also a higher risk of lupus flare during the puerperium. Good control of disease is paramount, since women with SLE who conceive when their disease has been quiescent for at least 6 months are less likely to have complications than 30.12 Safety of antirheumatic drugs during pregnancy and breastfeeding Drug Safe during pregnancy Safe during breastfeeding Comment Non-steroidal anti-inflammatory drugs (NSAIDs) Yes (< 20 weeks) Yes Hydroxychloroquine Yes Yes Glucocorticoids Yes Yes A good short-term option for disease flares Azathioprine Yes Yes Sulfasalazine Yes Yes Co-prescribe with folic acid Ciclosporin Yes Yes Data on breastfeeding limited Tacrolimus Yes Yes Mycophenolate No No Stop before planning pregnancy Methotrexate No No Stop 3 months before planning pregnancy Leflunomide No No Stop 2 years before planning pregnancy Cyclophosphamide No No Tumour necrosis factor (TNF) inhibitors Yes Yes Avoid live vaccines in the neonate for 6 months Adapted from Ateka-Barrutia O, Nelson-Piercy C. Connective tissue disease in pregnancy. Clin Med 2013; 131:580–584. 30.13 Systemic sclerosis (SSc) and pregnancy Subtype Effect of disease on pregnancy Localised SSc Good prognosis Raynaud’s may improve Oesophagitis may worsen CREST syndrome Good prognosis Raynaud’s may improve Oesophagitis may worsen Diffuse SSc Increased risk of: Pre-term delivery Pre-eclampsia Fetal growth restriction Low-birth-weight babies Maternal and fetal mortality (CREST = calcinosis, Raynaud’s phenomenon, oesophageal involvement, sclerodactyly and telangiectasia) 30.14 Differential diagnosis of lupus flare during pregnancy Clinical finding Lupus flare Pre-eclampsia Normal pregnancy Hypertension Yes Yes No Proteinuria Yes Yes No Red cells/casts in urine Yes No No Liver function tests Normal Abnormal Normal Anti-doublestranded DNA Increase Unchanged Unchanged C3 and C4 Low Elevated or unchanged from baseline Unchanged

1282 • MATERNAL MEDICINE end of pregnancy or in the months following delivery. It is a diagnosis of exclusion, made when other causes of heart failure have been ruled out. The cause is unknown but PPCM is more prevalent in women who are older, multiparous, hypertensive and Afro-Caribbean. It is treated by conventional medications for heart failure, including ACE inhibitors if necessary, and delivery of the baby. Many women recover within 3–6 months of diagnosis but the prognosis is variable. There is a significant chance of reduction in cardiac function in subsequent pregnancies. Dilated cardiomyopathy Dilated cardiomyopathy carries a poor prognosis if the prepregnancy ejection fraction is below 30% or if symptoms are in New York Heart Association grades 3 or 4. Management is as described for PPCM. Renal disease Renal tract infection Pregnancy predisposes women to urinary tract infection. If asymptomatic bacteriuria is discovered during pregnancy, it should be treated promptly with antibiotics, to prevent ascending renal tract infection. Pyelonephritis is more common in pregnancy due to the physiological dilatation of the upper renal tract; if it does occur, it can trigger premature labour. Acute kidney injury Acute kidney injury (AKI) may occur during pregnancy or in the puerperium due to a variety of causes (Box 30.15). Women with AKI caused by pre-eclampsia are prone to pulmonary oedema, and need very careful fluid balance to avoid fluid overload. In the post-partum period, AKI may occur as the result of post-partum haemorrhage or pre-eclampsia, and sometimes these occur in combination. Although pre-eclampsia resolves after delivery, AKI can be at its worst in the first few days post-partum, especially when exacerbated by obstetric haemorrhage. Glomerular disease Proteinuria caused by glomerular disease is usually exacerbated during pregnancy, and nephrotic syndrome may develop without any alteration in the underlying disease activity in individuals who had only slight proteinuria before pregnancy. This further increases the risk of venous thromboembolism, the leading cause of maternal deaths in developed countries. Chronic kidney disease Women with chronic kidney disease (CKD) are at increased risk of pre-eclampsia, fetal growth restriction, miscarriage, pre-term delivery and fetal death (Fig. 30.3). Pregnancy can also cause acceleration of maternal renal decline. The factors that influence pregnancy outcome for women with CKD are baseline renal function, hypertension, degree of proteinuria and the underlying cause of CKD. Women with CKD should have pre-pregnancy counselling, be closely monitored by a multidisciplinary team throughout pregnancy, and be given low-dose aspirin as prophylaxis against pre-eclampsia. Renal replacement therapy Fertility is reduced among women on renal replacement therapy and there is increased risk of adverse pregnancy outcomes. Cardiac disease Congenital heart disease Women who have a history of surgically corrected congenital heart disease generally tolerate pregnancy well, but are more likely to have babies with congenital heart disease and should be offered fetal cardiac scans. Acyanotic heart diseases, such as atrial septal defect, ventricular septal defect and patent ductus arteriosus, all have a good prognosis in pregnancy. Unrepaired cyanotic heart disease has a very poor prognosis in pregnancy, as does pulmonary hypertension, regardless of the underlying cause. Women with mechanical heart valves require anticoagulation throughout pregnancy but their anticoagulation should be planned with consideration of substituting warfarin with LMWH and aspirin during the first trimester to reduce the risk of warfarin embryopathy. If necessary, warfarin can be used during pregnancy, particularly in the second and third trimesters. Valvular heart disease The physiological changes of pregnancy may also unmask previously undiagnosed valvular disease. Women with regurgitant lesions, such as mitral regurgitation and aortic regurgitation, tolerate pregnancy better than those with stenotic lesions. Mitral stenosis causes a reduction in blood flow from the left atrium to left ventricle in diastole, which worsens during pregnancy due to the increased heart rate and hypervolaemia. Those with moderate to severe mitral stenosis (valve area < 1.5 cm2) are at particular risk and may develop arrhythmias, tachycardia and pulmonary oedema. Most patients can be managed medically with β-blockers, LMWH and furosemide as necessary. Surgical intervention is indicated if there is continued haemodynamic compromise despite optimal medical management. Myocardial infarction Pregnancy increases the risk of myocardial infarction. While atherosclerosis is the main cause in non-pregnant individuals, coronary artery dissection and coronary thrombosis secondary to the hypercoagulable state are more common causes during pregnancy. Management is similar to that of non-pregnant women, except that statins and glycoprotein IIb/IIIa inhibitors such as apixaban should be avoided. Clopidogrel can be given but should be stopped around the time of delivery to reduce the risk of uterine bleeding and to allow spinal anaesthesia to be used if necessary. Stenting can be performed, but bare-metal stents are preferred because drug-eluting stents require dual antiplatelet therapy that cannot be continued around the time of delivery. Aortic dissection Pregnancy is an independent risk factor for aortic dissection and this should be considered when a woman presents with acute severe chest pain during pregnancy. The vast majority of cases in pregnancy are ‘type A’, involving the ascending aorta (see Fig. 16.72, p. 506), and require careful control of hypertension, caesarean section to deliver the fetus, and emergency surgery to treat the aneurysm. Peripartum cardiomyopathy Peripartum cardiomyopathy (PPCM) presents with heart failure secondary to left ventricular systolic dysfunction towards the

Medical disorders in pregnancy • 1283

Acute fatty liver of pregnancy Acute fatty liver of pregnancy (AFLP) is a rare and serious condition that typically presents in the third trimester with vomiting, abdominal pain, jaundice and other symptoms (Box 30.16). It is more common in first pregnancies and multiple pregnancies, and is associated with male fetuses. Rarely, fulminant liver failure may occur. The diagnosis can usually be made on the basis of the clinical features, abnormal liver function tests (LFTs) and the appearances of fatty liver on ultrasound. A liver biopsy is rarely needed to make the diagnosis but shows microvascular steatosis. Management is with supportive care and by delivery of the fetus. The development of AFLP has been linked in some cases with an inherited deficiency of the enzyme long-chain acyl-CoA dehydrogenase (LCHAD) in the baby. Despite this, many women receiving renal replacement therapy have successful pregnancies. More intensive dialysis is recommended in pregnancy, and particular attention should be paid to addressing issues around blood pressure, fluid balance and anaemia. Renal transplant recipients Pregnancy should be delayed for a minimum of 12 months following renal transplantation, to allow the graft to stabilize, on minimum immunosuppressive drugs. The outcome is best for women with a well-functioning graft, with no proteinuria or hypertension. Women with renal transplants can deliver vaginally but in practice there is a higher incidence of caesarean section in this group, due to the higher incidence of pre-term delivery. Liver disease Specific causes of liver disease during pregnancy are discussed below. 30.15 Causes of acute kidney injury in pregnancy Mechanism Cause Features Pre-renal Hyperemesis gravidarum Nausea and vomiting Dehydration Presentation in first trimester Post-partum haemorrhage Vaginal bleeding immediately post-partum Placental abruption Abdominal pain or vaginal bleeding in second or third trimester Septic abortion Presentation with hypotension, shock and pyrexia Renal Pre-eclampsia Presentation in second and third trimesters with new-onset hypertension and proteinuria Thrombotic thrombocytopenic purpura Possible antenatal or post-partum presentation with headache, irritability and drowsiness Haematology shows thrombocytopenia and microangiopathic haemolytic anaemia Acute fatty liver of pregnancy Presentation with vomiting and abdominal pain in third trimester Abnormal liver function tests Liver ultrasound can be normal Acute interstitial nephritis Most common cause is use of non-steroidal anti-inflammatory drugs Post-renal Acute urinary retention Usual presentation is in third trimester due to enlarged uterus causing ureteric obstruction; sometimes presents post-partum Adapted from Palma-Reis I, Vais A, Nelson-Piercy C, et al. Renal disease and hypertension in pregnancy. Clin Med 2014; 13:57–62. Fig. 30.3 Adverse pregnancy outcomes in chronic kidney disease. Creatinine is in μmol/L. To convert to mg/dL, multiply by 0.011. Data from Williams D, Davison D. Chronic kidney disease in pregnancy. BMJ 2008; 336:211–115.

Fetal growth retardation Pre-term delivery Preeclampsia Fetal death Creatinine <125 Creatinine 125–180 Creatinine >180 Dialysis Percentage affected Adapted from Ch’ng CL, Morgan M, Hainsworth I, et al. Prospective study of liver dysfunction in pregnancy in Southwest Wales. Gut 2002; 51:876–880. 30.16 Criteria for diagnosis of acute fatty liver of pregnancy • Vomiting • Abdominal pain • Polydipsia/polyuria • Encephalopathy • Elevated bilirubin (> 14 μmol/L (> 0.82 mg/dL)) • Low glucose (< 4 mmol/L (< 72.4 mg/dL)) • Elevated urate (> 340 μmol/L (> 5.7 mg/dL)) • Leucocytosis (> 11 × 109/L) • Ascites or bright liver on ultrasound • Elevated transaminases (alanine/aspartate aminotransferase (ALT/ AST) > 42 U/L) • Elevated ammonia (> 47 μmol/L (> 81.7 mg/dL)) • Renal impairment (creatinine > 150 μmol/L (> 1.7 mg/dL)) • Coagulopathy (prothrombin time > 14 secs or activated partial thromboplastin time > 34 secs) • Microvascular steatosis on liver biopsy Acute fatty liver of pregnancy can be diagnosed when ≥6 of the above features are present in the absence of another explanation.

1284 • MATERNAL MEDICINE safety profile in pregnancy, such as lamotrigine, levetiracetam or carbamazepine. While pregnancy does not generally affect the frequency of seizures in women with well-controlled epilepsy, those who enter pregnancy with poorly controlled epilepsy are likely to deteriorate. The plasma levels of some AEDs such as lamotrigine can fall in pregnancy and checking drug levels can be helpful. Seizures are more common at the time of delivery and women should be advised to deliver in a unit staffed with personnel able to manage this. Idiopathic intracranial hypertension Idiopathic intracranial hypertension (IIH) may worsen during pregnancy due to weight gain. Treatment with acetazolamide can be continued during pregnancy but should be avoided in the first trimester due to lack of safety data. The mode of delivery is not affected by IIH and spinal analgesia can be given as normal. Migraine Migraine often improves during pregnancy but if attacks occur they should be managed with simple analgesia and antiemetics. If necessary, prophylaxis can be given with aspirin, β-blockers or tricyclic antidepressants. Safety data on use of triptans during pregnancy are limited but reassuring. Triptans can therefore be used for the treatment of migraine if other therapies are ineffective. Stroke Stroke is twice as common in pregnant women as in nonpregnant women of the same age. The risk is highest during the third trimester and puerperium. The management of stroke during pregnancy is similar to that in non-pregnant patients. The risk of cerebral venous thrombosis is greatly increased during pregnancy. The presentation is with headache, seizures and neurological deficits such as hemiparesis. If the diagnosis is suspected, neuroimaging should be performed with MRI or CT venography. Management of acute infarct should be as for the non-pregnant patient and include consideration of thrombolysis. Psychiatric disorders Mood changes are common during pregnancy but more severe psychiatric disorders, such as depression or psychosis, typically present within 2–4 weeks of delivery. These disorders are discussed in more detail on page 1206 and in Box 28.33. Haematological disease Anaemia The causes of anaemia during pregnancy are summarised in Box 30.17. Iron deficiency anaemia is most commonly due to a 20% increased demand for iron. In most cases, it responds well to oral iron supplementation, with a rise in haemoglobin of approximately 0.8 g/L per week. If the haemoglobin does not rise following a 4-week trial of iron supplementation, alternative causes of anaemia should be considered. Non-adherence to oral iron is common and intravenous iron should be considered in women with iron deficiency and failure of oral treatment. It is generally not necessary to investigate iron deficiency anaemia during pregnancy unless there is clinical evidence of gastrointestinal blood loss, which should be investigated in the normal way. HELLP syndrome The syndrome of haemolysis, elevated liver enzymes and low platelets (HELLP) is thought to be part of the spectrum of pre-eclampsia. It usually presents antenatally but can also appear for the first time in the postnatal period. The presenting symptoms can be the same as those of pre-eclampsia but can also include headache, right upper quadrant pain and visual disturbance. HELLP can be complicated by liver haematoma and capsular rupture. Management involves supportive care, control of hypertension, correction of coagulopathy and delivery of the fetus. Obstetric cholestasis Obstetric cholestasis is estimated to affect about 1% of pregnancies in Caucasians, although the prevalence is higher in Chinese and South Asian populations. The cause is incompletely understood but the condition is thought to be due in part to the cholestatic effect of high oestrogen levels. The typical presentation is in the third trimester with pruritus, particularly affecting the soles and palms. Laboratory testing reveals raised levels of bile acids and abnormal LFTs. The diagnosis can be made on the basis of these clinical features when other causes of liver dysfunction and pruritus have been excluded. Treatment is with ursodeoxycholic acid in a starting dose of 250 mg twice daily, which usually improves symptoms and liver function. Aqueous cream with menthol can also be effective in soothing pruritus. There is an increased risk of fetal mortality with evidence of a particularly high risk when bile acid levels are over 40 μmol/L (97.9 μg/mL). Treatment therefore aims to bring bile acids below 40 μmol/L and some centres induce labour before 40 weeks in an effort to reduce the risk. The risk of recurrence in future pregnancies is high. Viral hepatitis The course of hepatitis B is unchanged in pregnancy, but it is important to identify women who have active infection to reduce the risk of vertical transmission to the fetus; this risk is up to 90% in women who are hepatitis B e-antigen positive. Vaccinations and immunoglobulin should be given to infants of mothers who test positive for hepatitis B, and antiviral agents should be given to the mother after delivery. Vertical transmission rates of hepatitis C are low in the absence of HIV infection and so no action is required for the infant, unless there is co-infection with HIV; in this case, antiviral drugs should be considered. Pregnant women are at greater risk of contracting hepatitis E than the non-pregnant population. It is transferred via the faeco-oral route, and is usually a mild self-limiting illness outside of pregnancy. However, it can cause fulminant hepatic failure in up to 20% of pregnant women. Neurological disease Epilepsy Women with epilepsy should have pre-pregnancy counselling and should be advised to take high-dose folic acid from preconception; their antiepileptic drugs (AEDs) should also be reviewed. Maternal treatment with sodium valproate is associated with a higher rate of fetal malformations than other AEDs, and a reduction in intelligence quotient and an increased risk of autistic spectrum disorder in the offspring. Where possible, sodium valproate should be substituted for another AED with a better

Medical disorders in pregnancy • 1285

Venous thromboembolism The risk of venous thromboembolism (VTE) is 4–5 times higher in pregnancy than in non-pregnant women. DVT is the most common presentation and predominantly affects the left leg in pregnancy, for reasons that are incompletely understood. Doppler ultrasound scan is the investigation of choice, but MRI can also be used if proximal clot is suspected. Measurement of D-dimer is not useful in pregnancy because levels rise as part of normal pregnancy. Treatment of VTE in pregnancy is with LMWH at a higher dose than for the non-pregnant woman, based on the patient’s early pregnancy (booking) weight. Women with a previous history of VTE who are receiving warfarin or other oral anticoagulants as prophylaxis should have these stopped prior to conception and LMWH should be substituted. Further information British Thoracic Society/Scottish Intercollegiate Guidelines Network. SIGN 141 – British guideline on the management of asthma. Edinburgh: Health Improvement Scotland; 2014. Useful asthma guidelines. Royal College of Obstetricians and Gynaecologists. Thromboembolic disease in pregnancy and the puerperium: acute management. Green top guideline. London: RCOG; April 2015. A useful evidence-based guideline on the investigation of pulmonary embolism in pregnancy. Websites npeu.ox.ac.uk/mbrrace-uk National Perinatal Epidemiology Unit: a very useful resource with detailed and extensive information on causes of maternal deaths, stillbirths and infant deaths in the UK. Rhesus disease Women who are negative for the Rhesus antigen should be offered treatment with anti-RhD immunoglobulin around the time of delivery to reduce the risk of haemolytic disease of the newborn. More details are provided on page 933 and in Box 23.19. Thrombocytopenia The causes of thrombocytopenia during pregnancy are summarised in Box 30.18. The most common cause is gestational thrombocytopenia, which typically occurs towards the end of pregnancy and resolves spontaneously after delivery. It is not associated with adverse pregnancy outcomes and requires no specific intervention. Pregnancy may occur in women with preexisting idiopathic thrombocytopenic purpura (ITP, p. 971). This should be managed with glucocorticoids and/or immunoglobulin, with the aim of maintaining the platelet count above 80 × 109/L at the time of delivery, in case spinal anaesthesia or caesarean section is required. Thrombocytopenia may also occur as a component of haemolytic uraemic syndrome (HUS, p. 408) and thrombotic thrombocytopenic purpura (TTP, p. 979). Both are characterised by microangiopathic haemolytic anaemia, acute kidney injury and thrombocytopenia, but in TTP neurological symptoms and fever also occur. These conditions are rare but important to recognise since up to one-quarter of cases occur during pregnancy and the post-partum period. TTP is managed with plasma exchange, fresh frozen plasma and sometimes glucocorticoids or rituximab. Platelet transfusion should be avoided. 30.18 Causes of thrombocytopenia during pregnancy • Gestational thrombocytopenia • Idiopathic thrombocytopenic purpura • Systemic lupus erythematosus • HELLP (haemolysis, elevated liver enzymes and low platelets) • Haemolytic uraemic syndrome • Thrombotic thrombocytopenic purpura 30.17 Causes of anaemia in pregnancy Microcytic • Iron deficiency • Haemoglobinopathies • Thalassaemia Normocytic • Anaemia of chronic disease • Haemorrhage • Haemolysis Macrocytic • Vitamin B12/folate deficiency • Liver disease • Alcohol excess

7KLVSDJHLQWHQWLRQDOO\OHIWEODQN

Ch04-3 Clinical Medicine

21-31 Adolescent and transition medicine

31 Adolescent and transition medicine

Adolescent and transition medicine R Mann Transition from paediatric to adult health services 1288 Functional anatomy and physiology 1290 Endocrine changes 1290 Physical changes 1290 Cognitive and behavioural changes 1292 Investigations 1293 Clinical assessment 1293 Presenting problems in transition medicine 1294 Problems with adherence 1294 High-risk behaviour 1295 Unplanned pregnancy 1295 Clinical presentations 1296 Neurological disease 1296 Respiratory disease 1297 Cardiovascular disease 1297 Oncology 1298 Renal disease 1298 Organ transplantation 1299 Diabetes 1299 Gastrointestinal disease 1299 Rheumatology and bone disease 1300 Summary 1300

1288 • ADOLESCENT AND TRANSITION MEDICINE of children with complex pathology, and increasing prevalence of lifestyle-related conditions such as obesity, hypertension and type 2 diabetes. Specific factors that make transition planning important in young people with LTCs are outlined in Figure 31.1. Planning the process of transition from paediatric to adult health services and improving the assessment of young people as they enter those adult services have been shown to impact positively on long-term health outcomes. There is a need for physicians to gain new skills in the care of young people and adults who have conditions that have arisen in childhood. This includes developing specific skills in the management of adolescents and young adults, managing the process of transition and developing knowledge of relevant medical conditions. The overall approach to transition medicine, as well as important disease-specific issues, will be considered in this chapter. Transition from paediatric to adult health services Effectiveness of transition planning A review of the effectiveness of transition planning has confirmed improved health outcomes when specific interventions to improve coordination between adult and paediatric services are implemented. Most research in this field has been undertaken with young people with diabetes, and many of the outcome measures relate to that condition. The principles of transition planning and the potential benefits are, however, likely to be generalisable to other LTCs that present in childhood. Young people with serious LTCs are among the most complex and high-risk patients to care for in adulthood, and it is important to work closely with them as they move to adult services, to try to improve their long-term outcome. General principles of transition planning Paediatric services are organised and delivered in a very different way to adult medical services. They encompass a period of life that spans from infancy to independence, and progress from taking parents’ views as paramount to needing to recognise Historically, childhood illnesses were characterised by a series of acute episodes, often infective, on a background of an otherwise healthy patient. Adult medicine traditionally comprised patients with progressive conditions, and increasing pathology with advancing age. A number of factors have led to the recognition that boundaries between adult medicine and paediatric care are not clear-cut, and recent evidence has confirmed that anticipating and carefully planning the transition of children with long-term conditions (LTCs) into adult services improve care and outcomes. About 14% of children in the developed world are diagnosed with an LTC and in the majority of patients the disorder will persist into adulthood. Common illnesses include asthma, epilepsy, congenital heart disease, diabetes and childhood cancer (Box 31.1). Similar trends are developing worldwide, with increasing survival rates Fig. 31.1 Reasons to consider transition planning. Transition planning Survivors of previously lethal conditions New clinical specialties, e.g. adult congenital heart disease High rates of loss to follow-up Ongoing medical problems, or complications of previous therapy Complex physiological and behavioural changes Adolescence associated with non-adherence Improve outcome Fig. 31.2 Lifestyle changes during transition to adulthood. Autonomous Dependent Transition Employment Education Graduation Financially independent Financially dependent Employment/ benefits Adult relationships, family planning Pre-pubertal Puberty Independent living Live with family Leave home Patient takes responsibility Parents oversee care Loss of parental control 31.1 Important long-term conditions of childhood that affect adult health Neurology • Epilepsy • Cerebral palsy • Duchenne muscular dystrophy Respiratory medicine • Cystic fibrosis Endocrinology • Diabetes mellitus Cardiology • Hypertrophic obstructive cardiomyopathy • Congenital heart disease Nephrology • Renal insufficiency • Renal transplant Gastroenterology • Inflammatory bowel disease Rheumatology • Inflammatory rheumatic disease • Osteogenesis imperfecta • Hypophosphataemic rickets Oncology • Survivors of childhood cancer Infectious disease • HIV/AIDS • Malaria

Transition from paediatric to adult health services • 1289

needs consideration in terms of prescribing and drug doses. The general advice is that when prescribing a dose per kilogram, the optimal weight for height rather than actual weight should be used for obese young people. A systematic approach to transition planning Several steps need to be undertaken to develop a successful programme for transition of care. The key components are summarised in Box 31.2. The first step is to establish a policy in consultation with young people and train staff in the policy. Subsequently, systems need to be developed to identify patients in need of transition and track them as they pass through the programme. Adult health-care providers need to be identified and processes developed for introducing the young person to the adult team. This should be followed by written communication between the paediatric and adult teams, and then a first consultation with the adult team at which the transfer can be reviewed and the wishes of the young person. After transition, young people move from medical services that have been family-centred and focused around maximising the child’s development, to a service that encourages patient autonomy, in which employment and reproduction are important measures of outcome. At the same time as undergoing transition within medical services, young people are making multiple other transitions in their lives as they move from a dependent to an independent way of living (Fig. 31.2). They often move away from the family home, and parents who formerly held responsibility for patient management, coordination of care, communication and consent to treatments will be demoted to an advisory role. Paediatric services are not well placed to meet this change in focus from the patient as a child to the patient as an independent adult, and young people benefit from the move to adult services as long as their specific needs as a young adult are recognised. Principles of prescribing during transition Hepatic drug metabolism increases from neonatal levels during childhood, eventually decreasing to adult levels after puberty. Once puberty has been completed, teenagers can be considered, in pharmacokinetic and pharmacodynamic terms, to behave like adults. It is important to remember that many young people have considerably lower body mass and therefore body mass index (BMI) than adults, and care needs to be taken to avoid excessive dosage in physically smaller patients. Likewise, obesity 31.2 Core elements in developing a transitional care programme Establishing transition policy • Develop policy, with input from young people • Train staff in operation of policy Tracking and monitoring • Establish process to identify patients • Develop systems to track individual progress • Incorporate transition planning into clinical care Transition readiness • Identify suitable adult care provider • Establish process for introduction to adult team • Provide written information about joint first consultation Transition planning • Ensure communication between paediatric and adult teams • Identify need for handover consultation • Prepare written medical handover: Diagnosis Current treatment Previous key issues • Send relevant information in advance • Provide information and community support Transfer to adult services • Arrange first consultation • Review transfer package with team • Identify concerns of young person • Review young person’s health priorities • Update medical summary and emergency care plans Integration into adult services • Communicate with paediatrics and confirm transfer • Help young adult to access other adult services • Continue individualised care plan tailored to young person • Seek feedback from young adult about transition 31.3 Key features in assessing readiness for transition to adult services (K) Knowledge

  1. Describes condition, effects and prognosis
  2. Understands medication purpose and effects
  3. Understands treatment purposes and effects
  4. Knows key team members and their roles (S) Self-advocacy
  5. Can attend part/whole clinic appointment on their own
  6. Knows how to make appointments/alter appointments
  7. Has understanding of confidentiality
  8. Orders repeat prescriptions
  9. Takes some/complete responsibility for medication/other treatment
  10. Knows where to get help (H) Health and lifestyle
  11. Understands importance of diet/exercise/dental care
  12. Understands impact of smoking/alcohol/substance use
  13. Understands sexual health issues/pregnancy/sexually transmitted infections (A) Activities of daily living
  14. Self-care/meal preparation
  15. Independent travel/mobility
  16. Trips/overnight stays away from home
  17. Benefits/financial independence (V) Vocational
  18. Current and future education/impact of condition on career plans
  19. School attendance and performance
  20. Work experience and access to careers advice
  21. Outside activities and interests
  22. Disclosure to school/employer (P) Psychosocial
  23. Self-esteem/self-confidence
  24. Body/self-image
  25. Peer relationships/bullying
  26. Support networks/family/disclosure to friends
  27. Coping strategies (T) Transition
  28. Understands concept of transition
  29. Agrees transition plan
  30. Attends transition clinic
  31. Visits adult unit (if appropriate)
  32. Sees primary care team/other clinical staff independently

1290 • ADOLESCENT AND TRANSITION MEDICINE follicle production, ovulation and menstruation, as described on page 652 and shown in Figure 18.14. Other hormonal changes in all adolescents include a rise in adrenal androgens and a rise in growth hormone, which in turn stimulates production of insulin-like growth factors 1 and 2 (IGF-1 and IGF-2). Insulin production also rises by about 30% during puberty. These hormonal changes contribute to the biological, morphological and psychological changes seen during the teenage years. Adolescence (as opposed to puberty) comprises not only the physical changes of puberty, but also the wider emotional and psychological changes of progression into early adulthood. The emotional and psychological changes are associated with physical maturation but also with sociocultural influences. The normal feelings and behavioural development of normal adolescence are complex but tend to follow fairly predictable patterns. Physical changes In girls, there is an increased rate of growth, followed soon after by the development of breasts and pubic hair. Menstruation typically starts after the rate of growth has peaked. In boys, puberty begins with testicular enlargement, followed soon after by a growth spurt and the development of pubic hair. In clinical practice, Tanner staging is used as a method of documenting progression of physical changes that occur during puberty (Fig. 31.5). The average age at onset of puberty in the UK is about 11 years in girls and 12 years in boys but normal puberty has a very wide range of onset. Factors that are important in predicting age of onset of normal puberty include family history (age of onset is strongly predicted by the parents’ pattern of onset) and body mass, with heavier children entering puberty at a younger age. The current trends towards improved nutritional status and increased obesity in particular are driving earlier onset of puberty. Delayed puberty is defined to have occurred when the age at onset is more than 2.5 standard deviations above the national average, which in the UK is about 13 years in girls and 14 years in boys. If puberty is delayed beyond this point, investigations may be needed to determine the underlying cause, as detailed on page 653. Many children who have had long-term health conditions during childhood experience a delayed onset of puberty because chronic ill health slows longitudinal growth and causes functional hypogonadotrophic hypogonadism. Glucocorticoid therapy also contributes to growth retardation in children with chronic inflammatory diseases. An X-ray of the left wrist can be used to assess bone age accurately, and a bone age that is more than 2 years behind the chronological age should prompt consideration of further investigations (p. 654). Fig. 31.3 Timing of transition. Transfer to adult service with transfer package Prepare for adult model Discuss transfer Make aware of transition planning 12 years 14 years 16 years 18 years 20 years 22 years 24 years 26 years Integrate into adult care Initiate planning a care plan developed. There should subsequently be written communication between the adult and paediatric teams to confirm that handover has occurred, followed eventually by integration of the young person’s care into the adult service. A number of organisations have published guidelines to planning transition services. Two of the best known include the ‘Ready Steady Go’ programme in the UK and the American Academy of Paediatrics’ ‘Got Transition’ (see ‘Further information’). Details of the sorts of competencies that a young person might need before making a full transition to adult medical services are outlined in Box 31.3. When should transition happen? The optimum timing for transition is not specifically defined; it is a process that evolves over a number of years, during which puberty and then adolescence occur. Transition should generally be initiated at around 12 years of age. Completion time then varies from person to person, also depending on the model of adult services available. Most commonly, full transition occurs between 16 and 18 years of age (Fig. 31.3). This coincides with many other areas where young people are considered to have made the transition to adulthood, such as the completion of formal education. Marriage and children often follow. Functional anatomy and physiology Puberty and adolescence are developmental stages through which children progress during the second decade of life. During this phase, several physical, biochemical and emotional changes occur. The most important are discussed in more detail below. Endocrine changes The hormonal and physical stages of progression through puberty in males and females are summarised in Figure 31.4. Puberty is initiated by pulsatile increases in gonadotrophin-releasing hormone (GnRH) by the hypothalamus, which in turn stimulates pulsatile release of luteinising hormone (LH) and follicle-stimulating hormone (FSH) by the pituitary. In males, the increased production of LH stimulates Leydig cells in the testes to produce testosterone, and FSH acts on Sertoli cells to stimulate sperm production, as described on page 651 and shown in Figure 18.13. The rise in testosterone increases skeletal growth, promotes development of the male genital organs and stimulates growth of pubic, facial and axillary hair. In females, FSH and LH act on the ovary to promote

Functional anatomy and physiology • 1291

Fig. 31.4 Hormonal events of puberty. A In the ovary, FSH acts on granulosa cells to stimulate oestrogen production, whereas LH acts on theca cells to stimulate progesterone production. Androgens are also produced in small amounts by theca cells in response to LH (not shown). B In the male, LH acts on interstitial Leydig cells to stimulate testosterone production. FSH with testosterone acts on Sertoli cells to stimulate spermatogenesis. (ACTH = adrenocorticotrophic hormone; FSH = follicle-stimulating hormone; GnRH = gonadotrophin-releasing hormone; LH = luteinising hormone) From Smith RP. Netter’s Obstetrics and gynecology, 2nd edn. Philadelphia: Saunders, Elsevier, Inc.; 2008. Acne appears Axillary hair appears Breasts develop Uterus enlarges Menstruation begins Pubic hair appears Vaginal epithelium cornifies Epiphyseal union hastened Body contours rounded Adrenal cortices ACTH GnRH LH and FSH Prolactin Pituitary LH and FSH secretion increased Higher cerebral centres ‘trigger’ puberty Reticular zone enlarges Adrenal androgens increased Oestrogen produced Progesterone increased Ovaries A Acne appears Facial hair appears Musculature develops Larynx enlarges (voice deepens) Axillary hair appears Some breast enlargement may occur Pubic hair appears Penis, prostate and seminal vesicles enlarge Epiphyseal union hastened Adrenal cortices ACTH GnRH LH and FSH Prolactin Pituitary LH and LSH secretion increased Higher cerebral centres ‘trigger’ puberty Reticular zone enlarges Adrenal androgens increased Testosterone increased Testes B

1292 • ADOLESCENT AND TRANSITION MEDICINE Fig. 31.5 Tanner staging of puberty. Tanner stage I II III IV V Female Breast Pubic hair Pubic hair Mature stage. Projection of papilla with recession of areola to contour of breast Projection of areola and papilla to form mound above breast Further enlargement of breast and areola with no separation of contours Elevation of breast and papilla as a small mound Pre-adolescent Dark, coarse and curled hair extending to inner thighs Darker, coarse and curled hair but covering smaller area than in adult. No spread to medial surface of thighs Darker, coarse and curled hair Sparse, long and straight None Pre-adolescent None Penis, testes and scrotum of adult size Further growth in length and width of penis, testes and scrotum Growth of penis and further growth of testes and scrotum. Skin of scrotum becomes darker and more wrinkled Growth of testes and scrotum. Skin on scrotum reddens and becomes wrinkled Genitalia Male Dark, coarse and curled hair extending toward umbilicus Darker, coarse and curled hair but covering smaller area than in adult Darker, coarse and curled hair Sparse, long and straight Cognitive and behavioural changes As young people move from their early teenage years to later adolescence there is a move away from the family towards personal independence. This is often characterised by change from a self-centred focus, associated with a sense of awkwardness and worries about being normal, towards increased self-confidence and an awareness of weaknesses in parents and others in authority. In late adolescence, young people reach a stage of self-reliance, increased emotional stability and improved ability to think ideas through. Finally, young adults begin to develop firm belief systems, autonomy and independence. With time, there is reduced conflict with parents and other figures in authority and full maturity develops. In terms of cognition, there is a transition from being mostly interested in the present, in short-term outcomes and instant gratification, through to increased concern for the future and a greater focus on one’s longer-term role in life. Sexuality and relationships clarify during adolescence, and individuals move from early awkwardness and uncertainty to a firmer sense of their sexual identity, and then development of more serious and longer-term relationships. In terms of morals and values, young people move from a period of risk-taking behaviour and experimentation through to understanding the potential consequences of such behaviour for their future health and well-being. Young adults develop a greater capacity for setting personal goals and an increased focus on self-esteem. Finally, family, social and cultural traditions regain some of their previous importance, and by the time young people emerge from adolescence, they have usually developed insight and a greater focus on self-esteem and long-term well-being. It is the development of these more mature personality traits that are important for the more active role in health care that is needed to function well within an adult model of medicine. Some teenagers do vary slightly from these broad patterns but the feelings and behaviours described are, in general, considered normal for each stage of adolescence. Understanding these changes in emotional and psychological behaviour underpins the approaches that are needed to meet the challenges of managing long-term conditions in older teenagers and young adults.

Clinical assessment • 1293

assessment. Often, the first transition appointment is undertaken jointly with the paediatrician in a specialist transition clinic and this will enable a thorough face-to-face handover of all the key facts. A detailed transition referral letter should clearly describe the diagnosis, current and previous treatments, and key interventions that have been undertaken while the patient was under the care of paediatric services. It is important to check the main details with the young person and to make sure there are no other factors that they feel are of relevance. There are a few features in the history that merit special attention, particularly at the first consultation, as outlined in Box 31.5. Many young people with an LTC attend their first adult outpatient department consultation with their parents, and it is important either to create a time to ask personal and lifestyle-related questions separately from the main history – that is, privately – or to make sure that these can be confidentially explored in future. Investigations Several changes take place during adolescence in terms of skeletal growth, organ development and body composition, which can influence the interpretation of results. Examples include fusion of the epiphyses as puberty progresses, increases in bone mineral content and density as the skeleton grows, and changes in the reference range of certain biochemical tests. Most of these changes occur gradually during puberty and there are rarely abrupt alterations in adult biochemical concentrations. It is important to use age-adjusted biochemical reference ranges until puberty has been completed. Several biochemical changes take place in the composition of body fluids between infancy and puberty. Some of the key changes in biochemical markers are outlined in Box 31.4. More detail on reference ranges for specific analytes is provided in Box 35.9 (p. 1363). The elevation in alkaline phosphatase (ALP) levels during adolescence relates to the bone isoenzyme produced by osteoblasts in the growing skeleton during the growth spurt. Further investigations for raised levels of ALP are not required in adolescence, as long as other liver function tests, including γ-glutamyl transferase (GGT), are normal. In general, under normal physiological conditions, the reference ranges of most biochemical tests remain fairly constant between puberty and menopause in women and between puberty and middle age in men. Clinical assessment The initial patient consultation at transition is of vital importance for establishing a potentially life-long professional relationship with the patient, as well as identifying key features in the history, examination and assessment of their overall needs. Parents commonly attend a first adult appointment with their son or daughter, and it is usually necessary to allow longer for this initial 31.4 Biochemical changes during transition Analyte Comment Alanine aminotransferase (ALT) Increased during adolescence Activity may continue to rise, at least in men, until middle age Alkaline phosphatase (ALP) Activity higher in infancy, decreases during childhood, and rises again with skeletal growth during puberty Peak in females at median 11 years and in males at 13 years Levels decrease rapidly after puberty, particularly in girls; adult levels achieved after epiphyses fused Insulin-like growth factor 1 Levels 30% higher during adolescence Serum creatinine Increases steadily from infancy to puberty parallel to development of skeletal muscle; until puberty, there is little difference in concentration between males and females Uric acid concentration Decreases from high levels at birth until 7–10 years of age, then increases, especially in boys, until 16 years 31.5 Features in transition assessment Features of history and/or examination Reason History* Main/presenting condition and detailed review of clinical course Understand detail and severity of illness; understand which treatments have been undertaken and which have been successful Family history: Draw family tree of all first-degree and any relevant/affected second-degree family members Many long-term conditions arising during childhood have significant genetic and familial factors to be taken into account Current drug therapy, significant previous therapies Many drugs have significant long-term implications, levels may need monitoring, may have teratogenic effects to consider Any surgical or other relevant medical history Understand which treatments have been undertaken and which have been successful Pubertal status/age of menarche Helps assess disease severity plus patterns of growth Informs about patient’s reproductive health and family-planning wishes Social history: In education or in work? Receiving appropriate benefits/support? Financial or other practical concerns? Living with parents/left home? Assesses wider effects of patient’s health on their independent living, as well as their financial and practical circumstances Can be a proxy measure of disease severity and identifies their support mechanisms, which also helps in the assessment of their current needs Systems enquiry Any other related/unrelated symptoms or problems Physical examination Height, weight, calculation of body mass index Blood pressure Urinalysis if relevant Assessment of pubertal status General physical examination Although young people are often accompanied by a parent, examine them separately and use this opportunity to consider asking about private matters, such as partners, sexual activity, and drug or alcohol use *Throughout the first consultation, confidence and competence in decisionmaking/capacity to consent should be assessed. If there are concerns about capacity, clarify key decision-makers.

1294 • ADOLESCENT AND TRANSITION MEDICINE reported rates vary according to the method of assessment. Teenagers may also have varying adherence levels within their treatment regimen. An important example is in patients who have undergone organ transplantation, in whom low adherence to immunosuppressive medication is a significant cause of graft rejection and may cause death. Adherence merits careful consideration when caring for adolescents and young adults, and focusing on strategies to improve adherence at this initial stage of patient management can deliver life-long improvements in health outcomes. Young teenagers mainly believe in things that they have directly experienced and do not fully appreciate the unseen consequences of not taking their medications. In time, Presenting problems in transition medicine Problems with adherence Adherence is defined as ‘the extent to which a person’s behaviour, in terms of taking medications, following diets, or executing lifestyle changes, coincides with medical or health advice’. The term ‘adherence’ is used in preference to ‘compliance’ because it focuses on whether a person actively adheres to the regimen rather than passively follows the doctor’s orders. It also implies partnership and cooperation between the patient and the care-giver. More recently, clinicians have moved to seeking patients’ concordance with management plans. Concordance refers to a consultation process that has an underlying ethos of shared decision-making. It has become clear that current levels of adherence do not deliver the full benefits of medication. Historical paternalistic medical practice does not maximise the chances of patients adopting the changes and treatments they need to improve their outcomes. Reaching a concordant position with patients involves a range of approaches (such as patient-centredness or shared decision-making) and a number of specific actions (such as exploring anxieties about medication side-effects, individualising regimes to suit the patient’s lifestyle, offering a range of treatment options) and has not been evaluated comprehensively. Adherence to clinic attendance, investigation and treatment often falls significantly in adolescence and during transition to adult services. Measurement of adherence is challenging and 31.6 Factors affecting adherence Negative factors • Older adolescent • Mental health issues with care-giver • Family conflicts • Complex therapy • Medication with side-effects • Denial of illness Positive factors • Positive family functioning • Close friends • Internal locus of control • Treatment with immediate benefits • Patient’s belief in seriousness of illness and efficacy of treatment • Physician empathy Simplify regimen • Use once daily/twice daily regimes if possible • Match regimen to bedtime and meals • Use pill box or alarms on phone • Organise services around patient (combined clinics, flexible timing and appointments) Impart knowledge • Share decision-making • Provide clear instructions: Limit to three or four major points Use simple, everyday language Use written information or pamphlets and verbal education at all encounters • Supply addresses of quality websites • Provide advice on how to cope with medication costs Modify patient beliefs • Empower patients to self-manage their condition: Ask about their needs Ask what might help them become and remain adherent Ensure they understand the risks of not taking their medication Address fears and concerns about taking the medication Provide communication • Improve interviewing skills • Practise active listening • Provide emotional support – treat the whole patient and not just the disease • Provide clear, direct and thorough information • Elicit the patient’s input in treatment decisions • Allow adequate time for patients to ask questions • Build trust Leave the bias • Learn more about low health literacy and how it affects patient outcomes • Consider care of ethnically and socially diverse patient populations • Acknowledge biases in medical decision-making (intentional or unintentional) • Address dissonance of patient–provider race/ethnicity and language • Take extra time to overcome cultural barriers • Ask specifically about attitudes, beliefs and cultural norms around medication • Use culturally and linguistically appropriate targeted patient interventions • Increase engagement, activation and empowerment • Tailor education to the patient’s level of understanding Evaluate adherence • Direct: Number of repeat prescriptions Biomarkers of response Measurement of drug levels • Indirect: Self-reporting: ‘When did you last forget your medicine?’; ‘How often have you forgotten your medicines this week?’ 31.7 SIMPLE strategies to improve adherence Excerpted with permission from the American College of Preventive Medicine. Medication Adherence: Improving Health Outcomes Time Tool: A Resource from the American College of Preventive Medicine. 2011. Retrieved from https://webmail2.tst.nhs.uk/go/www.acpm.org/?MedAdhereTTProviders.

Presenting problems in transition medicine • 1295

are at greater risk of undertaking harmful behaviour and there is evidence that a poor long-term health outlook is associated with risk-taking behaviour earlier in life. Globally, the leading causes of death among adolescents are road injury, human immunodeficiency virus (HIV) infection, suicide, lower respiratory infections and interpersonal violence; many of these deaths are linked to risk-taking behaviours such as excess alcohol and drug intake. Quite apart from mortality, there are other significant adverse events linked to risk-taking behaviour in adolescents: excess alcohol ingestion is also associated with non-fatal road traffic accidents, unwanted and unprotected sexual activity, and violence as both perpetrator and victim. There are a number of theories about the neurodevelopmental changes associated with these behaviour changes. At around 11 years of age, the prefrontal cortex (PFC) and parietal lobes begin a period of pruning of neuronal axons. It is theorised that these changes represent the start of the process of increasing frontal lobe control. A separate process that occurs at the same time predisposes the adolescent to risk-taking behaviour and impulsivity: frontostriatal reward circuits mature relatively early and encourage the adolescent towards adult activities such as alcohol and drug use, and sexual intercourse, which carry potential health risks. At this stage, the PFC has not yet matured to the point where the individual can assess risk adequately. The PFC and its connections are structurally unable to provide sufficient control. It is thought that this maturational gap in PFC control of the pleasure-seeking brain systems is responsible for the risk-taking lifestyle that characterises the period of adolescence. A number of studies have investigated personality and other factors that contribute to different risk-taking behaviours during adolescence: essentially, younger adolescents and females tend to rate activities as being more risky, and are therefore less likely to undertake them. Older males and those of lower educational status are higher risk takers. Specific protective factors include high self-esteem and a strong orientation to an internal locus of control; young people who feel they have less control and influence over themselves and their behaviour are more likely to undertake high-risk activities. Many teenagers with serious long-term health conditions are disempowered in a number of ways and there is evidence that they are predisposed to be high risk takers during adolescence. Examples of risk-taking behaviour include not only alcohol and drug intake, but also non-adherence to medicines and other aspects of health care, such as diet in diabetes. It is not easy to affect behaviour during this period of nonadherence. Isolated educational intervention is not sufficient to improve outcome; for example, there is a wealth of evidence showing that teenagers know about the behaviours needed to prevent transmission of HIV, but many do not adhere to this advice. Long-term health-care providers have an invaluable role in supporting adolescents during this period of their development as adults, as many important health-related and lifestyle habits are established during this period: more than 90% of smokers start smoking in adolescence, and life-long habits around eating and exercise are laid down during the teenage years. Focusing on the needs of the emerging adult for autonomy and using the highest levels of communication and patient engagement significantly improve outcomes for patients with LTCs. Unplanned pregnancy In many parts of the world, females commonly undergo their first pregnancy during or just after adolescence. The median age for 31.8 History-taking in adolescent patients: risk-taking behaviours (‘HEADS’) Home life • Relationships • Social support • Household chores Education • School • Exams • Work experience • Career • University • Financial issues Activities • Peers, people that patients can rely on • Exercise and sport Driving • Aged 16 if disabled Drugs • Cigarettes and alcohol: how much, how often • Non-prescription drugs Diet • Nutritional content (calcium, vitamin D) • Weight • Caffeine (diet drinks) • Binges/vomiting Sex • Concerns • Periods • Contraception (in relation to medication) Sleep • Amount • Difficulty getting to sleep • Frequent waking • Early waking? Suicide • Depression • Mood • Disabled adolescent men high-risk From Segal TY. Adolescence: what the cystic fibrosis team needs to know. J R Soc Med 2008; 101(Suppl 1):15–27. adolescents learn to develop hypothetical thinking and to analyse more complex information and decision-making. The ability to engage in formal thinking is inconsistent at first, and at times of stress (such as during an illness) adolescents may regress to more simple ways of problem-solving. Despite their maturing skills, they may remain self-centred and feel invincible. Factors that positively and negatively affect adherence are outlined in Box 31.6. Interventions to improve adherence are summarised in Box 31.7. Recent literature suggests that two-way communication between patients and professionals about medicines leads to improved satisfaction with care, knowledge of the condition and treatment, adherence, health outcomes and fewer medicationrelated problems. Younger adults and those coming to adult services following transition from paediatric services have very different expectations in terms of the nature of the patient–doctor relationship and are more likely to require a more collaborative approach to development of management plans to maximise their concordance with treatment in the long term. High-risk behaviour The high-risk behaviour that can be undertaken by adolescents is well documented and is seen across many cultures. It is important to assess this by history-taking at the time of transition (Box 31.8) Adolescents who have had LTCs during childhood

1296 • ADOLESCENT AND TRANSITION MEDICINE controlled with first-line anticonvulsants in around 80% of cases. Young people who still have epilepsy or are on anticonvulsant therapy as they progress into adulthood are more likely to have underlying structural brain disease, such as cerebral palsy, or have more complex or syndromic epilepsy. In many of them, epilepsy may be associated with learning difficulties or other neurological conditions. Epilepsy presents several problems during transition. Adherence to medication can be an issue and patients with low adherence to epilepsy medicines have higher mortality, higher hospital admission rates and higher emergency department attendances. Conversely, high adherence rates at initiation of epilepsy therapy are associated with improved long-term seizure freedom and higher seizure freedom at 4 years. Epilepsy can also affect employment options for young people, as about 30% of patients still have breakthrough seizures while on treatment. Certain types of employment, such as working within the emergency services or armed forces, or becoming a pilot or driver of a heavy goods vehicle, may therefore not be possible. Driving restrictions may also limit options for some other occupations (p. 1103). Young women with epilepsy should be advised that oral contraceptives are less effective with enzyme-inducing antiepileptic drugs; they should also be made aware of the risk of teratogenicity with many antiepileptic drugs, most notably sodium valproate, which should be avoided in pregnancy if at all possible. Pre-conceptual counselling is desirable for all young girls with epilepsy and pre-conceptual folic acid supplementation is advisable to reduce the risk of neural tube defects. Alcohol use in moderation does not affect seizure control in the majority of patients, but withdrawal from alcohol in dependent patients is epileptogenic and heavy alcohol use should be discouraged. Information about marijuana and epilepsy risk is lacking, but regular marijuana use and excess drinking are associated with poor adherence to medication regimes and increased seizure risk. Cerebral palsy Cerebral palsy comprises a range of non-progressive neurological impairments, present from the time of birth or arising in early childhood. Although the neuropathology is non-progressive, the manifestation of problems can evolve, with progressive motor dysfunction related to increased spasticity and possibly progressive seizure activity. Patients with severe cerebral palsy present specific problems during transition and early adulthood. They may be paraplegic or quadriplegic and most non-ambulatory individuals have significant intellectual disability. This group of patients will be unable to live independently during adulthood and need ongoing long-term care. Delivering medical care to these individuals poses several problems, including practical issues such as consideration of capacity and consent to treatment. Other comorbidities include gastro-oesophageal reflux (often related to abnormal lower oesophageal function), seizures, and feeding difficulties often requiring gastrostomy. These individuals usually require a complex care package involving many members of the multidisciplinary team. There are also risks of abuse and neglect in the care of adults with severe disability and this needs to be borne in mind when considering atypical problems or unusual presentations in this vulnerable patient group. Depending on the severity of the patient’s condition, end-of-life care may need to be discussed and planned with the family and other care-givers. 31.9 Adolescent pregnancy rates Region Pregnancy rate (/1000 women aged 15–19 years) Tanzania

Kenya

Jamaica

Mexico

South Africa

USA

Pakistan

New Zealand

UK

Spain

France

Japan 5.3 Italy 4.5 South Korea 2.2 first pregnancy varies from 19 years in India and parts of Asia, through to 25 years in the USA and around 30 years in Australia and Western Europe. Teenage pregnancy rates are high across the world (Box 31.9). Information from the UK suggests that 1 in 6 pregnancies is unplanned, and 1.5% of women between the ages of 18 and 45 face an unplanned pregnancy each year. It is therefore vital to anticipate and discuss the issues surrounding reproductive health with all young people before and during transition, as well as during early adulthood. Young people with serious LTCs have a number of additional factors to be taken into consideration when discussing reproduction, and these discussions need to take place long before a family is planned. General physicians do not need to be able to undertake complex genetic counselling and investigation, but should be able to provide advice about the recurrence risk of common inherited conditions, as well as that of the more common multifactorial LTCs, many of which have an inherited or genetic component. Clinical presentations In almost every clinical setting, there is the potential for a young adult with a serious LTC that has arisen during childhood to present to adult physicians. Medical services can improve the care and outcome for this vulnerable group by planning a systematic approach to transition, as described above, and by focusing the clinical consultation on issues of relevance and importance to each particular patient. The key issues to consider for a number of the most common LTCs of childhood are discussed below. Neurological disease Epilepsy Epilepsy is a chronic disorder, the hallmark of which is recurrent, unprovoked seizures (p. 1097). Epilepsy that has presented during childhood, as opposed to adulthood, is less often associated with underlying central nervous system malignancy and is well

Clinical presentations • 1297

Muscular dystrophy The muscular dystrophies are a group of diseases that cause progressive weakness and loss of muscle mass. The disorders differ in terms of which muscle groups are affected, the degree of weakness, and the rate of disease and symptom progression. All the inherited muscular dystrophies that present during childhood need active management during transition (p. 1143). One of the most important and most severe conditions is Duchenne muscular dystrophy (DMD), which is associated with a progressive decline in mobility, coupled with cardiac dysfunction due to cardiomyopathy, and respiratory failure requiring respiratory support as the disease progresses. Physicians should ensure that the whole family are aware of the wider genetic issues. Female carriers of the DMD gene can suffer muscle fatigue and are at risk of cardiomyopathy, as well as there being obvious risks for their male offspring. On average, patients with DMD survive until their late teens to early twenties, and those with less severe muscular dystrophies, such as Becker dystrophy, survive until their thirties. Although fertility is reduced, young men with these conditions may themselves father children. Male offspring will be unaffected but all female infants of affected males will be carriers. As the muscular dystrophies progress, a complex package of care involving a multidisciplinary team is necessary; it should include respiratory input to assess the need for ventilatory support, which is a common endpoint for many patients. At the present time, there is no definitive treatment. Glucocorticoids (0.75 mg/ kg/day) have been shown to improve muscle strength and are frequently used, but carry an increased risk of osteoporosis and vertebral fractures. New therapeutic approaches are being developed with the aim of ameliorating disease progression in patients with nonsense mutations (p. 42). One involves the use of drugs such as ataluren, which promotes binding of transfer RNA (tRNA) molecules at the site of stop codons with a mismatch in one base (near-cognate tRNAs). These cause a full-length protein to be produced with an amino acid substitution rather than a truncated non-functional protein. Patients with DMD usually require social and financial support. It is important to consider end-of-life care plans with patients and family members. Involvement from palliative care teams, as well as psychological, spiritual and wider non-medical support, is essential. Respiratory disease Cystic fibrosis Cystic fibrosis (CF) is a single-gene autosomal recessive disorder that affects about 1 in 2000 to 1 in 3000 individuals of Caucasian descent (p. 580). Clinical manifestations are caused by defects in an ion transporter termed the cystic fibrosis transmembrane conductor regulator (CTFR) protein. With improved supportive care, the median survival in the UK is now more than 50 years. It is well recognised that young people with life-limiting conditions face particular challenges during transition: individuals often exhibit high-risk behaviour during adolescence, and this was particularly true in the past when long-term survival rates were poor. The rates of non-concordance with medication and with time-consuming physiotherapy and nebuliser regimes are high and adversely affect outcome and survival. Exercise tolerance and employment are likely to be restricted as time progresses, and patients need particular support managing the slow decline in function and well-being that occurs throughout their adult lives. In terms of fertility and child-bearing potential, the picture is complex and merits detailed discussion with patients. It is not often discussed openly by the paediatrician or during childhood, other than with the parents when the patient is young. The vas deferens is absent in 98% of males with CF and seminal vesicular dysfunction means that ejaculates are low in volume. While boys are infertile, newer reproductive therapies, such as the availability of intracytoplasmic sperm injection, mean that fatherhood is possible. The opportunity for assisted reproduction should be discussed early so that people can make informed choices at an appropriate stage of their lives. Females with CF who have good nutritional status and reasonable health status have normal fertility and genetic counselling should be offered early. Contraception needs to be discussed with women who are not planning a pregnancy, since pulmonary hypertension is an absolute contraindication for the oral contraceptive pill (OCP). Women also need to be advised about the effects of antibiotics on OCP effectiveness. New orally available small-molecule therapies, including lumacaftor and ivacaftor, have recently been licensed; they can partially rectify functional defects in the CTFR and have improved outcome. These drugs are having a positive effect on symptom control and are potentially disease-modifying. Other therapeutic approaches, including gene therapy and mRNA editing therapies, are also being explored as treatments for CF. Common issues encountered during transition of CF patients are summarised in Box 17.34 (p. 581). Cardiovascular disease Congenital heart disease Congenital heart disease (CHD) is the most common congenital anomaly, affecting about 1% of live births. Among birth defects, CHD is the leading cause of mortality. Maternal illnesses such as rubella and injection of teratogenic agents during pregnancy, along with paternal age, all play roles in pathogenesis. Although some chromosomal anomalies, such as trisomy 13, 18 and 21 and monosomy X (Turner’s syndrome), are strongly associated with CHD, these account for only 5% of cases. Microdeletion and single-gene mutations can also be important, such as in DiGeorge syndrome (22q11.2 microdeletion). Overall, the most common congenital valvular anomalies are aortic and pulmonary stenosis. The most common structural anomaly is ventricular septal defect. There is a wide range of severity of CHD but many patients with life-limiting conditions (usually complex structural anomalies such as tetralogy of Fallot or hypoplastic left heart syndrome) survive to adulthood. Genetic counselling of affected individuals is important, as there is a 1–2% recurrence risk of any cardiac anomaly in offspring. Affected patients should be transitioned to a cardiologist with experience in CHD since this has become a subspecialty in own right. More details are provided on page 531 and in Box 16.103 (p. 537). Hypertrophic obstructive cardiomyopathy Hypertrophic obstructive cardiomyopathy (HOCM, p. 539) is a genetic cardiovascular disease characterised by left ventricular wall hypertrophy, impaired diastolic filling and abnormalities of the mitral valve. These features can cause dynamic obstruction of the left ventricular outflow tract, diastolic dysfunction, myocardial dysfunction and an increased risk of supraventricular and ventricular tachyarrhythmias. HOCM is caused by mutations

1298 • ADOLESCENT AND TRANSITION MEDICINE necrosis, and angina or myocardial infarction arising from vasoocclusion or vasospasm. In addition to physical effects, children who have faced lifethreatening illness in childhood may experience psychological and family difficulties during adulthood. Cognitive impairment is more common in children who have received chemotherapy or radiotherapy to the brain, and problems can include lower IQ, problems with memory and attention, poor hand–eye coordination and behaviour/personality problems, combined with the wellrecognised and physical complications of cancer treatment in childhood. Increasing recognition of these issues has resulted in active monitoring programmes for survivors of childhood cancer, who are best seen in specialist ‘late effects’ multidisciplinary clinics, where teams include oncologists, psychologists and specialists from other relevant disciplines. Renal disease Chronic kidney disease (CKD, p. 415) accounts for some of the most complex long-term illnesses in childhood. The most common causes during childhood and adolescence are shown in Box 31.10. The primary pathology can be varied and many conditions have no specific treatment, but the overall approach to management of progressive renal insufficiency is the same. Internationally agreed definitions of CKD staging in children differ from those in adults and are summarised in Box 31.11. In adults the rate of albumin excretion is included in CKD definitions, as outcome correlates with the level of albuminuria, but in children similar data are lacking and so the staging system is based on glomerular filtration rate alone. The majority of children with affecting the genes that encode cardiac sarcomere proteins and is most frequently transmitted as an autosomal dominant trait. It may present for the first time during adolescence with cardiac arrest or sudden cardiac death. Predictive genetic testing is possible but challenging because of the large number of causal mutations. In clinical practice, careful analysis of the family history can be useful in identifying those at risk of inheriting the disease. If no gene anomaly has been identified within a family, first-degree relatives may need screening by electrocardiography (ECG) and echocardiography. Identification of a genetic anomaly is most helpful in allowing identification of family members who do not need echocardiograms or clinical follow-up. Children of affected parents should be screened every 3 years until puberty, and then annually until 20 years of age. If there is no evidence of HOCM in early adulthood, it is unlikely that the condition will develop in later life. Oncology Around 1 child in 500 will develop cancer by the age of 14 years. Leukaemia is the most common, accounting for about 33% of cases; central nervous system tumours are the next most common, accounting for around 25% of all childhood cancers. Fifty years ago, 75% of children diagnosed with cancer died, but overall survival rates now range from 75% to 80%. Between 60% and 70% of young adults who have survived childhood cancer will develop at least one medical disability, most commonly as a result of their therapy rather than their primary cancer. There is a 3–6-fold increased risk of a second cancer, with an absolute risk of about 10% before 50 years of age. It is therefore important for these individuals to be kept under surveillance during transition and beyond. Endocrine and reproductive disturbances are the most common late effects, affecting 40–60% of survivors. Infertility can be an issue in both males and females receiving cytotoxic medications, unless it has been possible to store semen and ovarian tissue in advance of treatment. Other long-term risks include hypopituitarism, growth hormone deficiency and pubertal delay (especially in boys) from brain irradiation. Radiotherapy to the neck can cause hypothyroidism and increases the risk of thyroid cancer. Total-body irradiation offered as conditioning for bone marrow transplantation affects both ovarian and testicular function, and many of the chemotherapeutic agents used have adverse effects on fertility. Chemotherapy-induced ovarian failure is typically associated with high-dose alkylating agents such as cyclophosphamide, and this is an independent risk factor for premature ovarian failure. In recent years, patients have been offered ovarian and testicular tissue retention and fertility issues are being discussed with families during childhood, but often the patients themselves have limited levels of knowledge of the details. Chemotherapy and radiotherapy in childhood significantly reduce ovarian reserves. When combined with the progressive ovarian decline that occurs in all women throughout adulthood there is a significant risk of premature menopause or ovarian failure, with 8% of survivors affected. Young women need to be aware of these risks during their early adulthood to help with family and lifestyle planning; for example, they may wish to plan to have children earlier in their adult life rather than risking ovarian decline. Cardiomyopathy is another complication of anthracyclines such as doxorubicin and daunorubicin. Serious cardiac complications include arrhythmias, dilated cardiomyopathy from myocardial 31.10 Causes of renal impairment in childhood and adolescence • Obstructive uropathy • Renal hypoplasia/dysplasia • Reflux nephropathy • Focal segmental glomerular sclerosis • Polycystic kidney disease 31.11 Staging of chronic kidney disease (CKD) in children over 2 years of age* Stage Glomerular filtration rate (GFR) (mL/min/1.73 m2) Description

90 Normal or high

60–89 Mildly decreased 3a 45–59 Mildly to moderately decreased 3b 30–44 Moderately to severely decreased

15–29 Severely decreased

< 15 Kidney failure *Kidney Disease: Improving Global Outcomes (KDIGO) 2012 classification. Chronic kidney disease is defined either as GFR < 60 mL/min/1.73 m2 for > 3 months, regardless of whether other CKD markers are present, or as GFR < 60 mL/ min/1.73 m2 accompanied by evidence of structural damage or other markers of kidney abnormalities, including proteinuria, albuminuria, and pathological abnormalities in histology or imaging. In adults, albumin excretion is also included in CKD staging as the level of albuminuria correlates to outcome. These data are lacking in children and so albuminuria is not used to classify paediatric CKD.

Clinical presentations • 1299

Diabetes Adherence and concordance with medication are a particular challenge in adolescents who have developed diabetes during childhood (p. 753). Studies of adolescents with type 1 diabetes have revealed that 25% were neglecting insulin injections, 81% were not following their diet, and 29% were not measuring their glucose level and were completing a daily diary with fictitious results. Research has also shown that the outcome of diabetes is improved with a formal transition programme (Box 31.12). Good control of diabetes is particularly important during this phase since microvascular disease often emerges around time of transition, although it can occur sooner in patients with early-onset diabetes. CKD stage 3 or higher will ultimately require renal replacement therapy but the timescale for reaching this stage can vary widely. The mainstay of support is to delay progression by treatment of secondary factors that are known to be associated with progressive decline in renal function: namely, hypertension, proteinuria and anaemia. Organ transplantation Children requiring renal replacement therapy are the most common recipients of kidney transplants in childhood. Liver and heart transplantation, followed by lung and small bowel transplantation, are well-recognised but less commonly undertaken procedures. Non-adherence to immunosuppressive regimes during adolescence is a well-known risk factor for graft failure. The reported incidence of graft failure due to non-adherence is 10–15% but this is likely to be an under-estimate. Rates of non-adherence are highest among adolescents and young adults. As well as non-adherence to immunosuppression, non-adherence to testing and clinic attendance adversely affects the care and outcome of around 1 in 8 kidney transplant patients. Poor adherence is associated with patients with worse psychological status and family dysfunction; adherence has been shown to improve with education and increased motivational factors, as might be expected. This offers the opportunity to improve graft survival. At present, 50% of cadaveric grafts and around 68% of live donor grafts are still functioning 10 years post-transplant. There is no clear difference between children and adults in survival of transplanted kidneys. Many medications used in transplant medicine and in renal disease can have long-term effects on health. Inhibition of linear growth is seen even with low doses of glucocorticoids, such as 0.125 mg/kg/day on a long-term basis. Alternate-day regimes are generally considered preferable in childhood. The height reduction associated with long-term glucocorticoid use in childhood is dose-dependent, and even for children with asthma treated with inhaled glucocorticoids, an average height reduction of 1.2 cm is reported. This is can also be associated with delayed puberty, as well as an increased risk of osteoporosis in adulthood. Post-transplant lymphoproliferative disorders (PTLDs) are a well-recognised and potentially life-threatening complication in solid organ recipients. PTLD is the most common malignancy complicating solid organ transplantation, accounting for 20% of all cancers. They represent a range of lymphoproliferative disorders, from infectious mononucleosis and lymphoid hyperplasia to malignant lymphoma. Most cases of PTLD are associated with Epstein–Barr virus (EBV), leading to uncontrolled B-cell proliferation and tumour formation. Up to 10% of solid organ transplant recipients develop PTLD but the risk is almost four times higher in patients under 20 years of age, as opposed to those aged 20–50. This increased risk relates mainly to the development of EBV infection after transplantation; most adults are already EBV-seropositive at the time of transplantation and therefore at lower risk of this complication. The type of organ transplant that has been undertaken predicts PTLD risk, with the cumulative incidence over 5 years ranging from 1–2% in haematopoietic cell transplant and liver transplants, 1–3% in renal transplants, 2–6% in heart transplants and 2–9% in lung transplants to as high as 11–33% in intestinal or multi-organ transplants. The different rates possibly relate to the varying degrees of immunosuppression required. The incidence of PTLD is highest in the first year after transplantation, when it is associated with the highest levels of immunosuppression. 31.12 Impact of transition planning on outcome in diabetes Intervention Outcome measures Disease-specific education Lower HbA1C Generic education/skills training Fewer acute complications: Hypoglycaemia Admissions with ketoacidosis Transition coordinator Lower rate of loss to follow-up Joint paediatric/adult clinic Fewer chronic complications: Hypertension Nephropathy Retinopathy Separate young adult clinic Improved self-management Improved disease-specific knowledge Out-of-hours phone support Improved screening for complications Enhanced follow-up Better quality-of-life scores Gastrointestinal disease Inflammatory bowel disease The prevalence of inflammatory bowel disease (IBD, p. 813) in childhood is increasing, and the incidence of Crohn’s disease (CD) in particular is rising in both children and adults, probably due to currently undefined environmental factors. Current treatment aims are outlined in Box 31.13. Standard measures include exclusive enteral nutrition for 6–8 weeks using a whole-protein (polymeric) formula, which induces initial remission in 80% of children. This is equivalent to glucocorticoid therapy but offers improved nutritional status and superior mucosal healing. Glucocorticoids can also be used to induce remission, as well as to treat exacerbations, but should be followed up by immunosuppressive therapy with azathioprine or methotrexate. Adolescents and children are more likely than adults to require biologics and around 20% need treatment with tumour necrosis factor alpha (TNF-α) inhibitors such as infliximab or adalimumab. Around 20% of children with CD require surgery within 5 years of diagnosis; limited resections and stricturoplasty are considered best practice to preserve gut length and prevent short bowel syndrome (p. 707). Children with ulcerative colitis (UC) are more likely than adults to present with pancolitis (approximately 80% versus 40–50% in adults). Mild disease should be treated initially with oral 5-ASA preparations such as mesalamine or sulfasalazine. If the response is inadequate, oral glucocorticoids can be used, but caution must be exercised because of the adverse effects on skeletal growth and bone mineral density. Thiopurines such as 6-mercaptopurine or azathioprine are frequently used as steroid-sparing agents,

1300 • ADOLESCENT AND TRANSITION MEDICINE and in young adults. Intravenous bisphosphonates are widely used in the treatment of children with osteogenesis imperfecta (those with long-bone deformities, vertebral compression fractures, and three or more fractures per year, in whom the benefit:risk ratio is thought to be positive), although the evidence base for prevention of fractures is poor and based on observational studies. There is much debate about whether continuing bisphosphonate therapy into adulthood is beneficial due to concerns about suppression of bone turnover in the long term. Affected individuals and their parents can find this change in treatment strategy confusing and it is important to explain the underlying rationale in order to manage expectations. Hypophosphataemic rickets Hypophosphataemic rickets is described in more detail on page 1052. Adherence to phosphate supplements and, to a lesser extent, vitamin D metabolites represents an important issue in optimising management during childhood and this becomes even more challenging in transitioning patients. While skeletal deformity does not progress following closure of the epiphyses, different problems arise in adolescent patients when there is suboptimal control of hypophosphataemia, including painful pseudofractures and arthralgia associated with enthesopathy. The renal phosphate leak tends to improve to an extent during adolescence and the requirement for phosphate is reduced, but most patients still require treatment with active vitamin D metabolites. Summary Young people who have suffered long-term conditions during childhood represent a particularly high-risk group of patients as they progress through adolescence to become young and, finally, mature adults. They bring with them specific medical risks and complications related to their previous medical treatment, and knowledge of these is important to identify the long-term complications of the therapies to which they have been exposed. They are a patient group that can display complex and often abnormal illness behaviour. Understanding this and implementing an effective process for transition from paediatric to adult services can reduce the significant risks that these patients face in early adulthood. As they mature and develop more adult intellectual and emotional behaviour patterns, the risks to their health and well-being reduce. Patients in transition can be a particularly challenging group to manage, but investment of time and effort at this stage of their lives can be extremely rewarding and can bring significant improvements in long-term health-related outcomes. Further information Books and journal articles Atreja A, Bellam N, Levy SR. Strategies to enhance patient adherence: Making it simple. MedGenMed 2005; 7:4. Crowley R, Wolfe I, Lock K, McKee M. Improving the transition between paediatric and adult healthcare: a systematic review. Arch Dis Child 2011; 96:548–553. Segal TY. Adolescence: what the cystic fibrosis team needs to know. J R Soc Med 2008; 101(Suppl 1):15–27. Websites acpm.org/?Adherence American College of Preventive Medicine: detailed review of adherence. GotTransition.org Sample clinical tools and measurement resources for quality improvement purposes. uhs.nhs.uk More clinical tools and measurement resources. with progression to anti-TNF-α therapy for those who still do not respond. There is less evidence for efficacy of TNF-α inhibitors in adolescents with UC than those with CD; they seem to be effective at inducing an initial response but less useful for maintaining long-term remission, since a significant proportion of patients still require colectomy (20% at 1 year) or long-term glucocorticoids. Ciclosporin is probably more effective than infliximab in teenagers with refractory UC. As with other adolescents who have long-term conditions, adherence to medication is particularly important to reduce the risk of relapse. In terms of lifestyle advice, smoking is a particular risk since it increases both the rate and severity of relapses. Body image can be a particular challenge for young adults with IBD, and those with colostomies or fistulae, for example, can find this part of their illness particularly difficult. Delayed puberty and short stature are important comorbidities, partly related to medication side effects and also to the nature of the inflammatory bowel disease itself. Rheumatology and bone disease Juvenile idiopathic arthritis Juvenile idiopathic arthritis (JIA) is the term used to describe a wide variety of inflammatory rheumatic diseases that present during childhood (p. 1026). Oligoarticular juvenile arthritis has a good prognosis and often remits during adulthood, and so transitioning patients to adult rheumatology services may not always be required. The same does not hold true for systemic JIA and polyarticular JIA, which often require long-term immunosuppressive therapy through transition and beyond into adulthood. Smoking is a risk because it increases the activity of inflammatory disease and reduces the effectiveness of biologics. Adherence to and concordance with medication remain a challenge, as in other chronic diseases. Functional limitation secondary to joint damage may limit employment opportunities. Contraceptive advice is important in patients on methotrexate. Glucocorticoid-induced osteoporosis Osteoporosis is a complication of long-term glucocorticoid therapy that may be required in patients with inflammatory disease, transplantation and DMD. There is a paucity of evidence about best practice in glucocorticoid-induced osteoporosis in children and adolescents, but in general the teenage years are a period of considerable bone mineral deposition and offer a chance to enhance bone mineral density significantly. It is important to ensure adequate calcium and vitamin D intake and to supplement if necessary. Therapy with bisphosphonates can be considered in symptomatic patients, although the evidence base for prevention of fractures is poor. Osteogenesis imperfecta Osteogenesis imperfecta (p. 1055) typically presents with multiple low-trauma fractures during infancy and childhood. Although fractures become less common during adolescence due to the increase in bone mass, they still occur frequently during transition 31.13 Treatment strategy in Crohn’s disease • Induce and maintain clinical remission • Optimise nutrition • Optimise bone health • Optimise growth and pubertal progress • Minimise adverse drug effects

Ch04-3 Clinical Medicine

22-32 Ageing and disease

32 Ageing and disease

Ageing and disease MD Witham Comprehensive Geriatric Assessment 1302 Demography 1304 Functional anatomy and physiology 1304 Biology of ageing 1304 Physiological changes of ageing 1305 Frailty and multimorbidity 1306 Investigations 1306 Comprehensive Geriatric Assessment 1306 Decisions about investigation and treatment 1306 Presenting problems in geriatric medicine 1307 Falls 1308 Dizziness 1309 Delirium 1309 Urinary incontinence 1309 Prescribing and deprescribing 1310 Other problems in old age 1311 Rehabilitation 1311

1302 • AGEING AND DISEASE Insets (Wasted hand, kyphosis) From Afzal Mir M. Atlas of clinical diagnosis, 2nd edn. Edinburgh: Saunders, Elsevier Inc.; 2003; ( Senile purpura) Forbes CD, Jackson WF. Clinical medicine, 3rd edn. Edinburgh: Mosby, Elsevier Inc.; 2004; (Venous ulceration) Mosti G. Compression and venous surgery for leg ulcers. Clin Plast Surg 2012; 39:269–280. Pulse Atrial fibrillation Hydration Skin turgor Oedema Erect and supine blood pressure Postural hypotension Hearing Wax Hearing aid used Muscle Wasting Strength Per rectum Faecal impaction Prostate size/consistency in men Anal tone Nutrition Body mass index (Height calculated from arm demispan or knee height to compensate for loss of vertebral height) Recent weight loss, e.g. loose skin folds Dentition/oral hygiene Joints Deformity Pain Swelling Range of movement Skin Wounds/ulcers Infection Swelling Gait and balance Get up and go test (see opposite) Walking aid used Vision Visual acuity Glasses worn/present Cataract Cognitive function Mini-mental state examination (see Ch. 28) Measurement of knee height (see Ch. 19) Severe kyphosis Wasting of small muscles of hands in rheumatoid arthritis Cataract Senile purpura Venous ulceration Full systems examination with particular attention to the above

Comprehensive Geriatric Assessment

Comprehensive Geriatric Assessment • 1303

Social assessment Home circumstances • Living alone, with another person or in a care home Activities of daily living (ADL) • Tasks for which help is needed: Domestic ADL: shopping, cooking, housework Personal ADL: bathing, dressing, walking • Informal help: relatives, friends, neighbours • Formal social services: home help, meals on wheels • Carer stress History • Slow down the pace • Ensure the patient can hear • Establish the speed of onset of the illness • If the presentation is vague, carry out a systematic enquiry • Obtain full details of: All drugs, especially any recent prescription changes Past medical history, even from many years previously Usual function: Can the patient walk normally? Has the patient noticed memory problems? Can the patient perform all household tasks? • Obtain a collateral history: confirm information with a relative or carer and the GP, particularly if the patient is confused or communication is limited by deafness or speech disturbance Multidisciplinary team (MDT) roles Team member Activity assessed and promoted Physiotherapist Mobility, balance and upper limb function Occupational therapist ADL, such as dressing, cooking Home environment and care needs Dietitian Nutrition Speech and language therapist Communication and swallowing Social worker Care needs and discharge planning; organisation of institutional care Nurse Motivation and initiation of activities; promotion of self-care Education Feeding, continence, skin care Communication with relatives and other professionals Assessment of care needs for discharge Doctor Diagnosis and management of medical problems Coordinator of assessment, management and rehabilitation programme 12 Get up and go test To assess gait and balance, ask the patient to stand up from a sitting position, walk 3 m, turn and go back to the chair. A normal performance takes less than 12 seconds. Unsteady on standing? Difficulty rising? Unsteady gait? Unsteady on turning? Unsteady on sitting down? Domains of Comprehensive Geriatric Assessment. Disease severity and comorbidity Mental health and cognition Support networks and needs Function and ability • Thorough to identify all comorbidities • Tailored to the patient’s stamina and ability to cooperate • Includes functional status: cognitive function, gait and balance, nutrition, and hearing and vision Examination

1304 • AGEING AND DISEASE to live for a further 10 years. However, rates of disability and chronic illness rise sharply with ageing and have a major impact on health and social services. In the UK, the reported prevalence of a chronic illness or disability sufficient to restrict daily activities is around 25% in those aged 50–64, but 66% in men and 75% in women aged over 85. Although the proportion of the population aged over 65 years is greater in developed countries, two-thirds of the world population aged over 65 live in developing countries at present, and this is projected to rise to 75% in 2025. The rate of population ageing is much faster in developing countries (Fig. 32.1) and so there will be less time to adjust to its impact. Functional anatomy and physiology Biology of ageing Ageing can be defined as a progressive accumulation through life of random molecular defects that build up within cells and tissues. Eventually, and despite multiple repair and maintenance mechanisms, these result in age-related functional impairment of tissues and organs. There is evidence that variants in many genes contribute to ageing. The implicated genes include those that are involved in regulation of DNA repair, telomere length (p. 41) and insulin signalling. Genetic factors only account for around 25% of the variance in human lifespan, however; nutritional and environmental factors determine the rest. At a cellular level, production of reactive oxygen species is thought to play a major role in ageing. These molecules cause oxidative damage at a number of targets: • Nuclear chromosomal DNA, causing mutations and deletions that ultimately lead to aberrant gene function and potential for malignancy. • Telomeres, the structures at the ends of chromosomes that shorten with each cell division because telomerase (which copies the end of the 3′ strand of linear DNA in germ cells) is absent in somatic cells. When telomeres are sufficiently eroded, cells stop dividing. It has been suggested that telomeres represent a ‘biological clock’ that prevents uncontrolled cell division and cancer. Telomeres are particularly shortened in patients with Fig. 32.1 Number of people aged 65 years and over projected in the world population. Millions

Year World Developing countries Developed countries 32.1 Mean life expectancy in years, UK and India Males Females UK India UK India At birth 79.1 65.1 83.0 67.2 At 60 years 22.8 16.7 25.5 18.9 At 70 years 15.0 10.9 17.1 12.4 At 80 years 8.7 7.5 9.9 8.0 Sweeping demographic change has meant that older people now represent the core practice of medicine in many countries. A good knowledge of the effects of ageing and the clinical problems associated with old age is therefore essential in most medical specialties. The older population is extremely diverse; a substantial proportion of 90-year-olds enjoy an active healthy life, while some 70-year-olds are severely disabled by chronic disease. The terms ‘chronological’ and ‘biological’ ageing have been coined to describe this phenomenon. Biological rather than chronological age is taken into consideration when making clinical decisions about, for example, the extent of investigation and intervention that is appropriate. Geriatric medicine is concerned particularly with frail older people, in whom physiological capacity is so reduced that they are incapacitated even by minor illness. They frequently have multiple comorbidities, and acute illness may present in non-specific ways, such as delirium, falls or loss of mobility and day-to-day functioning. These patients are prone to adverse drug reactions, partly because of polypharmacy and partly because of age-related changes in responses to drugs and their elimination (p. 32). Disability is common, but patients’ function can often be improved by the interventions of the multidisciplinary team (p. 1303). Older people have been neglected in research terms and, until recently, were rarely included in randomised controlled clinical trials. Accordingly, there is often little high-quality evidence on which to base practice. Demography The demography of all countries has changed rapidly in recent decades. For example, in the UK, the total population has grown by 11% over the last 30 years, but the number of people aged over 65 years has grown by 24%. The steepest rise occurred in those aged over 85 – from 600 000 in 1981 to 1.5 million in 2011; this number is projected to increase to 2.4 million by 2026, while the working-age population (20–64 years) is expected to grow by only 4% between 2011 and 2026. Similarly, the proportion of people over 65 in India has increased by 35.5% from 76 million in 2000 to 103 million in 2011, which is almost twice the rate of growth of the general population over this period. In both of these countries and many others across the world, the old-age dependency ratio, which is the ratio of people of working age for each person over retirement age, has substantially increased. Since young people support older members of the population both directly and indirectly through taxation and pension contributions, the consequences of a reduced ratio are far-reaching. It is important to emphasise, however, that many older people support the younger population, through the care of children and other older people. Life expectancy in the developed world is now prolonged, even in old age (Box 32.1); women aged 80 years can expect

Functional anatomy and physiology • 1305

the effects of pathology from those due to age alone. The fraction of older people who age without disease ultimately declines to very low levels, however, so that use of the term ‘normal’ becomes debatable. There is a marked increase in inter-individual variation in function with ageing; many physiological processes deteriorate substantially when measured across populations but some individuals show little or no change. This heterogeneity is a hallmark of ageing, meaning that each person must be assessed individually and that the same management cannot be applied unthinkingly to all people of a certain age. Although some genetic influences contribute to heterogeneity, environmental factors, such as poverty, nutrition, exercise, cigarette smoking and alcohol misuse, play a large part, and a healthy lifestyle should be encouraged even when old age has been reached. The effects of ageing are usually not enough to interfere with organ function under normal conditions but reserve capacity is significantly reduced. Some changes of ageing, such as depigmentation of the hair, are of no clinical significance. Figure 32.2 shows the many changes that occur with ageing that are clinically important. premature ageing due to Werner’s syndrome, in which DNA is damaged due to lack of a helicase. • Mitochondrial DNA and lipid peroxidation, resulting in reduced cellular energy production and ultimately cell death. • Proteins, especially those that are modified by glycosylation due to spontaneous reactions between proteins and sugars. These damage structure and function of the affected protein, which becomes resistant to breakdown. The rate at which damage occurs is variable and this is where the interplay with environment, and particularly nutrition, takes place. There is evidence in some organisms that this interplay is mediated by insulin signalling pathways. Chronic inflammation also plays an important role, again in part by driving the production of reactive oxygen species. Physiological changes of ageing The physiological features of normal ageing have been identified by examining disease-free populations of older people to separate Respiratory system • Reduced lung elasticity and alveolar support • Increased chest wall rigidity • Increased V/Q mismatch • Reduced cough and ciliary action CNS and muscle • Neuronal loss • Cochlear degeneration • Increased lens rigidity • Lens opacification • Anterior horn cell loss • Dorsal column loss • Slowed reaction times • Loss of type II muscle fibres • Reduction in muscle satellite cell numbers Cardiovascular system • Reduced maximum heart rate • Dilatation of aorta • Reduced elasticity of conduit/ capacitance vessels • Reduced number of pacing myocytes in sinoatrial node Endocrine system • Deterioration in pancreatic β-cell function Renal system • Loss of nephrons • Reduced glomerular filtration rate • Reduced tubular function Gastrointestinal system • Reduced motility Bones • Reduced bone mineral density Respiratory system • Reduced vital capacity and peak expiratory flow • Increased residual volume • Reduced inspiratory reserve volume • Reduced arterial oxygen saturation • Increased risk of infection CNS • Increased risk of delirium • Presbyacusis/high-tone hearing loss • Presbyopia/abnormal near vision • Cataract • Muscle weakness and wasting • Reduced position and vibration sense • Increased risk of falls Cardiovascular system • Reduced exercise tolerance • Widened aortic arch on X-ray • Widened pulse pressure • Increased risk of postural hypotension • Increased risk of atrial fibrillation Endocrine system • Increased risk of impaired glucose tolerance Renal system • Impaired fluid balance • Increased risk of dehydration/overload • Impaired drug metabolism and excretion Gastrointestinal system • Constipation Bones • Increased risk of osteoporosis and fracture Clinical consequences Changes with ageing • • Fig. 32.2 Features and consequences of normal ageing.

1306 • AGEING AND DISEASE cardiac investigation and drug treatment, but may benefit even further from an exercise programme to improve musculoskeletal function, balance and aerobic capacity, with nutritional support to restore lost weight. Establishing a patient’s level of frailty also helps inform decisions regarding further investigation and management, and the need for rehabilitation. Investigations Comprehensive Geriatric Assessment One of the most powerful tools in the management of older people is the Comprehensive Geriatric Assessment, which identifies all the relevant factors contributing to their presentation (p. 1302). Comprehensive Geriatric Assessment is in fact a misnomer; it is not merely an assessment, but a process of identifying and managing all relevant factors affecting the health and well-being of older people. It is iterative in nature, management being followed by reassessment and a new management plan. In frail patients with multiple pathology, it may be necessary to perform the assessment in stages to allow for their reduced stamina. The outcome should be a management plan that not only addresses the acute presenting problems but also improves the patient’s overall health and function. Comprehensive Geriatric Assessment is performed by a multidisciplinary team (p. 1303). Such an approach was pioneered by Dr Marjory Warren at the West Middlesex Hospital in London in the 1930s; her comprehensive assessment and rehabilitation of supposedly incurable, long-term bedridden older people revolutionised the approach of the medical profession to frail older people and laid the foundations for the modern specialty of geriatric medicine. There is excellent evidence from systematic reviews that Comprehensive Geriatric Assessment, when performed by a specialist team on a specialist geriatric medicine ward, reduces death or deterioration, increases the chances of living independently at home, and may also improve cognitive function in the short to medium term. Current evidence suggests that the process works when delivered on a specialist inpatient unit, but the evidence for effectiveness when it is delivered by a visiting team or in the community is less strong. Decisions about investigation and treatment Accurate diagnosis is important at all ages but frail older people may not be able to tolerate lengthy or invasive procedures, and diagnoses may be revealed for which patients could not withstand intensive or aggressive treatment. On the other hand, disability should never be dismissed as due to age alone. For example, it would be a mistake to supply a patient no longer able to climb stairs with a stair lift when simple tests would have revealed osteoarthritis of a hip and vitamin D deficiency, for which appropriate treatment would have restored his or her strength. So how do doctors decide when and how far to investigate? The views of the patient and family Older people may have strong views about the extent of investigation and the treatment they wish to receive, and these should be sought from the outset. A key issue is to establish what the patient wants from investigation and treatment. Many Frailty and multimorbidity Frailty is defined as the loss of an individual’s ability to withstand minor stresses because the reserves in function of several organ systems are so severely reduced that even a trivial illness or adverse drug reaction may result in organ failure and death. The same stresses would cause little upset in a fit person of the same age. It is important to understand the difference between ‘disability’, ‘multimorbidity’ and ‘frailty’. Disability indicates established loss of function while frailty indicates increased vulnerability to loss of function. Disability may arise from a single pathological event (such as a stroke) in an otherwise healthy individual. After recovery, function is largely stable and the patient may otherwise be in good health. When frailty and disability coexist, function deteriorates markedly even with minor illness, to the extent that the patient can no longer manage independently. Multimorbidity (the number of diagnoses present) is also not equivalent to frailty; it is quite possible to have several diagnoses without major impact on homeostatic reserve. Multimorbidity is, however, an important concept in its own right and is an almost invariable accompaniment to advanced age. Recent Scottish population-based data show that 60% of those aged 65 and over have at least two chronic diseases. Multimorbidity is a driver for future disability, hospitalisation and death, and often leads to polypharmacy, as multiple medications are used to treat each chronic disease individually. Current health-care systems are poorly equipped to manage multimorbidity; each disease is dealt with by a separate team of specialists, which at best places a high burden on the patient, and at worst leads to mutually incompatible approaches to management of each disease. Unfortunately, the term ‘frail’ is often used rather vaguely, sometimes to justify a lack of adequate investigation and intervention in older people. It can be specifically identified, however, by assessing function in a number of domains. Two main approaches to evaluating frailty exist: measurement of physiological function across a number of domains, an example being the Fried Frailty score (Box 32.2), or use of a score based on the number of deficits or problems, such as the Rockwood score. Frail older people particularly benefit from a clinical approach that addresses both the precipitating acute illness and their underlying loss of reserves. It may be possible to prevent further loss of function through early intervention; for example, a frail woman with myocardial infarction will benefit from specific Varies between populations. Grip cut-off is 30 kg for men and 18 kg for women in US adults; 5 m walk time cut-off is 7 seconds in US adults for both sexes. 32.2 How to assess a Fried Frailty score • Hand grip strength in bottom 20% of healthy elderly distribution • Walking speed in bottom 20% of healthy elderly distribution* • Self-reported exhaustion • Physical inactivity • At least 6 kg weight loss within 1 year Patient is defined as frail if 3 or more factors are present; 1–2 factors indicate a ‘pre-frail’ state.

Presenting problems in geriatric medicine • 1307

Presenting problems in geriatric medicine Characteristics of presenting problems in old age Problem-based practice is central to geriatric medicine. Most problems are multifactorial and there is rarely a single unifying diagnosis. All contributing factors have to be taken into account and attention to detail is paramount. Two patients who share the same presenting problem may have completely disparate diagnoses. A wide knowledge of adult medicine is required, as disease in any, and often many, of the organ systems has to be managed at the same time. There are a number of features that are particular to older patients. Late presentation Many people (of all ages) accept ill health as a consequence of ageing and may tolerate symptoms for lengthy periods before seeking medical advice. Comorbidities may also contribute to late presentation; in a patient whose mobility is limited by stroke, angina may only present when coronary artery disease is advanced, as the patient has been unable to exercise sufficiently to cause symptoms at an earlier stage. Atypical presentation Infection may present with delirium and without clinical pointers to the organ system affected. Stroke may present with falls rather than symptoms of focal weakness. Myocardial infarction may present as weakness and fatigue, without chest pain or dyspnoea. The reasons for these atypical presentations are not always easy to establish. Perception of pain is altered in old age, which may explain why myocardial infarction presents in other ways. The pyretic response is blunted in old age so that infection may not be obvious at first. Cognitive impairment may limit the patient’s ability to give a history of classical symptoms. Acute illness and changes in function Atypical presentations in frail elderly patients include ‘failure to cope’, ‘found on floor’, ‘delirium’ and ‘off feet’, but these are not diagnoses. The possibility that an acute illness has been the precipitant must always be considered. To establish whether the patient’s current status is a change from his or her usual level of function, it helps to ask a relative or carer (by phone if necessary). Investigations aimed at uncovering an acute illness will not be fruitful in a patient whose function has been deteriorating over several months but are important if function has suddenly changed. Multiple pathology Presentations in older patients have a more diverse differential diagnosis because multiple pathology is so common. There are frequently a number of causes for any single problem, and adverse effects from medication often contribute. A patient may fall because of osteoarthritis of the knees, postural hypotension due to diuretic therapy for hypertension, and poor vision due to cataracts. All these factors have to be addressed to prevent further falls and this principle holds true for most of the common presenting problems in old age. older people do not desire prolongation of life; rather they aspire to maintain physical function, gain relief from symptoms, and preserve the ability to live independently. Such aims differ widely between patients, however, and a careful exploration of what is important to the individual is essential. If the patient wishes, the views of relatives can also be taken into account. If the patient is not able to express a view or lacks the capacity to make decisions because of cognitive impairment or communication difficulties, then relatives’ input becomes particularly helpful. They may be able to give information on views previously expressed by the patient or on what the patient would have wanted under the current circumstances. However, families should never be made to feel responsible for difficult decisions. The patient’s general health Does this patient have the physical and mental capacity to tolerate the proposed investigation? Do they have the aerobic capacity to undergo bronchoscopy? Will delirium prevent them from remaining still in the magnetic resonance imaging (MRI) scanner? The more comorbidities a patient has, the less likely he or she will be able to withstand an invasive intervention. Will the investigation alter management? Would the patient be fit for, or benefit from, the treatment that would be indicated if investigation proved positive? The presence of comorbidity and frailty is more important than age itself in determining this. When a patient with severe heart failure and a previous disabling stroke presents with a suspicious mass lesion on chest X-ray, detailed investigation and staging may not be appropriate if they are not fit for surgery, radical radiotherapy or chemotherapy. On the other hand, if the same patient presented with dysphagia, investigation of the cause would be important, as they might be able to tolerate endoscopic treatment (for example, to palliate an obstructing oesophageal carcinoma). Will management benefit the patient? It is important to consider whether interventions that might be considered as standard-of-care for younger people are likely to be beneficial in frail older people. For example, while oral anticoagulation might be indicated by guidelines for a patient with atrial fibrillation, such treatment may not accord with the wishes of a patient in a care home who finds regular blood tests distressing, or who is more worried about bleeding than about avoiding a stroke. Another example would be the use of anti-osteoporosis medications to reduce the risk of fracture in very old patents, where the risk of death from other causes would be greater than the risk of fracture. Advance directives Advance directives or ‘living wills’ are statements made by adults at a time when they have the capacity to decide about the interventions they would refuse or accept in the future, should they no longer be able to make decisions or communicate them. An advance directive cannot authorise a doctor to do anything that is illegal and doctors are not bound to provide a specific treatment requested if, in their professional opinion, it is not clinically appropriate. However, any advance refusal of treatment, made when the patient was able to make decisions based on adequate information about their implications, is legally binding in the UK. It must be respected when it clearly applies to the patient’s present circumstances and when there is no reason to believe that the patient has changed his or her mind.

1308 • AGEING AND DISEASE in anyone falling over; people who lose consciousness do not always remember having done so. If loss of consciousness is suggested by the patient or witness, it is important to perform appropriate investigations (pp. 181 and 1080). Mechanical and recurrent falls Among patients who have tripped or are uncertain how they fell, those who have fallen more than once in the past year and those who are unsteady during a ‘get up and go’ test (p. 1303) require further assessment. Patients with recurrent falls are commonly frail, with multiple medical problems and chronic disabilities. Obviously, such patients may present with a fall resulting from an acute illness or syncope but they will remain at risk of further falls even when the acute illness has resolved. The risk factors for falls (Box 32.4) should be considered. If problems are identified with muscle strength, balance, vision or cognitive function, the causes of these must be identified by specific investigation, and treatment commenced if appropriate. Careful assessment of the patient’s gait may provide important clues to an underlying diagnosis (Box 32.5). Common pathologies identified include cerebrovascular disease (Ch. 26), Parkinson’s disease (p. 1112) and osteoarthritis of weight-bearing joints (p. 1007). Calculation of fracture risk using tools such as FRAX or QFracture should be performed and dual X-ray absorptiometry (DXA) bone density scanning considered in patients with a 10-year risk of major fracture of more than 10%. Prevention of falls and fractures Falls can be prevented by multiple risk factor intervention (Box 32.6). The most effective intervention is balance and strength training by physiotherapists or exercise practitioners; an alternative with good evidence is tai chi training. An assessment of the Approach to presenting problems in old age For the sake of clarity, the common presenting problems are described individually but, in reality, older patients often present with several at the same time, particularly delirium, incontinence and falls. These share some underlying causes and may precipitate each other. The approach to most presenting problems in old age can be summarised as follows: • Obtain a collateral history. Find out the patient’s usual status with regard to mobility and cognitive function from a relative or carer. Call these people by phone if they are not present. • Check all medication. Have there been any recent changes? • Search for and treat any acute illness (Box 32.3). • Identify and reverse predisposing risk factors. These depend on the presenting problem. Falls Around 30% of those over 65 years of age fall each year and this figure rises to more than 40% in those aged over 80. Although only 10–15% of falls result in serious injury, virtually all fragility fractures in the elderly are caused by falls. Age-related osteoporosis contributes to the dramatic rise in hip and other fragility fractures that occurs with ageing but the most important contributory factor is an increased risk of falling (Fig. 32.3). Falls also lead to loss of confidence and fear, and are frequently the ‘final straw’ that makes an older person decide to move to institutional care. Management will vary according to the underlying cause. Acute illness Falls are one of the classical atypical presentations of acute illness in frail people. The reduced reserves in older people’s neurological function mean that they are less able to maintain their balance when challenged by an acute illness. Suspicion should be high when falls have suddenly occurred over a period of a few days. Common underlying illnesses include infection, stroke, metabolic disturbance and heart failure. Thorough examination and investigation are required (Box 32.3). It is also important to establish whether any drug that precipitates falls, such as a psychotropic or hypotensive agent, has been started recently. Once the underlying acute illness has been treated, falls may stop. Blackouts A proportion of older people who ‘fall’ have, in fact, had a syncopal episode. A collateral history from a witness is of utmost importance Fig. 32.3 Age and bone mineral density (BMD) interact to influence fracture risk. Femoral neck BMD (g/cm2) Age 80 years 0.5

0.6 0.7 0.8 0.9 1.0 1.1 Age 70 years Age 60 years Hip fracture/100000 population 32.3 Screening investigations for acute illness • Full blood count • Urea and electrolytes, liver function tests, calcium and glucose • Chest X-ray • Electrocardiogram • C-reactive protein: useful marker for occult infection or inflammatory disease • Blood cultures if pyrexial 32.4 Risk factors for falls • Muscle weakness • History of falls • Gait or balance abnormality • Use of a walking aid • Visual impairment • Arthritis • Impaired activities of daily living • Depression • Cognitive impairment • Age over 80 years • Psychotropic medication

Presenting problems in geriatric medicine • 1309

Dizziness Dizziness is very common, affecting at least 30% of those aged over 65 years in community surveys. It can be disabling in its own right and is also a risk factor for falls. Acute dizziness is relatively straightforward and common causes include: • hypotension due to arrhythmia, myocardial infarction, gastrointestinal bleed or pulmonary embolism • posterior fossa stroke onset • vestibular neuronitis. Although older people more commonly present with recurrent dizzy spells and often find it difficult to describe the sensation they experience, the most effective way of establishing the cause(s) of the problem is nevertheless to determine which of the following is predominant (even if more than one is present): • lightheadedness, suggestive of reduced cerebral perfusion • vertigo, suggestive of labyrinthine or brainstem disease (p. 1086) • unsteadiness/poor balance, suggestive of joint or neurological disease. In lightheaded patients, structural cardiac disease (such as aortic stenosis) and arrhythmia must be considered, but disorders of autonomic cardiovascular control, such as vasovagal syndrome and postural hypotension, are the most common causes in old age. Antihypertensive medications may exacerbate these conditions. Further investigation and treatment are described on page 181. Vertigo in older patients is most commonly due to benign positional vertigo (p. 1086), but if other brainstem symptoms or signs are present, MRI of the brain is required to exclude a cerebello-pontine angle lesion. Delirium Delirium is a syndrome of transient, reversible cognitive dysfunction that affects 30% of older hospital inpatients. Differential diagnosis, assessment and management are discussed on page 183. Urinary incontinence Urinary incontinence is defined as the involuntary loss of urine and comes to medical attention when sufficiently severe to cause a social or hygiene problem. It occurs in all age groups but becomes more prevalent in old age, affecting about 15% of women and 10% of men aged over 65. It may lead to skin damage if severe and can be socially restricting. While agedependent changes in the lower urinary tract predispose older people to incontinence, it is not an inevitable consequence of ageing and requires investigation and appropriate treatment. Urinary incontinence is frequently precipitated by acute illness in old age and is commonly multifactorial (Fig. 32.4). The initial assessment should seek to identify and address contributory factors. If incontinence fails to resolve, further diagnosis and management should be pursued, as described on page 437. • Urge incontinence is usually due to detrusor over-activity and results in urgency and frequency. • Stress incontinence is almost exclusive to women and is due to weakness of the pelvic floor muscles, which allows leakage of urine when intra-abdominal pressure rises, such as on coughing. It may be compounded by atrophic 32.6 Interventions to reduce the risk of falls and fractures • Exercise (should include components of lower limb strength and balance training): Multimodal group exercise and tai chi both effective • Calcium and vitamin D supplementation: Evidence of effectiveness only in patients in institutional care Large doses of vitamin D may increase risk of falls and fractures • Home environment assessment and modification • Medication review: Particularly medications with central actions such as hypnotics but also those with anticholinergic and hypotensive actions • Cataract surgery: Effective if for first cataract Other vision interventions ineffective and may increase falls risk • Anti-slip shoes: Effective only in icy conditions • Cardiac pacemaker for carotid sinus hypersensitivity 32.5 Abnormal gaits and probable causes Gait abnormality Probable cause Antalgic Arthropathy Waddling Proximal myopathy Stamping Sensory neuropathy Foot drop Peripheral neuropathy or radiculopathy Ataxic Sensory neuropathy or cerebellar disease Shuffling/festination Parkinson’s disease Marche à petits pas Small-vessel cerebrovascular disease Hemiplegic Cerebral hemisphere lesion Apraxic Bilateral hemisphere lesions patient’s home environment for hazards should be undertaken by an occupational therapist, who may also provide personal alarms so that patients can summon help, should they fall again. Rationalising psychotropic medication may help to reduce sedation, although many older patients are reluctant to stop hypnotics. If postural hypotension is present (defined as a drop in blood pressure of > 20 mmHg systolic or > 10 mmHg diastolic pressure on standing from supine), reducing or stopping hypotensive drugs may be helpful. Evidence supporting the efficacy of other interventions for postural hypotension is lacking but drugs, including fludrocortisone and midodrine, are sometimes used to try to improve dizziness on standing. Other interventions, such as cataract extraction and podiatry, can also have a significant impact on function in those who fall. If osteoporosis is diagnosed, specific drug therapy should be considered (p. 1046). In the frailest patients, such as those in institutional care, calcium and vitamin D3 administration has been shown to reduce both falls and fracture rates, probably by exerting positive effects on bone mineral density and on neuromuscular function. Supplementation does not reduce falls risk beyond this very frail group, however, and very high doses of vitamin D may paradoxically increase the risk of falls and fractures. In the UK, government policy and National Institute for Health and Clinical Excellence guidelines (www.nice.org.uk) for falls prevention have led to the development of specific Falls and Fracture Prevention Services in many parts of the country.

1310 • AGEING AND DISEASE diseases (Box 32.7). However, the more drugs that are taken, the greater the risk of an adverse drug reaction (ADR). ADRs and the effects of drug interactions are discussed on page 21. They may result in symptoms, abnormal physical signs and altered laboratory test results (Box 32.8). ADRs are the cause of around 5% of all hospital admissions but account for up to 20% of admissions in those aged over 65. The risk of polypharmacy is compounded by age-related changes in pharmacodynamic and pharmacokinetic factors (p. 14), and by impaired homeostatic mechanisms, such as baroreceptor responses, plasma volume and electrolyte control. Older people are thus especially sensitive to drugs that can cause postural hypotension or volume depletion (Box 32.8). Non-adherence to drug therapy also rises with the number of drugs prescribed. The clinical presentations of ADRs are diverse, so for any presenting problem in old age the possibility that the patient’s medication is a contributory factor should always be considered. Failure to recognise this may lead to the use of a further drug to treat the problem, making matters worse, when the better vaginitis, associated with oestrogen deficiency in old age, which can be treated with oestrogen pessaries. • Overflow incontinence is most commonly seen in elderly men with prostatic enlargement, which obstructs bladder outflow. In patients with severe stroke disease or dementia, treatment may be ineffective, as frontal cortical inhibitory signals to bladder emptying are lost. A timed/prompted toileting programme may help. Other than in overflow incontinence, urinary catheterisation should never be viewed as first-line management, but may be required as a final resort if the perineal skin is at risk of breakdown or quality of life is affected. Prescribing and deprescribing The large number of comorbidities that accompany ageing often leads to polypharmacy. This has been defined as the use of four or more drugs, and is associated with several adverse outcomes including falls, hospitalisation and increased risk of death. While some of these outcomes are caused by drug–drug interactions and adverse effects, others are as much due to the underlying multimorbidities for which the drugs were prescribed in the first place In view of this, it is essential for prescribing for older people to be appropriate. For many older people, taking multiple drugs is appropriate, as such therapy is required to treat multiple Fig. 32.4 Assessment and management of urinary incontinence in old age. See also page 436 and NICE guideline on the Management of Incontinence in Women: nice.org.uk. (UTI = urinary tract infection) Urinary incontinence Overflow (residual volume > 100 mL) Surgical relief of obstruction (prostatectomy) Intermittent catheterisation if no obstruction Stress Pelvic floor muscle training Surgical intervention if unsuccessful If still incontinent: • Establish the pattern of urinary loss (diary is helpful) • Measure residual urine volume (by ultrasound) • Assess for vaginal prolapse and atrophic vaginitis (women) • Assess prostate by rectal examination (men) Address contributory factors: • UTI • Severe constipation • Diuretics • Hyperglycaemia • Hypercalcaemia • Restricted mobility • Acute delirium Urge Bladder retraining Antimuscarinic drugs (solifenacin, tolterodine) 32.8 Common adverse drug reactions in old age Drug class Adverse reaction NSAIDs Gastrointestinal bleeding and peptic ulceration Renal impairment Diuretics Renal impairment, electrolyte disturbance Gout Hypotension, postural hypotension Warfarin Bleeding ACE inhibitors Renal impairment, electrolyte disturbance Hypotension, postural hypotension β-blockers Bradycardia, heart block Hypotension, postural hypotension Opiates Constipation, vomiting Delirium Urinary retention Antidepressants Delirium Hyponatraemia (SSRIs) Hypotension, postural hypotension Falls Benzodiazepines Delirium Falls Anticholinergics Delirium Urinary retention Constipation (ACE = angiotensin-converting enzyme; NSAIDs = non-steroidal anti-inflammatory drugs; SSRIs = selective serotonin re-uptake inhibitors) 32.7 Factors leading to polypharmacy in old age • Multiple pathology • Poor patient education (see Box 2.20, p. 31) • Lack of routine review of all medications • Patient expectations of prescribing • Over-use of drug interventions by doctors • Attendance at multiple specialist clinics • Poor communication between specialists

Rehabilitation • 1311

Rehabilitation Rehabilitation aims to improve the ability of people of all ages to perform day-to-day activities and to optimise their physical, mental and social capabilities. Acute illness in older people is often associated with loss of their usual ability to walk or care for themselves, and common disabling conditions such as stroke, fractured neck of femur, arthritis and cardiorespiratory disease become increasingly prevalent with advancing age. Doctors tend to focus on health conditions and impairments but patients are more concerned with the effect on their activities and ability to participate in everyday life. The rehabilitation process Rehabilitation is a problem-solving process focused on improving the patient’s physical, psychological and social function. It entails: • Assessment. The nature and extent of the patient’s problems can be identified using the International Classification of Functioning, Disability and Health framework, which focuses on health conditions (such as stroke), the associated physical impairments (such as arm weakness caused by the stroke), the effect on activity (such as the inability to dress oneself due to arm weakness) and restriction of participation in activities (such as inability to go out of the house due to the inability to dress oneself). Such an approach helps to ensure a whole-person approach to participation in society, rather than a focus merely on disease. Specific assessment scales, such as the Elderly Mobility Scale or Barthel Index of Activities of Daily Living (Box 32.10), are useful to quantify components of disability but additional assessment is needed to determine the underlying causes or the interventions required in individual patients. • Goal-setting. Goals should be specific to the patient’s problems, realistic, and agreed between the patient and the rehabilitation team. • Intervention. This includes the active treatments needed to achieve the established goals and to maintain the patient’s health and quality of life. Interventions include hands-on treatment by therapists using a functional, task-orientated approach to improve day-to-day activities, and also psychological support and education. The emphasis on the type of intervention will be individualised, according to the patient’s disabilities, psychological status and progress. The patient and carer(s) must be active participants. • Re-assessment. There is ongoing re-evaluation of the patient’s function and progress towards the goals by the rehabilitation team, the patient and the carer. Interventions may be modified as a result. Multidisciplinary team working The core rehabilitation team includes all members of the multidisciplinary team (p. 1303). Others may also be involved, such as audiometrists to correct hearing impairment, podiatrists for foot problems, and orthoticists where a prosthesis or splinting is required. Good communication and mutual respect are essential. Regular team meetings allow sharing of assessments, agreement on rehabilitation goals and interventions, evaluation of progress and planning for the patient’s discharge home. Rehabilitation is not when the doctor orders ‘physiotherapy’ or ‘a home visit’ and takes no further role. course would be to stop or reduce the dose of the offending drug or to find an alternative. Appropriate prescribing and deprescribing The key to appropriate prescribing is first to ensure that medications are started only for reasons that accord with the patient’s goals and wishes. Thoughtless adherence to guidelines quickly leads to polypharmacy that may be inappropriate. Some medications (such as chronic use of non-steroidal anti-inflammatory medications) are much less suitable for older people because of the much higher risk of side-effects. Other medications, such as statins and bisphosphonates, lack evidence of efficacy in very old people, who may not live for long enough to derive benefit. Deprescribing is as important as prescribing in older people. Regular review of medications should be undertaken to ensure that medications are still required, to establish that they are still working, to check that they are not causing side-effects, and to ascertain whether the patient is actually taking them. If any of the above issues is problematic, the medication should be deprescribed. This may need to be done in a controlled manner, with dose reduction to ensure that rebound symptoms or withdrawal effects do not occur. The patient or carer should therefore be asked to bring all medication for review rather than the doctor relying on previous records; such reviews should take place regularly, not just at a point of crisis such as after a fall or on hospital admission. Other problems in old age A vast range of other presenting problems in older people present to many medical specialties. End-of-life care is an important facet of clinical practice in old age and is discussed on page 1354. Relevant sections in other chapters are referenced in Box 32.9. Within each chapter, ‘In Old Age’ boxes highlight the areas in which presentation or management differs from that in younger individuals. 32.9 Other presenting problems in old age • Hypothermia p. 166 • Dizziness and blackouts p. 181 • Delirium p. 183 • Infection pp. 218 and 228 • Fluid balance problems p. 360 • Heart failure p. 466 • Atrial fibrillation p. 472 • Hypertension p. 512 • Under-nutrition p. 710 • Diabetes mellitus p. 732 • Peptic ulceration p. 801 • Anaemia p. 954 • Painful joints p. 992 • Bone disease and fracture pp. 994 and 1049 • Stroke p. 1147 • Dementia p. 1191

1312 • AGEING AND DISEASE Rehabilitation outcomes There is evidence that rehabilitation improves functional outcomes in older people following acute illness, stroke and hip fracture. It also reduces mortality after stroke and hip fracture. These benefits accrue from complex multicomponent interventions, but occupational therapy to improve personal ADLs and individualised exercise interventions have now been shown to be effective in improving functional outcome in their own right. Further information Websites americangeriatrics.org American Geriatrics Society: education, careers vignettes from geriatricians, advocacy and clinical guidelines. bgs.org.uk British Geriatrics Society: useful publications on management of common problems in older people and links to other relevant websites. cochrane.org Cochrane review CD006211 Comprehensive geriatric assessment for older adults admitted to hospital; CD007146 Interventions for preventing falls in older people living in the community. eugms.org European Union Geriatric Medicine Society: research, position papers and educational resources. iagg.info International Association of Gerontology and Geriatrics: promoting care of older people and the science of gerontology globally; research, policy and educational resources. knowledge.scot.nhs.uk/effectiveolderpeoplecare.aspx Collates and summarises the Cochrane evidence for best practice in the healthcare and rehabilitation of frail older people. profane.co Prevention of Falls Network Earth: focuses on the prevention of falls and improvement of postural stability in older people. qfracture.org Fracture risk calculator validated in the UK population. Includes a wider range of risk factors than FRAX. shef.ac.uk/FRAX/tool.jsp Fracture risk calculator: can be used to calculate risk in several populations. Includes option to calculate with or without measurement of hip bone mineral density. The 20-point version is illustrated. The total score reflects the degree of dependency; scores of 14 and above are usually consistent with living in the community; scores below 10 suggest the patient is heavily dependent on carers. 32.10 How to assess dependency using the Modified Barthel Index Mobility Independent = 3 Needs help = 2 Wheelchair independent = 1 Immobile = 0 Stairs Independent = 2 Needs help = 1 Unable = 0 Transfers (e.g. from bed to chair) Independent = 3 Needs minor help = 2 Needs major help = 1 Unable = 0 Bladder Continent = 2 Occasional incontinence = 1 Incontinent = 0 Bowels Continent = 2 Occasional incontinence = 1 Incontinent = 0 Grooming Independent = 1 Needs help = 0 Toilet use Independent = 2 Needs help = 1 Unable = 0 Feeding Independent = 2 Needs help = 1 Unable = 0 Dressing Independent = 2 Needs some help = 1 Completely dependent = 0 Bathing Independent = 1 Needs help = 0

Ch04-3 Clinical Medicine

23-33 Oncology

33 Oncology

Oncology GG Dark Clinical examination of the cancer patient 1314 The 10 hallmarks of cancer 1316

  1. Genome instability and mutation 1316
  2. Resisting cell death 1316
  3. Sustaining proliferative signalling 1317
  4. Evading growth suppressors 1318
  5. Enabling replicative immortality 1318
  6. Inducing angiogenesis 1318
  7. Activating invasion and metastasis 1319
  8. Reprogramming energy metabolism 1319
  9. Tumour-promoting inflammation 1319
  10. Evading immune destruction 1320 Environmental and genetic determinants of cancer 1320 Investigations 1321 Histology 1322 Imaging 1323 Biochemical markers 1323 Presenting problems in oncology 1323 Palpable mass 1323 Weight loss and fever 1323 Thromboembolism 1324 Ectopic hormone production 1325 Neurological paraneoplastic syndromes 1325 Cutaneous manifestations of cancer 1326 Emergency complications of cancer 1326 Metastatic disease 1328 Therapeutics in oncology 1329 Surgical treatment 1330 Systemic chemotherapy 1330 Radiation therapy 1331 Hormone therapy 1332 Immunotherapy 1332 Biological therapies 1332 Evaluation of treatment 1332 Late toxicity of therapy 1332 Specific cancers 1333 Breast cancer 1333 Ovarian cancer 1334 Endometrial cancer 1334 Cervical cancer 1335 Head and neck tumours 1335 Carcinoma of unknown origin 1336 Multidisciplinary teams 1336

1314 • ONCOLOGY Clinical examination of the cancer patient Observation Breast Lymph nodes Neck Supraclavicular Axillary Antecubital Inguinal Para-aortic Face Conjunctival pallor Icterus, jaundice Horner’s syndrome Cushingoid features Cardiovascular Superior vena cava (SVC) obstruction Atrial fibrillation Pericardial effusion Hypo-/hypertension Abdomen Surgical scars Umbilical nodule Mass in epigastrium Visible peristalsis Abdominal distension Ascites Hepatomegaly Splenomegaly Renal mass Pelvic or adnexal mass Respiratory Stridor Consolidation Pleural effusion • Skin changes • Ascites • Cushingoid appearance • Cachexia • Dehydration Hands Clubbing Signs of smoking Pallor Tylosis of palms Periphery Calf tenderness, venous thrombosis Clubbing (if present in hands) Skin tethering above the nipple Cushing’s syndrome in a patient with ectopic adrenocorticotrophic hormone (ACTH) production Finger clubbing in lung cancer SVC obstruction in a patient with a mediastinal mass Skeletal survey Focal bone tenderness (pelvis, spine, long bones) Wrist tenderness (hypertrophic pulmonary osteoarthropathy) Neurological Focal neurological signs Sensory deficit Spinal cord compression Memory deficit Personality change Ascites (ovarian carcinoma)

Clinical examination of the cancer patient • 1315

Supraclavicular Axillary Epitrochlear Inguinal Femoral Popliteal fossa Pre-auricular Parotid Submandibular Submental Posterior cervical Supraclavicular Anterior cervical 3 Examination of the lymph nodes 7 Abdominal examination • Are there scars from previous surgery? • Is the umbilicus everted, suggesting ascites? • Is there a firm nodule at the umbilicus due to ovarian or gastric cancer metastasis, causing a Sister Mary Joseph nodule (p. 1334)? • Is there smooth hepatomegaly – possibly primary liver cancer or heart failure? • Is the liver firm or knobbly, suggesting metastasis? • Is the ascites too tense to demonstrate hepatomegaly? • Are other masses palpable in the abdomen? • Are there signs of obstruction or paralytic ileus with absence of bowel sounds? • Palpate for inguinal nodes (occasionally involved in ovarian cancer) • Percuss for flank dullness and shifting dullness • Perform vaginal and rectal examinations to detect adnexal or rectal masses Examination of the skin Important features of skin lesions that should alert suspicion include: • Asymmetry: irregular shape • Bleeding • Border: not a smooth edge • Colour: uneven, variegated or changing colour • Diameter: > 6 mm in diameter or growing • Itching or pain in a pre-existing mole 5 Superior vena cava obstruction • Venous distension of neck • Elevated but non-pulsatile jugular venous pulse • Venous distension of chest wall • Facial oedema • Cyanosis • Plethora of face • Oedema of arms 5 Pericardial effusion • Tachycardia • Falling blood pressure • Rising jugular venous pressure • Muffled heart sounds • Kussmaul’s sign (p. 544) 6 Malignant pleural effusions Large right pleural effusion Inspection Tachypnoea Palpation ↓Expansion on R Trachea and apex may be moved to L Percussion Stony dull R mid- and lower zones Auscultation Absent breath sounds and diminished or absent vocal resonance R base Crackles above effusion

1316 • ONCOLOGY

  1. Genome instability and mutation Random genetic mutations occur continuously throughout all cells of the body and very rarely confer a selective advantage on single cells, allowing overgrowth and dominance in local tissue environments. Multistep carcinogenesis results from successive clonal expansions of pre-malignant cells, each expansion being triggered by acquisition of a random enabling genetic mutation. Under normal circumstances, cellular DNA repair mechanisms are so effective that almost all spontaneous mutations are corrected without producing phenotypic changes, keeping the overall mutation rates very low. In cancer cells, the accumulation of mutations can be accelerated by compromising the surveillance systems that normally monitor genomic integrity and force genetically damaged cells into either senescence or apoptosis. They can therefore become more sensitive to mutagenic actions or develop DNA repair mechanism failure.
  2. Resisting cell death There are three principal mechanisms through which cell death occurs in healthy tissues: apoptosis, autophagy and necrosis. Apoptosis This is programmed cell death. It is frequently found at markedly reduced rates in cancers, particularly those of high grade or those resistant to treatment. The cellular apoptotic system has regulatory elements that sense intrinsic and extrinsic pro-apoptotic signals and initiate a cascade of proteolysis and cell disassembly with nuclear fragmentation, chromosomal condensation, and shrinking of the cell with loss of intercellular contact, followed by cellular fragmentation and the formation of apoptotic bodies that are phagocytosed by neighbouring cells. The most important regulator of apoptosis is the TP53 tumour suppressor gene, often described as the ‘guardian of the genome’, as it is able to induce apoptosis in response to sufficient levels of genomic damage. The largest initiator of apoptosis via TP53 is cellular injury, particularly that due to DNA damage from chemotherapy, oxidative damage and ultraviolet (UV) radiation. Autophagy This is a catabolic process during which cellular constituents are degraded by lysosomal machinery within the cell. It is an important physiological mechanism; it usually occurs at low levels in cells but can be induced in response to environmental stresses, particularly radiotherapy and cytotoxic chemotherapy, which induce elevated levels of autophagy that are cytoprotective for malignant cells, thus impeding rather than perpetuating the killing actions of these stress situations. Severely stressed cancer cells have been shown to shrink via autophagy to a state of reversible dormancy. Necrosis This is the premature death of cells and is characterised by the release of cellular contents into the local tissue microenvironment, in marked contrast to apoptosis, where cells are disassembled in a step-by-step fashion and the resulting cellular fragments are phagocytosed. Necrotic cell death results in the recruitment of inflammatory immune cells, promotion of angiogenesis, and release of stimulatory factors that increase cellular proliferation Fig. 33.1 The most commonly diagnosed cancers in the UK. (NHL = non-Hodgkin lymphoma) Statistics from Cancer Research UK website (http://info.cancerresearchuk.org). NHL Bladder Prostate Large bowel Lung Breast

Stomach Head and neck Oesophagus Melanoma Pancreas Ovary Leukaemia Kidney Body of uterus Other

Number of new cases (thousands) Male Female Cancer represents a significant economic burden for the global economy and is now the third leading cause of death worldwide. By 2030, it is projected that there will be 26 million new cancer cases and 17 million cancer deaths per year. The developing world is disproportionately affected by cancer and in 2008 developing nations accounted for 56% of new cancer cases and 75% of cancer deaths. These deaths happen in countries with limited or no access to treatment and with low per capita expenditure on health care. The most common solid organ malignancies arise in the lung, breast and gastrointestinal tract (Fig. 33.1), but the most common form worldwide is skin cancer. Cigarette smoking accounts for more than 20% of all global cancer deaths, 80% of lung cancer cases in men and 50% of lung cancer cases in women worldwide, which could be prevented by smoking cessation. Diet and alcohol contribute to a further 30% of cancers, including those of the stomach, colon, oesophagus, breast and liver. Lifestyle modification could reduce these if steps were taken to avoid animal fat and red meat, reduce alcohol, increase fibre, fresh fruit and vegetable intake, and avoid obesity. Infections account for a further 15% of cancers, including those of the cervix, stomach, liver, nasopharynx and bladder, and some of these could be prevented by infection control and vaccination. The 10 hallmarks of cancer The formation and growth of cancer constitute a multistep process, during which sequentially occurring gene mutations result in the formation of a cancerous cell. For cells to initiate carcinogenesis successfully, they require key characteristics, collectively referred to as the hallmarks of cancer.

The 10 hallmarks of cancer • 1317

that have occurred during DNA replication and thus preventing propagation of these errors to daughter cells. Although the duration of individual phases may vary, depending on cell and tissue type, most adult cells are in a G0 state at any one time. Cell cycle regulation The cell cycle is orchestrated by a number of molecular mechanisms: most importantly, by cyclins and cyclin-dependent kinases (CDKs). Cyclins bind to CDKs and are regulated by both activating and inactivating phosphorylation, with two main checkpoints at G1/S and G2/M transition. The genes that inhibit progression play an important part in tumour prevention and are referred to as tumour suppressor genes (e.g. TP53, TP21, TP16 genes). The products of these genes deactivate the cyclin–CDK complexes and are thus able to halt the cell cycle. The complexity of cell cycle control is susceptible to dysregulation, which may produce a malignant phenotype. Stimulation of the cell cycle Many cancer cells produce growth factors, which drive their own proliferation by a positive feedback known as autocrine stimulation. Examples include transforming growth factor-alpha (TGF-α) and platelet-derived growth factor (PDGF). Other cancer cells express growth factor receptors at increased levels due to gene amplification or express abnormal receptors that are permanently activated. This results in abnormal cell growth in response to physiological growth factor stimulation or even in the absence of growth factor stimulation (ligand-independent signalling). The epidermal growth factor receptor (EGFR) is often over-expressed in lung and gastrointestinal tumours and the human epidermal growth factor receptor 2 (HER2)/neu receptor is frequently over-expressed in breast cancer. Both receptors activate the Ras–Raf–mitogen activated protein (MAP) kinase pathway, causing cell proliferation. and tissue invasion, thereby enhancing rather than inhibiting carcinogenesis. 3. Sustaining proliferative signalling Cancer cells can sustain proliferation beyond what would be expected for normal cells; this is typically due to growth factors, which are able to bind to cell surface-bound receptors that activate an intracellular tyrosine kinase-mediated signalling cascade, ultimately leading to changes in gene expression and promoting cellular proliferation and growth. Sustained proliferative capacity can result from over-production of growth factor ligands or receptors and production of structurally altered receptors, which can signal in the absence of ligand binding and activation of intracellular signalling pathway components, so that signalling is no longer ligand-dependent. The cell cycle The cell cycle is composed of four ordered, strictly regulated phases referred to as G1 (gap 1), S (DNA synthesis), G2 (gap 2) and M (mitosis) (Fig. 33.2). Normal cells grown in culture will stop proliferating and enter a quiescent state called G0 once they become confluent or are deprived of serum or growth factors. The first gap phase (G1) prior to the initiation of DNA synthesis represents the period of commitment that separates M and S phases as cells prepare for DNA duplication. Cells in G0 and G1 are receptive to growth signals, but once they have passed a restriction point, they are committed to enter DNA synthesis (S phase). Cells demonstrate arrest at different points in G1 in response to different inhibitory growth signals. Mitogenic signals promote progression through G1 to S phase, utilising phosphorylation of the retinoblastoma gene product (pRB, p. 40). Following DNA synthesis, there is a second gap phase (G2) prior to mitosis (M), allowing cells to repair errors Fig. 33.2 The cell cycle and sites of action of chemotherapeutic agents. (CDK = cyclin-dependent kinase; RB = retinoblastoma gene) Quiescent DNA replication G2 Mitosis Terminal differentiation Apoptosis G2 checkpoint for DNA damage DNA replication incomplete Prophase → telophase Nuclear and cellular division Terminal differentiation Apoptosis Further growth or DNA repair S M G1 Cell growth G0 G1 checkpoint for Damaged DNA RB blocks TP53 → CDKs blocked Restriction point (regulated by growth factors) Antimetabolites Mitotic spindle poisons Topoisomerase inhibitors Antibiotics and alkylating agents (act on entire cycle) Cyclin A CDK2 Cyclin B CDK1 Cyclin D CDK4, 6 Cell growth Cyclin E CDK2

1318 • ONCOLOGY to telomeres, allowing continued cell division and thus preventing premature arrest of cellular replication. The telomerase enzyme is almost absent in normal cells but is expressed at significant levels in many human cancers. 6. Inducing angiogenesis All cancers require a functional vascular network to ensure continued growth and will be unable to grow beyond 1 mm3 without stimulating the development of a vascular supply. Tumours require sustenance in the form of nutrients and oxygen, as well as an ability to evacuate metabolic waste products and carbon dioxide. This entails the development of new blood vessels, which is termed angiogenesis (Figs 33.3 and 33.4). Angiogenesis is dependent on the production of angiogenic growth factors, of which vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF) are the best characterised. During tumour progression, an angiogenic switch is activated and remains on, causing normally quiescent vasculature to sprout new vessels continually that help sustain expanding tumour growth. Angiogenesis is governed by a balance of pro-angiogenic stimuli and angiogenesis inhibitors, such as thrombospondin (TSP)-1, which binds to transmembrane receptors on endothelial cells and evokes suppressive signals. A number of cells can contribute to the maintenance of a functional tumour vasculature and therefore sustain angiogenesis. These include pericytes and a variety of bone marrow-derived cells such as macrophages, neutrophils, mast cells and myeloid progenitors. 4. Evading growth suppressors In healthy tissues, cell-to-cell contact in dense cell populations acts as an inhibitory factor on proliferation. This contact inhibition is typically absent in many cancer cell populations. Growth-inhibitory factors can modulate the cell cycle regulators and produce activation of the CDK inhibitors, causing inhibition of the CDKs. Mutations within inhibitory proteins are common in cancer. Loss of restriction by disruption of pRB regulation can be found in human tumours, which produces a loss of restraint on transition from G1 to S phase of the cell cycle. Disruption of TP53 function will have downstream effects on p21 that alter the coordination of DNA repair with cycle arrest, and that result in the affected cell accumulating genomic defects. Down-regulation of p21 and p27, which can be found in tumours with normal TP53 function, correlates notably with high tumour grade and poor prognosis. 5. Enabling replicative immortality For cancer cells to evolve into macroscopic tumours, they need to acquire the ability for unlimited proliferation. Telomeric DNA sequences, which protect and stabilise chromosomal ends, play a central role in conferring this limitless replicative potential. During replication of normal cells, telomeres shorten progressively as small fragments of telomeric DNA are lost with successive cycles of replication. This shortening process is thought to represent a mitotic clock and eventually prevents the cell from dividing further. Telomerase, a specialised polymerase enzyme, adds nucleotides Fig. 33.3 Oncogenesis. The multistep origin of cancer, showing events implicated in cancer initiation, progression, invasion and metastasis. Basal lamina First mutation Inherited or acquired gain of oncogene Loss of tumour suppressor gene Normal epithelium Blood vessel Connective tissue Lymphatic First mutation Initial proliferation Small adenoma Further mutation Further mutation; subset selected for rapid growth Carcinoma Further mutation → invasion or metastasis Blood spread Lymphatic spread Ectopic growth factor production and autostimulation Failed apoptosis (e.g. TP53 mutation) Local invasion through basal lamina ↑ Angiogenesis to support tumour growth (see Fig. 33.4) Breakdown of connective tissue via tumour production of e.g. collagenase tissue metalloproteinases Loss of cell adhesion molecules e.g. E-cadherin

The 10 hallmarks of cancer • 1319

energy production to glycolysis, even in the presence of oxygen. This has been termed ‘aerobic glycolysis’. Up-regulation of glucose transporters, such as GLUT1, is the main mechanism through which aerobic glycolysis is achieved. This reprogramming of energy metabolism appears paradoxical, as overall energy production from glycolysis is significantly lower (18-fold) than that from oxidative phosphorylation. One explanation may be that the increased production of glycolytic intermediates can be fed into various biosynthetic pathways, including those that generate the nucleosides and amino acids, necessary for the production of new cells. 9. Tumour-promoting inflammation Almost all tumours show infiltration with immune cells on pathological investigation and historically this finding was thought to represent an attempt of the immune system to eradicate the cancer. It is now clear that tumour-associated inflammatory responses promote tumour formation and cancer progression. Cytokines are able to alter blood vessels to permit migration of leucocytes (mainly neutrophils), in order to permeate from the blood vessels into the tissue, a process known as extravasation. Migration across the endothelium occurs via the process of diapedesis, where chemokine gradients stimulate adhered leucocytes to move between endothelial cells and pass through the basement membrane into the surrounding tissues. Once within the tissue interstitium, leucocytes bind to extracellular matrix proteins via integrins and CD44 to prevent their loss from the site. As well as cell-derived mediators, several acellular biochemical cascade systems consisting of pre-formed plasma proteins act in parallel to initiate and propagate the inflammatory response. These include the complement system activated by bacteria, and the coagulation and fibrinolytic systems activated by necrosis, and also in burns and trauma, as well as cancer. Other bioactive molecules, such as growth factors and pro-angiogenic factors, may be released by inflammatory immune cells into the surrounding tumour microenvironment. In particular, the release of reactive 7. Activating invasion and metastasis Invasion and metastasis are complex processes involving multiple discrete steps; they begin with local tissue invasion, followed by infiltration of nearby blood and lymphatic vessels by cancer cells. Malignant cells are eventually transported through haematogenous and lymphatic spread to distant sites within the body, where they form micrometastases that will eventually grow into macroscopic metastatic lesions (see Fig. 33.3). Cadherin-1 (CDH1) is a calcium-dependent cell–cell adhesion glycoprotein that facilitates assembly of organised cell sheets in tissues, and increased expression is recognised as an antagonist of invasion and metastasis. In situ tumours usually retain CDH1 production, whereas loss of CDH1 production due to downregulation or occasional mutational inactivation of CDH1 has been observed in human cancers, supporting the theory that CDH1 plays a key role in suppression of invasion and metastasis. Cross-talk between cancer cells and cells of the surrounding stromal tissue is involved in the acquired capability for invasive growth and metastasis. Mesenchymal stem cells in tumour stroma have been found to secrete CCL5, a protein chemokine that helps recruit leucocytes into inflammatory sites. With the help of particular T-cell-derived cytokines (interleukin (IL)-2 and interferon-gamma (IFN-γ)), CCL5 induces proliferation and activation of natural killer cells and then acts reciprocally on cancer cells to stimulate invasive behaviour. Macrophages at the tumour periphery can foster local invasion by supplying matrix-degrading enzymes such as metalloproteinases and cysteine cathepsin proteases. 8. Reprogramming energy metabolism Under aerobic conditions, oxidative phosphorylation functions as the main metabolic pathway for energy production; cells process glucose, first to pyruvate via glycolysis and thereafter to carbon dioxide in the mitochondria. While under anaerobic conditions, glycolysis is favoured to produce adenosine triphosphate (ATP). Cancer cells can reprogram their glucose metabolism to limit Fig. 33.4 Angiogenesis, invasion and metastasis. A For any cancer to grow beyond 1 mm3, it must evoke a blood supply. B New vessel formation results from the release of angiogenic factors by the tumour cells and loss of inhibition of the endothelial cells. C The loss of cellular adhesion and disruption of the extracellular matrix allow cells to extravasate into the blood stream and metastasise to distant sites. (VEGF= vascular endothelial growth factor) Inhibition Loss of inhibition Viable tumour cell Apoptoptic tumour cell Angiogenic factors VEGF VEGF receptor Tissue factor αvβ3 integrin Plasminogen Coagulation factor Coagulation Fibrinogen Fibrin Cell adhesion Urokinase Urokinase receptor Proteolysis Plasmin A B C

1320 • ONCOLOGY Environmental and genetic determinants of cancer The majority of cancers do not have a single cause but rather are the result of a complex interaction between genetic factors and exposure to environmental carcinogens. These are often tumour type-specific but some general principles do apply. Environmental factors Environmental triggers for cancer have mainly been identified through epidemiological studies that examine patterns of distribution of cancers in patients in whom age, sex, presence of other illnesses, social class, geography and so on differ. Sometimes, these give strong pointers to the molecular or cellular causes of the disease, such as the association between aflatoxin production within contaminated food supplies and hepatocellular carcinomas. For many solid cancers, such as breast and colorectal, however, there is evidence of a multifactorial pathogenesis, even when there is a principal environmental cause (Box 33.1). Smoking is now established beyond all doubt as a major cause of lung cancer, but there are obviously additional predisposing factors since not all smokers develop cancer. Similarly, most carcinomas of the cervix are related to infection with human oxygen species, which are actively mutagenic, will accelerate the genetic evolution of surrounding cancer cells, enhancing growth and contributing to cancer progression. 10. Evading immune destruction The immune system operates as a significant barrier to tumour formation and progression, and the ability to escape from immunity is a hallmark of cancer development. Cancer cells continuously shed surface antigens into the circulatory system, prompting an immune response that includes cytotoxic T-cell, natural killer cell and macrophage production. The immune system is thought to provide continuous surveillance, with resultant elimination of cells that undergo malignant transformation. However, deficiencies in the development or function of CD8+ cytotoxic T lymphocytes, CD4+ Th1 helper T cells or natural killer cells can each lead to a demonstrable increase in cancer incidence. Also, highly immunogenic cancer cells may evade immune destruction by disabling components of the immune system. This is done through recruitment of inflammatory cells, including regulatory T cells and myeloid-derived suppressor cells, both actively immunosuppressive against the actions of cytotoxic lymphocytes (see Fig. 4.12, p. 80). Cancers develop and progress when there is loss of recognition by the immune system, lack of susceptibility due to escape from immune cell action and induction of immune dysfunction, often via inflammatory mediators. 33.1 Environmental factors that predispose to cancer Environmental aetiology Processes Diseases Occupational exposure (see ‘Radiation’ below) Dye and rubber manufacturing (aromatic amines) Bladder cancer Asbestos mining, construction work, shipbuilding (asbestos) Lung cancer and mesothelioma Vinyl chloride (PVC) manufacturing Liver angiosarcoma Petroleum industry (benzene) Acute leukaemia Chemicals Chemotherapy (e.g. melphalan, cyclophosphamide) Acute myeloid leukaemia Cigarette smoking Exposure to carcinogens from inhaled smoke Lung and bladder cancer Viral infection Epstein–Barr virus Burkitt’s lymphoma and nasopharyngeal cancer Human papillomavirus Cervical cancer Hepatitis B and C viruses Hepatocellular carcinoma Bacterial infection Helicobacter pylori Gastric MALT lymphomas, gastric cancer Parasitic infection Liver fluke (Opisthorchis sinensis) Cholangiocarcinoma Schistosoma haematobium Squamous cell bladder cancer Dietary factors Low-roughage/high-fat content diet Colonic cancer High nitrosamine intake Gastric cancer Aflatoxin from contamination of Aspergillus flavus Hepatocellular cancer Radiation UV exposure Basal cell carcinoma Melanoma Non-melanocytic skin cancer Nuclear fallout following explosion (e.g. Hiroshima) Leukaemia Solid tumours, e.g. thyroid Diagnostic exposure (e.g. CT) Cholangiocarcinoma following Thorotrast usage Occupational exposure (e.g. beryllium and strontium mining) Lung cancer Therapeutic radiotherapy Medullary thyroid cancer Sarcoma Inflammatory diseases Ulcerative colitis Colon cancer Hormonal Use of diethylstilbestrol Vaginal cancer Oestrogens Endometrial cancer Breast cancer (CT = computed tomography; MALT = mucosa-associated lymphoid tissue; UV = ultraviolet)

Investigations • 1321

100% penetrance and additional modulating factors, both genetic and environmental, are likely to be operative. Exploration of a possible genetic contribution is a key part of cancer management, especially with regard to ascertaining the risk for an affected patient’s offspring. Investigations When a patient is suspected of having cancer, a full history should be taken; specific questions should be included as to potential risk factors such as smoking and occupational exposures or potential complications of the disease. A thorough clinical examination is essential to identify sites of metastases, and to discover any other conditions that may have a bearing on the management plan (pp. 1314–1315). In order to make a diagnosis and to plan the most appropriate management, information is needed on: • the type of tumour • the extent of disease, as assessed by staging investigations • the patient’s general condition and any comorbidity. papillomavirus (HPV subtypes 16 and 18). For carcinomas of the bowel and breast, there is strong evidence of an environmental component. For example, the risk of breast cancer in women of Far Eastern origin remains relatively low when they first migrate to a country with a Western lifestyle, but rises in subsequent generations to approach that of the resident population of the host country. The precise environmental factor that causes this change is unclear but may include diet (higher intake of saturated fat and/or dairy products), reproductive patterns (later onset of first pregnancy) and lifestyle (increased use of artificial light and shift in diurnal rhythm). Genetic factors A number of inherited cancer syndromes are recognised that account for 5–10% of all cancers (Box 33.2). Their molecular basis is discussed in Chapter 3, but in general they result from inherited mutations in genes that regulate cell growth, cell death and apoptosis. Examples include the BRCA1, BRCA2 and AT (ataxia telangiectasia) genes that cause breast and some other cancers, the FAP gene that causes bowel cancer and the RB gene that causes retinoblastoma. Although carriers of these gene mutations have a greatly elevated risk of cancer, none has 33.2 Inherited cancer predisposition syndromes Syndrome Malignancies Inheritance Gene Ataxia telangiectasia Leukaemia, lymphoma, ovarian, gastric, brain, colon AR AT Bloom’s syndrome Leukaemia, tongue, oesophageal, colonic, Wilms’ tumour AR BLM Breast/ovarian Breast, ovarian, colonic, prostatic, pancreatic AD BRCA1, BRCA2 Cowden’s syndrome Breast, thyroid, gastrointestinal tract, pancreatic AD PTEN Familial adenomatous polyposis Colonic, upper gastrointestinal tract AD APC, MUTYH Familial atypical multiple mole melanoma (FAMMM) Melanoma, pancreas AD CDKN2A (TP16) Fanconi anaemia Leukaemia, oesophageal, skin, hepatoma AR FACA, FACC, FACD Gorlin’s syndrome Basal cell skin, brain AD PTCH Hereditary diffuse gastric cancer Diffuse gastric cancer AD E-cadherin Hereditary non-polyposis colon cancer (HNPCC) Colonic, endometrial, ovarian, pancreatic, gastric AD MSH2, MLH1, MSH6, PMS1, PMS2 Li–Fraumeni syndrome Sarcoma, breast, osteosarcoma, leukaemia, glioma, adrenocortical AD TP53 Multiple endocrine neoplasia (MEN) 1 Pancreatic islet cell, pituitary adenoma, parathyroid adenoma and hyperplasia AD MEN1 MEN 2 Medullary thyroid, phaeochromocytoma, parathyroid hyperplasia AD RET Neurofibromatosis 1 Neurofibrosarcoma, phaeochromocytoma, optic glioma AD NF1 Neurofibromatosis 2 Vestibular schwannoma AD NF2 Papillary renal cell cancer syndrome Renal cell cancer AD MET Peutz–Jeghers syndrome Colonic, ileal, breast, ovarian AD STK11 Prostate cancer Prostate AD HPC1 Retinoblastoma Retinoblastoma, osteosarcoma AD RB1 von Hippel–Lindau syndrome Haemangioblastoma of retina and CNS, renal cell, phaeochromocytoma AD VHL Wilms’ tumour Nephroblastoma, neuroblastoma, hepatoblastoma, rhabdomyosarcoma AD WT1 Xeroderma pigmentosum Skin, leukaemia, melanoma AR XPA, XPC, XPD (ERCC2), XPF (AD = autosomal dominant; AR = autosomal recessive; CNS = central nervous system)

1322 • ONCOLOGY informative when combined with knowledge of the clinical picture; biopsy results should therefore be reviewed and discussed within the context of a multidisciplinary team meeting. Light microscopy Examination of tumour samples by light microscopy remains the core method of cancer diagnosis and, in cases where the primary site is unclear, may give clues to the origin of the tumour: • Signet-ring cells favour a gastric primary. • Presence of melanin favours melanoma. • Mucin is common in gut/lung/breast/endometrial cancers, but particularly common in ovarian cancer and rare in renal cell or thyroid cancers. • Psammoma bodies are a feature of ovarian cancer (mucin +) and thyroid cancer (mucin −). Immunohistochemistry Immunohistochemical (IHC) staining for tumour markers can provide useful diagnostic information and can help with treatment decisions. Commonly used examples of IHC in clinical practice include: • Oestrogen (ER) and progesterone (PR) receptors. Positive results indicate that the tumour may be sensitive to hormonal manipulation. • Alpha-fetoprotein (AFP) and human chorionic gonadotrophin (hCG) with or without placental alkaline phosphatase (PLAP). These favour germ-cell tumours. • Prostate-specific antigen (PSA) and prostatic acid phosphatase (PAP). These favour prostate cancer. • Carcinoembryonic antigen (CEA), cytokeratin and epithelial membrane antigen (EMA). These favour epithelial carcinomas. • HER2 receptor. Breast cancers that have high levels of expression of HER2 indicate that the tumour may respond to trastuzumab (Herceptin), an antibody directed against the HER2 receptor. The pattern of immunoglobulin, T-cell receptor and cluster designation (CD) antigen expression on the surface is helpful in the diagnosis and classification of lymphomas. This can be achieved by IHC staining of biopsy samples or flow cytometry. Electron microscopy Electron microscopy (EM) can sometimes be of diagnostic value. Examples include the visualisation of melanosomes in amelanotic melanoma and dense core granules in neuro-endocrine tumours. EM may help to distinguish adenocarcinoma from mesothelioma, as the ultrastructural properties of these two diseases are different (mesothelioma appears to have long, narrow, branching microvilli while adenocarcinomas appear to have short, stubby microvilli). EM is also useful for differentiating spindle-cell tumours (sarcomas, melanomas, squamous cell cancers) from small round-cell tumours, again due to their ultrastructural differences. Cytogenetic analysis Some tumours demonstrate typical chromosomal changes that help in diagnosis. The utilisation of fluorescent in situ hybridisation (FISH) techniques can be useful in Ewing’s sarcoma and peripheral neuro-ectodermal tumours where there is a translocation between chromosome 11 and 22–t(11;22)(q24;q12). In some cases, gene amplification can be detected via FISH (e.g. determining over-expression of HER2/neu). The overall fitness of a patient is often assessed by the Eastern Cooperative Oncology Group (ECOG) performance status scale (Box 33.3). The outcome for patients with a performance status of 3 or 4 is worse in almost all malignancies than for those with a status of 0–2, and this has a strong influence on the approach to treatment in the individual patient. The process of staging determines the extent of the tumour; it entails clinical examination, imaging and, in some cases, surgery, to establish the extent of disease involvement. The outcome is recorded using a standard staging classification that allows comparisons to be made between different groups of patients. Therapeutic decisions and prognostic predictions can then be made using the evidence base for the disease. One of the most commonly used systems is the T (tumour), N (regional lymph nodes), M (metastatic sites) approach of the International Union against Cancer (UICC, Box 33.4). For some tumours, such as colon cancer, the Dukes system (p. 832) is used rather than the UICC classification. Histology Histological analysis of a biopsy or resected specimen is pivotal in clinching the diagnosis and in deciding on the best form of management. The results of histological analysis are most Extent of primary tumour* TX Not assessed T0 No tumour Increases in primary tumour size or depth of invasion T1 T2 T3 T4 Increased involvement of nodes* NX Not assessed N0 No nodal involvement N1 Increases in involvement N2/3 Presence of metastases MX Not assessed M0 Not present M1 Present *Exact criteria for size and region of nodal involvement have been defined for each anatomical site. } } 33.4 TNM classification 33.3 Eastern Cooperative Oncology Group (ECOG) performance status scale

Fully active, able to carry on all usual activities without restriction and without the aid of analgesics

Restricted in strenuous activity but ambulatory and able to carry out light work or pursue a sedentary occupation. This group also contains patients who are fully active, as in grade 0, but only with the aid of analgesics

Ambulatory and capable of all self-care but unable to work. Up and about more than 50% of waking hours

Capable of only limited self-care, confined to bed or chair more than 50% of waking hours

Completely disabled, unable to carry out any self-care and confined totally to bed or chair

Presenting problems in oncology • 1323

metastatic disease or from non-metastatic manifestations due to production of biologically active hormones by the tumour or as the result of an immune response to the tumour. The possible presentations are summarised in Boxes 33.6 and 33.7, and common presenting features discussed below. Although the incidence of cancer increases with patient age, the approach to investigation and management is similar at all ages (Box 33.8). Palpable mass A palpable mass detected by the patient or physician may be the first sign of cancer. Primary tumours of the thyroid, breast, testis and skin are often detected in this way, whereas palpable lymph nodes in the neck, groin or axilla may indicate secondary spread of tumour. Hepatomegaly may be the first sign of primary liver cancer or tumour metastasis, whereas skin cancer may present as an enlarging or changing pigmented lesion. Weight loss and fever Unintentional weight loss is a characteristic feature of advanced cancer, but can have other causes such as thyrotoxicosis, chronic inflammatory disease and chronic infective disorders. Fever can occur in any cancer secondary to infection, but may be a primary feature in Hodgkin and non-Hodgkin lymphoma, leukaemia, renal cancer and liver cancer. The presence of unexplained weight loss or fever warrants investigation to exclude the presence of occult malignancy. Imaging Imaging plays a critical role in oncology, not only in locating the primary tumour but also in staging the disease and determining the response to treatment. The imaging modality employed depends primarily on the site of the disease and likely patterns of spread, and may require more than one modality. Ultrasound Ultrasound is useful in characterising lesions within the liver, kidney, pancreas and reproductive organs. It can be used for guiding biopsies of tumours in breast and liver. Endoscopic ultrasound is helpful in staging upper gastrointestinal and pancreatic cancers, involving a special endoscope with an ultrasound probe attached. Computed tomography Computed tomography (CT) is a key investigation in cancer patients and is particularly useful in imaging the thorax and abdomen. With modern scanners it is possible to visualise the large bowel if it is prepared (CT colonography), allowing accurate detection of colorectal cancers and adenomas ≥ 10 mm. Magnetic resonance imaging Magnetic resonance imaging (MRI) has a high resolution and is the preferred technique for brain and pelvic imaging. It is widely employed for the staging of rectal, cervical and prostate cancers. Positron emission tomography Positron emission tomography (PET) visualises metabolic activity of tumour cells and is widely used, often in combination with CT (PET–CT), to evaluate the extent of the disease, particularly in the assessment of potential distant metastasis (Fig. 33.5). It can accurately assess the severity and spread of cancer by detecting tumour metabolic activity following injection of small amounts of radioactive tracers such as fluorodeoxyglucose (FDG). In addition to having a role in diagnosis, PET can be used in some patients to assess treatment response. Biochemical markers Many cancers produce substances called tumour markers, which can assist in diagnosis and surveillance. Some are useful in population screening, diagnosis, determining prognosis, response evaluation, detection of relapse and imaging of metastasis. Unfortunately, most tumour markers are neither sufficiently sensitive nor sufficiently specific to be used in isolation for diagnosis and need to be interpreted in the context of the other clinical features. Some can be used for antibody-directed therapy or imaging, however, where they have a greater role in diagnosis. Tumour markers in routine use are outlined in Box 33.5. Presenting problems in oncology In the early stages of cancer development, the number of malignant cells is small and the patient is usually asymptomatic. With tumour progression, localised signs or symptoms develop due to mass effects and/or invasion of local tissues. With further progression, symptoms may occur at distant sites as a result of Fig. 33.5 Positron emission tomography–computed tomography (PET–CT) images. A There is a neoplastic lesion (arrow) in the left axilla, evidenced by the increased uptake of fluorodeoxyglucose (FDG) tracers. B Imaging after chemotherapy, demonstrating that the abnormal uptake has disappeared and indicating a response to treatment. Courtesy of Dr J. Wilsdon, Freeman Hospital, Newcastle upon Tyne. A B

1324 • ONCOLOGY 33.5 Commonly used serum tumour markers Name Natural occurrence Tumours Alpha-fetoprotein (AFP) Glycoprotein found in yolk sac and fetal liver tissue. Transient elevation in liver diseases. Has a role in screening during pregnancy for the detection of neural tube defects and Down’s syndrome Ovarian non-seminomatous germ cell tumours (80%), testicular teratoma (80%), hepatocellular cancer (50%) Beta-2-microglobulin A human leucocyte antigen (HLA) common fragment present on surface of lymphocytes, macrophages and some epithelial cells. Can be elevated in autoimmune disease and renal glomerular disease Non-Hodgkin lymphoma, myeloma Calcitonin 32-amino-acid peptide from C cells of thyroid. Used to screen for MEN 2 Medullary cell carcinoma of thyroid Cancer antigen 125 (CA-125) Differentiation antigen of coelomic epithelium (Müller’s duct). Raised in any cause of ascites, pleural effusion or heart failure. Can be raised in inflammatory conditions Ovarian epithelial cancer (75%), gastrointestinal cancer (10%), lung cancer (5%) and breast cancer (5%) CA-19.9 A mucin found in epithelium of fetal stomach, intestine and pancreas. It is eliminated exclusively via bile and so any degree of cholestasis can cause levels to rise Pancreatic cancer (80%), mucinous tumour of the ovary (65%), gastric cancer (30%), colon cancer (30%) Carcinoembryonic antigen (CEA) Glycoprotein found in intestinal mucosa during embryonic and fetal life. Elevated in smokers, cirrhosis, chronic hepatitis, ulcerative colitis, pneumonia Colorectal cancer, particularly with liver metastasis, gastric cancer, breast cancer, lung cancer, mucinous cancer of the ovary Human chorionic gonadotrophin (hCG) Glycoprotein hormone, 14 kD α subunit and 24 kD β subunit from placental syncytiotrophoblasts. Used for disease monitoring in hydatidiform mole and as the basis of a pregnancy test Choriocarcinoma (100%), hydatidiform moles (97%), ovarian non-seminomatous germ cell tumours (50–80%), seminoma (15%) Placental alkaline phosphatase (PLAP) Isoenzyme of alkaline phosphatase Seminoma (40%), ovarian dysgerminoma (50%) Prostate-specific antigen (PSA) Glycoprotein member of human kallikrein gene family. PSA is a serine protease that liquefies semen in excretory ducts of prostate. Can be elevated in benign prostatic hypertrophy and prostatitis Prostate cancer (95%) Thyroglobulin Matrix protein for thyroid hormone synthesis in normal thyroid follicles Papillary and follicular thyroid cancer 33.6 Local features of malignant disease Symptom Typical site or possible tumour Haemorrhage Stomach, colon, bronchus, endometrium, bladder, kidney Lump Breast, lymph node (any site), testicle Bone pain or fracture Bone (primary sarcoma, secondary metastasis from breast, prostate, bronchus, thyroid, kidney) Skin abnormality Melanoma, basal cell carcinoma (rodent ulcer) Ulcer Oesophagus, stomach, anus, skin Dysphagia Oesophagus, bronchus, gastric Increasing constipation, abdominal discomfort or pain Colon, rectum, ovary Airway obstruction, stridor, cough, recurrent infection Bronchus, thyroid Odynophagia, early satiety, vomiting Bronchus, stomach, oesophagus, colon, rectum Abdominal swelling (ascites) Ovary, stomach, pancreas Thromboembolism Thrombosis and disseminated intravascular coagulation (DIC) are common complications in patients with cancer. The prothrombotic state is caused by cancer cells activating the coagulation system via factors such as tissue factor, cancer procoagulant and inflammatory cytokines. The interaction between tumour cells, monocytes/macrophages, platelets and endothelial cells can promote thrombus formation, as part of a host response to the cancer (i.e. acute phase, inflammation, angiogenesis) or via a reduction in the levels of inhibitors of coagulation or impairment

Presenting problems in oncology • 1325

parathyroid hormone-related protein (PTHrP). This can result in a wide variety of presentations, as summarised in Box 33.9. Further details on the presentation and management of ACTH- and vasopressin-producing tumours are given on page 670, and those of FGF23-producing tumours on page 1053. The management of hypercalcaemia associated with malignancy is discussed below. Neurological paraneoplastic syndromes These form a group of conditions associated with cancer that are thought to be due to an immunological response to the tumour that results in damage to the nervous system or muscle. The cancers most commonly implicated are those of the lung (small cell and non-small cell), pancreas, breast, prostate, ovary and lymphoma. • Peripheral neuropathy results from axonal degeneration or demyelination. • Encephalomyelitis can present with diverse symptoms, depending on which region of the brain is involved. Lumbar puncture shows raised protein in the cerebrospinal fluid and a pleocytosis, predominantly that of lymphocytes. In some centres, flow cytometry of the cerebrospinal fluid can be used to detect carcinomatous cells. MRI shows meningeal enhancement, particularly at the level of the brainstem, and anti-Hu antibodies may be detectable in serum. Encephalomyelitis is due to perivascular inflammation and selective neuronal degeneration. Most cases are caused by small cell lung cancer (75%). • Cerebellar degeneration may be the presenting feature of an underlying malignancy and presents with rapid onset of cerebellar ataxia. Diagnosis is by MRI or CT, which may show cerebellar atrophy. Patients with these neurological paraneoplastic syndromes may be found to have circulating anti-Yo, Tr and Hu antibodies, but these are not completely specific and negative results do not exclude the diagnosis. • Retinopathy is a rare complication of cancer and presents with blurred vision, episodic visual loss and impaired colour vision. If left untreated, it may lead to blindness. The diagnosis should be suspected if the electroretinogram is abnormal and anti-retinal antibodies are detected. • Lambert–Eaton myasthenic syndrome (LEMS) is due to underlying cancer in about 60% of cases. It presents with of fibrinolysis. Furthermore, the prothrombotic tendency can be enhanced by therapy such as surgery, chemotherapy, hormone therapy and radiotherapy, and by in-dwelling access devices (i.e. central venous catheters). In some patients, the thromboembolism is the first presenting feature of the underlying cancer. Ectopic hormone production In some cases, the first presentation of cancer is with a metabolic abnormality due to ectopic production of hormones by tumour cells, including insulin, ACTH, vasopressin (antidiuretic hormone, ADH), fibroblast growth factor (FGF)-23, erythropoietin and 33.8 Cancer in old age • Incidence: around 50% of cancers occur in the 15% of the population aged over 65 years. • Screening: women aged over 65 in the UK are not invited to breast cancer screening but can request it. Uptake is low despite increasing incidence with age. • Presentation: may be later for some cancers. When symptoms are non-specific, patients (and their doctors) may initially attribute them to age alone. • Life expectancy: an 80-year-old woman can expect to live 8 years, so cancer may still shorten life and an active approach remains appropriate. • Prognosis: histology, stage at presentation and observation for a brief period are better guides to outcome than age. • Rate of progression: malignancy may have a more indolent course. This is poorly understood but may be due to reduced effectiveness of angiogenesis with age, inhibiting the development of metastases. • Response to treatment: equivalent to that in younger people – well documented for a range of cancers and for surgery, radiotherapy, chemotherapy and hormonal therapy. • Treatment selection: chronological age is of minor importance compared to comorbid illness and patient choice. Although older patients can be treated effectively and safely, aggressive intervention is not appropriate for all. Symptom control may be all that is possible or desired by the patient. 33.7 Non-metastatic manifestations of malignant disease Feature Common cancer site associations Weight loss and anorexia Lung, gastrointestinal tract Fatigue Any Hypercalcaemia Myeloma, breast, kidney Prothrombotic tendency Ovary, pancreas, gastrointestinal tract SIADH Ectopic ACTH Small cell lung cancer Lambert–Eaton myasthenic syndrome Small cell lung cancer Subacute cerebellar degeneration Small cell lung cancer, ovarian cancer Acanthosis nigricans Stomach, oesophagus Dermatomyositis/polymyositis Stomach, lung (ACTH = adrenocorticotrophic hormone; SIADH = syndrome of inappropriate antidiuretic hormone (vasopressin) secretion) 33.9 Ectopic hormone production by tumours Hormone Consequence Tumours ACTH Cushing’s syndrome SCLC Erythropoietin Polycythaemia Kidney, hepatoma, cerebellar haemangioblastoma, uterine fibroids FGF-23 Hypophosphataemic osteomalacia Mesenchymal tumours PTHrP Hypercalcaemia NSCLC (squamous cell), breast, kidney Vasopressin (ADH) Hyponatraemia SCLC (ACTH = adrenocorticotrophic hormone; ADH = antidiuretic hormone; FGF = fibroblast growth factor; NSCLC = non-small cell lung cancer; PTHrP = parathyroid hormone-related protein; SCLC = small cell lung cancer)

1326 • ONCOLOGY neuron findings may predominate early on or in cases of nerve root compression. Management Spinal cord compression is a medical emergency and should be treated with analgesia and high-dose glucocorticoid therapy (Box 33.11). Neurosurgical intervention produces superior outcome and survival compared to radiotherapy alone, and should be considered first for all patients. Radiotherapy is used for the remaining patients and selected tumour types when the cancer is likely to be radiosensitive. The prognosis varies considerably, depending on tumour type, but the degree of neurological dysfunction at presentation is the strongest predictor of outcome, irrespective of the underlying diagnosis. Mobility can be preserved in more than 80% of patients who are ambulatory at presentation, but neurological function is seldom regained in patients with established deficits such as paraplegia. Superior vena cava obstruction Superior vena cava obstruction (SVCO) is a common complication of cancer that can occur through extrinsic compression or intravascular blockage. The most common causes of extrinsic compression are lung cancer, lymphoma and metastatic tumours. Patients with cancer can also develop SVCO due to intravascular blockage in association with a central catheter or thromboembolism secondary to the tumour. Clinical features The typical presentation is with oedema of the arms and face, distended neck and arm veins and dusky skin coloration over the chest, arms and face. Collateral vessels may develop over a period of weeks and the flow of blood in the collaterals helps to confirm the diagnosis. Headache secondary to cerebral oedema arising from the backflow pressure may also occur and tends to be aggravated by bending forwards, stooping or lying down. The severity of symptoms is related to the rate of obstruction and the development of a venous collateral circulation. Accordingly, symptoms may develop rapidly or gradually. Clinical features are summarised in Box 33.12. proximal muscle weakness that improves on exercise and is caused by the development of antibodies to presynaptic calcium channels (p. 1143). The diagnosis is made by electromyelogram (EMG), which shows a low-amplitude compound muscle action potential that enhances to near normal following exercise. • Dermatomyositis or polymyositis may be the first presentation of some cancers. Clinical features and management of these conditions are discussed on page 1039. Cutaneous manifestations of cancer Many cancers can present with skin manifestations that are not due to metastases: • Pruritus may be a presenting feature of lymphoma, leukaemia and central nervous system tumours. • Acanthosis nigricans may precede cancers by many years and is particularly associated with gastric cancer. • Vitiligo may be associated with malignant melanoma and is possibly due to an immune response to melanocytes. • Pemphigus may occur in lymphoma, Kaposi’s sarcoma and thymic tumours. • Dermatitis herpetiformis associated with coeliac disease may precede tumour development by many years, and is associated with gastrointestinal lymphoma. The clinical features and management of these skin conditions are discussed in Chapter 29. Emergency complications of cancer Spinal cord compression Spinal cord compression complicates 5% of cancers and is most common in myeloma, prostate, breast and lung cancers that involve bone. Cord compression often results from posterior extension of a vertebral body mass but intrathecal spinal cord metastases can cause similar signs and symptoms. The thoracic region is most commonly affected. Clinical features The earliest sign is back pain, particularly on coughing and lying flat. Subsequently, sensory changes develop in dermatomes below the level of compression and motor weakness distal to the block occurs. Finally, sphincter disturbance, causing urinary retention and bowel incontinence, is observed. Involvement of the lumbar spine may cause conus medullaris or cauda equina compression (Box 33.10). Physical examination reveals findings consistent with an upper motor neuron lesion, but lower motor 33.11 Management of suspected spinal cord compression • Confirm diagnosis with urgent MRI scan • Administer high-dose glucocorticoids: Dexamethasone 16 mg IV stat Dexamethasone 8 mg twice daily orally • Ensure adequate analgesia • Refer for surgical decompression or urgent radiotherapy 33.10 Comparison of features of neurological deficit Clinical feature Spinal cord Conus medullaris Cauda equina Weakness Symmetrical and profound Symmetrical and variable Asymmetrical, may be mild Reflexes Increased (or absent) knee and ankle reflexes with extensor plantar reflex Increased knee reflex, decreased ankle reflex, extensor plantar reflex Decreased knee and ankle reflexes with flexor plantar reflex Sensory loss Symmetrical, sensory level Symmetrical, saddle distribution Asymmetrical, radicular pattern Sphincters Late loss Early loss Often spared Progression Rapid Variable Variable

Emergency complications of cancer • 1327

Patients should initially be treated with intravenous 0.9% saline to improve renal function and increase urinary calcium excretion. This alone often results in clinical improvement. Concurrently, intravenous bisphosphonates should be given to inhibit bone resorption. Calcitonin acts rapidly to increase calcium excretion and to reduce bone resorption, and can be combined with fluid and bisphosphonate therapy for the first 24–48 hours in patients with life-threatening hypercalcaemia. Bisphosphonates will usually reduce the serum calcium levels to normal within 5 days, but, if not, treatment can be repeated. The duration of action is up to 4 weeks and repeated therapy can be given at 3–4-weekly intervals in the outpatient department. Hypercalcaemia is frequently a sign of tumour progression and the patient requires further investigation to establish disease status and review of the anti-cancer treatment strategy. Neutropenic fever Neutropenia is a common complication of malignancy. It is usually secondary to chemotherapy but may occur with radiotherapy if large amounts of bone marrow are irradiated; it may also be a component of pancytopenia due to malignant infiltration of the bone marrow. Neutropenic fever is defined as a pyrexia of 38°C for over 1 hour in a patient with a neutrophil count of < 0.5 × 109/L or < 1.0 × 109/L if the nadir is anticipated to drop to < 0.5 × 109/L in the next 24 hours. The risk of sepsis is related to the severity and duration of neutropenia and the presence of other risk factors, such as intravenous cannulae or bladder catheters. Neutropenic fever is an emergency in cancer patients as, if left untreated, it can result in sepsis with a high mortality rate. Clinical features The typical presentation is with high fever, and affected patients are often non-specifically unwell. Examination is usually unhelpful in defining a primary source of the infection. Hypotension is an adverse prognostic feature and may progress to systemic circulatory shutdown and organ failure. Investigations and management An infection screen should be performed to include blood cultures (both peripheral and from central lines), urine culture, chest X-ray, and swabs for culture (throat, central line, wound). High-dose intravenous antibiotics should then be commenced, pending the results of cultures. The standard approach is to commence empirical antibiotics according to local hospital policies agreed with microbiologists and based on the local antibiotic resistance patterns observed. First-line empirical therapy is either monotherapy with piperacillin–tazobactam or meropenem, or with the addition of gentamicin. Metronidazole may be added if anaerobic infection is suspected, and teicoplanin where Gram-positive infection is suspected (e.g. in patients with central lines). Antibiotics should be adjusted according to culture results, although these are often negative. If there is no response after 36–48 hours, antibiotics should be reviewed with microbiological advice, and antifungal cover should be considered Investigations and management The investigation of choice is a CT scan of the thorax to confirm the diagnosis and distinguish between extra- and intravascular causes. A biopsy should be obtained when the tumour type is unknown because tumour type has a major influence on treatment. CT of the head may be indicated if cerebral oedema is suspected. Tumours that are exquisitely sensitive to chemotherapy, such as germ cell tumours and lymphoma, can be treated with chemotherapy alone, but for most other tumours mediastinal radiotherapy is required. This relieves symptoms within 2 weeks in 50–90% of patients. In many centres, stenting is now increasingly favoured over radiotherapy, as it produces rapid results and can be repeated with reasonable effectiveness. This technique is particularly useful when dealing with tumours that are relatively chemo- or radio-resistant, such as non-small cell lung cancer or carcinoma of unknown primary. Where possible, these measures should be followed by treatment of the primary tumour, as long-term outcome is strongly dependent on the prognosis of the underlying cancer. Hypercalcaemia Hypercalcaemia is the most common metabolic disorder in patients with cancer and has a prevalence of up to 20% in cancer patients. The incidence is highest in myeloma and breast cancer (approximately 40%), intermediate in non-small cell lung cancer, and uncommon in colon, prostate and small cell lung carcinomas. It is most commonly due to over-production of PTHrP (80%), which binds to the PTH receptor and elevates serum calcium by stimulating osteoclastic bone resorption and increasing renal tubular reabsorption of calcium. Direct invasion of bone by metastases accounts for around 20% of cases while other mechanisms, such as ectopic PTH secretion, are rare. Clinical features The symptoms of hypercalcaemia are often non-specific and may mimic those of the underlying malignancy. They include drowsiness, delirium, nausea and vomiting, constipation, polyuria, polydipsia and dehydration. Investigations and management The diagnosis is made by measuring serum total calcium and adjusting for albumin. It is especially important to correct for albumin in cancer because hypoalbuminaemia is common and total calcium values under-estimate the level of ionised calcium. The principles of management are outlined in Box 33.13. Percentage of patients affected. 33.12 Common symptoms and physical findings in superior vena cava obstruction Symptoms • Dyspnoea (63%) • Facial swelling and head fullness (50%) • Cough (24%) • Arm swelling (18%) • Chest pain (15%) • Dysphagia (9%) Physical findings • Venous distension of neck (66%) • Venous distension of chest wall (54%) • Facial oedema (46%) • Cyanosis (20%) • Plethora of face (19%) • Oedema of arms (14%) 33.13 Medical management of severe hypercalcaemia • IV 0.9% saline 2–4 L/day • Zoledronic acid 4 mg IV or pamidronate 60–90 mg IV • For patients with severe, symptomatic hypercalcaemia that is refractory to zoledronic acid, denosumab (initial dose 60 mg SC, with repeat dosing based on response) is an alternative option

1328 • ONCOLOGY efficacy of these interventions has not been proven adequately in a randomised trial setting. Patients with brain metastases as the only manifestation of an undetected primary tumour have a more favourable prognosis, with an overall median survival of 13.4 months. Tumour type also influences prognosis; breast cancer patients have a better prognosis than those with other types of cancer, and those with colorectal cancer tend to have a poorer prognosis. Clinical features Presentation is with headaches (40–50%), focal neurological dysfunction (20–40%), cognitive dysfunction (35%), seizures (10–20%) and papilloedema (< 10%). Investigations and management The diagnosis can be confirmed by CT or contrast-enhanced MRI. Treatment options include high-dose glucocorticoids (dexamethasone 4 mg 4 times daily) for tumour-associated oedema, anticonvulsants for seizures, whole-brain radiotherapy and chemotherapy. Surgery may be considered for single sites of disease and can be curative; stereotactic radiotherapy may also be considered for solitary site involvement where surgery is not possible. Lung metastases These are common in breast cancer, colon cancer and tumours of the head and neck. The presentation is usually with a lesion on chest X-ray or CT. Solitary lesions require investigation, as single metastases can be difficult to distinguish from a primary lung tumour. Patients with two or more pulmonary nodules can be assumed to have metastases. The approach to treatment depends on the extent of disease in the lung and elsewhere. For solitary lesions, surgery should be considered, with a generous wedge resection. Radiotherapy, chemotherapy or endocrine therapy can be used as systemic treatment and is dependent on the underlying primary cancer diagnosis. Liver metastases Metastatic cancer in the liver can represent the sole or lifelimiting component of disease for many with colorectal cancer, ocular melanoma, neuro-endocrine tumours (NETs) and, less commonly, other tumour types. The most common clinical presentations are with right upper quadrant pain due to stretching of the liver capsule, jaundice, deranged liver function tests or an abnormality detected on imaging. In selected cases, resection of the metastasis can be contemplated. In colorectal cancer, successful resection of metastases improves 5-year survival from 3% to 30–40%. Other techniques, such as chemoembolisation or radiofrequency ablation, can also be used, provided the number (liposomal amphotericin B). Granulocyte–colony-stimulating factor (G–CSF) is not routinely used for all patients with neutropenia and guidelines for use have been established. Other supportive therapy, including intravenous fluids, inotrope therapy, ventilation or haemofiltration, may be required. Tumour lysis syndrome The acute destruction of a large number of cells can be associated with metabolic sequelae and is called tumour lysis syndrome. It is usually related to bulky, chemosensitive disease, including lymphoma, leukaemia and germ cell tumours. More rarely, it can occur spontaneously. Clinical features Cellular destruction results in the release of potassium, phosphate, nucleic acids and purines that can cause transient hypocalcaemia, hyperphosphataemia, hyperuricaemia and hyperkalaemia. This can lead to acute impairment of renal function and the precipitation of uric acid crystals in the renal tubular system. These can manifest with symptoms associated with multiple underlying electrolyte abnormalities, including fatigue, nausea, vomiting, cardiac arrhythmia, heart failure, syncope, tetany, seizures and sudden death. Investigations and management Serum biochemistry should be monitored regularly for 48–72 hours after treatment in patients at risk. Elevated serum potassium may be the earliest biochemical marker but pre-treatment serum lactate dehydrogenase (LDH) correlates with tumour bulk and may indicate increased risk. Good hydration and urine output should be maintained throughout treatment administration. Prophylaxis with allopurinol should be considered and recombinant urate oxidase (rasburicase) can be used to reduce uric acid levels when other treatments fail. Adequate hydration is vital, as it has a dilution effect on the extracellular fluid, improving electrolyte imbalance, and increases circulating volume, improving filtration in the kidneys. In high-risk patients, hydration should be commenced 24 hours before the start of treatment. If normal treatment methods fail to correct the problems, haemodialysis should be considered at an early stage to prevent progression to irreversibility. Metastatic disease Metastatic disease is the major cause of death in cancer patients and the principal cause of morbidity. For the majority, the aim of treatment is palliative but treatment of a solitary metastasis can occasionally be curative. Brain metastases Brain metastases occur in 10–30% of adults and 6–10% of children with cancer, and are an increasingly important cause of morbidity. Tumours that typically metastasise to the brain are shown in Box 33.14. Most involve the brain parenchyma but can also affect the cranial nerves, the blood vessels and other intracranial structures. In cases of solitary metastasis to the brain, the use of surgery and adjuvant radiotherapy has been shown to increase survival. Practices vary, however, for patients with more advanced brain metastases. In these cases, median survival without treatment is approximately 1 month. Glucocorticoids can increase survival to 2–3 months and wholebrain radiotherapy improves survival to 3–6 months, but the true 33.14 Primary tumour sites that metastasise to the brain Primary tumour Patients (%) Lung

Breast

Melanoma

Colon

Other known primary

Unknown primary

Therapeutics in oncology • 1329

or pleuritic in nature. Diagnosis and management of ascites are discussed on page 863. Investigations and management Pleural aspirate is the key investigation and may show the presence of malignant cells. Malignant effusions are commonly blood-stained and are exudates with a raised fluid to serum LDH ratio (> 0.6) and a raised fluid to serum protein ratio (> 0.5). Treatment should focus on palliation of symptoms and be tailored to the patient’s physical condition and prognosis. Aspiration alone may be an appropriate treatment in frail patients with a limited life expectancy (Box 33.15). Those who present with malignant pleural effusion as the initial manifestation of breast cancer, small cell lung cancer, germ cell tumours or lymphoma should have the fluid aspirated and should be given systemic chemotherapy to try to treat disease in the pleural space. Treatment options for patients with recurrent pleural effusion include pleurodesis, pleurectomy and pleuroperitoneal shunt. Ideally, pleurodesis should be attempted once effusions recur after initial drainage. Therapeutics in oncology Anti-cancer therapy may be either curative or palliative, and this distinction influences the approach to management of individual patients. The goal of treatment should be recorded in the medical notes. • Palliative chemotherapy is the most common treatment and is primarily used to treat patients with metastatic disease. The goal is an improvement in symptoms with a focus on improving quality of life, and any survival increments are secondary. As a result, the treatment should be well tolerated and should aim to minimise adverse effects. • Adjuvant chemotherapy is given after an initial intervention that is designed to cyto-reduce the tumour bulk and remove all macroscopic disease. Chemotherapy is then given with the intention of eradicating the micrometastatic disease that remains. The focus is on achieving an improvement in disease-free and overall survival. and size of metastases remain small. If these are not feasible, symptoms may respond to systemic chemotherapy. Bone metastases Bone is the third most common organ involved by metastasis, after lung and liver. Bone metastases are a major clinical problem in patients with myeloma and breast or prostate cancers, but other tumours that commonly metastasise to bone include those of the kidney and thyroid. Bone metastases are an increasing management problem in other tumour types that do not classically target bone, due to the prolonged survival of patients generally. Accordingly, effective management of bony metastases has become a focus in the treatment of patients with many incurable cancers. Clinical features The main presentations are with pain, pathological fractures and spinal cord compression (see above). The pain tends to be progressive and worst at night, and may be partially relieved by activity, but subsequently becomes more constant in nature and is exacerbated by movement. Most pathological fractures occur in metastatic breast cancer (53%); other tumour types associated with fracture include the kidney (11%), lung (8%), thyroid (5%), lymphoma (5%) and prostate (3%). Investigations and management The most sensitive way of detecting bone metastases is by isotope bone scan. This can have false-positive results in healing bone, particularly as a flare response following treatment and falsenegative results occur in multiple myeloma due to suppression of osteoblast activity. Plain X-ray films are therefore preferred for any sites of bone pain, as lytic lesions may not be detected by a bone scan. In patients with a single lesion, it is especially important to perform a biopsy to obtain a tissue diagnosis, since primary bone tumours may look very similar to metastases on X-ray. The main goals of management are: • pain relief • preservation and restoration of function • skeletal stabilisation • local tumour control (e.g. relief of tumour impingement on normal structure). Surgical intervention may be warranted where there is evidence of skeletal instability (e.g. anterior or posterior spinal column fracture) or an impending fracture (e.g. a large lytic lesion on a weight-bearing bone with more than 50% cortical involvement). Intravenous bisphosphonates (pamidronate, zoledronic acid or denosumab) are widely used for bone metastases and are effective at improving pain and in reducing further skeletal related events, such as fractures and hypercalcaemia. In certain types of cancer, such as breast and prostate, hormonal therapy may be effective. Radiotherapy, in the form of external beam therapy or systemic radionuclides (strontium treatment), can also be useful for these patients. In some settings (e.g. breast carcinoma), chemotherapy may be used in the management of bony metastases. Malignant pleural effusion This is a common complication of cancer and 40% of all pleural effusions are due to malignancy. The most common causes are lung and breast cancers, and the presence of an effusion indicates advanced and incurable disease. The presentation may be with dyspnoea, cough or chest discomfort, which can be dull 33.15 How to aspirate a malignant pleural effusion • Ask the patient to sit up and lean forwards slightly. • Identify a suitable site for aspiration. Typically, this should be in the mid-scapular line, below the top of the fluid level and above the diaphragm. • Confirm that the site is below the fluid level by reviewing the chest X-ray and percussing the chest. • Infiltrate the skin and the intercostal space immediately above the rib below with 1% lidocaine. • As you advance the needle, aspirate at each step prior to injecting the local anaesthetic. • On reaching the pleural cavity, you should be able to aspirate pleural fluid; when you do, note the depth of the needle. • Insert a thoracentesis needle into the pleural space by advancing it along the same track as was used for the local anaesthetic and connect it to a three-way tap and container to collect the fluid. • Drain the pleural effusion, to a maximum of 1.5 L. If the effusion is larger than this, repeat the procedure on further occasions as necessary. • Consider using ultrasound-guided placement of a drainage catheter if the effusion proves difficult to drain. • Permanent drains can be useful for some patients with recurrent effusions where pleurodesis is not possible.

1330 • ONCOLOGY Combination therapy The dosing schedule and interval are determined by the choice of drugs and recovery of the cancer and normal tissues. For most common chemotherapy regimens, the treatment is administered every 21 or 28 days, which defines one cycle. A course of treatment often uses up to 6 cycles of treatment. An increase in effectiveness can be achieved by changing the approach to treatment. In some cases this will increase toxicity too, but it can change the nature of the toxicity and such developments are evaluated in clinical trials. • Low-dose therapy is the standard approach and most palliative chemotherapy is given in this manner. The next cycle is started once bone marrow function has recovered sufficiently to start the treatment (neutrophils > 1.0 × 109/L and platelets > 100 × 109/L). • High-dose therapy uses a higher individual drug dose to achieve a higher cell kill but results in more bone marrow toxicity. This can be minimised by using G–CSF. This approach allows more drug to be delivered within the same schedule of administration, but the total received dose can be less than the intended dose due to limitations of non-haematological toxicity. • Dose-dense therapy involves fractionating the intended dose of drug and administering each fraction on a more frequent basis (often weekly). Each individual dose produces less toxicity but the anti-cancer effect is related to the accumulative dose over time. Such an approach can overcome drug resistance, produce a greater cell kill and, in some cases, produce a response with weekly administration when the 3-weekly schedule demonstrates a lack of response or even disease progression. • Alternating therapy involves giving different drugs in an alternating manner. This is most commonly used with haematological malignancies and is designed to treat different subpopulations of cancer cells where individual clones of cells might be resistant to one or more of the agents. Adverse effects Most cytotoxics have a narrow therapeutic window or index and can have significant adverse effects, as shown in Figure 33.6. Considerable supportive therapy is often required to enable patients to tolerate therapy and achieve benefit. Nausea and vomiting are common, but with modern antiemetics, regimens such as the combination of dexamethasone and highly selective 5-hydroxytryptamine (5-HT3, serotonin) receptor antagonists like ondansetron, most patients now receive chemotherapy without any significant problems. Myelosuppression is common to almost all cytotoxics and this not only limits the dose of drug but also can cause life-threatening complications. The risk of neutropenia can be reduced with the use of specific growth factors that accelerate the repopulation of myeloid precursor cells. The most commonly employed is G–CSF, which is widely used in conjunction with chemotherapy regimens that induce a high rate of neutropenia. More recently, it has been used to ‘accelerate’ the administration of chemotherapy, enabling standard doses to be given at shorter intervals where the rate-limiting factor has been the time taken for the peripheral neutrophil count to recover. Accelerated chemotherapy regimens have now been demonstrated to offer therapeutic advantages in small cell lung cancer, lymphoma and possibly breast cancer. • Neoadjuvant chemotherapy or primary medical therapy is where chemotherapy is administered first before a planned cyto-reductive procedure. This can result in a reduced requirement for surgery, increase the likelihood of successful debulking, reduce the duration of hospitalisation and improve the fitness of the patient prior to interval debulking. This approach has the same goals as adjuvant treatment but creates an opportunity for translational research to measure responses to treatment and correlate with subsequent specimens removed at the time of surgery. • Chemoprevention is the use of pharmacological agents to prevent cancer developing in patients identified as being at particular risk. The agents used therefore aim to modify risk and, as such, should not have significant adverse effects. Surgical treatment Surgery has a pivotal role in the management of cancer. There are three main situations in which it is necessary. Biopsy In the vast majority of cases, a histological or cytological diagnosis of cancer is necessary, and tissue will also provide important information such as tumour type and differentiation, to assist subsequent management. Cytology can be obtained with fine needle aspiration but a biopsy is usually preferred. This can be a core biopsy, an image-guided biopsy or an excision biopsy. Excision The main curative management of most solid cancers is surgical excision. In early, localised cases of colorectal, breast and lung cancer, cure rates are high with surgery. There is increasing evidence that outcome is related to surgical expertise, and most multidisciplinary teams include surgeons experienced in the management of a particular cancer. There are some cancers for which surgery is one of two or more options for primary management, and the role of the multidisciplinary team is to recommend appropriate treatment for a specific patient. Examples include prostate and transitional cell carcinoma of the bladder, in which radiotherapy and surgery may be equally effective. Palliation Surgical procedures are often the quickest and most effective way of palliating symptoms. Examples include the treatment of faecal incontinence with a defunctioning colostomy; fixation of pathological fractures and decompression of spinal cord compression; and the treatment of fungating skin lesions by ‘toilet’ surgery. A more specialist role for surgery is in resection of residual masses after chemotherapy and, in very selected cases, resection of metastases. Systemic chemotherapy Chemotherapeutic drugs are classified by their mode of action. They have the greatest activity in proliferating cells and this provides the rationale for their use in the treatment of cancer. Chemotherapeutic agents are not specific for cancer cells, however, and the side-effects of treatment are a result of their antiproliferative actions in normal tissues such as the bone marrow, skin and gut.

Therapeutics in oncology • 1331

of normal and tumour tissue. In addition, techniques such as conformal radiotherapy, in which shaped rather than conventional square or rectangular beams are used, allow much more precise targeting of therapy to the tumour, and reduce the volume of normal tissue irradiated by up to 40% compared to non-conformal techniques. Biological differences between normal and tumour tissues are used to obtain therapeutic gain. Fundamental to this is fractionation, which entails delivering the radiation as a number of small doses on a daily basis. This allows normal cells to recover from radiation damage but recovery occurs to a lesser degree in malignant cells. Fractionation regimens vary, but radical treatments given with curative intent are usually delivered in 20–30 fractions given daily on 5 days a week, over 4–6 weeks. Radiotherapy can be extremely useful for the alleviation of symptoms, and for palliative treatments such as this a smaller number of fractions (1–5) is usually adequate. Both normal and malignant tissues vary widely in their sensitivity to radiotherapy. Germ cell tumours and lymphomas are extremely radiosensitive and relatively low doses are adequate for cure, but most cancers require doses close to or beyond that which can be tolerated by adjacent normal structures. Normal tissue also varies in its radiosensitivity, the central nervous system, small bowel and lung being among the most sensitive. The side-effects of radiotherapy (see Fig. 33.6) depend on the normal tissues treated, their radiosensitivity and the dose delivered. Radiation therapy Radiation therapy (radiotherapy) involves treating the cancer with ionising radiation; for certain localised cancers it may be curative. Ionising radiation can be delivered by radiation emitted from the decay of radioactive isotopes or by high-energy radiation beams, usually X-rays. Three methods are usually employed: • Teletherapy: application from a distance by a linear accelerator. • Brachytherapy: direct application of a radioactive source on to or into a tumour. This allows the delivery of a very high, localised dose of radiation and is integral to the management of localised cancers of the head and neck, and cancer of the cervix and endometrium. • Intravenous injection of a radioisotope: such as 131iodine for cancer of the thyroid and 89strontium for the treatment of bone metastases from prostate cancer. The majority of treatments are delivered by linear accelerators, which produce electron or X-ray beams of high energy that are used to target tumour tissue. The biological effect of ionising radiation is to cause lethal and sublethal damage to DNA. Since normal tissues are also radiosensitive, treatment has to be designed to maximise exposure of the tumour and minimise exposure of normal tissues. This is possible with modern imaging techniques such as CT and MRI, which allow better visualisation Fig. 33.6 Adverse effects of chemotherapy and radiotherapy. Acute effects are shown in pink and late effects in blue. Alopecia Hair follicles Mucositis Oral mucosa Mucositis Oesophagus Fibrosis Lung Heart Upper GI tract Nausea and vomiting Breast tissue Bowel Mucositis, diarrhoea Small bowel Skin Sensory neuropathy Neural tissue Kidneys Renal impairment Fertility Thrombocytopenia Bone marrow Any organs Children Alopecia Mucositis Mucositis Cough ↑ Risk breast cancer Nausea, diarrhoea Premature gonadal failure Increased risk of malignancy Reduced growth Xerostomia Strictures ↑ Risk ischaemic heart disease Fibrosis Fibrosis and perforation Erythema and desquamation Telangiectasia, thinning of the skin Neutropenia, anaemia ↓ Haemoglobin, platelet count Neutropenia Arrhythmias Heart failure Motor neuropathy Nerve deafness Amenorrhoea Premature gonadal failure Chemotherapy (often drug-specific) Radiotherapy Erythema

1332 • ONCOLOGY Biological therapies Advances in knowledge about the molecular basis of cancer have resulted in the development of a new generation of treatments to block the signalling pathways responsible for the growth of specific tumours. This has created the potential to target cancer cells more selectively, with reduced toxicity to normal tissues. Some examples are discussed below, but in the years to come many more such agents will come into clinical use, with the potential to revolutionise our approach to some cancers. Gefitinib/erlotinib These agents inhibit the activity of the EGFR, which is overexpressed in many solid tumours. However, the drugs’ activity does not depend on the amount of receptor over-expression but rather on factors such as gene copy number and mutation status. Imatinib Imatinib was developed to inhibit the BCR-ABL gene product, tyrosine kinase, that is responsible for chronic myeloid leukaemia (p. 958), and it does this extremely effectively. It is also active in malignant gastrointestinal stromal tumour (GIST), a type of sarcoma that has over-expression of another cell surface tyrosine kinase, c-kit. This agent has good tolerability and is particularly useful in GIST, where conventional chemotherapy is less effective. Bevacizumab This is a humanised monoclonal antibody that inhibits vascular endothelial growth factor A (VEGF-A), a key stimulant of angiogenesis in tumours. Bevacizumab has activity in colorectal, lung, breast, renal and ovarian cancers, although the licence was subsequently revoked for breast cancer; while bevacizumab slows the rate of progression of metastatic breast cancer, it had little impact on survival or improved quality of life. Trastuzumab Trastuzumab (Herceptin) targets the HER2 receptor, an oncogene that is over-expressed in around one-third of breast cancers and in a number of other solid tumours (e.g. gastric cancer). It is effective as a single-agent therapy, but also improves survival in patients with advanced breast cancer when used in conjunction with chemotherapy. Unfortunately, trastuzumab can induce cardiac failure by an unknown biological mechanism, especially in combination with doxorubicin. Evaluation of treatment The evaluation of treatment includes an assessment of overall survival duration, response to treatment, remission rate, diseasefree survival and response duration, quality of life and treatment toxicity. Uniform criteria have been established to measure these, including the response evaluation criteria in solid tumours (RECIST, Box 33.16) and common toxicity criteria. This allows clinicians to inform patients accurately about the prognosis, effectiveness and toxicity of chemotherapy and empowers patients to take an active role in treatment decisions. Late toxicity of therapy The late toxicities of treatment for cancer are particularly important for patients where the multimodality therapy is given with curative Adverse effects An acute inflammatory reaction commonly occurs towards the end of most radical treatments and is localised to the area treated. For example, skin reactions are common with breast or chest wall radiotherapy, and proctitis and cystitis with treatment to the bladder or prostate. These acute reactions settle over a period of a few weeks after treatment, assuming normal tissue tolerance has not been exceeded. Late effects of radiotherapy develop 6 weeks or more after treatment and occur in 5–10% of patients. Examples include brachial nerve damage and subcutaneous fibrosis after breast cancer treatment, and shrinkage and fibrosis of the bladder after treatment for bladder cancer. There is a risk of inducing cancer after radiotherapy, which varies depending on the site treated and on whether the patient has had other treatment such as chemotherapy. Hormone therapy Hormone therapy is most commonly used in the treatment of breast cancer and prostate cancer. Breast tumours that are positive for expression of the oestrogen receptor (ER) respond well to anti-oestrogen therapy, and assessment of ER status is now standard in the diagnosis of breast cancer. Several drugs are now available that reduce oestrogen levels or block the effects of oestrogen on the receptor. When targeted appropriately, adjuvant hormone therapy reduces the risk of relapse and death at least as much as chemotherapy, and in advanced cases can induce stable disease and remissions that may last months to years, with acceptable toxicity. Hormonal manipulation may be effective in other cancers. In prostate cancer, hormonal therapy (e.g. luteinising hormone releasing hormone (LHRH) analogues such as goserelin and/or anti-androgens such as bicalutamide) aimed at reducing androgen levels can provide good long-term control of advanced disease, but there is no convincing evidence that it is an effective therapy following potentially curative surgery. Progestogens are active in the treatment of endometrial and breast cancer. In the metastatic setting, progestogen use (e.g. megestrol acetate) is associated with response rates of 20–40% in endometrial cancer. In breast cancer, progestogens are used in patients whose disease has progressed with conventional anti-oestrogen therapy. Their exact mechanism in this setting is not fully understood. Immunotherapy A profound stimulus to the patient’s immune system can sometimes alter the natural history of a malignancy, and the discovery of interferons was the impetus for much research. Although solid tumours show little benefit, interferons are active in melanoma and lymphoma, and there is evidence that they are beneficial as adjuvants (after surgery and chemotherapy, respectively) to delay recurrence. Whether interferon-induced stimulation of the immune system is capable of eradicating microscopic disease remains unproven. More powerful immune responses can be achieved with potent agents like IL-2 but the accompanying systemic toxicity is a problem still to be overcome. The most striking example of successful immunotherapy is that with rituximab, an antibody against the common B-cell antigen CD20. It increases complete response rates and improves survival in diffuse large cell non-Hodgkin lymphoma when combined with chemotherapy, and is effective in palliating advanced follicular non-Hodgkin lymphoma (p. 965).

Specific cancers • 1333

screening. It is multifocal in one-third of women and has a high risk of becoming invasive (10% at 5 years following excision only). Pure DCIS does not cause lymph node metastases, although these are found in 2% of cases where nodes are examined, owing to undetected invasive cancer. Lobular carcinoma in situ (LCIS) is a predisposing risk factor for developing cancer in either breast (7% at 10 years). The survival for breast cancer by stage is outlined in Box 33.18. Pathogenesis Both genetic and hormonal factors play a role; about 5–10% of breast cancers are hereditary and occur in patients with mutations of BRCA1, BRCA2, AT or TP53 genes. Prolonged oestrogen exposure associated with early menarche, late menopause and use of hormone replacement therapy (HRT) has been associated with an increased risk. Other risk factors include obesity, alcohol intake, nulliparity and late first pregnancy. There is no definite evidence linking use of the contraceptive pill to breast cancer. Clinical features Breast cancer usually presents as a result of mammographic screening or as a palpable mass with nipple discharge in 10% and pain in 7% of patients. Less common presentations include inflammatory carcinoma with diffuse induration of the skin of the intent, the patient is young and more patients are living longer. This can cause considerable morbidity: for example, radiotherapy can retard bone and cartilage growth, impair intellect and cognitive function, and cause dysfunction of the hypothalamus, pituitary and thyroid glands. Late consequences of chemotherapy include heart failure due to cardiotoxicity, pulmonary fibrosis, nephrotoxicity and neurotoxicity. Premature gonadal failure can result from chemotherapy or radiotherapy and leave a patient subfertile. Patients should be made aware of this before treatment is initiated, as it may be possible to store sperm for male patients before treatment starts; this should always be offered, if practical. Egg or embryo banking after in vitro fertilisation may be an option for young women. Sterility develops at higher radiotherapy doses but erectile dysfunction is seen in patients receiving high radiotherapy doses to the pelvis, as in prostate cancer. Additional social or psychological support may be required. Infertility and pubertal delay are potential late effects of therapy in children, especially boys. Second malignancies may be induced by cancer treatment and occur at greatest frequency following chemoradiation. Secondary acute leukaemia (mostly AML) can occur 1–2 years after treatment with topoisomerase II inhibitors, or 2–5 years after treatment with alkylating agents. The most common second malignancy within a radiation field is osteosarcoma but others include soft tissue sarcoma and leukaemia. Specific cancers The diagnosis and management of cancers are discussed in more detail elsewhere in the book (Box 33.17). Here we discuss the pathogenesis, clinical features, investigation and management of common tumours that are not covered elsewhere. Breast cancer Globally, the incidence of breast cancer is second only to that of lung cancer, and the disease represents the leading cause of cancer-related deaths among women. Invasive ductal carcinoma with or without ductal carcinoma in situ (DCIS) is the most common histology, accounting for 70%, whilst invasive lobular carcinoma accounts for most of the remaining cases. DCIS constitutes 20% of breast cancers detected by mammography 33.16 Response evaluation criteria in solid tumours (RECIST) Response Criteria Complete response (CR) Disappearance of all target lesions Partial response (PR) At least a 30% decrease in the sum of the longest diameter (LD) of target lesions, taking as reference the baseline sum LD Progressive disease (PD) At least a 20% increase in the sum of the LD of target lesions, taking as reference the smallest sum LD recorded since the treatment started and at least 5 mm increase or the appearance of one or more new lesions Stable disease (SD) Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum LD since the treatment started 33.17 Specific cancers covered in other chapters Bladder cancer p. 435 Colorectal cancer p. 827 Familial cancer syndromes p. 56 Gastric cancer p. 803 Hepatocellular carcinoma p. 890 Leukaemia p. 954 Lung cancer p. 598 Lymphoma p. 961 Mesothelioma p. 618 Myeloma p. 966 Oesophageal cancer p. 796 Pancreatic cancer p. 842 Prostate cancer p. 438 Renal cancer p. 434 Seminoma p. 439 Skin cancer p. 1229 Teratoma p. 439 Thyroid cancer p. 649 33.18 Five-year survival rates for breast cancer by stage Tumour stage Stage definition 5-year survival (%) I Tumour < 2 cm, no lymph nodes

II Tumour 2–5 cm and/or mobile axillary lymph nodes

III Chest wall or skin fixation and/or fixed axillary lymph nodes

IV Metastasis

1334 • ONCOLOGY Pathogenesis Genetic and environmental factors play a role. The risk of ovarian cancer is increased in patients with BRCA1 or BRCA2 mutations, and Lynch type II families (a subtype of hereditary non-polyposis colon cancer, HNPCC) have ovarian, endometrial, colorectal and gastric tumours due to mutations of mismatch repair enzymes. Advanced age, nulliparity, ovarian stimulation and Caucasian descent all increase the risk of ovarian cancer, while suppressed ovulation appears to protect, so pregnancy, prolonged breastfeeding and the contraceptive pill have all been shown to reduce the risk of ovarian cancer. Investigations Initial workup for patients with suspected ovarian cancer includes imaging in the form of ultrasound and CT. Serum levels of the tumour marker CA-125 are often measured. Surgery plays a key role in the diagnosis, staging and treatment of ovarian cancer, and in early cases, palpation of viscera, peritoneal washings and biopsies are generally performed to define disease extent. Management In early disease, surgery followed by adjuvant chemotherapy with carboplatin, or carboplatin plus paclitaxel, is the treatment of choice. Surgery should include removal of the tumour along with total abdominal hysterectomy, bilateral salpingooophorectomy, and omentectomy. Even in advanced disease, surgery is undertaken to debulk the tumour and is followed by adjuvant chemotherapy, typically using carboplatin and paclitaxel. Bevacizumab is indicated for patients with highgrade tumours that are suboptimally debulked or those with a more aggressive biological pattern. Monitoring for relapse is achieved through a combination of serum CA-125 and clinical examination with CT imaging for those with suspected relapse. Second-line chemotherapy is aimed at improving symptoms and should not be used for CA-125 elevation only in the absence of symptoms. Treatments can include further platinum/paclitaxel in combination, liposomal doxorubicin or topotecan. These regimens are associated with a response rate of 10–40%. The best responses are observed in patients with a treatment-free interval of more than 12 months. Endometrial cancer Endometrial cancer accounts for 4% of all female malignancies, producing a 1 in 73 lifetime risk. The majority of patients are post-menopausal, with a peak incidence at 50–60 years of age. Mortality from endometrial cancer is currently falling. The most common presentation is with post-menopausal bleeding, which often results in detection of the disease before distant spread has occurred. Pathogenesis Oestrogen plays an important role in the pathogenesis of endometrial cancer, and factors that increase the duration of oestrogen exposure, such as nulliparity, early menarche, late menopause and unopposed HRT, increase the risk. Endometrial cancer is 10 times more common in obese women and this is thought to be due to elevated levels of oestrogens. Investigations The diagnosis is confirmed by endometrial biopsy. breast, and this confers an adverse prognosis. Around 40% of patients will have axillary nodal disease, with likelihood correlating with increasing size of the primary tumour. Distant metastases are infrequently present at diagnosis and the most common sites of spread are bone (70%), lung (60%), liver (55%), pleura (40%), adrenals (35%), skin (30%) and brain (10–20%). Investigations Following clinical examination, patients should have imaging with mammography or ultrasound evaluation, and a biopsy using fine needle aspiration for cytology or core biopsy for histology. Histological assessment should be carried out to assess tumour type and to determine oestrogen and progesterone receptor (ER/PR) status and HER2 status. If distant spread is suspected, CT of the thorax and abdomen and an isotope bone scan are required. Molecular subtyping is being used to classify tumours into four major subtypes: luminal A, luminal B, HER2 type and basal-like (often called ‘triple negative’, as these tumours are ER-, PR- and HER2-negative). This may allow more targeted selection of therapies in future. Management Surgery is the mainstay of treatment for most patients, and this can range from a lumpectomy, where only the tumour is removed, to mastectomy, where the whole breast is removed. Breast-conserving surgery is as effective as mastectomy if complete excision with negative margins can be achieved. Lymph node sampling is performed at the time of surgery. Adjuvant radiotherapy is given to reduce the risk of local recurrence to 4–6%. Adjuvant hormonal therapy improves disease-free and overall survival in pre- and post-menopausal patients who have tumours that express ER. Patients at low risk, with tumours that are small and ER-positive, require only adjuvant hormonal therapy with tamoxifen. Patients with tumours that are ER-positive and who are pre-menopausal should receive an LHRH analogue. Aromatase inhibitors also have benefit in this setting but are still under investigation. Adjuvant chemotherapy is considered for patients at higher risk of recurrence. Factors that increase the risk of recurrence include a tumour of > 1 cm, a tumour that is ER-negative or the presence of involved axillary lymph nodes. Such patients should be offered adjuvant chemotherapy, which improves disease-free and overall survival. The role of adjuvant treatment has been studied by meta-analyses and data support the use of adjuvant trastuzumab, a humanised monoclonal antibody to HER2, in addition to standard chemotherapy for women with early HER2-positive breast cancer. Metastatic disease management includes radiotherapy to palliate painful bone metastases and second-line endocrine therapy with aromatase inhibitors, which inhibit peripheral oestrogen production in adrenal and adipose tissues. Advanced ER-negative disease may be treated with combination chemotherapy. Ovarian cancer Ovarian cancer is the most common gynaecological tumour in Western countries. Most ovarian cancers are epithelial in origin (90%), and up to 7% of women with ovarian cancer have a positive family history. Patients often present late in ovarian cancer with vague abdominal discomfort, low back pain, bloating, altered bowel habit and weight loss. Occasionally, peritoneal deposits are palpable as an omental ‘cake’ and nodules in the umbilicus (Sister Mary Joseph nodules).

Specific cancers • 1335

where oropharyngeal cancers are concerned. The rising incidence of oropharyngeal cancers, especially in the developed world, is thought to be secondary to HPV infection. Presentation depends on the location of the primary tumour and the extent of disease. For example, early laryngeal cancers may present with hoarseness, while more extensive local disease may present with pain due to invasion of local structures or with a lump in the neck. Patients who present late often have pulmonary symptoms, as this is the most common site of distant metastases (Box 33.19). Pathogenesis The tumours are strongly associated with a history of smoking and excess alcohol intake, but other recognised risk factors include Epstein–Barr virus for nasopharyngeal cancer and HPV infection for oropharyngeal tumours. Investigations Careful inspection of the primary site is required as part of the staging process, and most patients will require endoscopic evaluation and examination under anaesthesia. Tissue biopsies should be taken from the most accessible site. CT of the primary site and the thorax is the investigation of choice for visualising the tumour, while MRI may be useful in certain cases. Management Generally speaking, the majority of patients with early or locally advanced disease are treated with curative intent. In localised disease where there is no involvement of the lymph nodes, long-term remission can be achieved in up to 90% of patients with surgery or radiotherapy. The choice of surgery versus radiotherapy often depends on patient preference, as surgical treatment can be mutilating with an adverse cosmetic outcome. Patients with lymph node involvement or metastasis are treated with a combination of surgery and radiotherapy (often with chemotherapy as a radiosensitising agent – proven agents include cisplatin or cetuximab), and this produces long-term remission in approximately 60–70% of patients. Recurrent or metastatic tumour may be palliated with further surgery or radiotherapy to aid local control, and systemic chemotherapy has a response rate of around 20–30%. Second malignancies are common (3% Management Surgery is the treatment of choice and is used for staging. A hysterectomy and bilateral salpingo-oophorectomy are performed with peritoneal cytology and, in some cases, lymph node dissection. Where the tumour extends beyond the inner 50% of the myometrium or involves the cervix and local lymph nodes, or there is lymphovascular space invasion, adjuvant pelvic radiotherapy is recommended. Chemotherapy is used as adjuvant therapy and hormonal therapy and chemotherapy are used to palliate symptoms in recurrent disease. Cervical cancer This is the second most common gynaecological tumour worldwide and the leading cause of death from gynaecological cancer. The incidence is decreasing in developed countries but continues to rise in developing nations. The most common presentation is with an abnormal smear test, but with locally advanced disease the presentation is with vaginal bleeding, discomfort, discharge or symptoms attributable to involvement of adjacent structures, such as bladder, or rectal or pelvic wall. Occasionally, patients present with distant metastases to bone and lung. Pathogenesis There is a strong association between cervical cancer and sexual activity that includes sex at a young age and multiple sexual partners. Infection with HPV has an important causal role, and this has underpinned the introduction of programmes to immunise teenagers against HPV in an effort to prevent the later development of cervical cancer (p. 342). Investigations Diagnosis is made by smear or cone biopsy. Further examination may require cystoscopy and flexible sigmoidoscopy if there are symptoms referable to the bladder, colon or rectum. In contrast to other gynaecological malignancies, cervical cancer is a clinically staged disease, although MRI is often used to characterise the primary tumour. A routine chest X-ray should be obtained to help rule out pulmonary metastasis. CT of the abdomen and pelvis is performed to look for metastasis in the liver and lymph nodes, and to exclude hydronephrosis and hydroureter. Management This depends on the stage of disease. Pre-malignant disease can be treated with laser ablation or diathermy, whereas in microinvasive disease a large loop excision of the transformation zone (LLETZ) or a simple hysterectomy is employed. Invasive but localised disease requires radical surgery, while chemotherapy and radiotherapy, including brachytherapy, may be given as primary treatment, especially in patients with adverse prognostic features such as bulky or locally advanced disease, or lymph node or parametrium invasion. In metastatic disease, cisplatin-based chemotherapy may be beneficial in improving symptoms but does not increase survival significantly. Head and neck tumours Head and neck cancers are typically squamous tumours that arise in the nasopharynx, hypopharynx and larynx. They are most common in elderly males but now occur with increasing frequency in a younger cohort, as well as in women, especially 33.19 Common presenting features by location in head and neck cancer Hypopharynx • Dysphagia • Odynophagia • Referred otalgia • Enlarged lymph nodes Mouth • Non-healing ulcers • Ipsilateral otalgia Nasal cavity and sinuses • Discharge (bloody) or obstruction Nasopharynx • Nasal discharge or obstruction • Conduction deafness • Atypical facial pain • Diplopia • Hoarse voice • Horner’s syndrome Oropharynx • Dysphagia • Pain • Otalgia Salivary gland • Painless swelling • Facial nerve palsy

1336 • ONCOLOGY radiotherapy and surgical palliation can all be helpful. Some patients remain free of cancer for some years after resection of a single metastasis of an adenocarcinoma of unknown primary, justifying this approach in selected patients. In those with no obvious primary, systemic chemotherapy may achieve some reduction in tumour burden and alleviation of symptoms, but long-term survival is rare. Multidisciplinary teams The multidisciplinary team (MDT) is well established in oncology and meets on a regular basis to discuss patient progress and provide a forum for patient-centred, interdisciplinary communication to coordinate care and decision-making. It is a platform on which individual clinicians can discuss complex cases or situations and draw on the collective experience of the team membership to decide on the best approach for an individual patient. This can be particularly important when discussing patients with a rare condition or in a rare situation. Specific roles of the MDT include: • planning the diagnostic and staging procedures • deciding on the appropriate primary treatment modality (most commonly surgery but the use of neoadjuvant chemotherapy before interval surgery is increasing) • arranging review by the oncology team to plan assessment of the patient prior to systemic therapy or radiotherapy • discussing additional support requirements for the individual patient, such as physiotherapy; psychological support; symptom control; nutritional care or rehabilitation in the post-operative period • ensuring access to accurate information on treatment, prognosis, side-effects and other related matters, such as stoma care • planning surveillance strategies • ensuring the appropriate transition from treatment with curative intent to that of palliation of symptoms • promoting recruitment into clinical trials • agreeing on operational policies to deliver high-quality care to patients • planning and reviewing audit data to ensure the delivery of quality care to patients by the team. Further information Books and journal articles Cassidy J, Bissett D, Spence RAJ, et al. Oxford handbook of oncology, 4th edn. Oxford: Oxford University Press; 2015. Dark GG. Oncology at a glance. Chichester: Wiley–Blackwell; 2013. Hanahan D, Weinberg RA. The hallmarks of cancer: the next generation. Cell 2011; 144:646–674. Tobias J, Hochhauser D. Cancer and its management, 7th edn. Chichester: Wiley–Blackwell; 2014. Websites cancer.org American Cancer Society: clinical practice guidelines. ctep.cancer.gov/reporting/ctc.html Common toxicity criteria. info.cancerresearchuk.org/cancerstats/ A wide range of cancer statistics that can be sorted by type or geographical location. per year) following successful treatment for primary disease, and all patients should be encouraged to give up smoking and drinking alcohol to lower their risk. Carcinoma of unknown origin Some patients are found to have evidence of metastatic disease at their initial presentation, prior to diagnosis of a primary site. In many cases, a subsequent biopsy reveals adenocarcinoma but the primary site is not always clear. Investigations In this situation, there is a temptation to investigate the patient endlessly in order to determine the original primary site. There is a compromise, however, between exhaustive investigation and obtaining sufficient information to plan appropriate management. For all patients, histological examination of an accessible site of metastasis is required. The architecture of the tissue can assist the pathologist in determining the likely primary site, and therefore it is better to perform a biopsy rather than fine needle aspiration. The greater volume of tissue permits the use of immunohistochemistry. Extensive imaging to search for the primary is rarely indicated; a careful history to identify symptoms and risk factors (including familial) will often permit a judicious choice of imaging and other diagnostic tests, reserving additional tests for specific patients (Box 33.20). Management Management of the patient will depend on that person’s circumstances, as well as on the site(s) involved and the likely primary sites. The overriding principle is to ensure that a curable diagnosis has been excluded. For example, lung metastases from a testicular teratoma do not preclude cure; nor do one or two liver metastases from a colorectal cancer. Early discussion with an oncologist within a multidisciplinary team is essential and avoids unnecessary investigation; for example, a single hCG-based pregnancy test in a young man with lung metastases might confirm the presence of a teratoma and allow rapid administration of potentially curative chemotherapy. Treatment should not necessarily wait for a definitive diagnosis; appropriate analgesia, Offer when clinically appropriate. 33.20 Initial diagnostic tests in patients presenting with carcinoma of unknown primary • Detailed history and examination, including breast, nodal areas, skin, genital, rectal and pelvic regions • Full blood count, urea and electrolytes, renal function, liver function tests, calcium, urinalysis, lactate dehydrogenase • Chest X-ray • Myeloma screen (if lytic bone lesions) • CT scan of chest, abdomen and pelvis • Symptom-directed upper and lower gastrointestinal endoscopy • Tumour markers: prostate-specific antigen (PSA) in men, cancer antigen 125 (CA-125) in women with peritoneal malignancy or ascites, α-fetoprotein (AFP) and human chorionic gonadotrophin (hCG) • Testicular ultrasound (if clinical features suggest germ cell tumour) • Histological examination of biopsy, with immunohistochemistry if required

Ch04-3 Clinical Medicine

24-34 Pain and palliative care

34 Pain and palliative care

Pain and palliative care LA Colvin M Fallon Pain 1338 Functional anatomy and physiology 1338 Investigations 1342 Principles of management 1343 Interventions 1344 Chronic pain syndromes 1348 Palliative care 1349 Presenting problems in palliative care 1350 Pain 1350 Breathlessness 1353 Cough 1353 Nausea and vomiting 1353 Gastrointestinal obstruction 1354 Weight loss 1354 Anxiety and depression 1354 Delirium and agitation 1354 Dehydration 1354 Death and dying 1354

1338 • PAIN AND PALLIATIVE CARE velocity and are responsible for transmitting diffuse and poorly localised pain, as well as other sensations (Box 34.1). Sensory neurons (also known as primary afferent neurons) connect the spinal cord to the periphery and supply a defined territory or a dermatome, which can be used to identify the position of a nerve lesion (see Fig. 25.10, p. 1071). In healthy individuals dermatomes have distinct borders, but in pathological pain syndromes these may become blurred as the result of neuronal plasticity, which means that pain may be felt in an area adjacent to that supplied by a specific nerve root. Autonomic neurons also contain pain fibres and are responsible for transmitting visceral sensations, such as colic. In general, visceral pain is diffuse and less well localised than pain transmitted by sensory neurons. Anatomical features of the afferent pain pathway are illustrated in Figure 34.2. Pain signals are transmitted from the periphery to the spinal cord by sensory neurons. These have the following components: • A cell body, containing the nucleus, which is situated in the dorsal root ganglion close to the spinal cord. The cell body is essential for survival of the neuron, production of neurotransmitters and neuronal function. • The nerve fibre (axon) and peripheral nerve endings, which are located in the periphery and contain a range of receptors in the neuronal membrane. • Specialised receptors in the periphery, consisting of bare nerve endings known as nociceptors or pain receptors, which are activated by various mediators. They are situated mainly in the epidermis. • The central termination, which travels to the dorsal horn of the spinal cord to form the first central synapse with neurons that transmit pain sensation to the brain. When a noxious stimulus is encountered, activation of nociceptors leads to generation of an action potential, which travels upwards to the dorsal root ganglion and also stimulates the release of neurotransmitters that have secondary effects on surrounding neurons. Spinal cord Sensory neurons, through their central termination, synapse with second-order neurons in the dorsal horn of the spinal cord. There is considerable modulation of pain messages at Fig. 34.1 The biopsychosocial model of pain. The perception of pain as a symptom is dependent not only on sensory inputs but also on the individual’s cognitive reaction to the pain, their emotional state, their underlying disease and their social and cultural background. Illness and pain behaviour (underlying disease, impact on quality of life, fear avoidance) Social and cultural (socioeconomics, religion, family) Affect and emotional state (mood, self-efficacy) Cognition (catastrophising, acceptance) Sensory (genetic, anatomical, biomedical) 34.1 Types of nerve fibre Fibre type Diameter (μm) Conduction velocity (ms−1) Function Large myelinated Aα 12–20 70–120 Proprioception Motor to muscle fibres Aβ 5–12 30–70 Light touch, pressure A3–6 15–30 Motor to muscle spindles Small myelinated A 2–5 12–30 Well-localised pain Thermal sensation B < 3 3–15 Pre-ganglionic autonomic Unmyelinated C 0.4–1.3 0.5–3 Diffuse pain Poorly localised thermal sensation Post-ganglionic autonomic Pain Pain is defined as ‘an unpleasant sensory and emotional experience associated with actual or potential tissue damage or described in terms of such damage’. It is one of the most common symptoms for which people seek health-care advice. Our understanding of the mechanisms of pain has evolved considerably from Hippocrates’ suggestion in 450 BC that pain arose as a result of an imbalance in vital fluids. We now know that pain is a complex symptom that is influenced and modified by many social, cultural and emotional factors, as illustrated in Figure 34.1. The sensation of acute pain that occurs in response to inflammation or tissue damage plays an important role in protection from further injury. Chronic pain serves no useful function but results in significant distress and suffering for the patient affected, as well as having a wider societal impact. Functional anatomy and physiology The functional anatomy of the somatosensory system is shown in Figures 25.3 and 25.6 (pp. 1065 and 1068). Here, discussion will focus on the mechanisms and mediators that are involved in pain processing. Peripheral nerves Peripheral nerves contain several types of neuron. These can be classified into two groups, depending on whether or not they are surrounded by a myelin sheath. Myelinated neurons have a fast conduction velocity and are responsible for transmission of various sensory signals, such as proprioception, light touch, heat and cold, and the detection of localised pains, such as pin-prick. Unmyelinated fibres have a much slower conduction

Pain • 1339

of structures in the brain, where sensory, cognitive and emotional aspects are integrated. This is termed the pain neuromatrix (Fig. 34.2). Signals within the neuromatrix are multidirectional in nature, involving modulation of incoming messages by the cerebral cortex (top-down regulation), as well as a complex network of connections between other subcortical structures. Under normal conditions, there is a degree of descending inhibition from the brainstem that reduces input from peripheral stimuli. It is thought that chronic widespread pain (CWP) and opioid-induced hyperalgesia may result, at least in part, from abnormalities in central processing of pain signals. It has also been suggested that variations in the levels of descending inhibition between individuals may make some people more vulnerable than others to developing chronic pain. Over recent years, there has been increasing interest in the role that glial cells (see Fig. 25.1, p. 1064) play in pain processing. Both astrocytes and microglial cells can become activated in chronic pain states and release this site, both from local neurons within the spinal cord and from neurons that descend from the brain, as depicted in Figure 25.11 (p. 1072). Several neurotransmitters are involved in pain processing at this level and these are summarised in Box 34.2. They include amino acids, such as glycine and γ-aminobutyric acid (GABA), which are inhibitory, and glutamate, which is excitatory; neuropeptides, such as substance P and calcitonin gene-related peptide (CGRP); and endorphins. Whether or not they increase or decrease pain perception depends on the connectivity of the neurons on which they act. Central processing of pain The signals transmitted by second-order neurons in the spinal cord are relayed to the sensory cortex by third-order neurons, which synapse with second-order neurons in the thalamus. At this site, perception of pain is influenced by interactions between a range Fig. 34.2 Ascending and descending pain pathways. Ascending pathways are shown in blue and descending in red. Pain signals are detected in the periphery by nociceptors, which are activated by chemicals, changes in pH and cytokines. The signal is transmitted by the primary afferent neuron to the spinal cord, where there is a synapse with a second-order neuron, which transmits the signal onwards to the thalamus. Thereafter, the pain signal is transmitted to the cerebral cortex. The intensity of pain signals is subject to extensive modulation at several levels within the nervous system. Cognitive influences derived from the frontal lobe, coupled with sensory influences from cortex and emotional influences from the amygdyla, affect pain perception in the mid-brain around the periaqueductal gray matter (PAG) and the rostroventrolateral medulla (RVM) in the medulla. These structures form part of the descending modulatory systems, which, under normal circumstances, inhibit pain perception. In some chronic pain states, however, dysfunction of the descending pathways can occur, increasing pain. Primary afferent neuron Second-order neuron First central synapse Spinothalamic tract Dorsal root ganglion Peripheral input Spinal cord Medulla Mid-brain Cell body C fibre Nociceptors: chemicals, changes in pH, cytokines Thalamus PAG RVM Synapse Hypothalamus Amygdala Emotional Cognitive Sensory Sensory Emotional Cerebral cortex

1340 • PAIN AND PALLIATIVE CARE channels on nociceptors of primary afferent neurons (Fig. 34.3). The signalling pathways activated by these mediators generate action potentials, which are transmitted by sensory neurons to the spinal cord. If these pain-provoking stimuli persist, the activation threshold of sensory neurons is reduced, resulting in an increased transmission of pain signals to the spinal cord. Central sensitisation Sensitisation may also take place at the level of the spinal cord in response to a sustained painful stimulus. It can occur acutely and rapidly, such as immediately after surgery, or may progress to chronic changes, such as chronic infection, cancer, repeated surgery or multiple traumatic episodes. Glutamate, acting via the N-methyl-D-aspartate (NMDA) receptor complex, plays a key role in central sensitisation (Fig. 34.4). In response to a sustained peripheral painful stimulus, increased amounts of glutamate are released in the spinal cord, overcoming the inhibitory action of magnesium ions and resulting in activation of the NMDA receptor. This initiates a cascade of intracellular signalling events that lead to prolonged modifications of somatosensory processing, with amplification of pain responses within the spinal cord and continued neuronal firing, even after the noxious stimulus has stopped. This phenomenon is termed ‘after-discharge’. In neuropathic pain, prolonged activation of the NMDA pathway results in a decrease in the number of inhibitory interneurons, which further potentiates pain. Genetic determinants of pain perception There are marked ethnic and individual variations in how people respond to painful stimuli and studies in twins have estimated pro-inflammatory cytokines, as well as altering re-uptake of excitatory neurotransmitters such as glutamate, which can influence pain perception considerably. As our understanding of these processes improves, there is increasing potential to develop novel therapies targeted at these mediators, with some early clinical studies in neuropathic pain. Sensitisation Sensitisation is one of the key features of pain processing. It refers to the fact that both peripheral and central nervous systems adapt rapidly to the presence of pain, especially in response to tissue damage. This adaptive process is called neuronal plasticity. In some situations, neuronal plasticity can lead to prolonged changes in the pathways that are involved in detecting and processing nociceptive stimuli, resulting in chronic pain syndromes. The specific changes in key neurotransmitters and receptors differ between chronic pain states, with implications for the efficacy of treatments. For example, μ-opioid receptors are down-regulated in neuropathic pain, potentially leading to limited opioid responsiveness. Peripheral sensitisation Peripheral sensitisation can occur in association with a variety of clinical conditions, including sepsis, cancer, inflammatory disease, injury, surgery and obesity. The final common pathway by which sensitisation takes place in all of these conditions is inflammation. Inflammation is accompanied by increased capillary permeability and tissue oedema with the release of a diverse range of mediators, including bradykinin, hydrogen ions, prostaglandins and adenosine, which bind to receptors and ion 34.2 Neurotransmitters and receptors involved in pain processing in the spinal cord Neurotransmitter Receptor(s) Receptor type Comments* Amino acids Glutamate AMPA Ion channel Excitatory; permeable to cations: can be Ca2+, Na+ or K+, depending on subunit structure NMDA Ion channel Excitatory; blocked by Mg2+ in the resting state; block can be altered if membrane potential changes; permeable to Ca2+, Na+ and K+ Kainate Ion channel Post synaptic – excitatory Gp I GPCR Pre-synaptic – inhibitory through GABA release; permeable to Na+ and K+ Gp II GPCR Activates a range of signalling pathways; long-term effects on synaptic excitability Gp III GPCR Probably inhibitory; can decrease cAMP production; pre-synaptic; decreases glutamate release Glycine GlyR Ion channel Mainly inhibitory; permeable to Cl−; blocked by caffeine GABA GABAA Ion channel Mainly inhibitory in spinal cord; permeable to Cl−; indirectly modulated by benzodiazepines (increased ion channel opening); not specifically involved in nociception, generally depressant effect on spinal cord activity GABAB GPCR Predominantly inhibitory; activated by baclofen Neuropeptides Substance P Neurokinin receptors GPCR Mainly excitatory; increased in inflammation, decreased in neuropathic pain Cholecystokinin CCKRs1–8 GPCR Excitatory; clinical trials of antagonists in progress Calcitonin gene-related peptide CALCRL GPCR Excitatory; slows degradation of substance P; implicated in migraine Opioids Dynorphin OP1 (kappa) GPCR Excitatory?; may be pro-nociceptive β-endorphin OP3 (mu) GPCR Inhibitory Nociceptin ORL-1 GPCR Inhibitory; also expressed by immune cells *Excitatory = increased pain; inhibitory = reduced pain. (AMPA = α-amino 3-hydroxy, 5-methyl, 4-isoxazole propionic acid; CALCRL = calcitonin receptor-like receptor; cAMP = cyclic adenosine monophosphate; GABA = γ-aminobutyric acid; Gp = group; GPCR = G-protein-coupled receptor; NMDA = N-methyl-D-aspartate; OP = opioid; ORL = opioid-like receptor)

Pain • 1341

occur as the result of a single gene disorder, as summarised in Box 34.3. Most are due to mutations affecting ion channels that play a key role in neurotransmission (see Fig. 34.3), but other causes include mutations in the NTKR1 gene, which encodes the receptor for nerve growth factor, and mutations in the PDRM12 transcription factor, which is involved in neuron development. that the heritability of CWP ranges between 30% and 50%. In the general population, the individual variants in response to pain and perception of pain are most likely due to a complex interaction between genetic and environmental influences. Few variants have been identified with robust evidence of association with CWP. Several rare syndromes have been described, however, in which insensitivity to pain or heightened pain responses Fig. 34.3 Mechanisms of peripheral sensitisation. A Sensory nerve terminating with nociceptor in skin. B Peripheral nociceptors express various receptors and ion channels that act as mediators of pain. They include sodium channels implicated in congenital pain syndromes; the purinergic 2X (P2X) receptor for adenosine triphosphate (ATP); members of the transient receptor potential (TRP) superfamily of ion channel receptors, which detect changes in osmolality and temperature; acid-sensing ion channel (ASIC) receptors, which detect hydrogen ions; G-protein-coupled receptors, which detect bradykinin (BK), prostaglandins and ATP; and the neurotrophic tyrosine kinase 1 (NTRK1) receptor, which detects nerve growth factor (NGF). C Activation of these receptors by ligands, hydrogen ion [H+] and high temperature (> 42°C) amplifies action potentials, which increase pain signals and cause peripheral sensitisation. Adapted from Bennett DL, Woods CG. Painful and painless channelopathies. Reprinted with permission from Elsevier (The Lancet Neurol 2014; 13:587–599). Stimulus ATP Temperature or low pH Osmosis Cold or limitants Cool Low pH Mechanical Bradykinin Prostanoids ATP NGF Transducer P2X TRPV1/2 TRPV4 TRPA1 TRPM8 ASIC Unknown BK1/2 EP P2Y NTRK1 Kv HCN2 Nav1.7 Sensitisation Stimulus Agonists [H+] Receptors Response Nav1.8 Nav1.9 B A C Fig. 34.4 Mechanisms of central sensitisation. Post-synaptic activation of the N-methyl-D-aspartate (NMDA) receptor requires the amino acids glycine and glutamate, which bind to the NR1 and NR2 subunits, respectively; these amplify pain signals at the level of the spinal cord. In contrast, magnesium ions block receptor activation. Glutamate Amino acids (and other neurotransmitters) Pain signal Amplified signal Kinase Dorsal root ganglia Neurotransmitter changes Glycine NR1 NR2 Mg2+ Regulation of pain response NMDA receptor

1342 • PAIN AND PALLIATIVE CARE Nerve conduction studies Nerve conduction studies can be helpful in demonstrating and quantifying a definitive nerve lesion, either peripherally or centrally. They can be used to help differentiate between central and peripheral neuropathic pain. They do not, however, effectively examine small nerve fibre function. Nerve blocks Performing a nerve block with infiltration of a local anaesthetic such as 1% lidocaine can be used diagnostically, in assessing whether a pain syndrome is due to involvement of a specific nerve or nerve root. Where inflammation and or swelling may be contributing to the underlying pain – for example, if there is compression of a nerve root – then a mixture of local anaesthetic Fig. 34.5 Equipment for bedside sensory testing. Cotton wool Neurology pin Allodynia Warm and cool thermal rollers Increased or decreased thermal sensation Hyperalgesia 34.3 Genetic regulators of pain perception Gene (protein) Mutation (inheritance) Protein function Phenotypes SCN9A (Na,1.7) LoF (AR) Ion channel Absent pain, hypohydrosis, anosmia SCN9A (Na,1.7) GoF (AD) Ion channel Erythromelalgia, paroxysmal pain, burning pain, autonomic dysfunction SCN11A (Na,1.9) GoF (AD) Ion channel Absent pain, hyperhydrosis, muscular weakness, gut dysmotility SCN10A (Na,1.8) GoF (AD) Ion channel Burning pain, autonomic dysfunction TRPA1 (TRPA1) GoF (AD) Ion channel Absent pain PDRM12 (PDRM12) LoF (AR) Transcription factor; neuron development Absent pain NTRK1 (high-affinity NGF receptor) LoF (AR) Tyrosine kinase; promotes neuron development Absent pain; anhydrosis, mental retardation, increased cancer risk (AD = autosomal dominant; AR = autosomal recessive; GoF = gain of function; LoF = loss of function; NGF = nerve growth factor) Investigations Pain can be a presenting feature of a wide range of disorders and the first step in evaluation of a patient with pain should be to perform whatever investigations are required to define the underlying cause of the pain, unless this is already known. However, with most chronic pain syndromes, such as fibromyalgia, complex regional pain syndrome and CWP, investigations are negative and the diagnosis is made on the basis of clinical history and exclusion of other causes. Specific investigations that are useful in the assessment of selected patients with chronic pain are discussed below. Magnetic resonance imaging Magnetic resonance imaging (MRI) can be helpful in the assessment of an underlying cause in patients with focal pain that follows a nerve root or peripheral nerve distribution. Imaging is seldom helpful in individuals with CWP. Blood tests Blood tests are not generally helpful in the diagnosis of chronic pain, except in patients with peripheral neuropathy; in this case, a number of blood tests may be required to investigate the underlying causes of the neuropathy. Full details are provided in Box 25.86 (p. 1139). Genetic testing may be of value in patients with clinical features that point to an inherited disorder of pain processing (Box 34.3). Quantitative sensory testing Quantitative sensory testing can be helpful in the detailed assessment of patients with chronic pain. A simple set of tools can be used in the clinical setting (Fig. 34.5). Lightly touching the skin with a brush, swab or cotton-wool ball can be used to test for abnormalities of fine touch (allodynia). Assessing the patient’s response to a pin-prick can be used to test for abnormalities in mechanical hyperalgesia. Finally, touching the patient’s skin with warm and cool thermal rollers can be used to test for abnormalities of thermal sensation. An unaffected area of skin should be tested first, to establish normal sensation, before testing the affected area.

Pain • 1343

The past medical and medication history should be recorded and specific enquiry made about substance misuse and any previous history of physical or mental abuse. It is also useful to enquire specifically about the patient’s beliefs as to what is causing their pain, as well as what their expectation of treatment is; unless these are addressed, management may be less effective. There are some patient populations in whom particular challenges arise, often related to differences in communication ability. Strategies that can be used to overcome these difficulties are summarised in Box 34.5. Examination The patient’s general appearance should be noted, including ability to walk and use of a walking aid. In those with focal pain, neurological examination should be performed, focusing particularly on any areas of abnormal sensation, reflexes and evidence of muscle wasting. A general examination should be carried out to determine whether there is any evidence of an underlying physical disorder that can account for the pain. In addition to the use of investigations to find the underlying cause of pain, patients with persistent or chronic pain may benefit from sensory testing or diagnostic nerve blocks to explore the underlying mechanisms and direct treatment. For example, a combined femoral and sciatic nerve block may be used in a patient with lower limb amputation to assess whether the pain is predominantly peripherally or centrally generated. If the pain is not improved by an effective nerve block, then peripherally directed therapies are unlikely to be effective. and depot glucocorticoid may be helpful in alleviating pain. Nerve blockade can also be used to determine whether more radical therapies, such as nerve ablation, might be helpful in controlling pain, particularly that related to cancer. Pain scoring systems Various questionnaires and other instruments have been devised to localise pain, rate its severity and assess its impact on quality of life. Some of the most widely used are listed in Box 34.4. The distribution of pain can be documented on a diagram of the body, on which the patient can mark the sites that are painful. Similarly, other methods have been developed with which to assess the severity of pain using verbal, numerical and behavioural rating scales. Visual scoring systems employing different facial expressions may be of value in paediatric patients and those with cognitive impairment. Documenting changes in pain scores using questionnaires can be helpful in indicating to what extent drug treatments have been successful and can reduce the time taken to achieve pain control. Principles of management Effective management of chronic pain depends in part on the underlying cause but some general principles can be applied. In general terms, the treatment goals are to: • educate the patient • promote self-management • optimise function • enhance quality of life • control pain. Clinical history Biopsychosocial assessment A full biopsychosocial assessment should be performed in all patients with chronic pain. Although this is time-consuming, the time invested is likely to pay dividends in improving the long-term outcome for patients. A biopsychosocial assessment takes account of the underlying neurobiology of the condition in the context of wider influences, including cognition and beliefs, emotions, and social and cultural factors. For example, an individual with abdominal pain might respond differently if a close relative had recently died of gastric cancer than if a colleague had been off work with gastric upset. An accurate clinical history is important, taking note of the duration of pain, any precipitating and relieving factors, its location and, if the pain is located at more than one site, which site is the one that impacts most on the patient’s quality of life. The characteristics of the pain should be documented, by assessing whether it is described as dull, sharp, aching or burning. Associated features, such as hypersensitivity to fine touch or temperature, numbness, paraesthesia, tingling and formication (the feeling of insects crawling over the skin), should be noted. It is important to determine to what extent the pain is interfering with normal daily activities, such as work, leisure pursuits and sleep. The patient’s social circumstances and cultural background should be documented, including any caring responsibilities, employment status and social and family support. The intensity of pain should also be recorded, preferably using a validated questionnaire (Box 34.4). The patient’s mood should be assessed and, if evidence of low mood is detected, a suicide risk assessment should be considered (see Box 28.12, p. 1187). 34.4 Instruments used in the assessment of pain and its impact Instrument Comments Brief Pain Inventory Developed for use in cancer pain, validated and widely employed for chronic pain; based on 0–10 ratings of pain intensity and the impact of pain on a range of domains, including sleep, work and enjoyment of life Pain Detect, s-LANSS, DN-4 A number of screening questionnaires to aid diagnosis of neuropathic pain Pain Catastrophising Scale Developed to assess individual levels of catastrophising, encompassing three different domains: helplessness, rumination and magnification Tampa Scale of Kinesiophobia Measures how much an individual is fearful of movement Pain Self-efficacy Questionnaire Assesses individual beliefs about self-efficacy in the context of chronic pain, and how this impacts on function Visual analogue scale (VAS) Patient marks pain intensity on a horizontal line Localisation of pain Body chart, allowing the patient to indicate where pain is situated Beck Depression Inventory Assesses emotional function SF-36/EQ-5D Assesses health-related quality of life (DN-4 = Douleur Neuropathique questionnaire; EQ-5D = EuroQol 5-Domain questionnaire; SF-36 = Short Form 36; s-LANSS = self-completed Leeds Assessment of Neuropathic Signs and Symptoms)

1344 • PAIN AND PALLIATIVE CARE to the individual patient. A successful exercise programme can help overcome ‘fear avoidance’, a well-recognised problem in chronic pain, where patients associate activity with an increase in pain and therefore do progressively less activity, with resultant deconditioning. Because of this it is important to pace physical activity to ensure that patients do not cycle from over-activity, with a flare in pain, to fatigue and deconditioning. This can be done by working with patients to establish their baseline level of activity and using an individually tailored, graded exercise programme (Box 34.6). This may include normal household activities, as well as targeted exercises and stretches. Manual therapy covers a variety of hands-on treatments, including manipulation, mobilisation and massage. Manual therapy can be provided by a range of therapists, including physiotherapists, osteopaths and chiropractors. There is some evidence of shortterm benefit for manual therapy but limited evidence of long-term efficacy. Pharmacological therapies A range of analgesics can be used in the management of chronic pain but, for most of these, the evidence of long-term benefit is limited. In general, it is advisable to use a multimodal approach in the treatment of chronic pain, choosing different drugs to target pain processing at multiple points (Box 34.7). By employing different classes of analgesic, it is possible to use lower doses of each, thereby improving the side-effect profile. There is considerable inter-individual variability in response to analgesics, even within the same class. There are many reasons for this, including genetic variations in the enzymes that metabolise drugs. For example, the CYP2D6 gene encodes for a liver enzyme, cytochrome P450 2D6, which metabolises a number of commonly used analgesics. Genetic variation in CYP2D6 can influence circulating levels of many drugs, depending on whether Interventions Probably the most effective mode of treatment for pain is to identify the underlying cause. Examples include the use of immunosuppressive medication in inflammatory disease, chemotherapy, radiotherapy or hormone therapy in cancer, and antimicrobial therapy in patients with infection. There are many circumstances, however, in which the underlying cause of pain cannot be treated or the treatments available are incompletely effective. Under these circumstances, several management options are available. In all cases, a multidisciplinary approach is necessary that combines pharmacological management with supported self-management, and other specific interventions when appropriate. Supported self-management Self-management strategies are useful in the treatment of chronic pain. Self-management works best if the patient has some understanding of their chronic pain, and acceptance that it is unlikely to resolve completely. The aim is for patients to maximise their quality of life and function despite ongoing pain. Support for self-management can be delivered by health-care professionals, patients who suffer from the same condition or lay people, either on an individual basis, in a group setting or, increasingly, through web-based resources. There is a strong educational component to supported self-management, which seeks to generate an interaction between patient and tutor. The key aspects include: • increasing activity levels, while understanding and practising pacing techniques (not overdoing things and cycling between over- and under-activity) • using relaxation and mindfulness techniques as part of daily management • using medication when appropriate • having a plan to manage pain flares. There are a number of useful online self-help resources (see ‘Further reading’). Physical therapies There is strong evidence that exercise can help in the management of chronic pain. Several types of exercise have been successfully used delivered in various ways, through physiotherapists, exercise classes or individual tuition. In choosing a form of exercise therapy, it is important to tailor the approach most likely to be acceptable 34.6 Physical therapies for chronic pain Land-based • Walking • Gym work • Exercise classes • Yoga • Pilates • Tai-chi Water-based • Hydrotherapy • Swimming • Exercise classes 34.5 Challenges in pain assessment in particular patient populations Patient population Challenges Solutions Paediatric Assessment needs to be appropriate to developmental stage Consider visual tools to aid pain assessment Elderly May have impaired cognitive function Cultural factors may reduce self-reporting of pain Risk of adverse effects of medication increased Consider formal assessment of cognitive function Consider non-verbal assessment Consider visual tools to assess pain Employ a number of tools assessing pain behaviours Cognitive impairment Reporting and expression of pain may change Increased sensitivity to central nervous system effects of analgesics Perform formal assessment of cognitive function Use non-verbal assessment: facial expressions, vocalisations, body movements, changes in social interactions Substance misuse Response to analgesics altered Increased tolerance Increased risk of addiction Substance misuse may affect reporting of pain Seek specialist support early Ensure prescribing is safe

Pain • 1345

be employed with caution in elderly patients and those weighing less than 50 kg. Non-steroidal anti-inflammatory drugs Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used in the treatment of inflammatory pain and osteoarthritis. These drugs can be given systemically or locally and are discussed in more detail on page 1002. They are also useful in the management of pain in cancer patients, as discussed later in this chapter (p. 1350). Although widely prescribed, there is limited high-quality evidence of long-term efficacy in chronic pain, with a need for further studies in this area. Topical analgesics Topical capsaicin cream (0.025 or 0.075%) has some efficacy for osteoarthritis and may be used for neuropathic pain, although evidence of benefit is limited. A single application (done by a trained health-care professional) of a high-dose 8% capsaicin patch can give around 12 weeks of pain relief for neuropathic pain and can be repeated thereafter. Capsaicin is an agonist at the transient receptor potential vanilloid 1 (TRPV1) ion channel, found on some C fibres. Capsaicin activates the channel, causing an initial sensation of heat, but an analgesic effect subsequently results due to desensitisation of the channel. Lidocaine 5% patches can also be helpful in focal neuropathic pain and should be applied for 12 hours out of 24 hours, with up to 4–6 weeks before maximum benefit is seen. The mode of action is blockade of sodium channels in primary afferent neurons and nociceptors, which reduces peripheral input to the spinal cord. Adjuvant analgesics Adjuvant analgesics is the term used to cover a range of agents that are used in the treatment of neuropathic pain, usually in combination with classical analgesics. Typically, these agents 34.7 Pharmacological management of chronic pain Drug or class of drug Mechanism of action Paracetamol Central inhibition of COX-1 and COX-2 enzymes Mechanisms of action incompletely understood Non-steroidal anti-inflammatory drugs Inhibition of prostaglandin production Opioids Agonists at OP3 receptors at multiple levels in the central nervous system Blockade of ascending pain pathways Ketamine Antagonist of NMDA receptors Reduction of central sensitisation Gabapentin Pregabalin Inhibition of glutamate release by primary afferent neurons at first central synapse Decrease of excitatory neuronal activity Tricyclic antidepressants Inhibition of serotonin and noradrenaline (norepinephrine) re-uptake at synapses in the spinal cord, and also potential effects in the limbic system Inhibition of Na+ channels in neurons Serotonin (5-hydroxytryptamine, 5-HT) and noradrenaline (norepinephrine) re-uptake inhibitors Inhibition of serotonin and noradrenaline re-uptake at synapses in the spinal cord, and also potential effects in the limbic system Lidocaine patches Inhibition of Na+ in sensory neurons Capsaicin patch Activation of TRPV1 channels on subset of C fibres, causing selective pharmacological denervation, with a decrease in intra-epidermal nerve fibre density Nerve blocks with lidocaine and glucocorticoids Temporary denervation due to blockade of Na+ channels in sensory neurons Local anti-inflammatory effect (COX = cyclo-oxygenase; NMDA = N-methyl-D-aspartate; OP = opioid; TRPV1 = transient receptor potential vanilloid 1) someone is a rapid or poor metaboliser. This is particularly important if metabolites are active, as is the case with codeine and tramadol, which are metabolised to morphine. Genetic variations have also been described in the opioid receptors and downstream pathways that they affect, with good pre-clinical evidence that variations in mu opioid receptors alter analgesic response to different opioids. Because of this there is a good rationale to try different drugs, even ones from the same class, if there is an inadequate response or there are unacceptable side-effects with one agent. Whatever drug or combination of drugs is chosen, the key to successful pharmacological management is careful assessment and review, aiming for an acceptable balance between the benefits of treatment in providing pain relief, maximising function, and improving quality of life and adverse effects. Specific drug treatments are described below. Non-opioid analgesics Paracetamol Paracetamol is widely used in the treatment of mild to moderate pain. Its mechanism of action is incompletely understood but it is known to be a weak inhibitor of the cyclo-oxygenase type 1 (COX-1) and cyclo-oxygenase type 2 (COX-2) enzymes, providing weak anti-inflammatory properties. There is also some of evidence that it activates inhibitory descending spinal pathways, via a serotonergic mechanism. Other postulated mechanisms include endocannabinoid re-uptake inhibition, and inhibition of nitric oxide and tumour necrosis factor alpha. For migraine and tension-type headache it has moderate efficacy at a dose of 1000 mg. It is used widely for musculoskeletal disorders and osteoarthritis, with very little high-quality evidence that it is much better than placebo, even at doses of up to 4000 mg per day. Acute liver failure is a well-recognised complication of paracetamol overdose but this risk may also be increased with long-term use, even within the recommended dose range. In view of this, it should

1346 • PAIN AND PALLIATIVE CARE potassium permeability of neurons. Opioids are traditionally divided into subclasses of weak opioids, such as codeine and dihydrocodeine, and strong opioids, such as morphine and oxycodone. While tramadol is a weak agonist at the mu opioid receptor, it is classified as a strong opioid in some countries. The dosages and characteristics of commonly prescribed opioids are shown in Box 34.9. There has been a large increase in the use of strong opioids for chronic pain over the last 10–20 years. A number of factors contribute to this, including a rising incidence of chronic pain with an ageing population, reluctance to use NSAIDs because of cardiovascular and gastrointestinal adverse effects, changes in patient expectation, societal attitudes and availability of new formulations of opioids. There is evidence of short- to medium-term benefit for strong opioids in low back pain and osteoarthritis but there have been very few good-quality studies of long-term use. Additionally, there is increasing concern about potential harm from long-term use. This includes addiction, dependence, opioid-induced hyperalgesia, endocrine dysfunction, fracture risk (especially in the elderly), overdose and cardiovascular do not produce an immediate reduction in pain, but rather exert an analgesic effect over a longer timeframe through their effects on central processing of pain. They are of particular value when used in combination in the management of pain with a neuropathic component but require careful dose titration over a number of weeks, to reach a dose that balances efficacy with side-effects. While the response to individual agents is variable, it is often possible to find an agent or combination of agents that works for most patients. Opioid analgesics Opioids are a class of drugs that target opioid receptors. The original receptor classification was based on pharmacological activity (mu, delta, kappa), with the more recent International Union of Basic and Clinical Pharmacology (IUPHAR) classification being generally accepted in current use (Box 34.8). Opioid receptors are G-protein-coupled receptors. Ligand binding activates several intracellular signalling pathways, increasing cyclic adenosine monophosphate (cAMP) levels, as well as altering calcium and 34.8 Opioids and opioid receptors Endogenous ligand Receptor (IUPHAR) Alternative classification Potential sites Pharmacological effects Endomorphin 1 and 2 Met-enkephalin Dynorphin A Dynorphin B MOP Mu; OP3 Brain, spinal cord, peripheral nerves, immune cells Analgesia, reduced gastrointestinal motility, respiratory depression, pruritus Leu-enkephalin Met-enkephalin β-endorphin DOP Delta; OP1 Brain, spinal cord, peripheral nerves Analgesia, cardioprotection, thermoregulation Dynorphin A Dynorphin B β-endorphin KOP Kappa; OP2 Brain (nucleus accumbens, neocortex, brainstem, cerebellum) Analgesia, neuroendocrine (e.g. on hypothalamic–pituitary axis), diuresis, dysphoria Orphanin FQ (nociceptin) NOP Orphan; ORL-1; OP4 Nucleus raphe magnus, spinal cord, afferent neurons Opioid tolerance, anxiety, depression, increased appetite (IUPHAR = International Union of Basic and Clinical Pharmacology; OP = opioid; ORL = opioid-like receptor) 34.9 Commonly used opioids Opioid Typical starting dose Route Oral morphine equivalent Comments Morphine 10 mg Oral 10 mg Most widely used Codeine 100 mg Oral 10 mg Metabolised to morphine Dihydrocodeine 100 mg Oral 10 mg Semi-synthetic Tramadol 100 mg Oral 10 mg Synthetic Oxycodone 6.6 mg Oral 10 mg More predictable bioavailability than morphine Buprenorphine 5 μg/hr Transdermal 30 mg/day Patch change usually every 7 days (frequency of change dependent on manufacturer and dose); advantages in impaired renal function Fentanyl 12 μg/hr Transdermal 30 mg/day Use with care in opioid-naïve patients; patch change usually every 72 hrs Tapentadol 50 mg Oral 20 mg Use with care in opioid-naïve patients Hydromorphone 2 mg Oral 10 mg Semi-synthetic; hepatic metabolism Diamorphine 3 mg Subcutaneous, intramuscular, intravenous 10 mg Mainly used for acute pain or palliative care

Pain • 1347

34.10 Use of opioids in chronic pain Step Factors to take into account Comment

  1. Assess suitability for opioids Type of pain Neuropathic pain less likely to respond Likelihood of dependence History of substance or alcohol misuse, including stimulant misuse Co-morbidity Avoid use in conditions where adverse effects more likely: Chronic obstructive pulmonary disease Chronic liver disease Chronic kidney disease
  2. Discuss with patient Discuss potential benefits Improvement in pain Improvement in function Discuss adverse effects Nausea Constipation Drowsiness Establish treatment goal Improvement in function
  3. Plan treatment trial Set timescale Define duration of treatment Agree frequency of review Agree on dose Aim for lowest effective dose Set upper dose limit Agree on stopping rules Consider stopping if: Treatment goal is not met There is no dose response Tolerance develops rapidly events, with many of these adverse effects being dose-related. There is evidence that doses of more than 120 mg morphine equivalents per day are associated with increased harm, and regular review to assess ongoing benefit is needed in this patient group. A suggested strategy for using strong opioids in chronic pain is shown in Box 34.10. Psychological therapies The aims of psychological therapy are to increase coping skills and improve quality of life when facing the challenges of living with chronic pain. There are a range of ways in which psychological therapies can be delivered, including individual one-to-one sessions, group sessions, multidisciplinary pain management programmes, or web-based or telephone-based programmes. There is a good evidence for the use of a cognitive behavioural therapy (CBT)-based approach for chronic pain, delivered either individually or in a group. The overall aim is to reduce negative thoughts and beliefs, and develop positive coping strategies. The interaction between thoughts, behaviours and emotions is explored, and a problem-focused approach is used in therapy delivery. Relaxation techniques, such as biofeedback and mindfulness meditation, require a degree of stillness and withdrawal, with regular practice required for sustained benefit (see ‘Further information’). Acceptance and commitment therapy (ACT) is based on CBT principles but also uses components of mindfulness to improve psychological flexibility in the context of living with chronic pain. Stimulation therapies These range from minimally invasive procedures like acupuncture and transcutaneous electrical nerve stimulation (TENS) to more invasive techniques such as spinal cord stimulation. Acupuncture (Fig. 34.6) has been used successfully in Eastern medicine for centuries. The mechanisms are incompletely understood, although endorphin release may explain, in part, Fig. 34.6 Acupuncture. the analgesic effect. Acupuncture is particularly effective in pain related to muscle spasm, with some evidence of short-term benefit for patients with low back pain. Similar mechanisms probably apply to TENS, which is worth considering in many types of chronic pain. Neuromodulation, using implanted electrodes in the epidural space (or, more recently, adjacent to peripheral nerves), has been shown to be an effective option for neuropathic pain, including failed back surgery syndrome and chronic regional pain syndrome (see below). Specialist assessment and ongoing support is necessary, as there are many potential complications, including infection, malfunction and battery failure. The likelihood of success is increased when this technique is used within the context of multidisciplinary assessment and management.

1348 • PAIN AND PALLIATIVE CARE Complementary and alternative therapies Complementary techniques, such as herbal medicines, vitamins, homeopathy and reflexology, have been used for the treatment of chronic pain but with little evidence of efficacy. It should be noted that herbal medications may interact with conventional drugs, causing adverse effects as the result of drug–drug interactions. St John’s wort (Hypericum perforatum) interacts with many drugs, including many antidepressants used in chronic pain, with increased serotonergic effects. Grapefruit may also increase the risk of serotonergic effects with some antidepressants. Ginkgo biloba may interact with paracetamol to increase bleeding time. Nerve blocks and nerve ablation The use of specialist nerve blocks and nerve ablation therapy can be considered for pain that is unresponsive to less invasive approaches. If these are being considered, they should form part of a multidisciplinary management plan, with the aim of restoring function and reducing pain. Local anaesthetic with or without depot glucocorticoid (non-particulate for neuraxial administration) can be effective in some circumstances. Examples include occipital nerve blocks for migraine or cervicogenic headache and trigger point injections for myofascial pain. If there is limited compression of a spinal nerve root, the nerve root injections into the epidural space may help settle symptoms and avoid the need for surgical intervention. Neurodestructive procedures can also be employed for intractable pain but are rarely used outside the palliative care setting. Chronic pain syndromes Chronic pain is a feature of several recognised syndromes, which are discussed in more detail below. Neuropathic pain Neuropathic pain is defined as ‘pain associated with a lesion or disease of the somatosensory nervous system’. Neuropathic pain may be acute, such as in sciatica, which occurs as the result of a prolapsed disc, but is most problematic when it becomes chronic. Neuropathic pain causes major morbidity; in a recent study, 17% of those affected rated their quality of life as ‘worse than death’. The clinical features of neuropathic pain are summarised in Box 34.11. The diagnosis is easily missed and so careful assessment is vital, in order to make the diagnosis in the first place and then to direct management appropriately. An algorithm for the management of neuropathic pain is provided in Figure 34.7. It is important to recognise the negative impact of neuropathic pain on quality of life, which has been shown to be greater than with other types of chronic pain. As a result, appropriate support and multidisciplinary management should always be considered in addition to pharmacological therapies. Complex regional pain syndrome Complex regional pain syndrome (CRPS) is a type of neuropathic pain that affects one or more limbs. It was previously termed reflex sympathetic dystrophy (RSD), reflecting the fact the disease is thought to be caused in part by an abnormality in the autonomic nervous system. It is a rare syndrome, occurring in about 20 per 100 000 individuals, and is more common in females, typically presenting between the ages of 35 and 50. It is classified into type I CRPS, which may be precipitated by a traumatic event Fig. 34.7 Algorithm for pharmacological management of neuropathic pain. (SNRI = serotonin noradrenaline (norepinephrine) re-uptake inhibitor) Adapted from SIGN 136 and NeuPSIG recommendations (Finnerup NB, Attal N, Haroutounian S, et al. Pharmacotherapy for neuropathic pain in adults: a systematic review and meta-analysis. Reprinted with permission from Elsevier (The Lancet Neurol 2015; 14:162–173)). Are there clinical features of neuropathic pain? (Box 34.11) Assess likelihood of neuropathic pain Tricyclic antidepressant Gabapentin or pregabalin SNRI First line (moderate to high evidence; strong recommendation) Probable Possible Definite Response? Continue Yes Capsaicin patch Lidocaine patch Tramadol Second line (moderate evidence; weak recommendation) No Yes Response? Continue Botulinum toxin Strong opioids Third line (moderate evidence; weak recommendation) No Yes 34.11 Clinical features of neuropathic pain Characteristic Symptom or clinical feature* Descriptive term Spontaneous pain No stimulus required to evoke pain Positive sensory disturbance Light touch painful Dynamic allodynia Pressure painful Punctate allodynia Increased pain on pin-prick Hyperalgesia Cool and warm temperatures painful Thermal allodynia Negative sensory disturbance Numbness Loss of sensation Tingling Paraesthesia Loss of temperature sensitivity Other features Feeling of insects crawling over skin Formication Affected area feels abnormal Dysaesthesia *Symptoms may cluster, with a predominance of either positive or negative symptoms, or a mixture of both, reflecting differences in underlying mechanisms.

Palliative care • 1349

Fibromyalgia is a subtype of CWP in which there are myofascial trigger points, and is often associated with sleep disturbance. Clinical features and management of fibromyalgia are discussed in more detail on page 1018. Joint hypermobility syndrome Hypermobility can be associated with chronic musculoskeletal pain that often targets the joints and periarticular tissues. It is thought to be caused by abnormal stresses being placed on the joints and surrounding soft tissues due to ligament laxity, although the mechanisms are poorly understood since many people with hypermobile joints do not suffer pain. It is described in more detail on page 1059. Palliative care Palliative care is the term used to describe the active total care of patients with incurable disease. It can be distinguished from end-of-life care, which refers to the care of patients with far advanced, rapidly progressive disease that will soon prove fatal. The focus of palliative care is on symptom control alongside supportive care. While palliative care can and should be delivered at any stage of an incurable illness alongside optimal disease control, the focus of end-of-life care is on quality of life rather than prolongation of life or cure. Palliative care encompasses a distinct body of knowledge and skills that all good physicians must possess to allow them to care effectively for patients. Palliative care is traditionally seen as a means of managing distress and symptoms in patients with cancer, when metastatic disease has been diagnosed and death is seen as inevitable. There is, however, a growing recognition that the principles of palliative care and some of the interventions it uses are equally applicable in other conditions. Palliative may therefore be applied to any chronic disease state. For conditions other than cancer, the challenge is recognising when patients have entered the terminal phase of their illness, as there are fewer clear markers and the course of the illness is much more variable. Different chronic disease states progress at different rates, allowing some general trajectories of illness or dying to be defined (Fig. 34.8). These trajectories are useful in decision-making for individual patients and also in planning services. such as a fracture but is not associated with peripheral nerve damage, and type II CRPS, which is associated with a peripheral nerve lesion. The diagnosis is primarily clinical, based on the features shown in Box 34.12. Imaging with MRI or radionuclide bone scan may provide support for the diagnosis of type I CRPS in showing bone marrow oedema or increased tracer uptake localised to an affected site (p. 1055). Prompt diagnosis and early treatment with physiotherapy may prevent progression of symptoms. Management is as for neuropathic pain, additional approaches including graded motor imagery. Bisphosphonates have been used empirically for treatment but the evidence base for efficacy in controlling pain is weak. If medical management is incompletely effective, consideration should be given to the appropriateness of a spinal cord stimulator. Phantom limb pain Phantom limb is a common complication of amputation, occurring in up to 70% of patients. It is a form of neuropathic pain but can be particularly distressing, as the pain is felt in the area where the absent limb was previously. Although usually presenting after limb amputation, reports of phantom pain in other body parts have been reported, such as phantom breast pain following mastectomy. It is very often associated with phantom sensations, which are described as non-painful sensations in the absent body part and pain in the stump. Diagnostic nerve blocks may be helpful in directing therapy, with use of anti-neuropathic medications as outlined in Box 34.7. If there is a definite neuroma at the stump site that is interfering with prosthesis use, surgical review may be necessary. Chronic widespread pain Chronic widespread pain (CWP) is often associated with other features, such as fatigue and irritable bowel syndrome. The diagnosis of CRPS type 1 can be made if a patient has at least one symptom in at least three out of the four categories and at least one sign in two out of the four categories, and no other diagnosis can explain the symptoms. 34.12 Criteria for diagnosis of complex regional pain syndrome (CRPS) type 1 Category Symptom or sign Sensory Allodynia to: Temperature Light touch Deep somatic pressure Movement Hyperalgesia to pin-prick Vasomotor Temperature asymmetry Skin colour change and asymmetry Skin colour asymmetry Oedema/sudomotor Oedema Sweating change or asymmetry Motor/trophic Reduced range of motion Motor dysfunction: Weakness Tremor Dystonia Trophic changes: Hair Nails Skin Fig. 34.8 Archetypal trajectories of dying. Reproduced from Murray SA, Kendall M, Boyd K, et al. Illness trajectories and palliative care. BMJ 2005; 330:7498; reproduced with permission from the BMJ Publishing Group. High Death Cancer Organ failure Physical and cognitive frailty Function Low Time

1350 • PAIN AND PALLIATIVE CARE Management: pharmacological treatments Pharmacological treatments are the mainstay of management in cancer-associated pain. A stepwise approach is adopted, following the principles of the World Health Organisation (WHO) analgesic ladder (Fig. 34.9), in which analgesia that is appropriate for the degree of pain is prescribed first. Patients with mild pain should be started on a non-opioid analgesic drug, such as paracetamol (1 g 4 times daily) or an NSAID (step 1). If the patient fails to respond adequately or has moderate pain, a weak opioid, such as codeine (60 mg 4 times daily), should be added (step 2). This can be prescribed separately or in the form of the compound analgesic co-codamol. If pain relief is still not achieved or if the patient has severe pain, a strong opioid should be substituted for the weak opioid (step 3). If the pain is severe at the outset, strong opioids should be prescribed and increased or titrated according to the patient’s response. It is important not to move ‘sideways’ (change from one drug to another of equal potency), which is a common problem during step 2 of the analgesic ladder. Opioids Opioid analgesia plays a key role in patients with moderate to severe pain. Its successful use depends on appropriate assessment and a detailed explanation to the patient and carer about the benefits and potential side-effects of therapy. Morphine The ‘rapid decline’ trajectory following a gradual decline, as occurs in cancer, is the best-recognised pattern of the need for palliative care, although a similar trajectory may be observed in other conditions, such as motor neuron disease can. Many traditional hospice services are designed to meet the needs of people on this trajectory. Over recent years, improvements in management of malignant disease mean that some types of cancer may follow an erratic or intermittent decline trajectory. Many chronic diseases, such as advanced chronic obstructive pulmonary disease (COPD) and intractable congestive heart failure, carry as high a burden of symptoms as cancer, as well as psychological and family distress. The ‘palliative phase’ of these illnesses may be more difficult to identify because of periods of relative stability interspersed with acute episodes of severe illness. However, it is still possible to recognise those patients who may benefit from a palliative approach to their care. The challenge is that symptom management needs to be delivered at the same time as treatment for acute exacerbations. This leads to difficult decisions as to the balance between symptom relief and aggressive management of the underlying disease. The starting point of need for palliative care in these conditions is the point at which consideration of comfort and individual values becomes important in decision-making, often alongside management of the underlying disease. The third major trajectory is categorised by years of poor function and frailty before a relatively short terminal period; it is exemplified by dementia but is also increasingly true for patients with many different chronic illnesses. As medical advances extend survival, this mode of dying is being experienced by increasing numbers of people. The main challenge lies in providing nursing care and ensuring that plans are agreed for the time when medical intervention is no longer beneficial. In a situation where death is inevitable and foreseeable, palliative care balances the ‘standard textbook’ approach with the wishes and values of the patient and a realistic assessment of the benefits of medical interventions. This often results in a greater focus on comfort, symptom control and support for patient and family, and may enable withdrawal of both futile and burdensome interventions. In cases of prognostic uncertainty, open, honest and gentle communication with the patient and family is important. The most common symptoms in palliative care are discussed in the next section. Presenting problems in palliative care Pain Pain is a common problem in palliative care. It has been estimated that about two-thirds of patients with cancer experience moderate or severe pain, and a quarter have three or more different sites of pain. Many of these are of a mixed aetiology and about half of patients with cancer-associated pain have a neuropathic element. Clinical assessment Careful evaluation to identify the likely mechanisms of pain is important so that the most appropriate treatment can be given. Clinical features and suggested management strategies for common types of pain in cancer are shown in Box 34.13. The majority of patients with cancer-associated pain can be effectively managed using a stepwise approach, as outlined below. 34.13 Common types of pain in cancer Type of pain Features Management options Bone pain Tender area over bone Possible pain on movement NSAIDs Bisphosphonates Radiotherapy Increased intracranial pressure Headache, worse in the morning, associated with vomiting and occasionally delirium Glucocorticoids Radiotherapy Codeine Abdominal colic Intermittent, severe, spasmodic, associated with nausea or vomiting Antispasmodics Hyoscine butylbromide Liver capsule pain Right upper quadrant abdominal pain, often associated with tender enlarged liver Responds poorly to opioids Glucocorticoids Neuropathic pain Spontaneous pain Light touch, pressure and temperature changes are painful; increased pain on pin-prick Numbness, tingling or loss of temperature sensation Skin feels abnormal Anticonvulsants: Gabapentin Pregabalin Antidepressants Amitriptyline Duloxetine Ketamine Ischaemic pain Diffuse, severe, aching pain associated with evidence of poor perfusion Responds poorly to opioids NSAIDs Ketamine Incident pain Episodic pain usually related to movement or bowel spasm Intermittent short-acting opioids Nerve block (NSAIDs = non-steroidal anti-inflammatory drugs)

Palliative care • 1351

that psychological dependence is rare when opioids are used for cancer pain, unless a pre-existing dependence problem exists. Pharmacological tolerance is not usually a clinically relevant problem; however, physical dependence, which is physiological, as manifest by a physical withdrawal syndrome, can occur if opioids are suddenly discontinued. Nearly all types of cancer pain respond to morphine to some degree but there is a spectrum of response, such that in some patients the dose of opioid required to control neuropathic pain and all elements of metastatic bone pain may be high and associated with unacceptable side-effects. In these situations, other methods of analgesia, both pharmacological and nonpharmacological, should be explored and considered at an early stage. The most effective and appropriate route of morphine administration is oral but transdermal preparations of strong opioids (usually fentanyl) are useful in certain situations, such as in patients with dysphagia or those who are reluctant to take tablets on a regular basis. Diamorphine is a highly soluble strong opioid used for subcutaneous infusions, particularly in the last few days of life, but is only available in certain countries. Opioid-related adverse effects Adverse effects are a common problem with opioids, especially on initiating treatment and on increasing the dose. The most common side-effects are nausea, drowsiness, constipation and dry mouth, as summarised in Box 34.14. Nausea and vomiting can occur initially but usually settle after a few days. Drowsiness is usually transient at opioid initiation and dose increase. If it is persistent, an alternative opioid and/or a non-opioid should be considered. In acute dosing, respiratory depression can occur but this is rare in patients on regular opioids or in those starting on small, regular doses with appropriate titration. Tolerance usually develops to nausea, vomiting and drowsiness but not to constipation or dry mouth. All patients should therefore be prescribed a laxative, unless suffering from diarrhoea, and have access to an antiemetic and good mouth care, along with rationalisation of any concomitant medication that might exacerbate drowsiness. Newer developments include the use of preparations in which opioids are combined with opioid is the most commonly prescribed strong opioid, although there are several alternatives, as outlined in Box 34.9. Oral morphine takes about 20 minutes to exert an effect and usually provides pain relief for 4 hours. Most patients with continuous pain should be prescribed oral morphine every 4 hours initially, as this will provide continuous pain relief over the whole 24-hour period. Controlled-release morphine lasts for 12 or 24 hours, depending on the formulation, and if clinical circumstances dictate, a controlled-release formulation can be used to initiate and titrate morphine. The median effective morphine equivalent dose for cancer pain is about 200 mg per 24 hours. In addition to the regular dose of morphine, an extra dose of immediate-release (IR) morphine should be prescribed ‘as required’ for the treatment of breakthrough pain that has not been controlled by the regular prescription. As a rule of thumb, this additional dose should be one-sixth of the total 24-hour dose of opioid. The frequency of breakthrough doses should be dictated by their efficacy and any side-effects, rather than by a fixed time interval. A patient may require breakthrough analgesia as frequently as hourly if pain is severe, but this should lead to early review of the regular prescription. The patient or carer should note the timing of any breakthrough doses and the reason for them. These should be reviewed daily and the regular 4-hourly dose increased for the next 24 hours on the basis of: • the frequency of and reasons for breakthrough analgesia • the degree and acceptability of side-effects. The regular dose should be increased by adding the total of the breakthrough doses over the previous 24 hours, unless there are significant problems with unacceptable side-effects. When the correct dose has been established, a continuous release (CR) preparation can be prescribed, usually twice daily. Breakthrough analgesia used for movement-related pain is generally not included in background opioid dose titration. Attempts to control movement-related pain with background opioid dose will usually lead to over-medication and opioid-related side-effects. This can be a risk in metastatic bone pain. Some patients may have concerns about using opioids and it is vital for these to be explored. Patients should be reassured Fig. 34.9 The WHO analgesic ladder. From WHO. Cancer pain relief, 2nd edn. Geneva: WHO; 1996. Opioid for moderate to severe pain ± non-opioid ± adjuvant Opioid for mild to moderate pain ± non-opioid ± adjuvant Non-opioid ± adjuvant Pain persisting or increasing Pain persisting or increasing Freedom from cancer pain Pain 34.14 Opioid side-effects Side-effect Management Constipation Regular laxative Opioid/naloxone oral combination, in resistant constipation Dry mouth Frequent sips of iced water, soft white paraffin to lips, chlorhexidine mouthwashes twice daily, sugar-free gum, water or saliva sprays Nausea/vomiting Oral haloperidol 0.5–1 mg at night, oral metoclopramide 10 mg 3 times daily or oral domperidone 10 mg 3 times daily If constant, haloperidol or levomepromazine may be given parenterally to break the nausea cycle Sedation Explanation is very important Symptoms usually settle in a few days Avoid other sedating medication where possible Ensure appropriate use of adjuvant analgesics that can have an opioid-sparing effect May require an alternative opioid

1352 • PAIN AND PALLIATIVE CARE analgesic should be considered, the choice depending on the type of pain. Management: non-pharmacological treatments Neurodestructive interventions Neurodestructive techniques have an important role in the management of cancer pain, where life expectancy is limited. They should be used as part of an overall management plan and considered when the response to drug treatment has been inadequate. Intrathecal analgesia, delivered via either an external pump or a fully implanted device, is a good option, particularly where life expectancy is more than 3 months. Coeliac plexus blocks can be helpful for visceral pain, such as in pancreatic cancer. Lateral cordotomy to disrupt the spinothalamic tracts (either open or percutaneous) may be considered for unilateral chest wall pain, such as may occur in mesothelioma, where life expectancy is limited. Radiotherapy Radiotherapy is the treatment of choice for pain from bone metastases (see Box 34.13) and can also be considered for metastatic involvement at other sites. All patients with pain secondary to bone metastases should be considered for palliative radiotherapy, which can usually be given in a single dose. Physiotherapy Physiotherapy has a key role in the multidisciplinary approach to a wide spectrum of cancer-related symptoms, including the prevention and management of pain, muscle spasm, reduced mobility, muscle wasting and lymphoedema. Rehabilitation in palliative care has expanded and now includes pre-habilitation, which involves the use of proactive focused exercise to maintain muscle mass during cancer chemotherapy and in other chronic conditions such as COPD. Psychological techniques As with chronic pain, there is increasing use of psychological techniques in cancer pain management, which train the patient antagonists, such as naloxone. The naloxone is poorly absorbed and does not antagonise the systemic analgesic effect but rather acts locally to block opioid receptors in the gut, thereby reducing opioid-related constipation. Vivid dreams, visual hallucinations (often consisting of a sense of movement at the periphery of vision), delirium and myoclonus are typical of opioid-related toxicity and, if present, require urgent reassessment of the opioid dose. Biochemistry should also be checked to exclude renal impairment, dehydration, electrolyte disturbance or hypercalcaemia. Since opioid toxicity can occur at any dose, side-effects should be assessed regularly, but particularly after a dose increase. Pain should be reassessed to ensure that appropriate adjuvants are being used. Parenteral rehydration is often helpful to speed up excretion of active metabolites of morphine. The dose of opioid may need to be reduced or the opioid changed to a strong alternative. Different opioids have different side-effect profiles in different people. If a patient develops side-effects, switching to an alternative strong opioid may be helpful. Options include oxycodone, transdermal fentanyl, alfentanil, hydromorphone and occasionally methadone, any of which may produce a better balance of benefit against side-effects. Fentanyl and alfentanil have no renally excreted active metabolites and may be particularly useful in patients with renal failure. It is possible to switch between opioids but great care must be taken when doing so to make sure the dose is correct and to avoid prescribing too much or too little opioid. Adjuvant analgesics An adjuvant analgesic is a drug that has a primary indication other than pain but which provides analgesia in some painful conditions and may enhance the effect of the primary analgesic. Commonly used adjuvant analgesics in the palliative care setting are shown in Box 34.15. Some adjuvant analgesics may enhance the side-effect profile of the primary analgesic, and dose reductions of opioids may be required when an adjuvant analgesic is added. At each step of the WHO analgesic ladder, an adjuvant 34.15 Adjuvant analgesics in cancer pain Drug Example Indications Side-effects* NSAIDs Diclofenac Bone metastases, soft tissue infiltration, liver pain, inflammatory pain Gastric irritation and bleeding, fluid retention, headache Caution in renal impairment Glucocorticoids Dexamethasone 8–16 mg per day, titrated to lowest dose that controls pain Raised intracranial pressure, nerve compression, soft tissue infiltration, liver pain Gastric irritation if used together with NSAID, fluid retention, proximal muscle myopathy, delirium, Cushingoid appearance, candidiasis, hyperglycaemia Anticonvulsants Evidence strongest for: Gabapentin Pregabalin Duloxetine Neuropathic pain of any aetiology Mild sedation, tremor, delirium Exacerbation of opioid-related side-effects Tricyclic antidepressants Amitriptyline Neuropathic pain of any aetiology Sedation, dizziness, delirium, dry mouth, constipation, urinary retention Avoid in cardiac disease Exacerbation of opioid-related side-effects NMDA receptor blockers Ketamine Severe neuropathic pain (only under specialist supervision) Delirium, anxiety, agitation, hypertension *In old age, all drugs can cause delirium. (NMDA = N-methyl-D-aspartate; NSAIDs = non-steroidal anti-inflammatory drugs)

Palliative care • 1353

drugs. Vomiting related to raised intracranial pressure is worse in the morning. Different receptors are activated, depending on the cause or causes of the nausea (Fig. 34.10). For example, dopamine receptors in the chemotactic trigger zone in the fourth ventricle are stimulated by metabolic and drug causes of nausea, whereas gastric irritation stimulates histamine receptors in the vomiting centre via the vagus nerve. Reversible causes, such as hypercalcaemia and constipation, should be treated appropriately. Drug-induced causes should be considered and the offending drugs stopped if possible. As different classes of antiemetic drug act at different receptors, antiemetic therapy should be based on a careful assessment of the probable causes and a rational decision to use a particular class of drug (Box 34.16). to use coping strategies and behavioural techniques. Other issues related to the specific experience of a cancer diagnosis and cancer treatment may be complex, and individual therapy in addition to group-based approaches can be helpful. Stimulation therapies Acupuncture and TENS are low-risk stimulation therapies that may be useful in palliative care for management of pain and nausea. Complementary and alternative therapies Palliative care patients often seek symptom relief from both complementary and alternative therapies. While the evidence base is poorly developed, individual patients can gain significant benefits from the complementary therapies outlined on page 1348. It is critically important that patients are encouraged to discuss any alternative medicines they are considering, given the potential interactions with other therapies. Breathlessness Breathlessness is one of the most common symptoms in palliative care and is distressing for both patients and carers. Patients with breathlessness should be fully assessed to determine whether there is a reversible cause, such as a pleural effusion, heart failure or bronchospasm; if so, this should be managed in the normal way. If symptoms persist, additional measures may be necessary. There are many potential causes of dyspnoea in cancer patients and in other chronic diseases; apart from direct involvement of the lungs, muscle loss secondary to cachexia, anxiety and fear can all contribute. A cycle of panic and breathlessness, often associated with fear of dying, can be dominant. Exploration of precipitating factors is important and patient education about breathlessness and effective breathing has been shown to be effective. Non-pharmacological approaches that include using a hand-held fan, pacing, and following a tailored exercise programme can help. There is no evidence to suggest that oxygen therapy reduces the sensation of breathlessness in advanced cancer any better than cool airflow, and oxygen is indicated only if there is significant hypoxia. Opioids, through both their central and their peripheral action, can palliate breathlessness. Both oral and parenteral opioids are effective. A low dose should be used initially and titrated against symptoms, unless opioids are already being prescribed for pain, in which case the existing dose can be increased further. If anxiety is considered to be playing a significant role, a quick-acting benzodiazepine, such as lorazepam (used sublingually for rapid absorption), may also be useful. Cough Persistent unproductive cough can be helped by opioids, which have an antitussive effect. Troublesome respiratory secretions can be treated with hyoscine hydrobromide (400–600 μg every 4–8 hours), although dry mouth is a common adverse effect. As an alternative, glycopyrronium can be useful and is given by subcutaneous infusion (0.6–1.2 mg in 24 hours). Nausea and vomiting The presentation of nausea and vomiting differs depending on the underlying cause, of which there are many (p. 780). Large-volume vomiting with little nausea is common in intestinal obstruction, whereas constant nausea with little or no vomiting is often due to metabolic abnormalities or adverse effects of Fig. 34.10 Mechanisms of nausea. (ACh = acetylcholine; D2 = dopamine; 5-HT = 5-hydroxytryptamine, serotonin; H1 = histamine) Higher centres Vestibular input Vomiting centre H1, ACh, 5-HT Chemotactic trigger zone D2, 5-HT Vagal afferents Metabolic toxins Chemoreceptors Mechanoreceptors Retroperistalsis Gastric pyloric contraction Abdominal and thoracic wall contraction Peripheral circulation 34.16 Receptor site activity of antiemetic drugs Area Receptors Drugs Chemotactic trigger zone Dopamine2 5-HT Haloperidol Metoclopramide Vomiting centre Histamine1 Acetylcholine Cyclizine Levomepromazine Hyoscine Gut (gastric stasis) Metoclopramide Gut distension (vagal stimulation) Histamine1 Cyclizine Gut (chemoreceptors) 5-HT Levomepromazine (5-HT = 5-hydroxytryptamine, serotonin)

1354 • PAIN AND PALLIATIVE CARE Delirium and agitation Many patients become confused or agitated in the last days of life. It is important to identify and treat potentially reversible causes (p. 183), unless the patient is too close to death for this to be feasible. Early diagnosis and effective management of delirium are extremely important. As in other palliative situations, it may not be possible to identify and treat the underlying cause, and the focus of management should be to ensure that the patient is comfortable. It is important to distinguish between behavioural change due to pain and that due to delirium, as opioids will improve one and worsen the other. The management of delirium is detailed on page 209. It is important, even in the care of the actively dying patient, to treat delirium with antipsychotic medicines, such as haloperidol, rather than to regard it as distress or anxiety and use benzodiazepines only. Dehydration Deciding whether to give intravenous fluids can be difficult when a patient is very unwell and the prognosis is uncertain. A patient with a major stroke, who is unable to swallow but is expected to survive the event, will develop renal impairment and thirst if not given fluids and should be hydrated. On the other hand, when a patient has been deteriorating and is clearly dying, parenteral hydration needs very careful consideration and it is very important to manage this on an individual basis. Comfort and avoidance of distress in the family are the primary aims. Where a patient and family are happy with meticulous oral hygiene and care to reduce the sensation of dryness in the mouth, this is usually more appropriate and effective at the end of life than parenteral hydration, which by itself will not necessarily improve the sensation of dryness. In some patients, parenteral hydration will simply exacerbate pooling of secretions, causing noisy and distressing breathing. Each decision should be individual and discussed with the patient’s family. Death and dying Planning for dying There have been dramatic improvements in the medical treatment and care of patients with cancer and other illnesses over recent years but the inescapable fact remains that everyone will die at some time. Planning for death should be actively considered in patients with chronic diseases when the death is considered to be foreseeable or inevitable. Doctors rarely know exactly when a patient will die but are usually aware that an individual is about to die and that medical interventions are unlikely to extend life or improve its quality significantly. Most people wish their doctors to be honest about this situation to allow them time to think ahead, make plans and address practical issues. A few do not wish to discuss future deterioration or death; if this is felt to be the case, avoidance of discussion should be respected. For doctors, it is helpful to understand an individual’s wishes and values about medical interventions at this time, as this can help guide decisions about interventions. It is important to distinguish between interventions that will not provide clinical benefit (a medical decision) and those that do not confer sufficient benefit to be worthwhile (a decision that can only be reached with a patient’s involvement and consent). A common example of this would be decisions about not attempting cardiopulmonary resuscitation. The subcutaneous route is often required initially to overcome gastric stasis and poor absorption of oral medicines. Gastrointestinal obstruction Gastrointestinal obstruction is a frequent complication of intra-abdominal cancer. Patients may have multiple levels of obstruction and symptoms may vary greatly in nature and severity. Surgical mortality is high in patients with advanced disease and obstruction should normally be managed without surgery. The key to effective management is to address the presenting symptoms – colic, abdominal pain, nausea, vomiting, intestinal secretions – individually or in combination, using parenteral drugs that do not cause or worsen other symptoms. This can be problematic when a specific treatment worsens another symptom. Cyclizine improves nausea and colic responds well to anticholinergic agents, such as hyoscine butylbromide, but both slow gut motility. Nausea will improve with metoclopramide, although this is usually contraindicated in the presence of colic because of its prokinetic effect. There is some low-level evidence that glucocorticoids (dexamethasone 8 mg) can shorten the length of obstructive episodes. Somatostatin analogues, such as octreotide, will reduce intestinal secretions and therefore large-volume vomits. Occasionally, a nasogastric tube is required to reduce gaseous or fluid distension. Weight loss Patients with cancer lose weight for a variety of reasons, including reduced appetite or the effects of drug treatment, or as a consequence of low mood and anxiety. There is, however, a particularly challenging syndrome associated with weight loss, which is known as cancer cachexia. This results from an alteration of metabolism caused by a complex interaction of tumour-related factors and the body’s response to these factors, resulting in muscle loss, along with anorexia. Treatment involves prescribing exercise to maintain muscle mass and strengthen muscles, ensuring that there is an adequate calorie intake and providing nutritional supplements. Anti-inflammatory medication to attenuate systemic inflammation is the subject of research and many patients self-medicate with fish oil. Glucocorticoids can temporarily boost appetite and general well-being but may cause false weight gain by promoting fluid retention. Their benefits need to be weighed against the risk of side-effects, and glucocorticoids should generally be used on a short-term basis only. Anxiety and depression Anxiety and depression are common in palliative care but the diagnosis may be difficult, since the physical symptoms of depression are similar to those of advanced cancer. It is therefore important to realise that these symptoms are not inevitable in advanced cancer. Patients should still expect to look forward to things and to enjoy them, within the context of the situation. Simply asking the question ‘Do you think you are depressed?’ can be very useful in deciding with the patient whether antidepressants or psychological interventions may be of benefit (p. 1199). In this regard, psycho-oncology has been evolving rapidly and there is now good evidence for the role of ‘talk therapy’ in palliative care, along with other appropriate management of anxiety and depression. If antidepressants are required, citalopram and mirtazapine are good choices since they are generally well tolerated in patients with advanced disease.

Death and dying • 1355

for their care. Trust in the whole team will come through a solid lead working with a team who are appropriately informed and in sympathy with the patient’s situation, each having a clear role. Families and other carers are often unprepared for the challenge of caring for a dying person. It can be an exhausting experience, both emotionally and physically, and without a critical number of carers battle fatigue can ensue, resulting in urgent admissions. With much discussion about advance directives, we should not lose sight of the reality of changing circumstances and wishes. Good anticipatory care means not just providing for new physical symptoms, but also planning for any time when care at home becomes no longer possible. Capacity and advance directives The wishes of the patient are paramount in Western societies, whereas in other cultures the views of the family are equally important. If a patient is unable to express their view because of communication or cognitive impairment, that person is said to lack ‘capacity’. In order to decide what the patient would have wished, as much information as possible should be gained about any previously expressed wishes, along with the views of relatives and other health professionals. An advance directive is a previously recorded, written document of a patient’s wishes (p. 1307). It should carry the same weight in decisionmaking as a patient’s expressed wishes at that time, but may In general, people wish for a dignified and peaceful death and most prefer to die at home. Families also are grateful for the chance to prepare themselves for the death of a relative, by timely and gentle discussion with the doctor or other health professionals. Early discussion and effective planning improve the chances that an individual’s wishes will be achieved. There are two important caveats: firstly, wishes can and do change as the terminal situation evolves, and secondly, planning in general can only be done over time as patients form a relationship with professionals and evolve an understanding of the situation in which they find themselves. Structures for assessment and planning around end-of-life care are for guidance only and the focus should evolve with the individual patient. Diagnosing dying When patients with cancer or other conditions become bedbound, semi-comatose, unable to take tablets and only able to take sips of water, with no reversible cause, they are likely to be dying and many will have died within 2 days. Doctors are sometimes poor at recognising this and should be alert to the views of other members of the multidisciplinary team. A clear decision that the patient is dying should be agreed and recorded. Management of dying Once the conclusion has been reached that a patient is going to die in days to a few weeks, there is a significant shift in management (Box 34.17). Symptom control, relief of distress and care for the family become the most important elements of care. Medication and investigation are justifiable only if they contribute to these ends. When patients can no longer drink because they are dying, intravenous fluids are usually not necessary and may cause worsening of bronchial secretions; however, this is a decision that can be made only on an individual basis. Management should not be changed without discussion with the patient and/or family. Medicines should always be prescribed for the relief of symptoms. For example, morphine or diamorphine may be used to control pain, levomepromazine to control nausea, haloperidol to treat delirium, diazepam or midazolam to treat distress, and hyoscine hydrobromide to reduce respiratory secretions. Side-effects, such as drowsiness, may be acceptable if the principal aim of relieving distress is achieved. It is important to discuss and agree the aims of care with the patient’s family. Poor communication with families at this time is one of the most common reasons for family distress afterwards and for formal complaints. Ethical considerations The overwhelming force in caring for any patient must be to listen to that patient and family and take their wishes on board. Patients know when health-care professionals are just receiving the information, as opposed to receiving and understanding the information in the context of the patient, their illness and needs, their carers and the socioeconomic context. It is impossible to provide holistic care for a patient without this comprehension. Every patient is unique and it is important to avoid slipping into a tick-box mentality in addressing items that should be covered in patients with advanced, incurable disease. While the key to successful palliative care is effective interdisciplinary working, every patient needs to know who has overall responsibility 34.17 How to manage a patient who is dying Patient and family awareness • Assess patient’s and family’s awareness of the situation • Ensure family understands plan of care Medical interventions • Stop non-essential medications that do not contribute to symptom control • Stop inappropriate investigations and interventions, including routine observations Resuscitation • Complete Do Not Attempt Cardiopulmonary Resuscitation (DNACPR) form • Deactivate implantable defibrillator Symptom control • Ensure availability of parenteral medication for symptom relief Support for family • Make sure you have contact details for family, that you know when they want to be contacted and that they are aware of facilities available to them Religious and spiritual needs • Make sure any particular wishes are identified and followed Ongoing assessment • Family’s awareness of condition • Management of symptoms • Need for parenteral hydration Care after death • Make sure family know what they have to do • Notify other appropriate health professionals

1356 • PAIN AND PALLIATIVE CARE Further information Websites breathworks-mindfulness.org.uk An online resource to support learning the use of mindfulness to deal with pain, illness or stress. cuh.org.uk/breathlessness Information and resources from Cambridge University Hospital on managing breathlessness. hospiceuk.org A resource from UK hospices. mdanderson.org Brief Pain Inventory (Short Form) questionnaire. nhmrc.gov.au Australia and New Zealand College of Anaesthetists and Faculty of Pain Medicine. Acute pain management: scientific evidence, 3rd edn; 2010. npcrc.org Short-form McGill Pain questionnaire. paintoolkit.org Pain toolkit self-help resource for managing pain. palliativecareguidelines.scot.nhs.uk Regularly reviewed, evidence-based clinical guidelines. palliativedrugs.com Practical information about drugs used in palliative care. sign.ac.uk SIGN guideline 136 – Management of chronic pain. Journal articles Finnerup NB, Attal N, Haroutounian S, et al. Pharmacotherapy for neuropathic pain in adults: a systematic review and meta-analysis. Lancet Neurol 2015; 14:162–173. A comprehensive, high-quality review of the current evidence for the pharmacological management of neuropathic pain. not be sufficiently specific to be used in a particular clinical situation. The legal framework for decision-making varies in different countries. Euthanasia In the UK and Europe, between 3% and 6% of dying patients will ask a doctor to end their life. Many of these requests are transient; some are associated with poor control of physical symptoms or a depressive illness. All expressions of a wish to die are an opportunity to help the patient discuss and address unresolved issues and problems. Reversible causes, such as pain or depression, should be treated. Sometimes, patients may choose to discontinue life-prolonging treatments, such as diuretics or anticoagulation, following discussion and the provision of adequate alternative symptom control. However, there remain a small number of patients who have a sustained, competent wish to end their lives, despite good control of physical symptoms. Euthanasia is now permitted or legal under certain circumstances in some countries but remains illegal in many others; public, ethical and legal debate over this issue is likely to continue and is often influenced by many complex non-palliative care issues. The European Association for Palliative Care does not see euthanasia or physician-assisted suicide as part of the role of palliative care physicians.

Ch04-3 Clinical Medicine

25-35 Laboratory reference ranges

35 Laboratory reference ranges

Laboratory reference ranges SJ Jenks Notes on the international system of units (SI units) 1358 Laboratory reference ranges in adults 1358 Urea and electrolytes in venous blood 1358 Analytes in arterial blood 1358 Hormones in venous blood 1359 Other common analytes in venous blood 1360 Common analytes in urine 1361 Analytes in cerebrospinal fluid 1361 Analytes in faeces 1361 Haematological values 1362 Laboratory reference ranges in childhood and adolescence 1363 Laboratory reference ranges in pregnancy 1364

1358 • LABORATORY REFERENCE RANGES Laboratory reference ranges in adults Reference ranges are largely those used in the Departments of Clinical Biochemistry and Haematology, Lothian Health University Hospitals Division, Edinburgh, UK. Values are shown in both SI units and, where appropriate, non-SI units. Many reference ranges vary between laboratories, depending on the assay method used and on other factors; this is especially the case for enzyme assays. The origin of reference ranges and the interpretation of ‘abnormal’ results are discussed on page 3. No details are given here of the collection requirements, which may be critical to obtaining a meaningful result. Unless otherwise stated, reference ranges shown apply to adults; values in children may be different. Many analytes can be measured in either serum (the supernatant of clotted blood) or plasma (the supernatant of anticoagulated blood). A specific requirement for one or the other may depend on a kit manufacturer’s recommendations. In other instances, the distinction is critical. An example is fibrinogen, where plasma is required, since fibrinogen is largely absent from serum. In contrast, serum is required for electrophoresis to detect paraproteins because fibrinogen migrates as a discrete band in the zone of interest. 35.2 Analytes in arterial blood Analysis Reference range SI units Non-SI units Bicarbonate 21–29 mmol/L 21–29 mEq/L Hydrogen ion 37–45 nmol/L pH 7.35–7.43 PaCO2 4.5–6.0 kPa 34–45 mmHg PaO2 12–15 kPa 90–113 mmHg Oxygen saturation

97% 35.1 Urea and electrolytes in venous blood Analysis Reference range SI units Non-SI units Sodium 135–145 mmol/L 135–145 mEq/L Potassium* 3.6–5.0 mmol/L 3.6–5.0 mEq/L Chloride 95–107 mmol/L 95–107 mEq/L Urea 2.5–6.6 mmol/L 15–40 mg/dL Creatinine Male 64–111 μmol/L 0.72–1.26 mg/dL Female 50–98 μmol/L 0.57–1.11 mg/dL *Serum values are, on average, 0.3 mmol/L higher than plasma values. Notes on the international system of units (SI units) Système International (SI) units are a specific subset of the metre–kilogram–second system of units and were agreed on as the everyday currency for commercial and scientific work in 1960, following a series of international conferences organised by the International Bureau of Weights and Measures. SI units have been adopted widely in clinical laboratories but non-SI units are still used in many countries. For that reason, values in both units are given for common measurements throughout this textbook and commonly used non-SI units are shown in this chapter. The SI unit system is, however, recommended. Examples of basic SI units Length metre (m) Mass kilogram (kg) Amount of substance mole (mol) Energy joule (J) Pressure pascal (Pa) Volume The basic SI unit of volume is the cubic metre (1000 litres). For convenience, however, the litre (L) is used as the unit of volume in laboratory work. Examples of decimal multiples and submultiples of SI units Factor Name Prefix

megaM

kilok 10−1 decid 10−2 centic 10−3 millim 10−6 microμ 10−9 nanon 10−12 picop 10−15 femtof Exceptions to the use of SI units By convention, blood pressure is excluded from the SI unit system and is measured in mmHg (millimetres of mercury) rather than pascals. Mass concentrations such as g/L and μg/L are used in preference to molar concentrations for all protein measurements and for substances that do not have a sufficiently well-defined composition. Some enzymes and hormones are measured by ‘bioassay’, in which the activity in the sample is compared with the activity (rather than the mass) of a standard sample that is provided from a central source. For these assays, results are given in standardised ‘units’ (U/L), or ‘international units’ (IU/L), which depend on the activity in the standard sample and may not be readily converted to mass units.

Laboratory reference ranges in adults • 1359

35.3 Hormones in venous blood Hormone Reference range SI units Non-SI units Adrenocorticotrophic hormone (ACTH) (plasma) 1.5–13.9 pmol/L (0700–1000 hrs) 63 ng/L Aldosterone Supine (at least 30 mins) 30–440 pmol/L 1.09–15.9 ng/dL Erect (at least 1 hr) 110–860 pmol/L 3.97–31.0 ng/dL Cortisol Dynamic tests are required – see Box 18.53, p. 680 Follicle-stimulating hormone (FSH) Male 1.0–10.0 IU/L – Female 3.0–10.0 IU/L (early follicular) –

30 IU/L (post-menopausal) – Gastrin (plasma, fasting) < 40 pmol/L < 83 pg/mL Growth hormone (GH) Dynamic tests are usually required – see Box 18.55, p. 682 < 0.5 μg/L excludes acromegaly (if insulin-like growth factor 1 (IGF-1) in reference range) < 2 mIU/L 6 μg/L excludes GH deficiency 18 mIU/L Insulin Highly variable and interpretable only in relation to plasma glucose and body habitus Luteinising hormone (LH) Male 1.0–9.0 IU/L – Female 2.0–9.0 IU/L (early follicular) – 20 IU/L (post-menopausal) – 17β-Oestradiol Male < 160 pmol/L < 43 pg/mL Female: early follicular 75–140 pmol/L 20–38 pg/mL post-menopausal < 150 pmol/L < 41 pg/mL Parathyroid hormone (PTH) 1.6–6.9 pmol/L 16–69 pg/mL Progesterone (in luteal phase in women) Consistent with ovulation 30 nmol/L 9.3 ng/mL Probable ovulatory cycle 15–30 nmol/L 4.7–9.3 ng/mL Anovulatory cycle < 10 nmol/L < 3 ng/mL Prolactin (PRL) 60–500 mIU/L 2.8–23.5 ng/mL Renin concentration Supine (at least 30 mins) 5–40 mIU/L – Sitting (at least 15 mins) 5–45 mIU/L – Erect (at least 1 hr) 16–63 mIU/L – Testosterone Male 10–38 nmol/L 290–1090 ng/dL Female 0.3–1.9 nmol/L 10–90 ng/dL Thyroid-stimulating hormone (TSH) 0.2–4.5 mIU/L – Thyroxine (free), (free T4) 9–21 pmol/L 0.7–1.63 ng/dL Triiodothyronine (free), (free T3) 2.6–6.2 pmol/L 0.16–0.4 ng/dL Notes

  1. A number of hormones are unstable and collection details are critical to obtaining a meaningful result. Refer to local laboratory handbook.
  2. Values in the table are only a guideline; hormone levels can often be meaningfully understood only in relation to factors such as gender, age, time of day, pubertal status, stage of the menstrual cycle, pregnancy and menopausal status.
  3. Reference ranges are usually dependent on the method used for analysis and frequently differ between laboratories. Non-SI units also differ; those shown here are amongst those most widely used. Readers are encouraged to consult their local laboratory for non-SI units for individual analytes and their respective reference ranges.

1360 • LABORATORY REFERENCE RANGES Analyte Reference range SI units Non-SI units α1-antitrypsin 1.1–2.1 g/L 110–210 mg/dL Alanine aminotransferase (ALT) 10–50 U/L – Albumin 35–50 g/L 3.5–5.0 g/dL Alkaline phosphatase (ALP) 40–125 U/L – Amylase < 100 U/L – Aspartate aminotransferase (AST) 10–45 U/L – Bile acids (fasting) < 14 μmol/L – Bilirubin (total) 3–16 μmol/L 0.18–0.94 mg/dL Calcium (total) 2.1–2.6 mmol/L 4.2–5.2 mEq/L or 8.5–10.5 mg/dL Carboxyhaemoglobin 0.1–3.0% Levels of up to 8% may be found in heavy smokers – Caeruloplasmin 0.16–0.47 g/L 16–47 mg/dL Cholesterol (total) Ideal level varies according to cardiovascular risk (see cardiovascular risk chart, p. 511) HDL-cholesterol Ideal level varies according to cardiovascular risk, so reference ranges can be misleading. According to the National Cholesterol Education Programme Adult Treatment Panel III (ATPIII), a low HDL-cholesterol is < 1.0 mmol/L (< 40 mg/dL) Complement C3 0.81–1.57 g/L – C4 0.13–1.39 g/L – Total haemolytic complement 0.086–0.410 g/L – Copper 10–22 μmol/L 64–140 μg/dL C-reactive protein (CRP) < 5 mg/L Highly sensitive CRP assays also exist that measure lower values and may be useful in estimating cardiovascular risk Creatine kinase (CK; total) Male 55–170 U/L – Female 30–135 U/L – Creatine kinase MB isoenzyme < 6% of total CK – Ethanol Not normally detectable Marked intoxication 65–87 mmol/L 300–400 mg/dL Stupor 87–109 mmol/L 400–500 mg/dL Coma

109 mmol/L 500 mg/dL Analyte Reference range SI units Non-SI units γ-glutamyl transferase (GGT) Male 10–55 U/L Female 5–35 U/L – Glucose (fasting) 3.6–5.8 mmol/L 65–104 mg/dL See page 722 for definitions of impaired glucose tolerance and diabetes mellitus, and page 738 for definition of hypoglycaemia Glycated haemoglobin (HbA1c) 4.0–6.0% 20–42 mmol/mol Hb – See page 722 for diagnosis of diabetes mellitus Immunoglobulins (Ig) IgA 0.8–4.5 g/L – IgE 0–250 kU/L – IgG 6.0–15.0 g/L – IgM 0.35–2.90 g/L – Lactate 0.6–2.4 mmol/L 5.4–21.6 mg/dL Lactate dehydrogenase (LDH; total) 125–220 U/L – Lead < 0.5 μmol/L < 10 μg/dL Magnesium 0.75–1.0 mmol/L 1.5–2.0 mEq/L or 1.82–2.43 mg/dL Osmolality 280–296 mOsmol/kg – Osmolarity 280–296 mOsmol/L – Phosphate (fasting) 0.8–1.4 mmol/L 2.48–4.34 mg/dL Protein (total) 60–80 g/L 6–8 g/dL Triglycerides (fasting) 0.6–1.7 mmol/L 53–150 mg/dL Troponins Values consistent with myocardial infarction are crucially dependent on which troponin is measured (I or T) and on the method employed. Interpret in context of clinical presentation. See page 450 Tryptase 0–135 mg/L – Urate Male 0.12–0.42 mmol/L 2.0–7.0 mg/dL Female 0.12–0.36 mmol/L 2.0–6.0 mg/dL Vitamin D (25(OH)D) Normal 50 nmol/L 20 ng/mL Insufficiency 25–50 nmol/L 10–20 ng/ml Deficiency < 25 nmol/L < 10 ng/mL Zinc 10–18 μmol/L 65–118 μg/dL 35.4 Other common analytes in venous blood

Laboratory reference ranges in adults • 1361

35.5 Common analytes in urine Analyte Reference range SI units Non-SI units Albumin Definitions of microalbuminuria are given on page 394 Proteinuria is defined below Calcium (normal diet) Up to 7.5 mmol/24 hrs Up to 15 mEq/24 hrs or 300 mg/24 hrs Copper < 0.6 μmol/24 hrs < 38 μg/24 hrs Cortisol 20–180 nmol/24 hrs 7.2–65 μg/24 hrs Creatinine Male 6.3–23 mmol/24 hrs 712–2600 mg/24 hrs Female 4.1–15 mmol/24 hrs 463–1695 mg/24 hrs 5-Hydroxyindole-3-acetic acid (5-HIAA) 10–42 μmol/24 hrs 1.9–8.1 mg/24 hrs Metadrenalines Normetadrenaline 0.4–3.4 μmol/24 hrs 73–620 μg/24 hrs Metadrenaline 0.3–1.7 μmol/24 hrs 59–335 μg/24 hrs Oxalate 0.04–0.49 mmol/24 hrs 3.6–44 mg/24 hrs Phosphate 15–50 mmol/24 hrs 465–1548 mg/24 hrs Potassium* 25–100 mmol/24 hrs 25–100 mEq/24 hrs Protein < 0.3 g/L < 0.03 g/dL Sodium* 100–200 mmol/24 hrs 100–200 mEq/24 hrs Urate 1.2–3.0 mmol/24 hrs 202–504 mg/24 hrs Urea 170–600 mmol/24 hrs 10.2–36.0 g/24 hrs Zinc 3–21 μmol/24 hrs 195–1365 μg/24 hrs *The urinary output of electrolytes such as sodium and potassium is normally a reflection of dietary intake. This can vary widely. The values quoted are appropriate to a ‘Western’ diet. 35.7 Analytes in faeces Analyte Reference range SI units Non-SI units Calprotectin < 50 μg/g – Elastase

200 μg/g – 35.6 Analytes in cerebrospinal fluid Analysis Reference range SI units Non–SI units Cells < 5 × 106 cells/L (all mononuclear) < 5 cells/mm3 Glucose1 2.3–4.5 mmol/L 41–81 mg/dL IgG index2 < 0.65 – Total protein 0.14–0.45 g/L 0.014–0.045 g/dL 1Interpret in relation to plasma glucose. Values in CSF are typically approximately two-thirds of plasma levels. 2A crude index of increase in IgG attributable to intrathecal synthesis.

1362 • LABORATORY REFERENCE RANGES 35.8 Haematological values Analysis Reference range SI units Non-SI units Bleeding time (Ivy) < 8 mins – Blood volume Male 65–85 mL/kg – Female 60–80 mL/kg – Coagulation screen Prothrombin time (PT) 10.5–13.5 secs – Activated partial thromboplastin time (APTT) 26–36 secs – D-dimers Interpret in relation to clinical presentation < 200 ng/mL – Erythrocyte sedimentation rate (ESR) Higher values in older patients are not necessarily abnormal Adult male 0–10 mm/hr – Adult female 3–15 mm/hr – Ferritin Male (and post-menopausal female) 20–300 μg/L 20–300 ng/mL Female (pre-menopausal) 15–200 μg/L 15–200 ng/mL Fibrinogen 1.5–4.0 g/L 0.15–0.4 g/dL Folate Serum 2.8–20 μg/L 2.8–20 ng/mL Red cell 120–500 μg/L 120–500 ng/mL Haemoglobin Male 130–180 g/L 13–18 g/dL Female 115–165 g/L 11.5–16.5 g/dL Haptoglobin 0.4–2.4 g/L 0.04–0.24 g/dL Iron Male 14–32 μmol/L 78–178 μg/dL Female 10–28 μmol/L 56–157 μg/dL Leucocytes (adults) 4.0–11.0 × 109/L 4.0–11.0 × 103/mm3 Differential white cell count Neutrophil granulocytes 2.0–7.5 × 109/L 2.0–7.5 × 103/mm3 Lymphocytes 1.5–4.0 × 109/L 1.5–4.0 × 103/mm3 Monocytes 0.2–0.8 × 109/L 0.2–0.8 × 103/mm3 Eosinophil granulocytes 0.04–0.4 × 109/L 0.04–0.4 × 103/mm3 Basophil granulocytes 0.01–0.1 × 109/L 0.01–0.1 × 103/mm3 Mean cell haemoglobin (MCH) 27–32 pg – Mean cell volume (MCV) 78–98 fl – Packed cell volume (PCV) or haematocrit Male 0.40–0.54 – Female 0.37–0.47 – Platelets 150–350 × 109/L 150–350 × 103/mm3 Red cell count Male 4.5–6.5 × 1012/L 4.5–6.5 × 106/mm3 Female 3.8–5.8 × 1012/L 3.8–5.8 × 106/mm3 Red cell lifespan Mean 120 days – Half-life (51Cr) 25–35 days – Reticulocytes (adults) 25–85 × 109/L 25–85 × 103/mm3 Transferrin 2.0–4.0 g/L 0.2–0.4 g/dL Transferrin saturation Male 25–50% – Female 14–50% – Vitamin B12 Normal

210 ng/L – Intermediate 180–200 ng/L – Low < 180 ng/L –

Laboratory reference ranges in childhood and adolescence • 1363

Laboratory reference ranges in childhood and adolescence The levels of many analytes in blood vary due to the physiological changes that occur during growth and adolescence. Hospital laboratories may provide reference ranges that are ageadjusted or based on pubertal stage but this is not always the case. It is therefore important for the doctor requesting these tests to understand the impact of age and puberty on interpretation of the results. For example, a creatinine of 70 μmol/L (0.79 mg/dL) is perfectly normal for the majority of adults but may indicate significant renal impairment in a child. Reference ranges for hormone results are described according to the Tanner stages of puberty (p. 1290). Analyte Age/Pubertal stage Gender Reference range Alkaline phosphatase (ALP) < 1 year M, F 80–580 U/L 1–16 years M, F 100–400 U/L 16–20 years M 50–250 U/L F 40–200 U/L Creatinine < 1 year M, F 12–39 μmol/L (0.14–0.44 mg/dL) 1–4 years M, F 13–42 μmol/L (0.15–0.48 mg/dL) 4–12 years M, F 20–57 μmol/L (0.23–0.64 mg/dL) 12–15 years M, F 31–67 μmol/L (0.35–0.76 mg/dL) 15–18 years M 39–92 μmol/L (0.44–1.04 mg/dL) F 34–72 μmol/L (0.38–0.81 mg/dL) Folliclestimulating hormone (FSH) Prepubertal M < 3.0 IU/L (< 0.6 μg/L) F < 3.2 IU/L (< 0.64 μg/L) Pubertal stage 2 M < 6.6 IU/L (< 1.32 μg/L) F < 4.1 IU/L (< 0.82 μg/L) Pubertal stage 3 M 0.7–5.0 IU/L (0.14–1 μg/L) Pubertal stages 4–5 M 1.5–6.0 IU/L (0.3–1.2 μg/L) Pubertal stages 3–5 F 2.5–13.5 IU/L (0.5–2.7 μg/L) Insulin-like growth factor 1 < 7 years M 15–349 μg/L F 17–272 μg/L 8–16 years M 67–510 μg/L F 59–502 μg/L Analyte Age/Pubertal stage Gender Reference range Luteinising hormone (LH) Prepubertal M < 1.0 IU/L (< 0.1 μg/L) Pubertal stage 2 M < 3.0 IU/L (< 0.3 μg/L) Prepubertal and pubertal stage 2 F < 1.0 IU/L (< 0.1 μg/L) Pubertal stage 3 M 1.0–4.0 IU/L (0.1–0.4 μg/L) Pubertal stages 4–5 M 1.0–5.0 IU/L (0.1–0.6 μg/L) Pubertal stages 3–5 F 1.0–8.0 IU/L (0.1–0.9 μg/L) 17β-Oestradiol Prepubertal and pubertal stages 2–3 M < 75 pmol/L (< 20 pg/mL) Prepubertal and pubertal stage 2 F < 100 pmol/L (< 27 pg/mL) Pubertal stages 4–5 M < 130 pmol/L (< 35 pg/mL) Pubertal stages 3–5 F < 150 pmol/L (< 41 pg/mL) Testosterone Prepubertal M < 0.5 nmol/L (< 10 ng/dL) F < 0.6 nmol/L (< 20 ng/dL) Pubertal stage 2 M < 10.6 nmol/L (< 310 ng/dL) F < 1.4 nmol/L (< 40 ng/dL) Pubertal stage 3 M 0.4–30 nmol/L (10–870 ng/dL) Pubertal stage 4 M 5.6–30 nmol/L (160–870 ng/dL) Pubertal stage 5 M 10–30 nmol/L (290–870 ng/dL) Pubertal stages 3–5 F 0.4–1.9 nmol/L (10–50 ng/dL) Non-SI equivalents are given in brackets where appropriate. 35.9 Analytes that may be significantly affected by growth and puberty

1364 • LABORATORY REFERENCE RANGES Laboratory reference ranges in pregnancy and it is important for the clinician reviewing the results to be aware of this to enable appropriate interpretation and patient management. The levels of many analytes in blood vary during pregnancy, when many hormonal and metabolic changes occur. The standard adult reference ranges may therefore not be appropriate Further information Abbassi-Ghanavati M, Greer LG, Cunningham FG. Pregnancy and laboratory studies: a reference table for clinicians. Obstet Gynecol 2009; 114:1326–1331. Tanner JM, Whitehouse RH. Clinical longitudinal standards for height, weight, height velocity, weight velocity, and stages of puberty. Arch Dis Child 1976; 51:170–179. Non-SI equivalents are given in brackets where appropriate. 35.10 Analytes that may be significantly affected by pregnancy Analyte Reference range First trimester Second trimester Third trimester Alkaline phosphatase (ALP) 17–88 U/L 25–126 U/L 38–229 U/L Packed cell volume (PCV) or haematocrit 0.31–0.41 0.30–0.39 0.28–0.40 Haemoglobin 116–139 g/L 97–148 g/L 95–150 g/L Human chorionic gonadotrophin 4 weeks: 16–156 IU/L 4–9 weeks: 101–233 000 IU/L 9–13 weeks: 20 900–291 000 IU/L 4270–103 000 IU/L 2700–78 300 IU/L 17β-Oestradiol 690–9166 pmol/L (188–2497 pg/mL) 4691–26 401 pmol/L (1278–7192 pg/mL) 12 701–22 528 pmol/L (3460–6137 pg/mL) Progesterone 25–153 nmol/L (8–48 ng/mL) Not available 314–1088 nmol/L (99–342 ng/mL) Prolactin 765–4532 mIU/L (36–213 ng/mL) 2340–7021 mIU/L (110–330 ng/mL) 2914–7914 mIU/L (137–372 ng/mL) Thyroid-stimulating hormone (TSH) 0.60–3.40 mIU/L 0.37–3.60 mIU/L 0.38–4.04 mIU/L Thyroxine (free), (free T4) 10–18 pmol/L 0.77–1.40 ng/dL 9–16 pmol/L 0.70–1.24 ng/dL 8–14 pmol/L 0.62–1.09 ng/dL

Index A AAAs see Abdominal aortic aneurysms Abacavir, 324b for HIV/AIDS, 324–325, 324b hypersensitivity reaction of, 326 pharmacodynamics of, 180b Abaloparatide, for osteoporosis, 1048b,

Abatacept, for musculoskeletal disease, 1007, 1007b Abciximab, platelet inhibition, 500,

Abdomen examination of blood disease, 912f cancer, 1315b cardiovascular disease, 442f gastrointestinal disease, 764f liver and biliary disease, 846–847 renal and urinary tract disease, 382f–383f palpation of, 765b percussion of, 765b swelling of see Ascites Abdominal aortic aneurysms (AAAs), 505, 505b Abdominal compartment syndrome, diagnosis and management of,

Abdominal examination, 765b Abdominal pain, 787–789 acute, 787–789, 787b assessment of, 787, 788f chronic or recurrent, 789, 789b constant, 789 diabetic ketoacidosis and, 736, 736b investigations of, 787 irritable bowel syndrome and, 824 large bowel obstruction of, 789 liver abscess and, 880 in lower abdomen, 336 management of, 787–789 in old age, 788b pancreatitis acute, 837–839, 837b chronic, 839–841 peptic ulcer, perforated, 789 Abdominal tuberculosis, 812–813 Abducens (6th cranial) nerve, tests of, 1063b Abetalipoproteinaemia, 810 Abnormal movements, 1084–1086, 1085b Abnormal perceptions, 1086, 1181 ABO blood groups, 931–932, 933b ABO-incompatible red cell transfusion, 932–933 ABPA see Allergic bronchopulmonary aspergillosis ABPI see Ankle-brachial pressure index Abscess anorectal, 836 cerebral, 1124, 1124b, 1124f ‘collar-stud’, 590 infective endocarditis and, 527 intra-abdominal, 787b liver, 879–880, 893 amoebic, 880 in old age, 901b pyogenic, 879–880, 880b lung, 219f, 251f pancreatic, 219f perinephric, 430 pulmonary, 586–587 spinal epidural, 1125 Absence seizures, 1099 Absidia, 303 Absolute erythrocytosis, 925, 925b Absorption, 17–18 gastrointestinal tract, 17 interactions, 23 parenteral, 17 topical, 17–18 see also Malabsorption ABVD regimen, for Hodgkin lymphoma,

Acamprosate, 1195 Acanthosis, 1244 Acanthosis nigricans, 1265, 1325b,

Acarbose, 745–746 Accelerated hypertension, 514 Accessory (11th cranial) nerve, tests of, 1063b Acclimatisation to heat, 167 to high altitude, 168 Accommodation, 1198 ACCORD (Action to Control Cardiovascular Risk in Diabetes),

ACD see Anaemia(s), of chronic disease ACE (angiotensin-converting enzyme), 351–352 ACE inhibitors for acute coronary syndrome prevention, 498b adverse reactions of, 22b, 1310b angioedema, 1266b cough, 556 hyperkalemia, 363 for chronic kidney disease, 417 contraindication to, cirrhosis, 894b effect on renal function, 426, 427b for heart failure, 466, 466f dosages, 466b sites of action, 466f for hypertension, 513 for mitral regurgitation, 521 for myocardial infarction, 500–501 during pregnancy, 32b Acetaldehyde metabolism, 881 Page numbers followed by ‘f’ indicate figures, and ‘b’ indicate boxes. Acetazolamide, 354 for altitude illness, 168 for epilepsy, 1102b for idiopathic intracranial hypertension, 1133 Acetyl-CoA, 881 Acetylcholine, 767 Acetylcholinesterase (AChE), 1142f Acetylcysteine, 138 Achalasia of oesophagus, 794–795 AChE see Acetylcholinesterase Achilles tendinitis, 999 Achlorhydria, 803f, 808b, 941 Aciclovir for herpes virus infection, 126, 127b bone marrow transplant patients, 937b chickenpox/shingles, 239b genital, 342 HIV/AIDS, 315 viral encephalitis, 1122 nephrotoxicity, 427b in pregnancy, 120b Acid-base balance chronic kidney disease and, 418 disorders mixed, 367 presenting problems of, 364–367 homeostasis, 363–367 principal patterns of disturbances, 365b renal control of, 364 Acidosis lactic, 365 diabetic, 746 poisoning, 149b metabolic, 364–366 acute kidney injury and, 413 chronic kidney disease, 415 critically ill patients and, 180–181 diabetic ketoacidosis, 735 differential diagnosis, 558b hypothermia and, 166 malaria, 276b near-drowning, 170 poisoning and, 135b renal tubular, 365b respiratory, 367 Acids, poisoning, 136b Acinus, 548–549, 549f, 848, 848f Acitretin for atopic eczema, 1246 for psoriasis, 1227 Acne, 1241–1244, 1242f in adolescence, 1241b conglobata, 1242 cystic, 1242f excoriée, 1242 fulminans, 1242 secondary, 1242 vulgaris, 1241–1243 Acneiform eruptions, 1266b Acoustic neuroma, 1131 Acquired C1 inhibitor deficiency, 88 Acrochordon, 1235 Acrocyanosis, 84b, 950 Acrodermatitis chronica atrophicans,

Acrodermatitis enteropathica, 717 Acromegaly, 630f, 685–687, 686f musculoskeletal manifestations of,

ACTH see Adrenocorticotrophic hormone Actinic dermatitis, chronic, 1221b, 1222f Actinic keratosis, 1230b, 1231, 1231f Actinic prurigo, 1221b Actinomadura spp., 301 Actinomyces israelii, 261–262 Actinomyces spp., 103f Actinomycete infections, 261–262 Actinomycetes, 100–101 Actinomycetoma, 301 Action potential, 1065 Activated partial thromboplastin time (APTT), 920–921 reference range of, 1362b Active proctitis, 820 Activities of daily living (ADL), 1303b Barthel Index, 1311, 1312b Acupuncture, for pain management, 1347, 1347f Acute abdomen, 787–789, 787b, 788f Acute benign asbestos pleurisy, 618 Acute cholinergic syndrome, 146, 146b Acute circulatory failure, 199–200 Acute colonic ischaemia, 827 Acute colonic pseudo-obstruction, 835, 835b ‘Acute confusional states,’ in older people, 1080 Acute coronary syndrome, 493–501, 493b–494b, 494f–495f chest pain and, 455 clinical features of, 494–496, 495b complications of, 494–495 management of, 498–501, 498b, 499f see also Myocardial infarction Acute disseminated encephalomyelitis,

Acute eosinophilic pneumonia, 611 Acute fatty liver of pregnancy, 1283, 1283b Acute inflammation, 70–71, 71f acute phase response in, 70 resolution of, 71 septic shock and, 70–71 Acute inflammatory arthritis, 1017 Acute intermittent porphyria, 379b Acute interstitial nephritis (AIN), 402, 402b Acute interstitial pneumonia (AIP), 606b

1366 • INDEX Acute kidney injury (AKI), 411–415 causes of, 411f clinical features of, 411–413 dialysis for, indications for, 422b haemodialysis in, 422 interstitial, 402, 402b investigations of, 412b malaria, 276b management of, 413–414, 413b non-oliguric, 402 in old age, 414b pathophysiology of, 411 post-renal, 412b, 413 pre-renal, 411–412, 412b pregnancy and, 1282, 1283b recovery from, 414–415, 414f renal, 412–413, 412b renal replacement therapy, 414 Acute leukaemia, 955–958 investigations of, 955–956, 956f management of, 956–958 haematopoietic stem cell transplantation, 958 specific therapy, 956–957, 956b–957b supportive therapy, 957–958 outcome of, 958b prognosis of, 958 WHO classification of, 955b Acute limb ischaemia, 503, 503b, 503f Acute liver failure, 856–859 adverse prognostic criteria in, 858b causes of, 856f–857f classification of, 857b clinical assessment of, 857–858 complications of, 858b hepatic encephalopathy and, 857b hepatitis A and, 873 investigations for, 858, 858b management of, 858–859, 858b pathophysiology of, 857 Acute lung injury, 170 Acute lymphoblastic leukaemia (ALL), 955, 956f Acute medicine, 173–214 ambulatory care, 176, 176b decision to admit to hospital, 176 problems in, 176–187 Acute mountain sickness (AMS), 168 Acute myeloid leukaemia (AML), 955, 956f, 958b ‘Acute on chronic’ type II respiratory failure, 566–567, 566b Acute pancreatitis, 837–839, 837b causes of, 838b complications of, 838b management of, 839 pathophysiology of, 837, 838f Acute pericarditis, 542, 542b, 542f Acute phase proteins, 72 Acute phase response, 105 ferritin levels in, 941 musculoskeletal disease, 1017–1018 retroperitoneal fibrosis, 434 rheumatic disease, 1012 Acute Physiology Assessment and Chronic Health Evaluation (APACHE II), 214, 214b Acute renal failure see Acute kidney injury Acute respiratory distress syndrome (ARDS), 198 aetiology of, 198, 198b Berlin definition of, 198b diagnosis of, 198, 199f drug-induced, 612b management of, 198 mechanical ventilation in, 198 near-drowning victims and, 170 pathogenesis of, 198 severity of, 199b Acute rheumatic fever, 515–517, 516f investigations in, 517b Jones criteria for, 516b Acute severe breathlessness, 558 Acute skin failure, 1224–1225 Acute small bowel ischaemia, 827 Acute transmural anterior myocardial infarction, 497f Acute transmural inferolateral myocardial infarction, 498f Acute tubular necrosis (ATN), 402f drug-induced, 427b Adalimumab for inflammatory bowel disease, 820, 821b for inflammatory rheumatic disease, 1007b for psoriasis, 1250–1251 Adapalene, 1242–1243 Adaptive immune system, 67–70 ADCC see Antibody-dependent cellular cytotoxicity Addenbrooke’s Cognitive Examination- 3rd edition (ACE-III), 1181–1183 Addison’s disease, 671b Adductor tendinitis, 999b Adenine, 38, 39f Adenocarcinoma, 813 ampullary/periampullary, 842–844 of oesophagus, 796f–797f of pancreas, 842–844 of prostate, 438–439 of small intestine, 813 of unknown primary, 1336 Adenoma adrenal, 667b Conn’s syndrome, 675f Cushing’s syndrome, 667b, 669–670 bronchial gland, 603b colorectal, 776b, 827 familial adenomatous polyposis, 828–829, 829f hepatic, 893 parathyroid, 663 periampullary, 813 sebaceum, 1264 small intestine, 813 toxic, 638f, 649 Adenomyomatosis, of gallbladder, 909 Adenosine, 480b, 482, 482b Adenosine diphosphate see ADP Adenosine triphosphate see ATP Adenosquamous carcinoma of lung, 603b Adenoviruses, diarrhoea, 249 ADH see Antidiuretic hormone Adherence factors affecting, 1294b SIMPLE strategies for, 1294b Adhesion molecules, 77 ADHR see Autosomal dominant hypophosphataemic rickets Adipocytes, 725 Adipokines, 731 Adiponectin, 699 Adjustment disorders, 1187, 1201 prevalence of, 1180b ADL see Activities of daily living Adolescents, 1290 allergy in, 76b congenital heart disease in, 537b cystic fibrosis in, 581b diabetes mellitus in, 753–754, 753b–754b epilepsy in, 1103b haematological malignancy in, 955b infections in, 234, 235b inflammatory bowel disease in, 823b juvenile idiopathic arthritis in, 1027b laboratory reference range of, 1363 medical ophthalmology in, 1175b renal impairment in, 1298b ADP (adenosine diphosphate), 446f Adrenal crisis, 673b Adrenal disease, 1280 Adrenal glands, 665–676 disease classification of, 665b presenting problems of, 666–674 functional anatomy and physiology of, 665–666, 666f–667f incidental adrenal mass, 673–674 older people, 673b Adrenal hyperplasia, congenital, 676 Adrenal insufficiency, 671–673, 671b–673b Adrenal tumours Cushing’s syndrome, 669–670 see also Phaeochromocytoma Adrenalectomy, 675 for Cushing’s disease, 669 Adrenaline for allergy, 86 anaphylaxis, 75, 76b circulatory effects of, 206b self-injectable, prescription of, 76b for urticaria, 1254 Adrenarche, 666 β-Adrenoceptor antagonist, 1190b for thyrotoxicosis, in pregnancy,

for variceal bleeding, 869, 871 Adrenocorticotrophic hormone (ACTH) Cushing’s syndrome and, 667b ectopic, 667b, 1325b ectopic ACTH syndrome, 670 ectopic hormone production, 1325b excess, 672b hypopituitarism, 672b reference range of, venous blood, 1359b stimulation test, 672b Adrenoleukodystrophy, 1116b Adriamycin see Doxorubicin Adult-onset Still’s disease, 1040 Adult polycystic kidney disease (PKD), 405–406, 405b Advance directives, 1307 Advanced life support (ALS), 457 Adverse drug reactions (ADRs), 21–23 classification of, 22–23, 22b interactions, 23–24 in older people, 1310, 1310b pharmacovigilance, 23 prevalence of, 21–22, 21b–22b risk factors for, 21b TREND analysis of, 23b see also individual drugs Aedes aegypti Chikungunya virus, 250 dengue, 243 yellow fever, 244 AEDs (antiepilepsy drugs) see Anticonvulsants AF see Atrial fibrillation Affective mood disorders bipolar, 1198 organic, 1185b Affinity, 14 Affluence, health consequences of, 94 AFP (alpha-fetoprotein) hepatocellular carcinoma and, 890–891 as tumour markers, 1322, 1324b African tick bite fever, 270, 271b African trypanosomiasis (sleeping sickness), 278–279, 278f Afterload heart failure, 461 reduction, 465 Age/ageing, 1301–1312 biological, 1304 biology of, 1304–1305 chronological, 1304 physiological changes of, 1305, 1305f syndrome of premature ageing see Werner’s syndrome type 2 diabetes and, 732, 732b see also Older people Age-related macular degeneration,

Agglutination, cold, 950 Agglutination test, 108 for leishmaniasis, 283 for leptospirosis, 258 microscopic, 258 for sporotrichosis, 301 trypanosomiasis, 279 for tularaemia, 261 Aggrecan, 987 Aggregatibacter aphrophilusAggregatibacter actinomycetemcomitans, 528 Aggressive behaviour, 1188–1189, 1189f Agitation, in palliative care, 1354 Agnosia, 1086 Agonists, 14 Agoraphobia, 1200 Agranulocytosis, 644 AHR see Airway hyper-reactivity AIDS see HIV infection/AIDS Aids and appliances, for musculoskeletal disease, 1001 AIN see Acute interstitial nephritis AIP see Acute interstitial pneumonia Air embolism, during dialysis, 424b Air travel, 169 Airflow obstruction, 554f assessment in COPD, 575 Airway hyper-reactivity (AHR), 568, 568f Airway pressure release ventilation (APRV), 204 Airways, 548, 548f assessment of, in deteriorating patient, 188 in asthma, 568f defences, 550, 550f of envenomed patient, 152f obstruction of, 555, 1324b reactive dysfunction syndrome, 614 in sleep apnoea, 622 of stroke patients, 1159b upper airway diseases, 622–625 Akathisia, 1105–1106, 1197 AKI see Acute kidney injury Akinesia, 1113b ALA dehydratase deficiency, 379b Alanine aminotransferase (ALT), 852, 1360b Albendazole for cysticercosis, 298 for helminthic infections, 129 filariasis, 291 for hydatid cysts, 299 Albers-Schönberg disease, 1056 Albinism inheritance, 1258 oculocutaneous, 1258 Albright’s hereditary osteodystrophy, 51b, 664, 1017b Albumin in AKI, 416b liver blood biochemistry, 852 plasma, liver function test, 858 reference range of urine, 1361b venous blood, 1360b urinary, 1361b see also Hypoalbuminaemia Albumin solutions, for ascites, 864 Albuminuria, moderately elevated, 394 Alcohol, 94 abstinence from, 1194b amount in average drink, 880b coronary artery disease and, 486 dependence, 1194–1195, 1194b diabetes and, 744–745 drug interactions, 24b energy provided by, 694 liver disease and, 880–882 pharmacokinetics, 20b poisoning, 134b thiamin deficiency and, 714 see also Ethanol Alcohol misuse, 1184, 1194–1195 chronic, presentation and consequences of, 1194b clinical assessment of, 1184 clinical features of, 1194–1195 diagnosis of, 1195 effects of, 1194b, 1195 investigations of, 1184 liver disease see Alcoholic liver disease management of, 1195 maternal, 1194b in pancreatitis, 841 pathogenesis of, 1194 prevalence of, 1180b prognosis of, 1195

INDEX • 1367 Alcohol withdrawal syndrome, 1194, 1194b management of, 1195 Alcoholic fatty liver disease (AFLD),

Alcoholic liver disease, 880–882 clinical features of, 881–882, 881b liver function test (LFT) abnormality in, 854b in old age, 901b pathophysiology of, 881, 881b risk factors for, 880 Aldosterone, 666 deficiency, 363 plasma potassium and, 360 reference range of, 1359b resistance, 363 see also Hyperaldosteronism Alendronate for osteoporosis, 1048b timing of, 31b Alfacalcidol (1,25- dihydroxycholecalciferol), 665 Alfentanil, 209b Alginates, 793 sodium content of, 864b Alkaline phosphatase (ALP) liver function tests and, 852 placental, 1322, 1324b reference values of, venous blood, 1360b sclerosing cholangitis, 889 serum Paget’s disease, 1054 rickets/osteomalacia, 1052 in skeletal disease, 990b Alkalinisation, urinary, 136 Alkalis, poisoning, 136b Alkalosis hypokalaemic, Cushing’s syndrome,

metabolic, 366–367, 367f respiratory, 367 Alkylating agents, 936b Allele, 47 Allergen, 84 asthma, 568f avoidance of, 86 contact eczema, 1247 supervised exposure to, 86 Allergic alveolitis, extrinsic see Hypersensitivity pneumonitis Allergic bronchopulmonary aspergillosis (ABPA), 596, 596b, 596f Allergic contact eczema, 1247, 1247b, 1247f Allergic rhinitis, 622 Allergy, 84–86 in adolescence, 76b clinical features of, 85 clinical manifestations of, 85b diagnosis of, 85 food, 812 hygiene hypothesis, 84–85 to insect venom, 85 investigations of, 86 challenge tests, 86 eosinophilia, 86 mast cell tryptase, 86 patch tests, 1215, 1244 serum total IgE, 86 skin-prick tests, 86 specific IgE tests, 86 management of, 86 pathophysiology of, 84–85, 85f to peanut, 85 in pregnancy, 88b Allodynia, 1084 Allogeneic haematopoietic stem cell transplantation, 937 complications of, 937, 937b indications for, 936b Alloimmune haemolytic anaemia, 950 Allopurinol for acute leukaemia patients, 956b, 957–958 drug interactions of, 24b for gout, 1015–1016 hepatotoxicity, 32b, 894 pharmacodynamics, 20b renal stone prevention, 432–433, 433b for toxic epidermal necrolysis, 1254–1255 Alopecia, 1258–1259, 1259b androgenetic, 1259 scarring inflammatory, 1262f Alopecia areata hair in, 1258–1259, 1259f nails in, 1261 Alpha-fetoprotein (AFP) hepatocellular carcinoma and, 890–891 as tumour markers, 1322, 1324b Alpha-glucosidase inhibitors, for hyperglycaemia, 747 Alpha heavy chain disease, 813 Alpha particles, 164, 164f Alpha-thalassaemia, 954 Alpha1-antitrypsin deficiency, 48b, 897, 897f inheritance, 47b Alport’s syndrome, 403–404, 404f ALS see Advanced life support ALT see Alanine aminotransferase Alternaria, 572 Alternative therapies for cancer pain, 1353 for pain, 1348 Altitude, illnesses, 168–169 Aluminium osteomalacia and, 1053 poisoning from, 148 Aluminium hydroxide for diarrhoea, 809 phosphorus deficiency and, 716 for renal bone disease, 419 Alveolar macrophages, 303, 615 Alveolar microlithiasis, 613b Alveolar proteinosis, 613b Alveolitis extrinsic see Hypersensitivity pneumonitis fibrosing, 558b, 1024b non-eosinophilic, drug-induced, 612b Alzheimer’s disease, 1191b, 1192–1193, 1193f familial, 1192 see also Dementia Amanita phalloides poisoning, 150b Amantadine, 127, 127b for multiple sclerosis, 1110b for Parkinson’s disease, 1114 Amastigotes, leishmaniasis, 282f Amaurosis fugax, 1152 AmBisome, 283 Amelanotic melanoma, 1322 Amenorrhoea, 654–655, 654b American trypanosomiasis (Chagas’ disease), 279–280 Amikacin for actinomycetoma, 301 for nocardiosis, 261 Amiloride, 360, 864 for diabetes insipidus, 688 mineralocorticoid excess, 675 Amino acids, 697, 697b essential, 697b metabolism, 850 disorders of, 369–370 Aminoglycosides, 116b, 122 adverse effects of, 122 for brucellosis, 254 dosing of, 122f mechanism of action, 116b nephrotoxicity, 32b pharmacokinetics of, 122 in pregnancy, 120b Aminopenicillins, 120, 120b Aminophylline for asthma, 573, 573f for COPD, 578 Aminosalicylates, for inflammatory bowel disease, 821b Aminotransferases acute liver failure and, 858 elevated, common causes of, 859b hypothermia, 166 liver function tests, 852 non-alcoholic fatty liver disease and,

reference range of, 1360b viral hepatitis, 874f Amiodarone adverse reactions pigmentation, 1258b pulmonary fibrosis, 612 for arrhythmias, 479b–480b, 481 atrial fibrillation, 471–472 atrial flutter, 470 tachycardia, 475 causing thyroid dysfunction, 636b, 638f, 647–648, 647f for heart failure, 467 hepatotoxicity of, 894b structure of, 647f thyrotoxicosis, 639, 647–648 Amitriptyline, 1199b for fibromyalgia, 1018–1019 for functional dyspepsia, 802–803 for headache, 1095 for herpes zoster, 240 for irritable bowel syndrome, 825 for migraine prevention, 1096 multiple sclerosis, 1110b for musculoskeletal pain, 995 for neuropathic pain, 1350b, 1352b for pain management, 1350b for post-herpetic neuralgia, 240 for psychiatric disorder, 1199b Amlodipine for angina, 491b unstable, 500 for hypertension, 513 Ammonia, 384 hepatic encephalopathy and, 865 Ammonium chloride, 366 Amnesia, 1080–1081 persistent, 1081 post-ictal, 1081 transient global, 1081 Amniocentesis, 56 Amniotic fluid embolism (AFE), pregnancy and, 1275 Amodiaquine, for malaria, 277 Amoebiasis, 286–287, 286f incubation period of, 111b Amoebic dysentery, 287 Amoebic liver abscess, 287, 880 Amoeboma, 286–287, 286f Amoxicillin, 117b for diphtheria, 266 for Helicobacter pylori eradication,

for listeriosis, 260 for Lyme disease, 256 for pneumonia, 585b for skin reactions, infectious mononucleosis, 242 for urinary tract infection, 428 Amphetamines, misuse of, 143 Amphotericin/amphotericin B, 125b,

for aspergillosis, 598 for blastomycosis, 304 for candidiasis, 302 for coccidioidomycosis, 304 for cryptococcal meningitis, HIV-related, 321 for fusariosis, 302–303 for histoplasmosis, 304 for leishmaniasis, 283 lipid formulations of, 126 for mucormycosis, 303 for mycetoma, 301 nephrotoxicity, 365b, 427b for neutropenic fever, 1327–1328 for Penicillium (Talaromyces) marneffei infection, 303 for sporotrichosis, 301 Ampicillin, 117b, 120b for cerebral abscess, 1124b drug interactions of, 121 for listeriosis, 260 for liver abscess, 880 for meningitis, 1120b for paratyphoid fever, 260–261 skin reactions, 1266b infectious mononucleosis, 242, 242f Ampulla of Vater, carcinoma of, 907–908 AMS see Acute mountain sickness Amsacrine, for acute leukemia, 957b Amsler chart, 1168, 1168f Amygdala, 1066 Amylase, 768, 770b pancreatic, 695–697 reference range of, venous blood, 1360b salivary, 62–63 serum hypothermia, 166 pancreatitis, 563b, 839 Amyloid A, serum, 70 Amyloid angiopathy, 1155b, 1191b Amyloid deposition, type 2 diabetes,

Amyloid in plaques, in Alzheimer’s disease, 1192, 1193f Amyloidosis, 81, 1264 causes of, 82b heart disease, 541 multiple myeloma, 410b rheumatoid arthritis, 1024–1025 Amylose, 695–697 ANA see Antinuclear antibody Anaemia(s), 717, 913, 913b, 923–925, 940–951, 941f after peptic ulcer surgery, 801 aplastic, 968–969 autoimmune haemolytic, 949–950 causes of, 923b of chronic disease (ACD), 942b, 942f,

chronic kidney disease and, 419, 419b clinical assessment of, 923 haemolytic, 923, 945–951 alloimmune, 950 autoimmune, 949–950 causes of, 946f, 947 microangiopathic, 950 non-immune, 950 HIV-related, 322 investigations of, 923–925, 924f iron deficiency, 940–943 alimentary tract disorders, 793 blood loss in, 940–941 confirmation of, 941–942, 942b investigations in, 941–942 malabsorption in, 941, 942f management of, 943 physiological demands in, 941, 941b pregnancy and, 1284 megaloblastic, 940, 943–945 clinical features of, 943b investigations in, 944b management of, 945 microangiopathic haemolytic, 408,

microcytic, 925 in rheumatoid arthritis, 1024–1025 normochromic normocytic, 853 in old age, 954b pernicious, 944 pregnancy and, 1284, 1285b primary idiopathic acquired aplastic, 968–969, 968b secondary aplastic, 969, 969b sickle-cell, 923, 951–953 clinical features of, 952–953, 952f epidemiology of, 951, 951f investigations of, 953 management of, 953 pathogenesis of, 951–952 in pregnancy, 953b prognosis of, 953 Anagrelide, 970 Anakinra, for musculoskeletal disease,

Anal canal, 771f Anal fissure, 836

1368 • INDEX Analgesia for acute coronary syndrome, 498 for back pain, 997 cholecystitis, 905 in intensive care, 209, 209b for low back pain, 997 for musculoskeletal disease, 1002 myocardial infarction, 498 for osteoarthritis, 1012 for palliative care, 1350 for pancreatic cancer, 842–844 for pancreatitis, 839 for pleural pain, 584 for post-herpetic neuralgia, 240 for psoriatic arthritis, 1033–1034 for reactive arthritis, 1032 for renal colic, 432 Analgesic ladder (WHO), 1351f Analgesics adjuvant for cancer pain, 1352, 1352b for pain, 1345–1346 poisoning from, 137–138 see also specific drugs Anaphase, 40 Anaphylactic shock, 204, 206b Anaphylactoid reactions, 75, 75b Anaphylaxis, 75–76, 339 causes of, 75b clinical assessment of, 75–76 clinical manifestations of, 75f differential diagnosis of, 76b gastrointestinal, 812 management of, 76, 76b Anaplastic carcinoma, 650 ANCAs (antineutrophil cytoplasmic antibodies), 992 Ancylostoma caninum, 294 Ancylostoma duodenale, 288, 288f Ancylostomiasis (hookworm), 288–289, 288f Andersen disease, 370b Andersen-Tawil syndrome, 1145b Androgen receptor antagonism, 659b Androgen replacement therapy for adrenal insufficiency, 673 options for, 656b Androgens adrenal, 666 in older women, 660b Anergy, 82 Aneuploidy, 51 Aneurysm aortic, 505–506 abdominal, 505b saccular, 508 ventricular, 496 see also Microaneurysms Angelman’s syndrome, 44b, 51b Angina, 487–493, 487b–488b clinical features of, 488, 488b investigations for, 488, 489f–490f management of, 488–489 drug therapy, 489–491, 490b non-pharmacological treatments, 491–493, 491f–492f, 493b in old age, 493b prognosis of, 493 recurrent, in acute coronary syndrome, 495 stable advice to patients with, 489b risk stratification in, 488b Angina equivalent, 180 Angiodysplasia, 782–783 Angioedema, 87–88, 87f drug-induced, 1266b hereditary, 88 types of, 87b Angiogenesis, 1318, 1319f Angiography coronary, 143 CT, 452, 452f hepatic, 854 magnetic resonance, 869 mesenteric, 783, 813 of nervous system, 1072 visceral, 782–783 Angiomatosis, bacillary, 272 Angioplasty for renal artery stenosis, 407–408 for stoke, 1160 Angiosarcoma, 1320b Angiostrongylus cantonensis, 294 Angiotensin-converting enzyme see ACE Angiotensin-converting enzyme inhibitors see ACE inhibitors Angiotensin II, 666 Angiotensin II receptor blockers effect on renal function, 407b microalbuminuria in diabetes, 758 renal failure, 417 Angiotensin receptor blockers for heart failure, 466, 466b for hypertension, 513 Angular cheilitis, HIV/AIDS, 316 Angular stomatitis, 714, 764f, 817 Anhedonia, 1181 Anion gap acidosis, 365 poisoning, 135b Anisakiasis, 294 Anismus, 834 Ankle-brachial pressure index (ABPI),

Ankle pain, 999 Ankylosing spondylitis (AS), 1028b, 1030–1031 clinical features of, 1030, 1030b investigations of, 1030–1031, 1030f–1031f management of, 1031 Annular erythemas, 1265 Annulus fibrosus, 444 Anogenital warts, 342–343 Anorectal abscesses, 836 Anorectal disorders, 835–836 Anorectal motility test, 778 Anorexia in cancer patients, 1325b in rheumatoid arthritis, 1023 Anorexia nervosa, 1203–1204, 1204b features of, 785 in osteoporosis, 1047–1048 Anosmia, 653 Anosognosia, 1192–1193 ANP see Atrial natriuretic peptide Anserine bursitis, 999b Antacids for bile reflux, 801 drug interactions of, 23 sodium content of, 864b Antagonists, 14 Antalgic gait, 1086, 1309b Anterior pituitary hormone deficiency, 681b Anterior tibial compartment syndrome,

Anthracyclines, 936b Anthrax, 266–267 bioterrorism, 111 clinical features of, 267 cutaneous, 267 gastrointestinal, 267 immunisation for, 115b incubation period of, 111b inhalational, 267 management of, 267 skin, 1238 Anthropometry, 693b Anti-α4β7 integrin, for inflammatory bowel disease, 821b Anti-androgen therapy, for polycystic ovarian syndrome, 659b Anti-anginal therapy, for acute coronary syndrome, 500 Anti-anxiety drugs, 1190b Anti-arrhythmic drugs, 479–482 adverse reactions of, 926b classification of, 479b by site of action, 479f dosages of, 480b principal uses of, 480b–481b side-effects of, 480b see also individual drugs Anti-cancer therapy see Chemotherapy Anti-CCP antibodies, 563b, 607 Anti-CD20 monoclonal antibody rituximab, for chronic lymphocytic leukaemia, 960 Anti-centromere antibody, 992b Anti-citrullinated peptide antibodies (ACPAs), 991 Anti-D, 933 Anti-DNA antibodies, 991 Anti-glomerular basement membrane disease, 398b–399b, 401 Anti-herpesvirus agents, 126–127, 127b Anti-histone antibody, 992b Anti-infective agents, 1226 Anti-inflammatory cascade, 196 Anti-inflammatory therapy for asthma, 571 for osteoarthritis, 1011b see also individual drugs Anti-influenza agents, 127 Anti-Jo-1 (anti-histidyl-tRNA synthase), 992b Anti-La antibody (anti-SS-B), 992b Anti-liver-kidney microsomal (LKM) antibodies, 886 Anti-oestrogen, 1332 Anti-phospholipid syndrome, 1281 Anti-ribonucleoprotein antibody (anti-RNP), 992b Anti-RNA polymerase, 992b Anti-RO antibody (anti-SS-A), 992b Anti-Scl-70 (anti-topoisomerase I antibody), 992b Anti-Smith antibody, 992b Anti-smooth muscle antibodies, 886, 886b Anti-thymocyte globulin (ATG), 89b Anti-TNF therapy for ankylosing spondylitis, 1031 for inflammatory bowel disease, 821b–822b, 822 for rheumatoid arthritis, 1006 Anti-topoisomerase I antibody, 992b Antibacterial agents, 120–124 aminoglycosides, 116b beta-lactam, 116b, 120–121 folate antagonists, 123 glycopeptides, 123 lincosamides, 122 macrolide, 116b, 121–122 nitroimidazoles, 124 quinolones, 122–123, 123b target and mechanism of action of, 116b therapeutic drug monitoring, 119 Antibiotic therapy for acne, 1242–1243 for acute leukaemia, 957 adverse reactions of, 22b, 926b for bronchiectasis, 579 for cerebral abscess, 1124 for cholecystitis, 905 for choledocholithiasis, 906 for community-acquired pneumonia, 584, 585b for cystic fibrosis, 580 for diabetic foot ulcers, 761–762 diarrhoea associated with, 104b for gastroenteritis/acute diarrhoea,

for Helicobacter pylori eradication,

hepatotoxicity and, 864b for infective endocarditis, 529b, 530 for inflammatory bowel disease, 821b for meningitis, 1118 for osteomyelitis, 1021 for pneumonia community-acquired, 583 hospital-acquired, 586 suppurative/aspirational, 587 prophylactic for pancreatitis, 839 for spontaneous bacterial peritonitis, 864 for variceal bleeding, 869 for respiratory tract infections bronchiectasis, 790 COPD, 578 cystic fibrosis, 580 pneumonia see Pneumonia, above for rheumatic fever, 517 for sepsis, 197, 197b for septic arthritis, 1020, 1020b for skin disease, 1227 sodium content of, 864b for staphylococcal infections see individual infections for urinary tract infection, 428 Antibody/antibodies classes and properties of, 68b in coeliac disease, 806–807 deficiency in, 73b primary, 78–79, 78f, 79b detection of, 106–108, 109f see also Autoantibodies Antibody-dependent cellular cytotoxicity (ADCC), 67–69 Anticardiolipin antibodies, 1157b Anticholinergics adverse reactions of, 1310b for bladder dysfunction, 1094b for COPD, 577 for Parkinson’s disease, 1114 poisoning, 150b Anticholinesterases for Alzheimer’s disease, 1193 for myasthenia gravis, 1142 non-antivenom, 159 α1-Antichymotrypsin, 70 Anticoagulants/anticoagulation, 938–940 adverse reactions of, 22b for atrial fibrillation, stroke prevention, 472b coagulation screening, 1362b direct oral, 940 drug interactions, 940 indications for, 938b modes of action of, 938b monitoring, 922 for obliterative cardiomyopathy, 541 in old age, 1160b poisoning, 148b in pregnancy, 941b prosthetic heart valves and, 527b for pulmonary embolism, 621 risk assessment of, 940b rodenticides, 148b for stroke patients, 1157b for venous thromboembolism, 975–976 see also specific anticoagulants Anticodon, 40 Anticonvulsants for epilepsy, 1101–1102, 1102b choice of drug, 1102b withdrawing, 1102–1103 for pain management, 1352b poisoning, 141b skin reactions, 1266b use in pregnancy, 1284 Antidepressants, 1190b, 1199b, 1200 adverse reactions of, 926b, 1310b for alcohol withdrawal, 1195 for anxiety disorders, 1201 in older people, 1310b poisoning from, 138–139 tricyclic, 1199, 1199b poisoning from, 138–139, 139b, 139f Antidiabetic agents, poisoning from, 141 Antidiarrhoeal agents, 230 for inflammatory bowel disease, 821b for irritable bowel syndrome, 826f Antidiuretic hormone (ADH), 350–351 ectopic hormone production, 1325b inappropriate secretion, 357b cancer patients, 1325b Antiemetic drugs, receptor site activity of, 1353b Antiepilepsy drugs (AEDs) see Anticonvulsants Antifreeze poisoning, 147 Antifungal agents, 125–126, 125b Antigen processing and presentation,

Antiglobulin (Coombs) test, 948f

INDEX • 1369 Antihistamines for allergy, 86 for eczema, 1244 for food allergy, 812 for pruritus, 1220 for skin disease, 1227 for urticaria, 1254 Antihypertensive drugs, 513, 514b, 515f adverse reactions of, 926b for chronic kidney disease, 416–417 for gout, 1016 Antimalarials, 128, 1252 adverse reactions of, 926b poisoning, 141b prophylactic, 119b see also individual drugs Antimetabolites, 936b, 1317f Antimicrobial agents combination therapy, 116 for infective gastroenteritis, 230 pharmacokinetics and pharmacodynamics of, 118–119, 119f in pregnancy, 120b resistance to, 116–118, 118f selection, 117b susceptibility testing, 109, 109f target and mechanism of action of, 116b therapeutic drug monitoring, 119 see also Antibiotic therapy Antimicrobial stewardship, 115, 115f Antimicrobial therapy, 117b action and spectrum, 116, 117b duration of, 118, 119b empiric versus targeted therapy, 116, 117f in old age, 120b principles of, 116–120 prophylactic, 119–120, 119b see also Antibiotic therapy Antimitochondrial antibodies, 886b,

Antimonials, for leishmaniasis, 128, 283 Antimotility agents, 230 Antimycobacterial agents, 125 Antineutrophil cytoplasmic antibodies (ANCAs), 389 Antineutrophil cytoplasmic antibodyassociated vasculitis (AAV), 1041, 1041f Antinuclear antibody (ANA) in autoimmune hepatitis, 886b in musculoskeletal disease, 991, 991b Antioxidants, 550 Antiparasitic agents, 128–129 Antiphospholipid antibodies, 991–992 Antiphospholipid syndrome (APS), 977–978, 978b Antiplatelet drugs, 938b for angina, 489 for myocardial infarction, 498b for obliterative cardiomyopathy, 541 for stroke prevention, 1161f Antiproteinases, 550 Antipsychotic drugs, 1190b adverse reactions of, 22b, 1198b for agitation, 1354 poisoning from, 141 for schizophrenia, 1198b Antiretroviral therapy, 127b, 324–327, 324b complications of, 325–326 criteria for, 325 monitoring efficacy of, 325 in pregnancy, 326–327 resistance to, 325 selection of, 324–325 see also individual drugs Antirheumatic drugs during pregnancy and breastfeeding, 1281b slow-acting (DMARDs) see Disease-modifying antirheumatic drugs Antisecretory agents, 230 Antiseptics, 586, 1226 Antithrombin deficiency, 977 Antithrombotic therapy, 938–940, 938b for acute coronary syndrome, 500 prophylaxis, for venous thromboembolism, 976–977, 977b Antithyroid drugs adverse reactions of, 926b for Graves’ thyrotoxicosis, 644, 644b in pregnancy, 1279 α1-Antitrypsin faecal clearance of, 811 liver disease, 854b liver histology in, 897f reference range of, venous blood, 1360b Antivenom, 159, 159b, 160f Antiviral agents, 126–128, 127b see also Antiretroviral therapy Anuria, 391, 391b Anxiety/anxiety disorders, 1186, 1200–1201 alcohol and, 1194 classification of, 1200b clinical features of, 1200 diagnosis of, 1200 differential diagnosis of, 1186b generalised, 1200 investigations of, 1186 management of, 1186, 1200–1201 in palliative care, 1354 panic disorder, 1200 phobic, 1200 prevalence of, 1180b in stroke patients, 1159f symptoms of, 1186b Aorta ascending dilatation of, 451f syphilis and, 338 coarctation of, 508, 534, 534f diseases of, 505–514 Aortic aneurysm, 505–506 abdominal, 505b Aortic dissection, 506–508, 506f–508f, 507b pregnancy and, 1282 Aortic regurgitation, 443b, 524–525, 524b clinical features of, 524–525, 524b, 525f investigations of, 525, 525b chest X-ray for, 451f Aortic stenosis, 443b, 521–524, 522b, 522f causes of, 521b Doppler echocardiography for, 451f investigations of, 522–524, 523b, 523f in old age, 524b Aortic valve, disease, 521–525 Aortitis, 508 APACHE II, 214 APD see Automated peritoneal dialysis Aphonia, psychogenic, 624 Aphthous ulceration, 790, 790b Apixaban, 938b Aplastic anaemias, 968–969 Aplastic crisis, 947, 952–953 Apo A1 deficiency, 375, 375b Apo A1 Milano, 375, 375b Apocrine sweat glands, 1213–1214 Apolipoproteins, 371 Apoptosis, 41, 1316 Apoptotic bodies, 41 Appearance, in psychiatric interview,

Appendicitis, acute, 788 Apraxia, 1086 gait, 1087, 1309b Apremilast, for musculoskeletal disease, 1004b, 1005 Apronectomy, 704 APTT see Activated partial thromboplastin time Arachnoiditis, 996–997 Arboviruses, 1121–1122 ARDS see Acute respiratory distress syndrome Arginine, 697b Arms, assessment of, 983f Aromatase inhibitors for cancer treatment, 1334 osteoporosis and, 1046b Arrhythmias, 468–479, 468f in acute coronary syndrome, 495, 495b during dialysis, 424b electrophysiology of, 454 hypothermia and, 166f management of, 479–484 drugs, 479–482, 479b–482b, 479f non-pharmacological treatments, 482–484 see also specific arrhythmias Arrhythmogenic ventricular cardiomyopathy, 540 Arsenic, poisoning, 149, 149b Arsenism, 149, 149b Artemisinin (qinghaosu) derivatives,

Arterial blood analysis of, 1358b critically ill patients, 179 respiratory failure, 199b Arterial disease hepatic, 898 leg ulcers due to, 1223–1224 Arterial gas embolism (AGE), 170 Arterial pressure waveform, 206 Arterial pulse, examination of, 443b Arterialisation, 422–423 Arteriography, renal, 389 Artesunate, for malaria, 277 Arthritis acute inflammatory, 1017 crystal-induced, 1012–1018 HIV-related, 321 juvenile idiopathic, 1026–1027 in adolescence, 1027b clinical features of, 1027b oligoarticular, 1300 transition medicine and, 1300 monoarthritis acute, 992–993, 993b chronic inflammatory, 992 mutilans, 1033 osteoarthritis, 1007–1012 polyarthritis see Polyarthritis psoriatic, 1032–1034 CASPAR criteria for, 1032b clinical features of, 1032–1033, 1033f investigations for, 1033 management for, 1033–1034 pathophysiology of, 1032 reactive, 1031–1032 rheumatoid, 1021–1026 algorithm for, 1026f biologic therapy for, 1026 cardiac involvement in, 1024 clinical features of, 1023–1025, 1023f criteria for diagnosis of, 1023b DMARD therapy for, 1025–1026 extra-articular, 1024b investigations in, 1025, 1025b, 1026f management of, 1025–1026 nodules in, 1023–1024, 1024f non-pharmacological therapy for,

ocular involvement in, 1024 pathophysiology of, 1022–1023, 1022f peripheral neuropathy in, 1024 in pregnancy, 1026b, 1280 pregnancy and, 1280 pulmonary involvement in, 1024 serositis in, 1024 spinal cord compression in, 1024, 1025f surgery for, 1026 systemic, 1023 vasculitis in, 1024 septic, 1019–1020 systemic lupus erythematosus and,

viral, 1020–1021 Arthrodesis, 1002b Arthropathy in parvovirus B19 infection, 237b psoriasis and, 1249 reactive, sexually acquired, 340 rheumatological manifestations of,

Arthroplasty, 1002b Asacol, for inflammatory bowel disease, 821b Asbestos-related lung and pleural diseases, 617–618 Asbestosis, 618 Ascariasis, 233b Ascaris lumbricoides (roundworm), 289–290, 906 Ascending and descending pain pathways, 1339f Ascites, 847b, 862–864, 1324b appearance and analysis of, 863b Budd-Chiari syndrome and, 899 causes of, 862b cirrhosis and, 867 hepatorenal syndrome and, 864 management of, 863–864 oedema, 395–396 pancreatic, 839 pathogenesis of, 863f pathology of, 862–863 portal hypertension and, 869 prognosis of, 864 renal failure and, 864 serum- ascites albumin gradient (SAAG) and, 863 spontaneous bacterial peritonitis and,

Ascorbic acid see Vitamin C Aspartate, 697b Aspartate aminotransferase (AST),

Aspergillosis, 301 bronchopulmonary classification of, 596b Aspergillus clavatus, 616b Aspergillus flavus, 1320b Aspergillus nodule, 597 Aspergillus spp., in immunocompromised patients,

Asphyxia/asphyxiation laryngeal obstruction, 624–625 self-harm, 1187 Aspiration, pleural, 563–564 Aspiration pneumonia, 586–587 Aspirin for acute coronary syndrome prevention, 498b adverse reactions of, 22b for angina, 489 asthma association, 568 atrial fibrillation, stroke prevention,

coronary artery bypass grafting, 491–492 drug interactions, 24b for hypertension, 513 for myocardial infarction, 500 poisoning, 138 for rheumatic fever, 517 for stroke patients, 1160 timing of, 31b AST see Aspartate aminotransferase Asteatotic eczema, 1247 Asterixis, 864–865 Asthma, 567–573, 567f clinical features of, 568–569 control, levels of, 570b diagnosis of, 569, 569b, 569f–570f exacerbations of, 572–573, 572b–573b, 573f and gastro-oesophageal reflux disease, 791–792 management of, 569–570, 571f occupational, 613–614, 614b, 614f pathophysiology of, 568, 568f in pregnancy, 570b, 1277 prognosis of, 573 Astrocytes, 1064–1065 Astrocytoma, 1075f

1370 • INDEX Astrovirus, 249 Asymmetrical inflammatory mono-/ oligoarthritis, 1032 Asymptomatic bacteriuria, 429 Ataxia(s), 1115 acquired, 1115b cerebellar, 1325 inherited, 1116b stroke and, 1153 Ataxia telangiectasia, 1321b genes, 1321 Ataxic gait, 1087, 1309b Atazanavir, 324b Atenolol for angina, 500 drug interactions of, 24b for hypertension, 513 Atheroembolism, 390b, 503–504, 504b Atherosclerosis in old age, 505b renal artery stenosis and, 406 six stages of, 485f Athetosis, 1086 Athlete’s foot, 1240 Atmospheric pollution, 94 ATN see Acute tubular necrosis Atomic absorption (AA), 348b Atonic seizures, 1100 Atopic eczema, 1245–1246 clinical features of, 1245, 1246f complications of, 1246b investigations of, 1245, 1246b management of, 1246 pathogenesis of, 1245 rash in, 1217b, 1246b Atopy, 84, 86 see also Allergy Atorvastatin, 501 Atovaquone, for malaria, 128 ATP (adenosine triphosphate), myocardial contraction and,

ATP synthase, 49b Atria, 444, 444f Atrial ectopic beats, 469–470, 470f Atrial fibrillation (AF), 470–473, 471f causes of, 471b management of, 471–473 mechanisms of, 471f in old age, 472b paroxysmal, 471–472 persistent, 472–473 stroke risk in, 473b Atrial flutter, 470, 470f Atrial myxoma, 541–542 Atrial natriuretic peptide (ANP), 351 Atrial septal defect, 534–535, 535f Atrial tachycardia, 470 Atrioventricular (AV) block, 477–478, 477f–478f, 478b Atrioventricular (AV) node, 445, 445f re-entrant tachycardia, 473, 474f Atrophy, definition of, 1226, 1226f Atropine for acute cholinergic syndrome, 146 for AV block, 478 for carbamate poisoning, 147 cardiotoxic drug poisoning, 140 for organophosphorus poisoning,

for sinus bradycardia, 469 Auerbach’s plexus, 771–772 Auscultation examination of, respiratory system, 546f of heart, 443b malignant pleural effusions, 1315b Austin Flint murmur, 524 Australian tick typhus, 271b Autoantibodies autoimmune disease and, 83, 83f autoimmune hepatitis and, 886b and musculoskeletal disease, 991 primary biliary cholangitis and, 887–888 thyroid, 637b Autofluorescence, of visual disorders,

Autoimmune connective tissue disease, 1018, 1034–1040 Autoimmune disease, 81–84 clinical features of, 83 gene polymorphisms associated with, 82b investigations of, 83–84 autoantibodies in, 83, 83f complement in, 84 cryoglobulins in, 84, 84b of liver, 885–890 management of, 84 pathophysiology of, 82–83 Autoimmune haemolytic anaemia, 949–950 Autoimmune hepatitis, 886–887 conditions associated with, 886b liver function test (LFT) abnormality in, 854b primary biliary cholangitis and, 888 Autoimmune lymphoproliferative syndrome, 80 Autoimmune pancreatitis, 841 Autoimmune polyendocrine syndromes, 689, 689b Autoimmune thyroid disease, 639b, 643–646 Autologous haematopoietic stem cell transplantation, 936–938 Automated peritoneal dialysis (APD),

Automated threshold perimetry, 1168 Autonomic dysfunction, somatoform,

Autonomic nervous system, 1068 Autonomic neuropathy, diabetic, 760, 760b ‘Autonomic storm’, 155 Autonomy, patients, 1288–1289 Autophagy, 1316 Autopsy, 213 Autosomal dominant hypophosphataemic rickets (ADHR), 1050b Autosomal dominant inheritance, 46–47, 47b Autosomal recessive inheritance, 47b,

Autosomes, 38 AV see Atrioventricular Avascular cornea, 1166 Avid sodium retention, nephrotic syndrome and, 395b Axial spondyloarthritis, 1028b, 1029–1030, 1029f Axial spondyloarthropathy, 1028–1031, 1029f Axons, peripheral nerve, 1064–1065 Azathioprine adverse reactions of, 22 for autoimmune haemolysis, 950 for autoimmune hepatitis, 886–887 drug interactions of, 24b for eczema, 1246 hepatotoxicity, 894b for inflammatory bowel disease, 821b,

liver transplantation and, 901 for musculoskeletal disease, 1004b,

systemic lupus erythematosus,

for myasthenia gravis, 1142b for primary biliary cholangitis, 888 for rheumatoid arthritis, 1026b transplant patients, 89b, 425–426 Azelaic acid, 1242–1244 Azithromycin, 117b for bacillary angiomatosis, HIV/AIDS patients, 315–316 for cystic fibrosis, 581b for Mycobacterium avium complex, 315b for STIs chlamydial infection, 341b syphilis, 339 for trachoma, 273 Azole antifungals, 126 Aztreonam, 117b, 120b, 121 B B-cell receptor, 68, 68f B lymphocytes (B cells), 68, 68f, 917 Babesia microti, 226b Babesiosis, 278 Bacillary angiomatosis, 272 HIV-related, 315–316 Bacillary dysentery, 265 Bacille Calmette-Guérin see BCG Bacillus anthracis, 266 Bacillus cereus, food poisoning, 262, 262f Bacillus spp., 102f Back, examination of, cardiology, 442f Back pain, 995–997 red flags for, 996b triage assessment of, 996f see also Low back pain Background radiation, 164 Baclofen, for multiple sclerosis, 1110b Bacteraemia, 106 Staphylococcus aureus, 225 Bacteraemic leptospirosis, 257 Bacteria, 100–101, 101b, 102f endogenous commensal, 63 exotoxin, disease caused by, 104b identification of, 102f Bacterial cultures, for gastrointestinal infection, 777 Bacterial infections, 250–273 after HSCT, 937b and cancer, 1320b chlamydial, 272–273, 272b gastrointestinal, 262–265 with neurological involvement, 267 respiratory, 265–267 rickettsial, 270–272, 271b of skin, 1235–1238 soft tissues and bones, 250–254 systemic, 254–262 see also specific infections Bacterial keratitis, 1173 Bacterial meningitis, 1118–1120 causes of, 1119b cerebrospinal fluid in, 1119 clinical features of, 1119, 1119b headache and, 185, 185b investigations of, 1119–1120, 1119f, 1120b management of, 1120, 1120b pathophysiology of, 1119 Bacterial swab, for leg ulcers, 1224 Bacteriology, skin, 1215 Bacteriophage, 100 Bacteriuria asymptomatic, 429 catheter-related, 429–430 Bacteroides fragilis, 586 Bacteroides spp., 103f, 117b Bad news, 1185 Baker’s (popliteal) cyst, 999b, 1023 rupture, 1023 Balance altered, 1086 see also Dizziness; Vertigo Balanitis, 333 anaerobic, 334b circinate, 334b plasma cell (of Zoon), 334b Balanoposthitis, 333 Balkan nephropathy, 403 Ballism, 1086 Balloon dilatation, 434 Balloon tamponade, for variceal bleeding, 870–871, 870f Balloon valvuloplasty for aortic valve, 524 for mitral valve, 519, 519b, 519f Balsalazide, 821b Balsam of Peru, 1247b ‘Bamboo’ spine, 1030–1031, 1031f Band ligation, 870 Bandages, for leg ulcers, 1223 Banding, for variceal bleeding, 869 Barbiturates, 142b misuse of, 1195 skin reactions of, 1266b withdrawal effects of, 16b Bardet-Biedl syndrome, 404b Bare lymphocyte syndromes, 79 Bariatric surgery, for obesity, 702f–703f, 703–704, 703b Baricitinib, for musculoskeletal disease, 1004b Baritosis, 614–615 Barium enema for constipation, 787 for diverticulosis, 833 for gastrointestinal tuberculosis, 590 for inflammatory bowel disease, 819–820 for oesophageal diseases, 778 for pharyngeal pouch, 794 Barotrauma, 171 Barrett’s (columnar lined) oesophagus, 792–793, 793f carcinoma and, 796 Barthel Index of Activities of Daily Living, 1311, 1312b Bartonella henselae, 272, 315–316 Bartonella quintana, 272, 315–316 Bartonellosis, 272, 272b Bartter’s syndrome, 361 Basal cell carcinoma, 1229–1230, 1229f, 1230b Basal cell papilloma, 1234, 1234f Basal ganglia, 1066–1067 Basal metabolic rate (BMR), 694, 695f in over-nutrition, 694 Basement membrane, 1212, 1213f Basic calcium phosphate (BCP) deposition disease, 1017–1018, 1017b Basic life support (BLS), 456–457 Basophil granulocytes, 1362b Basophilia, 926b Basophilic stippling, 921f Basophils, 66–67, 917, 926b, 926f count, 1362b Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), 1029 Bath Ankylosing Spondylitis Functional Index (BASFI), 1029 Battery acid poisoning, 794 Bayes’ theorem, 5 BCG (bacille Calmette-Guérin) for leprosy, 270 for tuberculosis, 594 BCP see Basic calcium phosphate BCR see Breakpoint cluster region Beau’s lines, 1261, 1261f Becker muscular dystrophy, 48b Becker’s disease, 1145b Beckwith-Wiedemann syndrome, 51b Beclometasone, 17–18 Bedside procedures, for safe transfusion, 934, 934f–935f Behaviour assessment of, in psychiatric interview, 1181 disturbed and aggressive, 1188–1189, 1189f in old age, 1189b high-risk, transition medicine and,

history-taking in, 1295b personality and, 1295 protective factors in, 1295 theories in, 1295 psychiatric disorders and, 1183 Behaviour therapy, 1190 Behavioural rating scales, for pain,

Behçet’s disease, 1043–1044, 1043f, 1044b Beighton score, modified, 1059 Bejel, 254, 254b Beliefs, abnormal, 1181 Belimumab, for musculoskeletal disease, 1006–1007, 1007b Bell’s palsy, 1082–1083 Bence Jones protein, 394–395 Bence Jones proteinuria, 966–967 Bendroflumethiazide, 22b Benign oesophageal stricture, 793, 795–796, 796b Benign paroxysmal positional vertigo, 1104, 1104f

INDEX • 1371 Benign prostatic enlargement (BPE), 437–438 treatment for, 438b Benign prostatic hyperplasia (BPH), 437 Benserazide, 1113 Benzamides, substituted, 1198b Benzathine benzylpenicillin, for syphilis,

Benzbromarone, 1016 Benzene, 1320b Benzimidazoles, for helminthic infections, 129 Benzisoxazole, 1198b Benznidazole, for trypanosomiasis, 128 Benzocaine, allergy, 1247b Benzodiazepines, 1190b adverse reactions of, 22b, 1310b alcohol withdrawal, 1195 for anxiety disorders, 1190b, 1201 delirium, 1310b misuse of, 142 overdose, 142 respiratory depression and, 1188–1189 stress reactions, 1201 withdrawal, 1186b Benzoyl peroxide, 1242–1243 Benzylpenicillin, 120b for cerebral abscess, 1124b for meningitis, 1120b for neurosyphilis, 1125 procaine see Procaine penicillin Bereavement, 1184 Beri-beri, 714 Bernoulli equation, modified, 451–452 Berylliosis, 616 Beta-adrenoceptor blockers, for heart failure, 467 Beta-blockers adverse reactions of, 22b, 1310b for anxiety disorder, 1201 for essential tremor, 1115 for hypertension, 513 poisoning from, 140 for thyrotoxicosis, 637–638 Beta-chain haemoglobinopathy, 953 Beta-lactam antibiotics, 116b, 120–121 adverse reactions of, 120–121 drug interactions of, 121 mechanism of action, 116b pharmacokinetics of, 120 Beta particles, 164, 164f Beta-thalassaemia, 953–954 diagnostic features of, 954b management and prevention of, 953–954, 954b Beta-2-microglobulin, as tumour markers, 1324b Bevacizumab, 1332 Bi-level ventilation, 202 Bicarbonate, 349b arterial blood of, 1358b in diabetic ketoacidosis, 738 see also Sodium bicarbonate Bicarbonate system, 364, 364f Biguanides, for hyperglycaemia, 746 Bilateral diaphragmatic weakness, 627 Bile, 850–851 reflux, 801 Bile acid diarrhoea, 809 Bile acid-sequestering resins, 376–377 Bile duct, tumours of, 907–908 Bile salts, 768f Bilharziasis see Schistosomiasis Biliary colic, 904 Biliary disease, 902–909 autoimmune, 885–890 clinical examination of, 846f extrahepatic, 902–903 intrahepatic, 902 inflammatory and immune disease and, 902 investigation of, 852–855, 852b see also Liver disease Biliary obstruction, pregnancy and, 900 Biliary sludge, 904 Biliary sphincterotomy, 906 Biliary system, functional anatomy of, 849–850 Bilirubin alcoholic hepatitis and, 882 excretion of, 851f Gilbert’s syndrome and, 897 liver blood biochemistry and, 852 metabolism of, 850–851 plasma acute liver failure and, 858 jaundice and, 860 viral hepatitis, 872 reference range of, venous blood, 1360b see also Hyperbilirubinaemia Bioavailability, 17 Biochemical disorders, clinical examination of, 346–348, 346f Biochemical investigations, 348–349, 348b Biochemical markers, cancer, 1323, 1324b Biochemical tests, for liver disease, 852–853 Biochemistry, 388–389 of bone disease, 990–991 of coeliac disease, 807 Biological therapies for cancer, 1332 for musculoskeletal disease, 1006–1007, 1006f for psychiatric disorders, 1190 for skin disease, 1228 Biopsy, 776 bone, 992 brain, 1078 cancer diagnosis, 1330 liver, 855, 855b, 884 for hepatocellular carcinoma, 891 for lung cancer, 601 muscle, 992, 1078 for neurological disease, 1078 pleural, 563–564 renal, 391, 391b skin, 1214–1215 synovial, 992 temporal artery, 992 tissue, in musculoskeletal disease,

Bioterrorism, 111 Biotin, 715 deficiency, 715 dietary sources of, 711b reference nutrient intake of, 711b 2,3-Biphosphoglycerate (2,3-BPG), 915–916 Bipolar disorder, 1199–1200 prevalence of, 1180b Birch oral allergy syndrome, 85 Bird fancier’s lung, 616b Bisacodyl, 834b Bismuth, 230, 800 Bisoprolol, 466b for angina, 490 for arrhythmias, 481 for hypertension, 513 Bisphosphonates adverse effects of, 1048b for bone metastases, 1329 for giant cell arteritis, 1043b for multiple myeloma, 968 osteomalacia and, 1053 for osteoporosis, 1047–1048, 1047f, 1048b for Paget’s disease, 1054 Bites snake, 158b spider, 161 Bithionol, 129 Bitot’s spots, 713 Blackheads see Comedone Blackouts, 1080 alcoholic, 1195 in older people, 1308 Bladder, 386 disturbance, 1093–1094 dysfunction, 1093–1094, 1094b flaccid, 1093 multiple sclerosis and, 1109–1110 ultrasound of, 389 Bladder neck, obstruction, 437 Blastomyces dermatitidis, 304 Blastomycosis, 304 Blatchford score, 780 Bleeding, 913–914, 913b, 927–929 clinical assessment of, 928–929 gastrointestinal, 780–783 in haemophilia A, 972 investigation of, 929 supportive therapy for, 957 variceal see Variceal bleeding see also Haemorrhage Bleeding disorders, 920–922, 970–975 acquired, 974–975 rare inherited, 974 Bleeding time, 921, 1362b Bleomycin Hodgkin lymphoma, 963 pigmentation from, 1258b for viral warts, 1239 ‘Blind loop syndrome’, 808–809 Blindness, night, 713 Blisters, 1211f, 1218–1219 acquired, 1218b clinical assessment of, 1218f, 1219 definition of, 1218 investigations and management of,

α-Blockers for benign prostatic enlargement, 438 for hypertension, 513, 514b for phaeochromocytoma, 675–676 Blood arterial, analytes in, 1358b components of, 931b culture, 106, 107f–108f, 225–226, 225b functional anatomy and physiology of, 914–919 oxygenation in, 190 Blood-brain barrier, 1064–1065 Blood cells, 915–917 see also Platelets; Red cells Blood count for acute kidney injury, 416b for gastrointestinal bleeding, 777–778 for hepatobiliary disease, 853 for musculoskeletal disease, 990 see also Platelets; Red cells Blood diseases clinical examination of, 912–914, 912f investigation of, 919–923 ophthalmic features of, 1164b pregnancy and, 1284–1285 anaemia as, 1284, 1285b Rhesus disease as, 1285 thrombocytopenia as, 1285, 1285b venous thromboembolism as, 1285 presenting problems in, 923–930 principles of management of, 930–940 pruritus and, 1219b rheumatological manifestations of,

in systemic lupus erythematosus, 1035–1036 see also individual disorders Blood donation, 930–931, 932f Blood film examination, 920, 921b, 921f Blood flow Doppler echocardiography for, 451–452, 451f respiration and, 447–448 through heart, 444f resistance to, 447 Blood glucose, of stroke patients, 1159b Blood loss, 940–941 Blood pool imaging, for cardiovascular system, 454 Blood pressure effects of respiration on, 447b in endocrine disease, 630f examination of, respiratory system, 546f optimal target, 513b of stroke patients, 1159b see also Hypertension Blood products, 930–931, 931b Blood-stream infection, 225, 225b see also Bacteraemia Blood supply, to liver, 848–849, 848f Blood tests for abdominal pain, 787 for cerebrovascular disease, 1151–1152 for diabetes mellitus, 726 for gastrointestinal bleeding, 777 for hepatobiliary disease, 853 for inflammatory bowel disease, 818 for malabsorption, 785f for musculoskeletal disease, 990–992 for neurological disease, 1077 older people, 923b for pain, 1342, 1342b for pneumonia, 584b for renal disease, 388–389 for skin disease, 1215–1216 for stroke, 1151–1152 see also Haematological values Blood transfusion, 930–936 adverse effects of, 931–933 exchange for malaria, 277 for megaloblastic anaemia, 945 for sickle-cell disease, 953 in intensive care, 211 in major haemorrhage, 934–936 other immunological complications of,

safe transfusion procedures in, 934 for sickle-cell anaemia, 953 Blood vessels imaging of, 1074 see also Vascular Blood volume, reference range of, 1362b Bloom’s syndrome, 1321b BLS see Basic life support Blue naevi, 1235 Blurred vision, of ophthalmic disease,

BMD see Bone mineral density BMI see Body mass index BMR see Basal metabolic rate BNP see Brain natriuretic peptide Body composition, measures of, 693b Body dysmorphic disorder, 1202 Body fat, in endocrine disease, 630f Body lice, 1241 Body mass index (BMI) cardiovascular disease risk and, 699f clinical assessment of, 693b diabetes risk and, 699f obesity and, 700, 700b of older people, 1302f pancreatitis and, 837b Body packers/stuffers, 144, 144f ‘Boerhaave’s syndrome’, 797 Bohr effect, 190 Bone anatomy of, 984–985 biopsy, 992 cortical, 984f in endocrine disease, 630f fractures see Fractures infection, 1019–1021 in old age, 1020b matrix, 985 metabolism, pregnancy and, 1272 mineral, 985 mineralisation, 985 pain, 1324b remodelling, 985, 985f–986f, 986b resorption, 985, 985f trabecular, 984f tumours, 1056–1057 metastatic, 1329 woven, 985 Bone disease, 1044–1056 biochemical abnormalities in, 990b metabolic after gastric resection, 801 chronic kidney disease and, 418–419 metastatic, 1057 in bone scintigraphy, 988–989 in tuberculosis, 591 see also individual disorders

1372 • INDEX Bone lining cells, 985 Bone marrow, 914, 914f examination of, 920, 922f Bone marrow stromal cells, 985 Bone marrow transplantation (BMT), for severe combined immune deficiency, 80 Bone mineral density (BMD), 989–990 Borrelia burgdorferi, 255 Borrelia infections, 255–257, 256b Botfly, 235f Botulinum toxin, 104b, 1126, 1126b for achalasia, 795 for dystonia, 1116 for hemifacial spasm, 1116 Bouchard nodes, 982f, 1009 Bouginage, 775f, 793 Boutonneuse fever, 271b Bovine serum albumin (BSA), 729 Bovine spongiform encephalopathy (BSE), 1127 Bowel disturbance, 1093–1094 whole bowel irrigation, 136 see also Colon; Small intestine Bowen’s disease, 1230b, 1232, 1232f BPH see Benign prostatic hyperplasia Brachial plexopathy, 1141 Brachial plexus lesions, 1141b Brachytherapy, 1331 Bradykinesia, 1069 Brain alcohol-related damage, 1195 arterial circulation of, 1150f biopsy, 1078 cerebral hemispheres, 1066–1067, 1066b, 1067f damage due to alcohol, 1195 lesions, 1071–1072, 1072b schizophrenia, 1196 structure and function of, psychiatric disorders and, 1183 tumours, 1129–1132, 1129b, 1129f clinical features of, 1129 investigations of, 1130, 1130f management of, 1130–1131 metastatic, 1328, 1328b prognosis of, 1131 venous circulation of, 1151f see also specific regions, and entries under cerebral Brain death classification of, 212b organ donation after, 213 UK criteria for diagnosis of, 211b Brain injury, from critical illness, 211, 211b–212b Brain natriuretic peptide (BNP), 351,

Brainstem, 1067, 1067f death, 211 encephalitis, 1122 lesions, 1083–1084 Breakpoint cluster region (BCR) abl oncogene, 958 Philadelphia chromosome, 958 Breast cancer, 1333–1334 clinical features of, 1333–1334 investigations of, 1334 management of, 1334 in older people, 1325b pathogenesis of, 1333 screening, 1325b staging, 1333b survival rates for, 1333, 1333b Breastfeeding HIV infection/AIDS and, 326–327 safety of antirheumatic drugs during, 1281b Breasts, in endocrine disease, 630f Breath tests, gastroenterology, 777 Breathing assessment of, in deteriorating patient, 188 control of, 549 in divers, 170 Kussmaul, 415 of stroke patients, 1159b see also Respiration Breathlessness, 557–558 acute, 179–181, 558b clinical assessment of, 179–180 clinical features in, 180b investigations of, 180–181 presentation of, 179, 179f severe, 558 chronic exertional, 557–558, 558b in COPD, 575 differential diagnosis of, 557, 558b in lung cancer, 600 in palliative care, 1353 pathophysiology of, 557, 557f in pregnancy, 1274–1275, 1275b psychogenic, 558b Briquet’s syndrome, 1202 Bristol stool chart, 229, 229f British National Formulary, 28 Broca’s area, 1070 Bromocriptine for brain tumours, 1130 for neuroleptic malignant syndrome, 1197–1198 for Parkinson’s disease, 1114b for prolactinoma, 685, 685b Bronchial artery, 549f angiography, 560f embolisation, 597 Bronchial gland adenoma, 603b Bronchial gland carcinoma, 603b Bronchial obstruction in lung cancer, 600, 600b, 600f radiological features of, 551, 552f Bronchiectasis, 578–579, 578b–579b, 579f Bronchoalveolar carcinoma, 603b Bronchodilators for acute exacerbations of COPD,

for chronic obstructive pulmonary disease (COPD), 576 Bronchopulmonary aspergillosis, classification of, 596b Bronchopulmonary segments, 548f Bronchoscopy, 553 in haemoptysis, 560 in lung cancer, 601, 601f in mediastinal tumours, 604 Bronchus, tumours of, 598–605 Brown-Séquard syndrome, 1083, 1136 Bruce Protocol, for exercise ECG, 449–450 Brucella abortus, 254 Brucella canis, 254 Brucella melitensis, 254 Brucella suis, 254 Brucellosis, 254 clinical features of, 254, 255f diagnosis of, 254 incubation period of, 111b management of, 254, 255b in pregnancy, 235b Brudzinski’s sign, 1118 Brugada syndrome, 477 Brugia malayi infection, 233b, 291, 291f BSA see Bovine serum albumin BSE see Bovine spongiform encephalopathy BTK gene, X-linked agammaglobulinaemia and, 78 Bubonic plague, 259 Buccal administration, 17 Budd-Chiari syndrome, 898–899 acute liver failure and, 857–858 Budesonide (BUD), 821b Buerger’s disease, 504 Bulbar palsy, 1093, 1093b Bulimia nervosa, 1204, 1204b Bullae, in lungs, 552b, 575 Bullous disease, 1254–1257 Bullous eruptions, drug-induced, 1266b Bullous impetigo, 1218b Bullous lupus erythematosus, 1255b Bullous pemphigoid, 1255–1256, 1255b, 1256f Bumetanide for hypertension, 513 for oedema, 396 Bundle branch block, 478–479, 478b, 478f Bundle of His, 445 Bupropion, 139b Burch-Wartofsky scoring system, for thyrotoxic crisis, 639b Burkholderia pseudomallei, 261 Burkitt’s lymphoma, 1320b Burns haemolysis and, 950 sunburn, 1221f Burrow, definition of, 1241 Bursae, 987 Bursitis anserine, 998b deep infrapatellar, 998b ischiogluteal, 999b olecranon, 998b pre-patellar, 998b superficial, 998b trochanteric, 998, 999b, 999f Buruli ulcer, 254 Buschke-Löwenstein tumour, 343 Buspirone, 139b Busulfan drug-induced pigmentation, 1258b hepatotoxicity of, 894b Butterfly rash, 982f Button hole deformity of fingers,

Butyrophenones, 1190b for schizophrenia, 1198b Byssinosis, 614, 616b C C-peptide, 724, 724f, 727 C-reactive protein (CRP), 63 abnormal, conditions associated with, 72b in acute phase response, 70 inflammation and, 71–72 reference range of, venous blood, 1360b C1 inhibitor deficiency (hereditary angioedema), 87 acquired, 88 C4d staining, 89 CA-19.9, as tumour markers, 1324b Cabergoline for brain tumours, 1130 nephrotoxicity, 427b for Parkinson’s disease, 1114b for prolactinoma, 685b CABG see Coronary artery bypass grafting Cabozantinib, for medullary carcinoma,

Cachexia, cancer, 693f CADASIL, 1095 Cadherin-1 (CDH1), 1319 Cadmium, lung cancer, 618 Caecum, cancer, 831 Caeruloplasmin, 1360b Wilson’s disease, 896 Café au lait spot, 1131f Caffeine, 716 cagA see Cytotoxin-associated gene Calabar swelling, 292 Calcific periarthritis, 1017, 1017f Calcification artery, 452 metastatic, 369 in musculoskeletal disease, 988 Calcimimetic agents, 419 Calcineurin inhibitors, 1226 Calcinosis crystal-associated arthritis and deposition in connective tissue, 1013b nephrocalcinosis, 427b, 431 Calcipotriol, 1250 Calcitonin for Paget’s disease, 1054b as tumor markers, 1324b Calcitonin gene-related peptide (CGRP), 771–772 Calcitriol (1,25-dihydroxycholecalciferol), for hypoparathyroidism, 665 Calcium, 716 absorption, 716 acute kidney injury and, 416b deficiency, 716 dietary sources of, 717b excess, 716 homeostasis, 367 in myocardial contraction, 446 for osteoporosis, 1048, 1048b pregnancy and, 1272 reference nutrient intake of, 717b reference range of urine, 1361b venous blood, 1360b in skeletal disease, 990b stone, prevention of, 433b see also Hypercalcaemia; Hypocalcaemia Calcium and vitamin D supplements,

Calcium antagonists (channel blockers) adverse reactions of, 22b for angina, 491b for arrhythmias, 472 for hypertension, 513 for hypertrophic cardiomyopathy, 540 for mitral stenosis, 519 poisoning from, 140 for pulmonary hypertension, 622 for Raynaud’s phenomenon, 1038 Calcium carbonate, 419 Calcium gluconate, 368 cardiotoxic drug poisoning, 140 drug interactions, 24b for hypermagnesaemia, 368 Calcium oxalate crystal, 147 stones, 431b Calcium phosphate, stones, 431b Calcium pyrophosphate crystals, 663 Calcium pyrophosphate dihydrate (CPPD) crystal deposition disease, 1016–1017 Calcium therapy for hypoparathyroidism, 665 for osteoporosis, 1047 for rickets/osteomalacia, 1052 tetany, 663 Calculi (stones) gallbladder see Gallstones renal, 431, 431b staghorn, 431, 432f urinary, 431 see also Gallstones Calicivirus, 872b Calprotectin, faecal, 777b, 1361b ‘Cameron lesions’, 793 Campbell de Morgan spots, 1234, 1234f Campylobacter jejuni Guillain-Barré syndrome, 1140 infection, 262 Camurati-Engelmann disease, 1056 Canakinumab for gout, 1015 for musculoskeletal disease, 1007, 1007b Canalicular system, 918 Cancer, 1316, 1316f, 1333b aetiology, environmental, 1320b biochemical markers, 1323 breast, 1333–1334 clinical features of, 1333–1334 investigations of, 1334 management of, 1334 pathogenesis of, 1333 staging, 1333b survival rates for, 1333, 1333b cervical, 1335 investigations in, 1335 management of, 1335 pathogenesis of, 1335 childhood, 1298 clinical examination of, 1314, 1314f colorectal, 830–833 clinical features of, 831 dietary risk factors for, 830b familial adenomatous polyposis, 828–829, 829b, 829f

INDEX • 1373 investigations of, 832, 833f management of, 832 modified Dukes classification and survival of, 832f non-dietary risk factors for, 830b pathogenesis of, 830f pathophysiology of, 830–831, 831f prevention and screening of, 832–833 determinants of, 1320–1321 environmental, 1320–1321, 1320b genetic, 1321, 1321b ectopic hormone production, 1325, 1325b emergency complications of, 1326–1328 endometrial, 1334–1335 investigations of, 1334 management of, 1335 pathogenesis of, 1334 of gallbladder, 904 hallmarks of, 1316–1320 activating invasion and metastasis,

angiogenesis, 1318, 1319f enabling replicative immortality,

evading growth suppressors, 1318 evading immune destruction, 1320 genome instability/mutation, 1316 reprogramming energy metabolism,

resisting cell death, 1316–1317 sustaining proliferative signalling,

tumour-promoting inflammation, 1319–1320 histology of, 1322 cytogenetic analysis, 1322 electron microscopy, 1322 immunohistochemistry, 1322 light microscopy, 1322 HIV-related, 322, 323b imaging for, 1323 inheritance, 1321b investigations of, 1321–1323, 1322b local features of, 1324b lung, 599–603, 599f burden of, 598b cell types in, 599b clinical features of, 599–601 investigations of, 601–602 management of, 602–603 non-metastatic extrapulmonary manifestations of, 601b occupational, 618 pathology of, 599, 599f prognosis for, 603, 603b metastatic disease, 1328–1329 neurological paraneoplastic syndromes, 1325–1326 obesity and, 698f in older people, 1325b oral, 790, 790b ovarian, 1334 investigations of, 1334 management of, 1334 pathogenesis of, 1334 predisposition syndromes, 1321b presenting problems of, 1323–1326, 1324b–1325b renal cell, 434–435, 435f screening, breast cancer, 1325b staging, TNM classification, 1322b therapeutics for, 1329–1333 adjuvant, 1329 biological, 1332 chemoprevention, 1330 chemotherapy, 1330 hormonal, 1332 immunotherapy, 1332 neoadjuvant, 1330 palliative, 1329 radiation therapy, 1331–1332 surgical, 1330 of unknown origin, 1336, 1336b see also Chemotherapy; specific cancers Cancer antigen 19.9 (CA-19.9), 1324b Cancer antigen 125 (CA-125), 1324b Cancer cachexia, 693f Candesartan for heart failure, 466b for myocardial infarction, 500–501 Candida albicans, 300 Candida dubliniensis, 302 Candida glabrata, 302 Candida krusei, 302 Candida parapsilosis, 302 Candida spp., 100, 103f endocarditis, 528 Candida tropicalis, 302 Candidiasis, 334b, 336b acute disseminated, 302 chronic disseminated, 302 genital, 735b oesophageal, 794 oral, 790 skin, 1240 superficial, 300 systemic, 302 Cannabis, 143 CAPD see Continuous ambulatory peritoneal dialysis Capecitabine, 832 Caplan’s syndrome, 610–611 Capnocytophaga canimorsus, 226b Capnography, 175f Capsaicin for herpes zoster, 240 for osteoarthritis, 1003–1004 topical, 315 Capsule endoscopy, 774–776, 775f wireless, 775f, 776b Capsulitis (frozen shoulder), 997–998 Caput medusae, 868 Carbamate insecticides, 146–147 Carbamazepine for epilepsy, 1102b hyponatraemia, 1103b multiple sclerosis, 1110b pharmacodynamics, 20b poisoning, 141b for status epilepticus, 1081b for trigeminal neuralgia, 1097 Carbapenems, 120b, 121 Carbaryl, 1241 Carbenoxolone, 361 sodium content of, 864b Carbidopa, 1113 Carbimazole for Graves’ thyrotoxicosis, 644 for thyrotoxicosis, in pregnancy,

Carbohydrates, 695–697 in diabetic diet, 743–744 dietary, 696b energy provided by, 694 recommended intake, 698b digestion of, 768 metabolism, 850 disorders of, 370 see also Diabetes mellitus effects of insulin in, 723b Carbon dioxide arterial blood (PaCO2), 204, 1358b removal of, extracorporeal, 204 Carbon monoxide poisoning, 134b, 144–145 Carbonic acid/bicarbonate buffer system, 363–364 Carbonic anhydrase, 717 Carbonic anhydrase inhibitors, for hypervolaemia, 354 Carboplatin, 1334 Carboxyhaemoglobin, reference range of, 1360b Carboxypenicillins, 121 Carbuncles, 1237, 1237f Carcinoembryonic antigen (CEA), 1322, 1324b Carcinoid syndrome pellagra, 714 valvular heart disease, 526 Carcinoid tumours gastric, 805 lung, 603b Carcinoma at ampulla of Vater, 907–908 anaplastic, 650 basal cell, 1229–1230, 1229f, 1230b, 1324b bronchial gland, 603b bronchoalveolar, 603b fibrolamellar hepatocellular, 892 follicular, 649 of gallbladder, 907 gastric, 803–804, 804f hepatocellular, 890–892, 891f chemotherapy for, 892 cirrhosis and, 890 fibrolamellar, 892 hepatic resection for, 891 hepatitis B and, 873 liver biopsy for, 891 liver transplantation for, 891 management of, 892f in old age, 901b percutaneous therapy for, 891 screening for, 890–891 trans-arterial chemo-embolisation for, 892 medullary, 650 of oesophagus, 796–797 of pancreas, 843f papillary, 649 squamous, 796b skin, 1230–1231, 1231f of unknown origin, 1336, 1336b see also sites of carcinoma Carcinoma in situ, 1230b Card agglutination trypanosomiasis test (CATT), 279 Cardiac arrest, 456–457, 456b, 456f chain of survival in, 457, 458f clinical assessment and management of, 456–457, 457f–458f post, 200–201 acute management of, 201, 201b prognosis of, 201, 201b Cardiac arrhythmias, 1198 Cardiac biomarkers, 450 for acute coronary syndrome, 497, 498f Cardiac catheterisation, 453–454, 453f aortic regurgitation, 525b aortic stenosis, 523b mitral valve disease, 519, 521b Cardiac death, organ donation after,

Cardiac disease, 899 HIV-related, 322 in pregnancy, 1282 aortic dissection, 1282 congenital, 1282 dilated cardiomyopathy, 1282 myocardial infarction, 1282 peripartum cardiomyopathy, 1282 valvular, 1282 Cardiac glycosides see Digoxin Cardiac output, 447–448 heart failure, 461 Cardiac pacemakers code, 483b permanent, 469, 483, 483b rate-responsive, 483 temporary, 482–483, 483f Cardiac peptides, 446–447 Cardiac resynchronisation therapy, for arrhythmias, 484 Cardiac tamponade, 447–448, 544, 544b see also Heart Cardiac transplantation, 467–468 Cardiac tumours, 541–542 Cardiobacterium hominis, 528 Cardiogenic shock, 199–200, 206b causes of, 200f downward spiral of, 199, 200f Cardiology, 441–544 Cardiomegaly, 450 Cardiomyopathy, 538–541, 539f, 541b arrhythmogenic ventricular, 540 dilated, 1282 HIV-associated, 322 hypertrophic obstructive, 1297–1298 obliterative, 541 peripartum, pregnancy and, 1282 restrictive, 540 septic, 198 types of, 539f Cardiopulmonary resuscitation (CPR), 213b see also Basic life support Cardiothoracic ratio, 450 Cardiotoxicity, venom and, 155 Cardiovascular disease chronic kidney disease and, 420 congenital, 531–538 hypertension see Hypertension investigation of, 448–454 New Heart Association (NYHA) functional classification of, 454, 454b ophthalmic features of, 1165b presenting problems in, 454–468 in rheumatoid arthritis, 1024 risk of, obesity, 699f syphilis, 338 in systemic lupus erythematosus,

transition medicine and, 1297–1298 congenital heart disease, 1297 hypertrophic obstructive cardiomyopathy, 1297–1298 Cardiovascular medications, poisoning from, 140 Cardiovascular risk prediction chart, 511f Cardiovascular support, in intensive care, 204–208 advanced haemodynamic monitoring, 206, 207b, 207f fluid and vasopressor use, 206, 206b initial resuscitation, 204–206, 206b mechanical, 206–208 Cardiovascular system clinical examination of, 442–444, 442f pregnancy and, 1272 Cardioversion, 482 atrial fibrillation, 470–471 direct current (DC), 470 ventricular tachycardia, 475 Carditis, 515–516 Care see Health care Carey Coombs murmur, 515–516 Carnitine-palmitoyl transferase (CPT) deficiency, 1144b Caroli’s disease, 902 Carotenes, 712–713 Carotid endarterectomy, 1160 Carotid pulse, 166, 189 Carpal tunnel syndrome, 1058 diabetes, 760 rheumatoid arthritis, 1024 Carrion’s disease, 272 Cartilage articular, 987, 987f calcification of, 988 osteoarthritis in, 1010 Carvedilol, 869 for arrhythmias, 481 for hypertension, 513 Casal’s necklace, 714, 715f Caspases, 41 Caspofungin, 125b, 126 for acute leukaemia patients, 957 for aspergillosis, 598 Cassava, 839–840 Castleman’s disease, 220b, 248 Cat scratch disease, 272 Cataplexy, 1105 Cataract diabetics, 756b in ophthalmological conditions, 1174 ‘snowflake’, 1177 Catatonia, 1196–1197 Catechol-O-methyl-transferase (COMT) inhibitors, for Parkinson’s disease, 1114 Catecholamines, 666 drug interactions, 24b Catephen, for anogenital warts, 343 Cathepsin K, 985

1374 • INDEX Catheter ablation therapy, 484, 484f for arrhythmias, 470 Catheters/catheterisation bacteriuria, 429–430 bladder dysfunction, 1094b cardiac, 453–454, 453f aortic regurgitation, 525b aortic stenosis, 523b mitral valve disease, 519, 521b pulmonary artery, critically ill patients, 206, 207f Cathinones, 143 CATT see Card agglutination trypanosomiasis test Cauda equina syndrome, 997b Caudal regression syndrome, 1278–1279 Caval filters, for pulmonary embolism,

Cawthorne-Cooksey exercises, 1104 CBT see Cognitive behaviour therapy CCK see Cholecystokinin CD4 cells, in HIV infection/AIDS, 309–310 CD4+ T lymphocytes, 70 CD8+ T lymphocytes, 70 CDKs see Cyclin-dependent kinases CEA see Carcinoembryonic antigen Cefaclor, 121b Cefalexin, 121b for urinary tract infection, 428 Cefazolin, 121b Cefepime, 117b, 121b Cefixime, 121b for gonorrhoea, 340b Cefotaxime, 117b, 121b for cerebral abscess, 1124b for meningitis, 1120b for spontaneous bacterial peritonitis,

Cefoxitin, 121b Cefradine, 121b Ceftaroline, 121b Ceftazidime, 117b, 121b for bronchiectasis, 579 for melioidosis, 261 Ceftobiprole, 121b Ceftriaxone, 117b, 121b for leptospirosis, 258–259 for meningitis, 1120b for nocardiosis, 261 for pneumonia, 319 for pyogenic meningitis, 1120b for STIs congenital syphilis, 339 gonorrhoea, 340b for Whipple’s disease, 809 Cefuroxime, 117b, 121b for cerebral abscess, 1124b for cholecystitis, 905 for empyema, 565 for meningitis, 1120b for pneumonia, 585b, 586 prophylactic, 119b Cefuroxime axetil, 256 Celecoxib, 1003b Cell adhesion molecules, 1318f Cell body, 1338 Cell cycle, 1317, 1317f regulation, 1317 stimulation, 1317 Cell differentiation, 40–41 Cell migration, 40–41 Cell surface antigens, 917 Cells cerebrospinal fluid analysis of, 1077, 1078b, 1361b death of, 41, 1316–1317 programmed (apoptosis), 1316 division of, 40–41 of nervous system, 1064–1065, 1064f senescence of, 41 Cellular immunity, 69–70, 69f Cellulitis, 1237, 1237f anaerobic, 227 clinical assessment of, 187 investigation of, 187 Central core disease, 1145b Central nervous system (CNS) HIV infection/AIDS, 309–310 tuberculosis, 591 Central sensitisation, 1340, 1341f Central termination, 1338 Central venous catheter infections, 225–226 Central venous pressure, monitoring of, 175f, 190b Cephalosporin, 117b, 121, 121b for cholecystitis, 905 for pneumonia, 586 in pregnancy, 120b renal or hepatic disease, 32b for septic arthritis, 1020 for variceal bleeding, 869, 869b Cephamycins, 121 Cerebellar ataxia, 1325 Cerebellar degeneration, cancer-related, 1325, 1325b Cerebellar dysfunction, 1134 Cerebellum, 1069 Cerebral abscess, 1124, 1124b, 1124f Cerebral cortex anatomy of, 1067f lobar functions of, 1066b effects of damage, 1066b Cerebral hemispheres, 1066–1067, 1066b, 1067f lesions, 1084 Cerebral infarction, 1153–1154, 1153f–1154f Cerebral ischaemia, 967f Cerebral oedema acute liver failure and, 857 high-altitude, 168 hypoglycaemia, 740 stroke patients, 1154–1155 Cerebral palsy, transition medicine and,

Cerebral perfusion pressure (CPP), 208 Cerebral toxoplasmosis, HIV-related, 315b, 320, 320f Cerebral tumours see Brain, tumours Cerebral venous disease, 1162 causes of, 1162b clinical features of, 1162, 1162b investigations and management of,

Cerebrospinal fluid (CSF), 1067 analysis, 1077, 1078b, 1361b circulation, 1128b encephalomyelitis, 1110 Guillain-Barré syndrome, 1140 meningitis, 1118, 1121 multiple sclerosis, 1108 result of, interpretation of, 1077, 1078b in subacute sclerosing panencephalitis, 1123 syphilis and, 339 in viral encephalitis, 1122 see also Lumbar puncture Cerebrotendinous xanthomatosis, 375b Cerebrovascular disease see specific conditions Certolizumab, for musculoskeletal disease, 1007b Cervical cancer, 1335 HIV-related, 322 investigations of, 1335 management of, 1335 pathogenesis of, 1335 Cervical cord compression, 1134f in cervical spondylosis, 1134f in rheumatoid arthritis, 1024b Cervical spine myelopathy, 1134–1135 radiculopathy, 1134, 1134f spondylosis, 1134–1135, 1134f subluxation of, 1024, 1025f Cervicitis, gonococcal, 335 Cestode infections, 233b, 297–299 Cetirizine, 1227 Cetuximab, 832, 1335–1336 CF see Cystic fibrosis CFTR see Cystic fibrosis transmembrane conductor regulator (CFTR) protein CFU-E (colony-forming unit erythroid), 914–915 CFU-GM (colony-forming unitgranulocyte, monocyte), 914 CFU-Meg (colony-forming unitmegakaryocyte), 914, 918 CGRP (calcitonin gene-related peptide), 771–772 Chagas’ disease, 279–280 transfusion-transmitted, 930–931 Chain of infection, 100f Chain of survival, in cardiac arrest, 457, 458f Chancre, 333–334 trypanosomal, 278 Chancroid, 341b Channelopathies, 1144, 1145b Charcoal, activated, 136, 136b antidiabetic overdose, 141 digoxin/oleander poisoning, 140 NSAID overdose, 138 salicylate poisoning, 138 tricyclic antidepressant poisoning,

Charcot joints, 1057, 1058f Charcot-Marie-Tooth disease (CMT),

Charcot neuroarthropathy, 762 Charcot’s triad, 861–862 acute cholangitis and, 905 Charles Bonnet’s syndrome, 1088 Cheese worker’s lung, 616b Cheiroarthropathy, 1057 Chelating agents, 165 Chemical cholestasis, 902 Chemical poisoning, 144–149 Chemical warfare agents, poisoning from, 149, 149b Chemicals, in haemolysis, 950 Chemo-embolisation, hepatocellular carcinoma, 892 Chemokine receptor inhibitor, 324b Chemoprevention, 1330 Chemoprophylaxis, 112b for malaria, 277, 278b Chemotherapy, 936, 936b, 1330 adjuvant, 1329 breast cancer, 1334 adverse effects, 1330, 1331f for brain tumours, 1130–1131 combination therapy, 1330 for hepatocellular carcinoma, 892 for high-grade NHL, 966 for Hodgkin lymphoma, 963 leukaemia acute, 956b chronic lymphocytic, 960 chronic myeloid, 959 for low-grade NHL, 965 for lung cancer, 602–603 for multiple myeloma, 968 neoadjuvant, 1330 palliative, 1329 platinum-based, 602–603 for prostate cancer, 439 for tuberculosis, 592–594 Chernobyl, 164 Chest infection, in stroke patients, 1159f Chest pain, 176–179, 454–455 associated features of, 177–178, 178f cardiac disease, aortic dissection,

characteristics of, 177 clinical assessment of, 178 differential diagnosis of, 177b investigations of, 178–179, 179b ischaemic, 454f onset of, 177 pregnancy and, 1275 in respiratory disease, 558 site and radiation of, 177 Chest radiography/X-ray, 450 for bronchiectasis, 579 cardiovascular disorders for aortic regurgitation, 451f for chronic constrictive pericarditis, 544f for heart failure, 464, 464f for mitral valve, 451f for myocardial infarction, 497–498 of cardiovascular system, 450 for COPD, 575 for empyema, 564f of pacemaker/defibrillator, 467f for pleural effusion, 563 pregnancy and, 1274 for respiratory disease abnormalities, 552b ARDS, 199f aspergillosis, 597f asthma, 569 bronchial obstruction/lung collapse, 600f bronchiectasis, 579 COPD, 575 empyema, 564f haemoptysis, 560 HIV-related pulmonary disease, 318b, 318f–319f interpretation, 551b interstitial, 605f lobar collapse, 552f mediastinal tumours, 604f pleural effusion, 563 pleural plaques, 617f Pneumocystis jirovecii pneumonia, 318f pneumonia, 585 pneumothorax, 626 pulmonary embolism, 619b, 619f pulmonary hypertension, 622f sarcoidosis, 609b silicosis, 615f tuberculosis, 590f, 592f Chest wall deformities, 628 Chickenpox, 238–239 clinical features of, 238–239, 238f diagnosis of, 239 incubation period of, 111b management and prevention of, 239, 239b periods of infectivity, 111b rash, 238 varicella zoster immunoglobulin, 240b Chiclero ulcers, 285 Chief cells, 661 Chikungunya virus, 250 Chilblains, 167 Child-bearing potential, cystic fibrosis and, 1297 Child-Pugh classification, cirrhosis prognosis and, 867b Childbirth, associated psychiatric disorders, 1206 Childhood absence epilepsy, 1100b Childhood cancer therapy, late effects of, 689 Children diabetes mellitus in, 753–754, 754b important long-term conditions of, adult health affected by, 1288b inflammatory bowel disease and, 823,

laboratory reference range of, 1363 osteomyelitis in, 1021 renal impairment in, causes of, 1298b STI in, 332–333 Chiropractic, 826b Chlamydia pneumoniae, 272b Chlamydia psittaci, 272b Chlamydia spp., 272 Chlamydia trachomatis, 100–101, 117b,

in pregnancy, 235b, 332b Chlamydial infection, 340–341 in men, 340 in reactive arthritis, 1031 treatment of, 341b urethritis, 333 in women, 340–341 Chloasma, 1258 Chlorambucil for chronic lymphocytic leukaemia,

for non-Hodgkin’s lymphoma, 965 for Waldenström macroglobulinaemia,

INDEX • 1375 Chloramphenicol, 117b, 124 contraindication to, in pregnancy, 120b mechanism of action, 116b for meningitis, 1120b for plague, 259 in pregnancy, 120b for pyogenic meningitis, 1120b in renal/hepatic disease, 32b for rickettsial fevers, 271–272 Chloride, 349b, 718 channelopathies, 1145b reference range of, venous blood, 1358b Chloroquine adverse reactions of, 22 pigmentation, 1258b leprosy reactions, 270 for malaria, 128, 278b myopathy, 1057b poisoning, 141b resistance to, 273, 277 Chlorphenamine, 33b anaphylaxis, 76b diphtheria, 625 pruritus, 935f Chlorpromazine for acute diarrhoea, 230 for alcohol withdrawal, 1195 for cholestatic hepatitis, 894 hepatotoxicity, 894b long QT syndrome, 476b poisoning, 141 for rabies, 1122 for schizophrenia, 1197 Chlorpropamide, neutropenia, 926b Cholangiocarcinoma, 892, 907, 907f primary sclerosing cholangitis and,

Cholangiography, 906 for hepatobiliary disease, 854–855 percutaneous transhepatic (PTC), 854–855 for sclerosing cholangitis, 888 Cholangiopancreatography endoscopic retrograde see ERCP magnetic resonance see MRCP Cholangiopathy, HIV-related, 318 Cholangitis acute, 905 liver flukes, 297, 297b primary biliary, 887–888 IgG4-associated, 890, 909 primary sclerosing, 888–890 recurrent pyogenic, 906–907 Cholecalciferol see Vitamin D Cholecystectomy in old age, 909b for pancreatitis, 839 post-cholecystectomy syndrome, 908b Cholecystitis, 905 acalculous, 905 acute, 788, 905 in old age, 909b chronic, 905 gallstones and, 904 pregnancy and, 900 Cholecystography, oral, 909 Cholecystokinin (CCK), 768, 768f, 772b Cholecystolithiasis, 904 Choledochal cysts, 903, 903f Choledochojejunostomy, 842–844 Choledocholithiasis, 904, 906–907 endoscopic retrograde cholangiopancreatography for, 906f endoscopic ultrasound for, 906f Choledochoscopy, 906 Cholera, 104b, 264–265 clinical features of, 265 diagnosis and management of,

fluid loss, 265 incubation period of, 111b prevention of, 265 ‘Cholera sicca’, 265 Cholestasis, 894 benign recurrent intrahepatic, 902 biliary cirrhosis, 903 chemical, 902 obstetric (of pregnancy), 1220b, 1284 pruritus, 1220b pure, 894 sclerosing cholangitis, 889 Cholestatic jaundice, 860b–862b, 861–862 Cholesterol, 370 absorption of, 697 atheroembolism, 390b dietary, 698b gallstones, 903, 903b low-density lipoproteins, 371–372 metabolism of, 81 reference range of, venous blood, 1360b transport of, 372–373 see also Hypercholesterolaemia Cholesterol absorption inhibitors, 371 Cholesterol emboli, 409, 409f Cholesterol ester transfer protein (CETP), 373 Cholesterol gallstones, 903, 903b Cholesterolosis of gallbladder, 909 Choline salicylate, 790 Cholinergic syndrome, organophosphate poisoning, 146, 146b Chondrocalcinosis, 1016, 1016b, 1016f Chondrocytes in osteoarthritis, 1008 tumours, 1056b Chondroitin sulphate, 987 for osteoarthritis, 1012 Chondroma, 1056b Chondrosarcoma, 1056b, 1057 CHOP regimen, for non-Hodgkin lymphoma, 966 Chorea, 1085 causes of, 1085b in Huntington’s disease, 1085 Chorionic villus sampling, 56 Choroid, of eye, 1167 Choroid plexus, 1132f Christmas disease, 973–974 Chromatin, 38, 38f Chromatography, 348b Chromium, 718 deficiency, 718 Chromoblastomycosis, 300–301 Chromosomal disorders, 44b, 45f see also specific conditions Chromosomes, 38, 38f, 51–52, 52f abnormalities see Mutation(s) analysis of, 45f leukaemia, 955–956 myelodysplastic syndromes, 960–961 deletions, 52 duplication, 44, 45f sex, 38 see also X chromosome; Y chromosome translocations of, 805 Chronic allograft failure, 89 Chronic bronchitis, 555b, 573–574 Chronic cavitary pulmonary aspergillosis, 597, 597f Chronic cold agglutinin disease, 950 Chronic constrictive pericarditis, 543–544, 543b, 544f Chronic demyelinating polyneuropathy, 1139b, 1141 Chronic eosinophilic pneumonia, 611–612 Chronic exertional breathlessness, 557–558, 558b Chronic fatigue syndrome, 1202 Chronic fibrosing pulmonary aspergillosis, 597 Chronic graft-versus-host disease, 937 Chronic granulomatous disease, 77 Chronic inflammation, 71 Chronic interstitial nephritis, 402–403, 403b Chronic intestinal pseudo-obstruction, 810–811, 811b Chronic kidney disease, 415–420, 417b causes of, 415b haemodialysis in, 422–423 indications for dialysis for, 422b osteodystrophy and, 419f physical signs of, 416f pregnancy and, 1282, 1283f staging of, in children over 2 years of age, 1298b transition medicine and, 1298–1299 Chronic laryngitis, 624, 624b Chronic liver failure causes of, 856f, 867b cirrhosis and, 867 Chronic lymphocytic leukaemia (CLL), 959–960 clinical features of, 959 investigations of, 959–960 management of, 960 prognosis of, 960 staging of, 960b Chronic meningococcaemia, 1119 Chronic mesenteric ischaemia, 827 Chronic myeloid leukaemia (CML), 958–959 characteristics of, 958 clinical features of, 958 investigations of, 959 management of, 959 accelerated phase, 959 blast crisis, 959 chronic phase, 959, 959b natural history of, 958 Chronic obstructive pulmonary disease see COPD Chronic pain syndrome, 1348–1349 Chronic pancreatitis, 839–841, 840b complications of, 840b investigations of, 840, 841b, 841f management of complications of, 841 pathophysiology of, 840f Chronic pulmonary aspergillosis (CPA), 596–597 Chronic pulmonary tuberculosis, complications of, 590b Chronic renal failure see Renal failure, chronic Chronic respiratory failure, 566–567 management of, 566–567, 566b Chronic rheumatic heart disease, 517 Chronic venous insufficiency, 187 Chronic widespread pain, 1349 CHRPE see Congenital hypertrophy of the retinal pigment epithelium Chrysops, loiasis, 292 Churg-Strauss syndrome, 1043 Chvostek’s sign, 367 Chylomicrons, 697 Chylothorax, 562–563 Chyluria, lymphatic filariasis, 291 Chymotrypsinogen, 770b Ciclesonide, 571 Ciclosporin adverse reactions of chronic interstitial nephritis, 427b musculoskeletal, 1057b proximal myopathy, 1145f for aplastic anaemias, 969 asthma, 572 drug interactions, 24b eczema, 1246 heart transplant patients, 467 HSCT, 937 immunosuppression, 89b for inflammatory bowel disease, 821b for lichen planus, 1252 liver transplant patients, 901 lung transplant patients, 567 for primary biliary cholangitis, 888 for psoriasis, 1250 for pyoderma gangrenosum, 1261–1262 for skin disease, 1227–1228 Ciclosporin A, for musculoskeletal disease, 1004b, 1005 Cidofovir as antiviral agents, 127b CMV, 243 for herpesvirus infection, 126, 127b Cigarette smoke, in lower airway defences, 550 Ciguatera poisoning, 149–150 Cilia, 62–63 Ciliary body, of eye, 1167 Ciliary dysfunction syndromes, 578b,

Ciliary dysmotility syndrome, 550 Cilostazol, 504 Cimetidine drug interactions of, 24 neutropenia, 926b for urticaria, 1254 Cinacalcet, for primary hyperparathyroidism, 664 Ciprofloxacin, 117b, 123b for anthrax, 267 for bacillary dysentery, 265 for bronchiectasis, 579 for brucellosis, 255b for cholera, 265 drug interactions of, 23 for inflammatory bowel disease, 823 for intestinal bacterial overgrowth, 808–809 for meningococcal infection, 1120 for plague, 259 for primary sclerosing cholangitis, 890 prophylactic, 119b for Q fever, 272 for spontaneous bacterial peritonitis,

for STIs chancroid, 341b gonorrhoea, 340b for urinary tract infection, 429b for variceal bleeding, 869 Circinate balanitis, 334b, 1031 Circulation assessment of, in deteriorating patient, 189 coronary, 444–445 enterohepatic, 19 portal, 384, 385f of stroke patients, 1159b Circulatory collapse, pregnancy and,

Circulatory failure (shock), 193 acute, 199–200 Circumduction, 1086 Circumflex artery (CX) in coronary circulation, 444–445, 445f with stenosis, 453f Cirrhosis, 866–867 alcoholic, 881–882, 881b ascites and, 867 biliary, secondary, 903 causes of, 866b–867b Child-Pugh classification of, 867b cryptogenic, 884 drugs to be avoided in, 894b haemochromatosis, 866–867 hepatic encephalopathy and, 865 hepatic fibrosis and, 866, 866f hepatitis B and, 873, 876 hepatitis C and, 877 hepatocellular carcinoma and, 890 macronodular, 866 management of, 867 micronodular, 866 non-alcoholic fatty liver disease and, 882–883, 883f portal hypertension and, 869 survival in, 868b, 868f Cisplatin for head and neck tumours, 1335–1336 hypomagnesaemia and, 368b nephrotoxicity, 427b polyneuropathy, 1139b Citalopram, 1199b Citric acid (Krebs) cycle, 49, 714 Citrobacter freundii, 225 Citrobacter spp., 117b CJD see Creutzfeldt-Jakob disease CK see Creatine kinase Clarithromycin drug interactions, 24b H. pylori eradication, 800

1376 • INDEX for leprosy, 269 for Mycobacterium avium complex, 315b for pneumonia, 585b in pregnancy, 120b Clasp-knife phenomenon, 1068–1069 Classical syndromes, 633 Claude syndrome, 1072b Clearance, 19 CLI (critical limb ischaemia), 502–503 Climate change, 94 Clindamycin, 117b for acne vulgaris, 1242–1243 for babesiosis, 278 for gas gangrene, 227 for malaria, 277b for MRSA, 252 for necrotising fasciitis, 227 in pregnancy, 120b for septic arthritis, 1020b Clinical biochemistry, 345–380 Clinical decision-making, 10–12 in cognitive biases, 11 dealing with uncertainty during, 5–6 in deciding pre-test probability, 11 in evidence-based history and examination, 11 heuristic, 7b in human factors, 11 in interpreting results, 11 in person-centred EBM and patient information, 12 in post-test probability, 11 in reducing cognitive error, 11 reducing errors in, 9–10 cognitive debiasing strategies, 8f, 9–10 effective team communication, 10, 10b using clinical prediction rules and other decision aids, 10 in treatment threshold, 11 Clinical endpoints, 35–36 Clinical genetics, 37–59 Clinical immunology, 61–90 functional anatomy and physiology in, 62–70, 62f Clinical pharmacology, 14–19 Clinical reasoning, 2, 2f Clinical skills, 3, 3f Clinical therapeutics, 13–36 Clinical trials, 27–28, 28f Clobazam, 1102b Clobetasol, 334b, 336b, 1226b Clobetasone butyrate, 1226b for eczema, 1244 Clock drawing test, 1149f Clofazimine for leprosy, 269 pigmentation from, 1258b for tuberculosis, 125 Clomethiazole, effect of old age, 32b Clomifene, for infertility, 656–657 Clomipramine, 1199b for narcolepsy, 1105 Clonal expansion, 68, 68f Clonazepam for epilepsy, 1102b for periodic limb movement syndrome, 1106 for sleep disorders, 1105 Clonic seizures, 1100 Clonidine diarrhoea, 761b opiate withdrawal, 1196 Clonorchiasis, 297b Clonorchis sinensis, choledocholithiasis and, 906 Clonorchis spp., 129 Clopidogrel for angina, 489 for myocardial infarction, 498b,

for peripheral arterial disease, 504b pharmacokinetics, 20b platelet inhibition, 918 for stroke prevention, 1161f Clostridium botulinum, 104b, 1126 Clostridium difficile, 103f, 104b, 117b, 264, 264f Clostridium novyi, in injecting drug-user, 222–223 Clostridium perfringens anaerobic cellulitis from, 227 food poisoning, 262 Clostridium perfringens sepsis, 950 Clostridium spp., 102f–103f Clostridium tetani, 104b Clotrimazole, 125b for erythrasma, 1238 Clotting see Coagulation Clotting factors, 850, 918–919 Clozapine drug interactions, 24b schizophrenia, 1198b Clubbing, 1261, 1261f finger, 546f, 559, 559b, 559f asbestosis, 618 in lung cancer, 600 Cluster headache, 1096 CMV (cytomegalovirus) see Cytomegalovirus (CMV) infection CNS see Central nervous system Co-amoxiclav, 117b cholestatic hepatitis and, 894 for empyema, 565 hepatotoxicity of, 894b prophylactic, 119b for respiratory tract infection, pneumonia, 585b, 586 for urinary tract infection, 428 Co-artemether, 277 Co-phenoxylate, for inflammatory bowel disease, 821b Co-trimoxazole, 117b, 123 for brucellosis, 255b for cyclosporiasis, 287–288 for HIV infection/AIDS, 323–324, 323b for melioidosis, 261 for meningitis, 1120b for mycetoma, 301 for nocardiosis, 261 for Pneumocystis jirovecii pneumonia,

haematopoietic stem cell transplantation, 937b leukaemia patients, 957 prophylactic, 119b toxoplasmosis, HIV/AIDS patients,

for Whipple’s disease, 809 Coagulation, disseminated intravascular,

Coagulation disorders, 971–975 Coagulation factors, 850, 930 complications of therapy, in haemophilia A, 973 Coagulation screen, 922b, 1362b in disseminated intravascular coagulation, 921–922 Coagulation system, 918–919 activation of, 196 investigation of, 920–923 Coagulation tests, for hepatobiliary disease, 853 Coagulopathy, causes of, 972b Coal tar, 1250 Coal worker’s pneumoconiosis (CWP),

Cobalt, 718 Cocaine, misuse of, 143 Coccidioidomycosis, 304 Codeine cirrhosis and, 894b diarrhoea, 801 irritable bowel syndrome, 826f headache, 1096 pharmacokinetics, 20b Codons, 40 Coeliac disease, 805–807 clinical features of, 806 disease associations of, 806b investigations of, 806–807 liver function test (LFT) abnormality in, 854b pathophysiology of, 805, 806f Coeliac plexus neurolysis, 842–844 Coexisting disease, in choosing drugs,

Coffee, 716 type 1 diabetes and, 729 Cognitive behaviour therapy (CBT),

for eating disorders, 1204 for obsessive-compulsive disorder,

for schizophrenia, 1198 for somatoform disorder, 1203 Cognitive biases, 6–9, 11 in human factors, 9, 9f, 11 in medicine, 7–9, 8f in type 1 and type 2 thinking, 7, 7b, 7f Cognitive debiasing strategies, 8f, 9–10 history and physical examination in, 9 mnemonics and checklists in, 9 problem lists and differential diagnosis in, 9 red flags and ROWS (‘rule out worst case scenario’) in, 9–10 Cognitive function, assessment of, 1181–1183, 1182f Cognitive impairment, 1181 chemotherapy and, 1298 HIV-associated, 319–320 Cognitive therapy, 1190 Colchicine for Behçet’s disease, 1044 for CPPD crystal deposition disease,

for familial Mediterranean fever, 81 for gout, 1015 Cold agglutinin disease, 950 Cold antibodies, 949 Cold injury, 166–167 Colesevelam, 376–377 Colestipol, 376–377 Colestyramine, 376–377 for irritable bowel syndrome, 826f for post-cholecystectomy syndrome,

pruritus, 888, 1220b for radiation enteritis, 810 Colic biliary, 904 renal, 396 Colipase, 770b Colistin, 117b Colitis collagenous, 824 microscopic, 824 pseudomembranous, 104b ulcerative see Ulcerative colitis Collagen, 1213f in osteoarthritis, 1008 Collagenase, 64, 71 Colon, 770, 771f acute colonic pseudo-obstruction,

disorders of, 827–836 tumours of, 827–833 Colon cancer, hereditary non-polyposis, 831b Colonoscopy, 776, 776b for abdominal pain, 789 for colorectal cancer, 832 for gastrointestinal haemorrhage, 782–783 Colony-forming unit-granulocyte, monocyte (CFU-GM), 914 Colorectal cancer, 830–833 clinical features of, 831 dietary risk factors for, 830b familial adenomatous polyposis, 828–829, 829b, 829f, 1321b investigations of, 832, 833f management of, 832 modified Dukes classification and survival of, 832f non-dietary risk factors for, 830b pathogenesis of, 830f pathophysiology of, 830–831, 831f prevention and screening of, 832–833 Colorimetric chemical reaction, 348b Columnar lined (Barrett’s) oesophagus (CLO), 792 Coma, 1080 causes of, 194b definition of, 194 poisoning, 137b stroke patients in, 1153 Combination therapy, for hypertension,

Combined inhaled glucocorticoids and bronchodilators, for chronic obstructive pulmonary disease (COPD), 576 Comedone, definition of, 1242 Common variable immune deficiency,

Community-acquired pneumonia, 582–585, 582f clinical features of, 582–583 discharge and follow-up of, 585 investigations of, 583, 584b management of, 583–584 organisms causing, 582b prognosis for, 585 Comorbidities, in older people, 1307 Compartment syndrome abdominal, 195 identification of, 187b in injecting drug-user, 222–223 Competitive antagonist, 14 Complement, 66, 66f alternate pathway for, 66 autoimmune disease and, 84 classical pathway for, 66 deficiency in, 73b lectin pathway for, 66 pathway deficiencies in, 78 total haemolytic, 1360b Complement fixation test (CFT), 107–108 Complementary therapies for cancer pain, 1353 for pain, 1348 Complex regional pain syndrome (CRPS), 1348–1349, 1349b type 1, 1055, 1055f Compressed air, physics of breathing, 170b Concentration, 1181 Concordance, 1294 Condyloma, 343 Condylomata lata, 337 Confrontation, for visual fields, 631b Confusion/confusional states, 1196 cerebral oedema, 168 Congenital abnormalities, in pancreas, 842–844 Congenital adrenal hyperplasia, 676 hirsutism and, 658b Congenital heart disease, 531–538, 531b, 532f in adolescent, 537b adult, 537–538 cyanotic, 537b pregnancy and, 1282 transition medicine and, 1297 Congenital hypertrophy of the retinal pigment epithelium (CHRPE),

Congenital thyroid disease, 650–651 Congestive ‘portal hypertensive’ gastropathy, 871 Coning, 1077 Conjunctiva, 1164 Conjunctivitis, 1173 gonococcal, 339 Connective tissue disease, 1262–1263 respiratory involvement in, 610–611, 610b Conn’s syndrome, 361 Consanguinity, 48 Conscious level, decreased, 194–195 assessment of, 186f, 194–195, 194b management of, 195 Consent, artificial nutritional support, 710b Conservative treatment, for chronic kidney disease, 421 Clarithromycin (Continued)

INDEX • 1377 Constipation, 786–787 causes of, 786b clinical assessment of, 786–787 disorders of, 834–835 diverticulosis and, 833 in old age, 834b simple, 834 in stroke patients, 1159b Constitutional delay, of puberty, 653 Contact inhibition, 1318 Continence, faecal, 770 Continuous ambulatory peritoneal dialysis (CAPD), 424, 425b Continuous murmurs, 461 Continuous positive airway pressure (CPAP), 199b, 202 for drowning victims, 170 Continuous positive pressure ventilation,

Continuous venovenous haemofiltration (CVVH), 423 Contraception cystic fibrosis and, 1297 in epilepsy, 1103 Contrast media, nephrotoxicity and, 390b Contrast radiology, 773f Conversion (dissociative) disorder, 1202, 1202b COPD, 547f, 573–578 BODE index in, 577b classification of, 576b clinical features of, 575, 575b chronic exertional breathlessness, 575, 575b exacerbations of, 572–573 acute, 577–578 investigations of, 575–576 management of, 576–577, 576f, 577b occupational, 614 in old age, 578b pathophysiology of, 574–575, 574f prognosis of, 577 risk factors for, 574b Copper, 718 deficiency, 703b dietary sources of, 717b excessive, Wilson’s disease, 896 refeeding diet, 705b reference nutrient intake of, 717b reference range of urine, 1361b venous blood, 1360b Copper sulphate, poisoning from, 148 Copy number variations (CNV), 44, 44b, 45f Cor pulmonale, 550 Cornea, of eye, 1166–1167 Coronary angiography, for acute coronary syndrome, 498 Coronary artery, 444–445, 445f angiography of, 452f calcification, 452 with stenosis, 453f Coronary artery bypass grafting (CABG) for angina, 488, 491–493, 492f vs. PCI, 493b Coronary artery disease, 484–502, 487b clinical manifestations of, 485b Coronary artery dissection, pregnancy and, 1282 Coronary circulation, 444–445, 445f Coronary heart disease, obesity and, 698–699, 699f Coronary revascularisation, 467 Coronavirus, 111b Corrosives oesophagitis, 794 poisoning from, 147–148 Cortical (volitional) influences, in control of breathing, 549 Corticobasal degeneration, 1115 Corticosteroids biosynthetic enzyme defects, 671b for congenital adrenal hyperplasia,

see also Cortisol; Glucocorticoids; Hydrocortisone; Mineralocorticoids; Prednisolone Corticotrophin-releasing hormone (CRH), 633f Cortisol, 665 deficiency, hypopituitarism, 682 reference range of urine, 1361b venous blood, 1359b see also Hydrocortisone Corynebacterium diphtheriae, 104b Corynebacterium minutissimum, 1238 Corynebacterium spp., 103f Cough, 556, 556b aetiology of, 556 in asthma, 568 bovine, 600, 624 in COPD, 575 headache and, 1097b at high altitude, 168–169 in laryngeal nerve, paralysing, 553 in lung cancer, 599 in palliative care, 1353 in pneumonia, 582–583 refractory, 169 and upper airway defences, 550 in upper respiratory tract infection, 581–582 Cough reflex, 556 Coumarins, 938b, 939–940 Counselling, dietary for coeliac disease, 807 for hyperlipidaemia, 375–376 Coupled enzymatic reaction, 348b Courvoisier’s Law, 861–862 Cowden’s syndrome, 1321b Cowpox, 249 Coxiella burnetii, 100–101, 272 Coxsackie virus infections, 240 ‘Crack’ cocaine, 143 Cramps, heat, 167 Cranial nerves damage to, 1089b of envenomed patient, 152f examination of, 1063b nuclei, 1067 see also specific nerves by name Craniopharyngioma, 687, 687f Creams, 1225b Creatine kinase (CK) in hypothermia, 166 in muscular dystrophies, 1143–1144 reference range of, venous blood, 1360b Creatinine, 349b in acute kidney injury, 416b in hepatorenal syndrome, 864 reference range of urine, 1361b venous blood and, 1358b Creatinine phosphokinase (CPK) elevated serum, causes of, 991b in myopathy, 990–991 in myositis, 990–991 Cretinism, 717 Creutzfeldt-Jakob disease (CJD), 1127, 1127b variant, 933 Crigler-Najjar syndrome, 860b Critical care/critical illness, 173–214 admission requirement, 176 clinical examination in, 174, 174f in context of congenital conditions, 201, 202b disorders causing, 196–201 acute circulatory failure as, 199–200 acute respiratory distress syndrome as, 198 post cardiac arrest as, 200–201 sepsis and systemic inflammatory response as, 196–198 monitoring in, 175–176, 175b, 175f nutrition, 210 outcomes of, 211–214 adverse neurological, 211–212 discharge from intensive care as,

in older patient, 212 withdrawal of active treatment and death in intensive care as, 213 oxygen therapy in, 191, 191b referral, 212 renal support, 208 respiratory support, 202–204 scoring systems in, 213–214, 214b withdrawal of care, 213 Critical care medicine, decisions around intensive care admission in, 201, 202b Critical illness polyneuropathy, 211 Critical limb ischaemia, 502–503 Crohn’s colitis, primary sclerosing cholangitis and, 888 Crohn’s disease clinical features of, 816–817 cutaneous, 1263 ileal, 816f–817f management of, 820–823 pathophysiology of, 816, 816f refractory, 824 small bowel, differential diagnosis of, 817b treatment strategy for, 1300b Cross-infection, 103 see also Health care-associated infection Crust, skin, definition of, 1216 Cruveilhier-Baumgarten syndrome,

Cryoglobulinaemic vasculitis, 1043 Cryoglobulins, 1043 autoimmune disease and, 84 classification of, 84b Cryoprecipitate, 931b Cryotherapy for anogenital warts, 343 for basal cell papilloma, 1234 for granuloma annulare, 1263 for molluscum contagiosum, 343 for sarcoidosis, 1263 for skin disease, 1228 for warts, 343 Cryptic tuberculosis, 589b Cryptococcal meningitis, HIV-related,

Cryptococcosis, 302, 302f HIV-related, 315b prevention of, 324 Cryptogenic cirrhosis, 884 Cryptorchidism, in hypogonadism, 653 Cryptosporidia/cryptosporidiosis, 287,

HIV-related, 317b, 317f Crystal formation, 387, 427b, 1012, 1013f drug-induced, 427b Crystal-induced arthritis, 1012–1018, 1013b, 1013f Crystalloids, 782 CT (computed tomography) for acute respiratory distress syndrome, 198, 199f of aldosterone-producing adenoma, 674, 675f for cancer, 1323, 1323f of cardiovascular system, 452 coronary angiography, 452, 452f for decreased conscious level, 195, 195f of gastrointestinal tract, 773–774 for headache, 185–186 for hepatobiliary disease, 854 for cirrhosis, 854f multidetector, for hepatocellular carcinoma, 891 for musculoskeletal disease, 989 for neurological disease, 1073b cerebral abscess, 1124 epilepsy, 1101b stroke, 1151, 1157–1158, 1158b of phaeochromocytoma, 675, 676f for polycystic disease, 893f for renal disease, 389 for respiratory disease, 552, 553f aspergilloma, 597f bronchiectasis, 579f hypersensitivity pneumonitis, 617f interstitial lung disease, 605f pleural thickening, 618f pulmonary fibrosis, 607f for splenomegaly, 927 CTLA4, 70 Cullen’s sign, 837–838 Culture, blood, 106, 107f–108f Cupulolithiasis, 1104 CURB-65, 583f Curettage, for skin disease, 1228 Cushing’s disease, management of, 669 Cushing’s syndrome, 666–670 aetiology of, 667 classification of, 667b clinical assessment of, 667, 668f hirsutism and, 658b investigations of, 667–669, 669f–670f management of, 669–670 Cutaneous leishmaniasis, 284–285, 285b, 285f Cyanide poisoning, 135b Cyclical hormone replacement therapy, for amenorrhoea, 655 Cyclical vomiting syndrome, 803 Cyclicity of cortisol secretion, in Cushing’s syndrome, 668 Cyclin-dependent kinases (CDKs),

Cyclo-oxygenase, 1002–1003, 1003f Cyclophosphamide, 1320b for Churg-Strauss syndrome, 1043 glomerulonephritis, 400 for juvenile dermatomyositis, 1040 for leukaemias, 960, 963 for musculoskeletal disease, 1004b,

for neuromyelitis optica, 1110 for non-Hodgkin lymphoma, 965 for pemphigus, 1256 for rheumatic disease, 1004b for SLE, 1036 for vasculitis, 1041 for warm autoimmune haemolysis,

Cyclospora cayetanensis, 287–288 Cyclosporiasis, 287–288 Cypermethrin, 148b Cyproterone acetate, 659b for acne, 1243 for alopecia, 1259 for prostate cancer, 439 Cystathionine β-synthase deficiency,

Cysteine, 697b Cystic fibrosis (CF), 580–581, 580f, 581b, 842, 902 contraception and, 1297 fertility and child-bearing potential in,

transition medicine and, 1297 Cystic fibrosis transmembrane conductor regulator (CFTR) protein, 1297 Cysticercosis, 297f–298f, 298 Cystinuria, 405 Cystoisospora belli diarrhoea, HIV-related, 315b Cystoisosporiasis, HIV-related, 317b Cysts Baker’s (popliteal), 999b, 1023 rupture, 1023 choledochal, 903, 903f hydatid, liver and, 880 Cytarabine for acute leukaemia, 957b for chronic myeloid leukaemia, 959 Cytochrome P450, 18 Cytogenetic analysis, 1322 Cytokeratin, as tumour markers, 1322, 1324b Cytokines, 64–66, 65b, 65f asthma, 568 cancer, 1319 defects in, 78 immune response regulation, 65b pro-inflammatory, 70, 1005 Cytology, in respiratory disease, 554

1378 • INDEX Cytomegalovirus (CMV) infection, 238b, 242–243 after HSCT, 937b clinical features of, 242–243 encephalitis, 320 investigations of, 243 liver transplantation and, 901 management of, 243 polyradiculitis, 321 in pregnancy, 235b viral hepatitis and, 878 Cytopathic hypoxia, 197f Cytosine, 38 Cytotoxic oedema, 1153–1154 Cytotoxic therapy, for myelofibrosis, 969 Cytotoxin-associated gene (cagA), 798f D D-dimers pulmonary embolism, 620 reference range of, 1362b venous thromboembolism, 976 Dabigatran etexilate, indications for, 938b Dacarbazine, for Hodgkin lymphoma,

Dactylitis, 1032, 1034f Danaparoid, for heparin-induced thrombocytopenia, 939 Dandruff, 1246 Dane particle, 873 Dantrolene, 1197–1198 Dantron, 834b Dapsone, 123, 1227–1228 adverse effects of, 123 for dermatitis herpetiformis, 807 for erythema nodosum, 1265 haemolysis from, 950 for leprosy, 269 for linear IgA disease, 1256–1257 neutropenia and, 926b for Pneumocystis jirovecii pneumonia, 323–324 poisoning, 136b prophylactic, 119b for pyoderma gangrenosum, 1261–1262 ‘Dapsone syndrome’, 123 Daptomycin, 117b, 123 mechanism of action, 116b Darunavir, 324b Daunorubicin, for acute leukaemia, 957b DCCT (Diabetes Control and Complications Trial), 756–757 DDAVP see Desmopressin DDT, 148b de Musset’s sign, 524b De novo mutation, 47 De Quervain’s tenosynovitis, 998 de Quervain’s thyroiditis, 646–647 ‘Dead-in-bed syndrome’, 739–740 Deafness Alport’s syndrome, 403 Lassa fever, 245b Paget’s disease, 1054 Pendred’s syndrome, 640f quinine toxicity, 141b rubella, 237b salicylate overdose, 138 Death and dying, 1354–1356, 1355b advance directives, 1307 brainstem, 211 diagnosis of, 1355 ethical considerations in, 1355 intensive care and, 213 management of, 1355 see also Brain death; Palliative care; Sudden death Death certificate, completed, 98f Debrisoquine, 58 DEC see Diethylcarbamazine Decision-making see Clinical decision-making Decompression, for musculoskeletal disease, 999 Decompression illness in aviators, 168 in divers, 170–171, 170b–171b Decontamination, 133f Deep infrapatellar bursitis, 999b Deep vein thrombosis (DVT) air travel and, 169 investigation of, 187, 187f pre-test probability of, 187b pregnancy and, 1285 magnetic resonance imaging for,

presentation of, 186 in stroke patients, 1159f warfarin for, 939 see also Venous thromboembolism/ thrombosis DEET (diethyltoluamide), malaria prevention, 277 Defecation disorders of see Constipation obstructed, 778 Defensins, 62–63, 769 Defibrillation, 457 for arrhythmias, 482 implantable cardiac defibrillators, 467, 483–484, 483b heart failure, 467, 467f public access, 457 Dehydration cerebral, hypernatraemia and, 359–360 cholera, 265 diabetics, 729–730 gastric outlet obstruction, 801–802 heat exhaustion and, 167 in palliative care, 1354 in type 1 diabetes, 729–730 see also Water, depletion Dehydroepiandrosterone sulfate (DHEAS), 672 Déjerine-Klumpke paralysis, 1141b Delayed oesophageal clearance, 791 Delayed puberty, 653–654, 653b, 1290 Deletions, 42, 45f Delirium, 183–184, 1080, 1184 clinical assessment of, 184 diagnosis of, 183b hepatic encephalopathy and, 864–865 in intensive care, 209 investigations of, 184, 184f in older people, 1309, 1310b in palliative care, 1354 presentation of, 183–184 prevalence of, 1180b risk factors for, 183b Delirium tremens, 1194 Delta antigen, 877 Delta virus see Hepatitis D virus Delusional disorders, 1197, 1197b Delusional parasitosis, 1202 Delusional perception, 1196–1197 Delusions, 1181, 1184 differential diagnosis, 1197b schizophrenia, 1197b Demeclocycline, 687b Dementia, 1191–1194 alcoholic, 1195 fronto-temporal, 1193–1194, 1193f HIV-associated, 319 investigations of, 1192, 1192b Lewy body, 1194 management of, 1192 nutrition and, 711, 711f pathogenesis of, 1192 pellagra and, 714 subtypes and causes of, 1191b vascular, 1191b see also Alzheimer’s disease Demography, in older people, 1304, 1304f Demyelination acute disseminated encephalomyelitis and, 1110 multiple sclerosis and, 1106–1110 transverse myelitis and, 1110 from vitamin B12 deficiency, 715 Dendritic cells, 64 Dengue, 243–244 clinical features of, 243–244, 243b–244b diagnosis of, 244 endemic zones of, 243f management and prevention of, 244 in pregnancy, 235b Dengue haemorrhagic fever, incubation period of, 111b Denosumab for bone metastases, 1329 for osteoporosis, 1048, 1048b Dental caries, fluoride and, 718 11-Deoxycorticosterone-secreting adrenal tumour, 674b Depolarisation, cardiac conduction system, 445f Deposition disorders, 1264 Depressants, misuse of, 141–143 Depression, 1198–1199 alcohol and, 1195 diagnosis of, 1199 investigations of, 1199 low mood due to, 1185 management of, 1199 manic, 1200 and medical illness, 1199b negative cognitive triad associated with, 1190b in old age, 1189b in palliative care, 1354 pathogenesis of, 1198–1199 post-partum, 1206 prevalence of, 1180b prognosis of, 1199 in stroke patients, 1159f symptoms of, 1185b unipolar, 1198 Dermatitis chronic actinic, 1221b exfoliative, 1266b herpetiformis, 807, 1255b, 1256,

pellagra and, 714, 715f seborrhoeic, HIV-related, 314 see also Eczema Dermatobia hominis, 300 Dermatofibroma, 1235 Dermatology, 1209–1267 Dermatomyositis/polymyositis, 1039–1040, 1039f, 1260f,

in cancer patients, 1325b, 1326 Dermatophyte infections, 1239, 1240f Dermatoscopy, 1214, 1217f Dermatoses, 334b, 336b Dermis, 1212 Dermoscopy, 1214 Des-amino-des-aspartate-arginine vasopressin, for diabetes insipidus, 688 Desensitisation, 16 Desmopressin (DDAVP), in haemophilia A, 973 Desmosomes, 1212 Deterioration early warning scores for, 188, 188f–189f immediate assessment of, 188–189 management for, location for, 189–190, 190b medical emergency team and, 188, 189b presentations of, 190–195 decreased conscious level as, 194–195 decreased urine output/ deteriorating renal function as,

hypertension as, 193–194 hypotension as, 193 hypoxaemia as, 190–191 tachycardia as, 191–193 tachypnoea as, 190 Detrusor muscle, 386 failure of, 437 over-activity, 436b Detrusor-sphincter dyssynergia, 1093 Developing countries epilepsy in, 1097 tetanus in, 1125–1126 Devic’s disease, 1110 Dexamethasone adjunctive, for bacterial meningitis, 1120b for altitude illness, 168 for brain tumours, 1130 for Cushing’s syndrome, 668 for gastrointestinal obstruction, 1354 for high-altitude cerebral oedema, 168 for meningitis, 1120b for pain management, 1352b for spinal cord compression, 1326b for thyrotoxicosis, 639 Dexamethasone suppression test (DST), for Cushing’s syndrome, 700 Dexamfetamine, 1105 Dextran, 1266b Dextropropoxyphene, 142b poisoning, 142b Dextrose, 353b hypoglycaemia, 141 DFMO see Eflornithine DHA see Docosahexaenoic acid Di George syndrome, genetics, 44b Diabetes Control and Complications Trial (DCCT), 756–757 Diabetes insipidus, 687–688, 687b pregnancy and, 1280 Diabetes mellitus, 409, 719–762 adherence and concordance in, 1299 in adolescents, 753–754, 753b–754b aetiology and pathogenesis of, 728–734 air travel and, 169 bronzed, 895 causes of visual loss in people with,

in children, 753–754, 754b classification of, 733b clinical examination of patient with, 720–721, 720f, 721b complications of, 755–762, 756b pathophysiology of, 756 prevention of, 756–757 diagnosis of, 726b, 727–728 functional anatomy and physiology and, 723–725 gestational, 1278, 1278b diagnosis of, 1278 management of, 1278 screening for, 1278 glomerular filtration rate and, 417f impact of transition planning on, 1299b investigations of, 725–728 management of, 741–755, 755f alcohol in, 744–745 dietary, 743–744, 744b driving and, 745, 745b drugs to reduce hyperglycaemia in, 745–748 exercise in, 744 insulin therapy in, 748–751 Ramadan and, 745, 745b review in, 743b therapeutic goals in, 742–743, 743f transplantation in, 752, 753f weight management in, 744 monogenic, 733–734, 733b mortality in, 755, 756b in old age, 757b ophthalmic features of, 1165b pre-operative assessment of, 754b pregnancy and, 752–753, 1278–1279 presenting problems of, 734–741 prevalence of, 722, 722f rheumatological manifestations of,

risk of, 698–699, 699f, 700b transition medicine and, 1299 type 1, 728–730 in adults, 730 classical features of, 735b environmental predisposition in,

genetic predisposition of, 728–729 metabolic disturbances in, 729–730, 730f pathology of, 728, 729f risk of, 729b

INDEX • 1379 type 2, 730–732 classical features of, 735b drugs in treatment of, 746b environmental factors of, 732 genetic predisposition of, 731–732 hereditary haemochromatosis and,

insulin resistance in, 730–731 management of, 742f metabolic disturbances in, 732 pancreatic β-cell failure in, 731 pathology of, 730–731, 731f risk of, 731b sibling risk of, 731b in young adults, 753–754 Diabetic amyotrophy, 759 Diabetic eye disease, in ophthalmological conditions, 1174–1177 Diabetic foot, 759f, 761–762 aetiology of, 761 clinical features of, 761b management of, 761–762, 762b, 762f Diabetic glomerulosclerosis, nodular, 757, 758f Diabetic ketoacidosis, 729–730, 735–738 in adolescence, 753b clinical features of, 736, 736b investigations of, 736 management of, 736–738, 737b bicarbonate in, 738 fluid replacement in, 737 insulin in, 737 ongoing, 738 phosphate in, 738 potassium in, 738 pathogenesis of, 735–736, 736b severe, indications of, 736b Diabetic macular oedema, management of, 1176–1177 Diabetic microangiopathy, 756 Diabetic nephropathy, 757–758 diagnosis and screening for, 757 management of, 757–758 natural history of, 757, 758f Diabetic neuropathy, 758–761 classification of, 759b clinical features of, 758–761 management of, 761, 761b risk factors for, 757b Diabetic osteopathy, rheumatological manifestations of, 1057 Diabetic retinopathy, 757, 1174–1177, 1176f clinical features of, 1175–1176 management of proliferative, 1176 pathogenesis of, 1175 prevention of, 1177 screening of, 1177 Diagnosis, 29 Diagnostic error, problem of, 2, 2b Diagnostic tests, use and interpretation of, 3–5 factors other than disease, 4, 4b normal values, 3, 4f operating characteristics, 4 prevalence of disease, 5, 6f sensitivity and specificity, 4–5, 5b, 5f Dialyser hypersensitivity, 424b Dialysis amyloidosis associated with, 82b gastrointestinal, 136 hyperkalaemia, 363 peritoneal, 424 poisoning, 136 renal AKI, 413–414, 422b CKD, 419 in old age, 422b SLE, 410–411 see also Haemodialysis 3,4-Diaminopyridine, for Lambert-Eaton myasthenic syndrome, 1143 Diamorphine for myocardial infarction, 498 for palliative care, 1351, 1355 Diaphragm disorders of, 627 eventration of, 627 Diaphragmatic hernias, 627 Diarrhoea, 783 acute, 227–230, 228b, 783 clinical assessment of, 228–229 differential diagnosis of, 228b investigations of, 229 management of, 229–230 after peptic ulcer surgery, 801 amoebic dysentery, 287 antibiotic-associated, 104b antimicrobial-associated, 230 bloody, 816 cholera, 264–265 chronic or relapsing, 233, 233b, 783, 784b diabetic, 761b enteral feeding and, 707b faecal incontinence, 835, 835b,

HIV-related, 316–317 inflammatory bowel disease, 816–817 irritable bowel syndrome, 824 malabsorption, 783–784 pellagra and, 714 traveller’s, 232b tropical, 232–233 Zollinger-Ellison syndrome, 802 Diascopy, 1214 Diastolic murmurs, 460 Diathermy, gastrointestinal bleeding, 775f Diazepam acute poisoning, 145, 147 adverse reactions of, 22b alcohol withdrawal, 1195 convulsions, 145 for disturbed behaviour, 1188–1189 drug interactions of, 23 in renal/hepatic disease, 32b for status epilepticus, 1081b Diazoxide for hypertrichosis, 1259, 1266b for neuro-endocrine tumours (NETs),

Dibenzodiazepines, 1198b Dibenzothiazepines, 1198b DIC see Disseminated intravascular coagulation Diclofenac, 1003b for actinic keratosis, 1231 for hepatocyte necrosis, 894 for renal colic, 432 Didanosine, 321 Dieldrin, 148b Diet(s) acute coronary syndrome and, 501 cancer and, 1320b gallstones and, 903 in gastro-oesophageal reflux disease,

gluten-free, 807 high protein, obesity, 701b low carbohydrate, 701b low fat, 701b modification of, for gestational diabetes, 1278 refeeding, 705b for renal failure, acute kidney injury,

starvation, 702 type 2 diabetes and, 732 vegan, 697 very-low-calorie, 702 weight loss, 701–702, 701b Diet history elements of, 693b obesity and, 700 Dietary deficiency, 944 Dietary supplements, 712 Diethylcarbamazine (DEC), 129 Dietl’s crisis, 396 Differentiated carcinoma, in thyroid disease, 649–650 Diffuse idiopathic skeletal hyperostosis (DISH), 1058–1059, 1058f Diffuse infiltrative lymphocytosis syndrome, HIV-related, 321–322, 322f Diffuse parenchymal lung disease (DPLD), 605–610, 605b, 606f, 607b Diffuse pleural thickening (DPT), 618, 618f DiGeorge syndrome, 79 Digestion, 767 Digital photography, 1168 Digoxin adverse reactions of, 22b for arrhythmias, 469b atrial fibrillation, 471–472 atrial flutter, 470 drug interactions of, 24b effect of old age, 32b for heart failure, 467 for mitral valve disease, 519, 521b plasma concentration, 36b for pulmonary hypertension, 621–622 toxicity/poisoning, 137b, 140 Digoxin-specific antibody fragments,

Dihydrocodeine for musculoskeletal disease, 1002 poisoning, 142b Dihydropyridines for angina, 490–491 for hypertension, 513, 514b overdose, 140 see also individual drugs 1,25-Dihydroxycholecalciferol (calcitriol) for hypoparathyroidism, 665 for osteoporosis, 1049 pseudohypoparathyroidism, 665 1,25-Dihydroxyvitamin D, 384–386 Diiodotyrosine (DIT), 635f Dilated cardiomyopathy, 539 pregnancy and, 1282 Diloxanide furoate, 129 Diltiazem for angina, 490–491 for aortic dissection, 508 for arrhythmias, 472, 479f for atrial fibrillation, 472 drug eruptions, 1266b for hypertension, 513 Diltiazem cream, for anal fissure, 836 Dilute Russell viper venom time (DRVVT), 978 Diphencyprone, 1239 Diphenoxylate, 230, 808–809 Diphenylbutylpiperidines, 1198b Diphtheria, 104b, 265–266, 266b clinical features of, 266 incubation period of, 111b management of, 266 prevention of, 266 prophylaxis for, 119b Diplopia, 1088–1089 in Graves’ disease, 631b, 645f intracranial hypertension and, 1133 Dipyridamole, platelet inhibition, 918 Direct-acting nucleoside/nucleotide antiviral agents for hepatitis B, 876 for hepatitis C, 878, 878b, 879f Direct antiglobulin tests, 948f Direct Coombs test, in warm autoimmune haemolysis, 949 Direct oral anticoagulants (DOACs),

Directly observed therapy, for tuberculosis, 594–595 Dirofilaria immitis, 293 Disability in deteriorating patient, 189 International Classification of Functioning, Disability and Health, 1311 in older people, 1306 Discharge, from intensive care, 213, 214b Discitis, 1021 Discoid eczema, 1246 Discriminant function (DF), 882 Disease, choosing drugs for features of, 29 severity of, 29 Disease Activity Score 28 (DAS28), in rheumatoid arthritis, 1025, 1026f Disease-modifying antirheumatic drugs (DMARDs), for musculoskeletal disease, 1004–1005, 1004b psoriatic arthritis, 1033–1034 reactive arthritis, 1032 rheumatoid arthritis, 1025–1026 Disopyramide for arrhythmias, 476b, 479–480, 479b for cardiomyopathy, 540 Disseminated intravascular coagulation (DIC), 196, 978–979, 978b Dissociative conversion disorders, 1202, 1202b Dissociative drugs, poisoning from, 144 Distal interphalangeal joint arthritis, 1032, 1034f Distribution drug, 18, 29 volume of, 18, 18f interactions, 23 Disturbed behaviour, 1188–1189, 1189f Disulfiram, 1195 DIT see Diiodotyrosine Dithranol, 1250 Diuretics adverse reactions of, 22b, 355, 1310b for ascites, 864 clinical use of, 355 drug eruptions, 1266b drug interactions of, 24b for heart failure, 465, 465f for hypertension, 513, 514b for hypervolaemia, 354–355 loop-acting, 355b for mitral regurgitation, 521b for obliterative cardiomyopathy, 541 for oedema, 396 osmotic, 355 potassium-sparing, 355 in pregnancy, 1276 resistance to, 355 timing of, 31b see also Thiazides Diverticulitis, acute, 788 Diverticulosis, 833–834 human colon in, 833f jejunal, 773f Diving-related illness, 170–171 Dizziness, 1080 in older people, 181b, 1309 DMARDs see Disease-modifying antirheumatic drugs DNA, 38, 38f analysis, for neurological disease,

mitochondrial, 49, 1305 nuclear chromosomal, 1304 proviral, 309–310 repair of, 41 transcription, 38–40 Dobutamine, 206b Docosahexaenoic acid (DHA), 377 Dominant negative mutations, 45 Domperidone, 1096 Donath-Landsteiner antibody, 950 Donepezil, 1193 Donor lymphocyte infusion (DLI), 937 Donor-recipient cross-matching, 89 Donovanosis, 341b Dopamine, low-dose, AKI, 413 Dopamine agonists for acromegaly, 686–687 for Parkinson’s disease, 1114, 1114b pregnancy, 685 for prolactinoma, 685, 685b and renal dysfunction, 427b for restless legs syndrome, 1105–1106 Dopamine antagonists for gastroparesis, 761b and prolactin concentrations, 684 Dopamine dysregulation syndrome,

1380 • INDEX Doppler echocardiography, 451–452, 451f for aortic dissection, 507–508, 508f for atrial septal defect, 535f colour-flow Doppler, 452f three-dimensional, 452 for valvular regurgitation, 451–452 Doppler ultrasound for haemorrhoids, 835–836 for hepatobiliary disease, 853–854 for leg ulcers, 1224 for venous thromboembolism, 187 Doripenem, 120b Dose-response curves, 14–16, 15f Dosulepin, 1199b Down’s syndrome (trisomy 21), 44b acute hepatitis B and, 875 Doxapram, 567 Doxazosin, 513, 675–676 Doxorubicin cardiotoxicity, 541b hepatocellular cancers, 892 liposomal, for ovarian cancer, 1334 myocarditis and, 538 for non-Hodgkin’s lymphoma, 965 Doxycycline, 117b for anthrax, 267 for bacillary angiomatosis, HIV/AIDS patients, 315–316 for brucellosis, 255b for cholera, 265 drug eruption, 1267f for filariasis, 291 for leptospirosis, 258–259 for louse-borne relapsing fever, 257 for Lyme disease, 256 for malaria, 278b for melioidosis, 261 for onchocerciasis, 293 for plague, 259 for Q fever, 272 for reactive arthritis, 1032 for relapsing fever, 257 for rickettsial fevers, 271–272 skin infections, 1238 for STIs chlamydial infection, 341b granuloma inguinale, 341b lymphogranuloma venereum, 341b syphilis, 339 for Whipple’s disease, 809 DPLD see Diffuse parenchymal lung disease DPP-4 inhibitors, for hyperglycaemia, 747–748 Dracunculiasis, 293 Dracunculus medinensis, 293 DRESS, 1266b Dressings, 1226–1227, 1227b Dressler’s syndrome, in acute coronary syndrome, 496 Dribble, post-micturition, 437 Drinking, 1184, 1194 Driving diabetes mellitus and, 745, 745b restrictions in, epilepsy and, 1296 Dronedarone, 471–472, 479b–480b,

Drowning/near-drowning, 169–170, 169b Drug eruptions, 1251, 1265–1267 clinical features of, 1266b, 1267 exanthematous, 1266b fixed, 1266b investigations and management of, 1267, 1267b phototoxicity, 1221b rash in, 1217b types of, 1265b, 1267f Drug history, 21b Drug misuse, 93, 1184, 1184b causing stroke, 1157b polydrug misuse, 1196 psychosis, 1195–1196 tetanus and, 1125 Drug rashes, HIV-related, 316 Drug-related disorders eosinophilia, 123 neutropenia, 926b obesity and, 700b phototoxicity, 1221b psychosis, 1197b renal, 426, 427b Drug resistance, 16 Drug-resistant TB, 595, 595b Drug sensitivity testing, for tuberculosis,

Drug therapy adverse outcomes of, 21–26 duration of, 30 monitoring of, 34–36 patient adherence to, 29 stopping, 31 Drugs absorption, 17–18, 17f, 29 abuse, 21 adverse reactions of, 21–23, 22b classification of, 22–23, 22b dose-related, 16 inter-individual variation in, 19, 20b in older people, 1310, 1310b pharmacovigilance, 23 prevalence of, 21–22, 21b–22b risk factors for, 21b TREND analysis of, 23b clinical and surrogate endpoints in, 35–36 controlled, 26, 33–34 cost of, 29 development, 26–27, 26b–27b distribution, 18, 29 dosage regimens of, 29–30 frequency of, 30 repeated, 19 timing of, 30, 31b dose-response curves of, 14–16, 15f dose titration of, 30 efficacy, 16, 29 elimination, 18–19 excretion, 17f, 18–19, 29 formulation of, 30 hospital discharge, 33 interactions, 23–24 avoiding, 24, 29 mechanisms of, 23–24 pharmaceutical, 24b pharmacodynamic, 24b pharmacokinetic, 24b licensing, 26–27 lung disease due to, 612–613, 612b management, 26–28 cost-effectiveness evaluation, 28, 28b evidence evaluation, 27–28 implementing recommendations,

use of, 27–28 marketing, 26–27 metabolism, 18, 29 interactions, 24 of misuse, 141–144 for oesophagitis, 794 plasma concentrations of, 36, 36b potency of, 16 regulation of, 26–28 route of administration of, 17f, 30, 30b topical administration of, 17–18 toxicity, 21 DRVVT see Dilute Russell viper venom time Dry drowning, 169 Dubin-Johnson syndrome, 860b Duchenne muscular dystrophy (DMD), 48b transition medicine and, 1297 Ductopenia, 894 Duloxetine, for pain management, 1350b Duodenal biopsy, 806 Duodenal switch, 703b Duodenal ulcers, 782, 799f Duodenogastro-oesophageal reflux,

Duodenum, functional anatomy of, 766–767, 766f Duplex kidneys, 434 Duplication, 44, 45f Dupuytren’s contracture, 1059 cirrhosis and, 867 Dusts, lung disease and, 616–617, 616b Dwarfism, zinc deficiency, 717 DXA (dual x-ray absorptiometry) in bone mineral density, 989–990 for fractures, 1308 indications for, 1046b for musculoskeletal disease, 990f Dysarthria, 1087–1088, 1093 causes of, 1087b Dysbetalipoproteinaemia, 375 Dysdiadochokinesis, 1069 Dysentery, bacillary, 111b Dysexecutive syndrome, 1094 Dysgraphia, 1086 Dyshormonogenesis, 650 Dyslexia, 1086 Dyslipidaemia, in pregnancy, 377b Dysmetria, 1069 Dyspepsia, 779 alarm features in, 779b causes of, 779b functional, 802–803 gallstone, 904 investigations of, 780f, 802 Dysphagia, 778, 1093 investigations of, 778, 779f oesophagus, 1324b in stroke patients, 1158 Dysphasia, 1088 Dysphonia, 1087 Dysthymia, 1198 Dystonia, 1086, 1116 poisoning, 137b Dystrophia myotonica, 1191b Dysuria, 396 E E-cadherin (CDH1) gene, 803 E-selectin, 447 Early-onset osteoarthritis, 1011, 1011b Ears freezing injuries and, 166 squamous cell carcinoma, 1231 Eastern Cooperative Oncology Group (ECOG) performance scale, 1322, 1322b Eating disorders, 1203–1204, 1204b Ebola virus disease, 246–247 Eccrine sweat glands, 1213–1214 ECF see Extracellular fluid ECF (epirubicin, cisplatin and 5-fluorouracil), 804 ECG (electrocardiogram), 448–450, 448f 12-lead, 448–449, 448b, 449f for acute coronary syndrome, 496–497, 497f AKI, 422b ambulatory, 450 angina, 487 for aortic dissection, 507–508 for aortic regurgitation, 525b for aortic stenosis, 523f for atrial ectopic beats, 470f for atrial fibrillation, 471f for atrial flutter, 470f for AV block, 477f–478f for AV nodal re-entrant tachycardia, 473f cardiac cycle, 460f for cardiac tamponade, 544 for chest pain, 178–179 for critically ill patients, 178 for endocarditis, 530 exercise, 449–450, 450b for hyperkalemia, 363 for hypokalaemia, 361 for left ventricular hypertrophy, 523f for mitral stenosis, 519 for myocardial infarction, 448 for myocardial ischaemia, 448 for pericarditis, 542, 542f for pulmonary embolism, 619b, 620 reading, 448b for sinoatrial disease, 469f for supraventricular tachycardia, 473f for syncope/presyncope, 183 for torsades de pointes, 476f in tricyclic antidepressant poisoning, 139f for ventricular ectopic beats, 475f for ventricular fibrillation, 475 for ventricular tachycardia, 475f for Wolff-Parkinson-White syndrome, 474f Echinocandins, 125b, 126 Echinococcus granulosus, 298–299, 299f Echocardiography, 451–452 for acute coronary syndrome, 498 for angina, 488 for aortic dissection, 508f for aortic stenosis, 523f for atrial septal defect, 535f for cardiac tamponade, 544 for critically ill patients, 206 Doppler, 451–452, 451f–452f ventricular septal defect, 536 for endocarditis, 530 for ‘four-chamber’ view, 452f for heart failure, 464 for hypertrophic cardiomyopathy, 540 indications for, 451b for left ventricular hypertrophy, 540 for mitral regurgitation, 520f for myocarditis, 538 for papillary muscle rupture, 496 for pericardial effusion, 543f for pulmonary embolism, 620 stress, 452 for tetralogy of Fallot, 537 three-dimensional, 452 transoesophageal, 179, 452 transthoracic, 451 two-dimensional, 452 valvular disease aortic, 522–524 mitral, 519 tricuspid, 526 for ventricular aneurysm, 496 Echovirus infections, 240 Eclampsia, hypertension and, 1276–1277 ECOG (Eastern Cooperative Oncology Group) performance scale, 1322, 1322b Econazole, 125b, 335b Ecstasy (drug), 143 Ecthyma, 1236 Ectoparasites, 299–300 Ectopia lentis, 370 Ectopic ACTH syndrome, management of, 670 Ectopic pregnancy, 336 Ectopic ureters, 434 Eculizumab, 66 Eczema, 1244–1247 allergic contact, 1247, 1247b, 1247f asteatotic, 1247 atopic, 1245–1246 rash in, 1217b classification of, 1244b clinical features of, 1244 clinical morphology of, 1244b discoid, 1246 gravitational, 1247 investigations of, 1244 irritant, 1247 management of, 1244–1245, 1245f in nails, 1261 pruritus, 1219b seborrhoeic, 1246 Edoxaban, 938b Edrophonium bromide, for myasthenia gravis diagnosis, 1142 EDTA (ethylenediamine-tetra-acetic acid), 386b Education food allergy and, 812 infection control, 112b in musculoskeletal disease, 1000–1001 fibromyalgia, 1018 mechanical back pain, 997 osteoarthritis, 1011–1012

INDEX • 1381 Edwards’ syndrome (trisomy 18), 44b EEG (electroencephalography), 1074–1076 for dementia, 1192 for epilepsy, 1075f, 1076 for hepatic encephalopathy, 865 for sleep disorders, 1071 for viral encephalitis, 1122 Efavirenz, 324b, 325 Efficacy, 16, 29 Eflornithine (DFMO), for trypanosomiasis,

Eflornithine cream, 659 Ehlers-Danlos disease, 970 Eicosapentaenoic acid (EPA), 377 Eisenmenger’s syndrome, congenital heart disease and, 533 Ejaculatory failure, 1094 Elastase, 71 faecal, 1361b Elbow pain, 998, 998b Elderly Mobility Scale, 1311 Electrical cardioversion, for arrhythmias,

Electroclinical epilepsy syndromes, 1100b Electroconvulsive therapy, 1190 Electroencephalography see EEG Electrofulguration, 343 Electrolyte balance, 353b assessment, in hospitalised patients, 353b in renal failure, chronic, 418 Electrolyte disturbances, acute kidney injury and, 414 Electrolytes absorption and secretion of, 769, 769f acute kidney injury and, 416b basic daily requirements, 353b distribution of, 349, 349f homeostasis, 349 interpretation of, 349b loss of, in diabetic ketoacidosis, 736b reference range of, venous blood, 1358b Electromagnetic spectrum, 1222f Electromyography see EMG Electron microscopy (EM), 105, 1322 for sexually transmitted infections,

Electrophoresis, 348b Electrophysiology, 454 Elevated mood, 1186 Elimination of drugs, 18–19 kinetics, 18f, 19 ELISA, 106–107, 109f for Clostridium difficile, 264 for dengue, 244 for hydatid cyst, 299 for leishmaniasis, 283 for leptospirosis, 258 for Lyme disease, 256 for lymphatic filariasis, 291 for schistosomiasis, 296 for strongyloidiasis, 289 Elliptocyte, 915 Elliptocytosis, hereditary, 947–948 Embolism in acute coronary syndrome, 496 in acute limb ischaemia, 503, 504b arterial gas, 170 pulmonary, 619–621 acute massive, 200 clinical features of, 619, 619b investigations of, 619–620, 619f–620f management of, 620–621 in pregnancy, 620b prognosis for, 621 in stroke patients, 1159f EMG (electromyography), 1076 for motor neuron disease, 1117 in musculoskeletal disease, 992 Emollients, 1225 for eczema, 1247 for pruritus, 1220 in pregnancy, 1220b for psoriasis, 1250 for skin disease, 1226 Emphysema, 549 computed tomography of, 552, 576f lung transplantation for, 567, 567b pathology of, 575f in respiratory function abnormalities, 555b Employment, 1198 epilepsy and, 1296 Empyema, 564–565, 564b, 564f–565f subdural, 1125 Emtricitabine, 119b, 324b Enalapril for heart failure, 466b for hypertension, 513 for myocardial infarction, 500–501 Encapsulated bacteria infection, after HSCT, 937b Encephalitis brainstem, 1122 viral, 1121–1123 West Nile, 1121–1122 Encephalomyelitis acute disseminated, 1110 cancer-related, 1325 Encephalopathy hepatic, 847b, 864–865 acute liver failure and, 856–857 clinical grade of, assessment for, 857b differential diagnosis of, 865b factors precipitating, 865b Wernicke’s, 714 Endemic typhus, 271, 271b Endobronchial ultrasound (EBUS),

Endocarditis, 1035 gonococcal, 340 infective, 527–531, 528b, 531b acute, 529 antimicrobial treatment of, 530b in old age, 527b post-operative, 529 prevention of, 531 subacute, 528–529, 529b, 529f Endocrine axes, 633f Endocrine disease classification of, 632b clinical examination in, 630–632, 630f, 631b investigation of, 633, 633b ophthalmic features of, 1165b pathology of, 632–633 pregnancy and, 1279–1280 presenting problems of, 633, 634b pruritus and, 1219b rheumatological manifestations of,

Endocrine glands, functional anatomy and physiology of, 632, 632f–633f Endocrine pancreas disease classification of, 677b presenting problems in, 676–678 Endocrine system, pregnancy and,

Endocrine treatment, for prostate cancer, 439 Endocrinology, 629–689 of adrenal glands, 665–676 endocrine glands, disorders affecting, 688–689 of endocrine pancreas and gastrointestinal tract, 676–679 of hypothalamus and pituitary gland, 679–688 reproductive system, 651–661 of thyroid gland, 634–651 Endometrial cancer, 1334–1335 investigations of, 1334 management of, 1335 pathogenesis of, 1334 Endometriosis, 837 Endomitotic reduplication, 918 Endophthalmitis, 1173–1174, 1174f Endoplasmic reticulum (ER), 40 Endoscopic examination, of respiratory system, 553 Endoscopic retrograde cholangiopancreatography see ERCP Endoscopic ultrasound, 774 for choledocholithiasis, 906f for hepatobiliary disease, 855 Endoscopy, 774–776, 775f for abdominal pain, 789 for achalasia, 795 capsule, 774–776, 775f wireless, 775f, 776b for corrosive oesophagitis, 794 double balloon, 776, 776b for dysphagia, 778, 779f for gastric outlet obstruction, 801–802 gastrointestinal haemorrhage, 782, 782f for gastrointestinal haemorrhage, 782, 782f for inflammatory bowel disease, 818–819 for obscure bleeding, 783f for oesophageal cancer, 796–797, 796f for oesophageal candidiasis, 317f for oesophageal varices, 865f in old age, 776b for peptic ulcer, 799 for pharyngeal pouch, 794 for portal hypertension, 869 of respiratory system, 553 upper gastrointestinal, 774, 775b wireless capsule, 775f, 776b Endosulfan, 148b Endothelial cells, of liver, 848 Endothelial damage, 950 Endothelin 1 (ET1), 447, 849f Endothelium, 447 Endotoxin, 104 Endotracheal intubation, critically ill patients, 190b, 208 Energy expenditure, 694, 695f increased, 704b intake, 695f, 701 decreased, 704b requirements, 698b Energy balance, 694–695, 695f altered, disorders of, 698–711 determinants of, 694, 695f in old age, 710b regulation of, 694–695, 696f and reproduction, 696f Energy-yielding nutrients, 695–697 WHO recommendations, 698b Engerix, for hepatitis B, 876 Enhanced Liver Fibrosis (ELF) serological assay, 855 Entacapone, for Parkinson’s disease,

Entactogens, 143 Entamoeba histolytica, 286 life cycle of, 286f liver abscess from, 286 see also Amoebiasis Entecavir, 876 Enteral administration, 17 Enteral feeding, 707, 707b Enteric nervous system, 771–772 Enteritis, radiation, 809–810, 810b Enterobacter spp., 103f, 117b Enterobacteriaceae, 103f Enterobius vermicularis (threadworm), 290, 290f Enterococcus faecalis, 103f, 117b Enterococcus faecium, 103f, 117b Enterocytes, 371 Enterohaemorrhagic Escherichia coli (EHEC), 227–228 Enterohepatic circulation, 19 Enterokinase, 768 Enteropathic (spondylo)arthritis, 1034 Enteropathy, protein-losing, 811, 811b Enteroscopy, double balloon, 776, 776b Enterovirus 71, 250 Enthesis, 987–988 Enthesitis, 1033 Enthesitis-related arthritis (ERA), 1027 Enthesopathy, patella ligament, 999b Entrapment neuropathy, 1139–1140, 1139b Envenomation, 151–162 diagnosis of, 159 envenomed patient bedside test in, 153, 153f evaluation of, 152, 152f general approach to, 156–160 treatment, 159–160 follow-up, 160 hospital assessment and management for, 158–159 evidence of, 158–159 laboratory investigations, 159 life-threatening problems, 158 local effects, 155, 155b overview of, 154 by specific animals, 160–162 systemic effects, 155, 155b venom, 154 venomous animals, 154–155, 154b, 156b–158b Environment, early, psychiatric disorders and, 1183 Environmental factors in disease, cancer, 1320–1321, 1320b of gastro-oesophageal reflux disease,

of inflammatory bowel disease, 830 Environmental medicine, 163–172 extremes of temperature and, 165–168 high altitude and, 168–169 humanitarian crisis and, 171–172 radiation exposure and, 164–165 under water and, 169–171 Environmental poisoning, 149, 149b Enzymes drugs acting on, 15b pancreatic, chronic pancreatitis,

Eosinophil granulocytes, 1362b Eosinophilia, 233–234, 233b–234b, 926b, 927 allergy and, 86 tropical, 233–234, 233b–234b Eosinophilic gastroenteritis, 811–812 Eosinophilic granulomatosis with polyangiitis, 1043 Eosinophilic oesophagitis, 794 Eosinophils, 917, 926b, 926f count, 1362b EPA see Eicosapentaenoic acid Ependymal cells, 1064–1065 Epidemic typhus, 271, 271b Epidemiology, 95–97, 95b understanding causes and effect, 95–97, 95b, 97b, 97f Epidermal growth factor receptor,

Epidermal necrolysis, toxic, 1254–1255, 1254b, 1254f, 1266b Epidermis, 1212, 1213f Epidermolysis bullosa acquisita, 1255b, 1257 classification of, 1254b dystrophic, 1229, 1254b Epididymo-orchitis, 240 Epilepsy, 1097–1104 in adolescence, 1103b classification of, 1098b clinical features of, 1098–1100 contraception in, 1103 focal, 1098, 1098f generalised, 1098, 1098f investigations of, 1100–1101, 1101b brain imaging, 1101b EEG, 1075f, 1076 single seizure, 1100 management of, 1101–1103 antiepileptic drugs for, 1101–1102, 1102b immediate care, 1101, 1101b lifestyle advice, 1101, 1102b monitoring, 1102 surgery, 1102 in old age, 1103b

1382 • INDEX outcome after 20 years, 1101b pathophysiology of, 1097–1098 pregnancy and, 1284 in pregnancy and reproduction, 1103, 1103b prognosis of, 1103 seizure types, 1098–1100, 1098b absence, 1099 atonic, 1100 clonic, 1100 focal, 1099, 1099b generalised, 1099–1100 myoclonic, 1099–1100 tonic, 1100 tonic-clonic, 1099, 1099b temporal lobe, 1185, 1197, 1197b transition medicine and, 1296 Epilepsy syndromes, 1100, 1100b Epileptic spasms, 1100 Epimysium, 987–988 Epinephrine for allergy, 86 self-injectable, prescription of, 76b Epiphysis, 984 femoral, 1007–1008 Epirubicin, 804 Episcleritis, 1172 Epistaxis cirrhosis, 867b dengue, 244 granulomatosis with polyangiitis,

leptospirosis, 258 systemic vasculitis, 1041b Epithelial membrane antigen (EMA), as tumour markers, 1322, 1324b Eplerenone for heart failure, 465 for mineralocorticoid excess, 675 for myocardial infarction, 501 Epley manoeuvre, 1104 Epo see Erythropoietin Epoprostenol see Prostacyclin EPs see Evoked potentials Epstein-Barr virus (EBV) cancer and, 1320b hepatitis and, 871–872 post-transplant lymphoproliferative disorders and, 1299 viral hepatitis and, 878 Epstein-Barr virus infection, 238b, 241–242 clinical features of, 241–242 complications of, 241–242, 242b investigations of, 242 management of, 242 Eptifibatide, platelet inhibition, 918 Eradication, for gastrointestinal haemorrhage, 782 ERCP (endoscopic retrograde cholangiopancreatography), 776, 777b, 854–855 for cholangiocarcinoma, 907f for cholangitis, 905 for choledocholithiasis, 906f for pancreatic cancer, 842 for pancreatitis, acute, 839 Erectile dysfunction, 440, 440b in diabetes mellitus, 760–761 Erectile failure, 1094 Ergocalciferol, 713 Ergotamine, 1096 Erlotinib, 1332 Erosions in rheumatoid arthritis, 988 skin, definition of, 1218 Erosive osteoarthritis, 1011 Ertapenem, 117b, 120b Erysipelas, 1237, 1237f Erythema, palmar, 635–636, 866–867, 1194b Erythema ab igne, 840 Erythema infectiosum, 237b Erythema multiforme, 1221b, 1264, 1264b, 1265f, 1266b Erythema nodosum, 1265, 1265b–1266b Erythrasma, 1238 Erythrocyte sedimentation rate (ESR) abnormal, conditions associated with, 72b inflammation and, 72 reference range of, 1362b Erythrocytosis, 925 classification and causes of, 925b Erythroderma, 1224 Erythromycin, 119b for acne, 1242–1243 for diphtheria, 266 for erythrasma, 1238 for Lyme disease, 256 for pneumonia, 585b in pregnancy, 120b prophylactic, 119b for relapsing fever, 257 for rheumatic fever, 517 for rosacea, 1244 for STIs chancroid, 341b chlamydial infection, 341b granuloma inguinale, 341b lymphogranuloma venereum, 341b syphilis, 339 for tetanus, 1126 Erythropoiesis, impaired, 237b Erythropoietic porphyria, congenital, 379b Erythropoietic protoporphyria (EPP), 379b, 1264 Erythropoietin (Epo), 915 chronic renal failure and, 419 ectopic hormone production, 1325b Escherichia coli, 100, 103f, 104b, 263–264 entero-aggregative, 263–264 entero-invasive, 263 enterohaemorrhagic, 263–264 enteropathogenic, 263 spontaneous bacterial peritonitis and,

verocytotoxigenic, 263f Escitalopram, 1199b ESR see Erythrocyte sedimentation rate Essential fatty acids, 697, 697f Essential thrombocythaemia, 969–970 Essential tremor, 1115 Etanercept, for musculoskeletal disease, 1007b Ethambutol, 125 Mycobacterium avium complex, 315b polyneuropathy, 1139b for tuberculosis, 593, 593b Ethanol pharmacokinetics of, 20b poisoning, 135b reference range of, 1360b see also Alcohol Ethics in artificial nutritional support, 710b in genomic age, 59 Ethnicity, type 2 diabetes and, 732 Ethosuximide, 1100b Ethylene glycol poisoning, 135b, 147, 147f Ethylenediamine-tetra-acetic acid (EDTA), 386b Etidronate, for Paget’s disease, 1054b Etoposide for acute leukaemia, 957b for testicular tumours, 440 Etoricoxib, 1003b Euchromatin, 38–39 Eukaryotes, 101–102 Eumycetoma, 301 Euphoria, 1196 Euthanasia, 1356 Euvolaemia with hypernatraemia, 359b with hyponatraemia, 357 Evidence-based medicine, 10 Evoked potentials (EPs), 1076–1077, 1077f Evolutionary selection, 45–46 Ewing’s sarcoma, 1057 Exanthem, enteroviral, 240 Exanthem subitum, 238 Excessive daytime sleepiness, 1105 Exchange transfusion for malaria, 277 for megaloblastic anaemia, 945 for sickle-cell disease, 953 Excision, for cancer, 1330 Excision arthroplasty, 1002b Excision biopsy, for skin disease, 1228 Excitatory neurotoxins, 155 Excoriation, definition of, 1241 Excretion of drugs, 17f, 18–19, 29 interactions, 24 Exemplar medicine sick-day card, 418b Exenatide, 747 Exercise(s) acute coronary syndrome and, 501 arrhythmias and, 450b asthma, 568, 570f chest pain and, 455 COPD, 574 diabetes and, 744 heart disease and, 537b hypoglycaemia and, 740 insulin levels and, 740 for musculoskeletal disease, 1001 ankylosing spondylitis, 1031 fibromyalgia, 1018–1019 osteoarthritis, 1012 Exercise ECG, 449–450, 450b Exercise testing for angina, 488 for COPD, 575 for myocardial infarction, 450b for respiratory function testing, 556 Exertion headache, 1097 Exfoliative dermatitis, drug-induced, 1266b Exogenous androgen administration, hirsutism and, 658b Exons, 39f Exophthalmos, in Graves’ disease, 631b Expiration, of lungs, 548 Explanation, for somatoform disorders,

Extracellular fluid (ECF), 349 Extracorporeal membrane oxygenation (ECMO) principles of, 205f venous-arterial, 207–208 venous-venous, 204 Extracorporeal shock wave lithotripsy (ESWL), 906 Extractable nuclear antigens (ENAs), antibodies to, 991 Extrahepatic portal vein obstruction, portal hypertension and, 868 Extraocular muscles, 1164 of right eye, 1165f Extrapyramidal gait, 1087 Extrapyramidal system, 1069 Extravascular haemolysis, 946–947 Extubation, in intensive care, 210 Eye disease, HIV-related, 319–321, 319f Eye movement desensitisation and reprocessing (EMDR), 1201–1202 Eyelid, 1164 retraction, of ophthalmic disease,

Eyes, 1164–1168 blood supply of, 1168 of envenomed patient, 152f examination of diabetes mellitus, 721b respiratory system, 546f inflammatory arthritis in, 994b main structure of, 1167f rheumatoid arthritis in, 1024 Ezetimibe, 376 F F-fluorodeoxyglucose (FDG), 553 Fabry’s disease, 371b Face angioedema, 87f examination of musculoskeletal system, 982f respiratory system, 546f frostbite, 166 hemifacial spasm in, 1116 numbness of, 1080 skin disease see individual conditions superior vena cava obstruction, 1326 Facial (7th cranial) nerve palsy, 1082–1083 tests of, 1063b Facial pain, 1080 Facial warts, 1238 Facial weakness, 1082–1083 Facioscapulohumeral dystrophy, 1143b Factitious disorder, 1205–1206 Factitious fever, 220b Factor II, 972b Factor V, 919 Leiden, 923b, 972b, 977 stroke, 1157b Factor VII, 919 deficiency, 928, 974 Factor VIII concentrate, 972–973 haemophilia A, 971 inhibitor bypass activity (FEIBA), 973 Factor IX, 972 concentrate, 973–974 deficiency, 973–974 haemophilia B, 973–974 Factor XI deficiency, 974 Faecal antigen test, for Helicobacter pylori infection, 782 Faecal continence, 770 Faecal impaction, 834 Faecal incontinence, 835, 835b, 1094 Faeces analytes, 1361b Faints see Syncope Falciparum malaria, 231 Falls older people, 1308–1309, 1308b–1309b, 1308f prevention, 1308–1309 Famciclovir, for herpes virus infection, 126, 127b genital, 342 Familial adenomatous polyposis, 828–829, 829f, 1321b Familial hypercholesterolaemia, 374, 374b Familial hypocalciuric hypercalcaemia,

pregnancy and, 1280 Familial Mediterranean fever (FMF), 81 Family behaviour therapy (FBT), for eating disorders, 1203–1204 Family history, 56 of allergic disease, 85 genetic disease, 46 of melanoma, 1232 ovarian cancer and, 1334 of psoriasis, 1247–1248 psychiatric disorders and, 1181b of vitiligo, 1257 Family tree see Pedigree Famine, 704–705 Fanconi anaemia, 1321b Fanconi’s syndrome, 366, 405 multiple myeloma and, 410b Farmer’s lung, 616b Fasciculations, 146b, 148b, 158b, 1063b Fasciculi, 987–988 Fasciola hepatica, choledocholithiasis and, 906 Fascioliasis, 297b Fat-pad syndrome, 999b Fatal familial insomnia, 1127b Fatigue in cancer patients, 1325b chronic fatigue syndrome, 1202 fibromyalgia, 1018 multiple sclerosis, 1110b primary biliary cholangitis and, 888 rheumatoid arthritis, 1023 Fats, 697, 697f body, distribution of, 699 see also Obesity in diabetic diet, 744 digestion and absorption of, 768 distribution of, clinical assessment for, 693b Epilepsy (Continued)

INDEX • 1383 energy provided by, 694 malabsorption, small bowel disease and, 809 normal metabolism of, 725 recommended intake, 698b Fatty acids essential, 697, 697f free, 697 n-3, 376 polyunsaturated, 697f trans, 697 Fatty liver alcoholic, 881, 881b non-alcoholic, 882–885, 883f Febrile response, 104 Febuxostat, for gout, 1016 Feeding enteral (tube), 707, 707b, 839 for famine management, 705 gastrostomy, 707, 707b, 708f parenteral, 707–708 post-pyloric, 707 Felty’s syndrome, 1024–1025, 1025b Female, reproductive system of, 652, 652f Femoral neck fractures, 994 Femoral stretch test, 996–997 Ferritin in acute phase response, 70 adult-onset Still’s disease, 1040 anaemia of chronic disease, 943 haemochromatosis and, 895 iron deficiency anaemia, 941, 942b megaloblastic anaemia, 944b in old age, 954b reference range of, 1362b Ferrous gluconate, 943 Ferrous sulphate, 943 Fertility cystic fibrosis and, 1297 renal replacement therapy and, 1282–1283 Festination, 1087, 1309b Fetor hepaticus, 857–858 portal hypertension and, 868 Fever(s), 217b, 218–225 accompanying features of, 217b acute rheumatic, 515–517, 516f investigations in, 517b Jones criteria for, 516b African tick bite, 270, 271b boutonneuse, 271b in cancer patients, 1323 clinical assessment of, 218, 218b factitious, 220b febrile response, 104 HIV-related, 313–314, 313f–314f in immunocompromised host, 223–224 inhalation (‘humidifier’), 617 in injection drug-user, 222–223, 222f–223f intermittent, 74 investigations of, 218 with localising symptoms or signs, 218, 219f louse-borne relapsing, 256b, 257, 257f management of, 218 neutropenic, 224 in cancer patients, 1327–1328 post-transplantation, 224–225, 224b recurrent, 217b rickettsial, 270–272 Rocky mountain spotted, 270, 271b scrub typhus, 270–271, 271b streptococcal scarlet, 252, 253f tick-borne relapsing, 256b, 257 trench, 272 tropical, 230–232 causes of, 231b clinical assessment of, 230–232, 232b history taking in, 231b investigations of, 232, 232b management of, 231f, 232 typhoid, 260, 260b of unknown origin see Pyrexia of unknown origin viral haemorrhagic, 245–247, 245b yellow, 243f, 244–245 incubation period of, 245b Fexofenadine, 1227 FGF see Fibroblast growth factor Fibrates, 377 hyperlipidaemia management, 377–378 muscle pain, 1000b Fibre, dietary, 697 Fibrin, 1319f Fibrinogen in acute phase response, 70 concentration of, 922b reference range of, 1362b Fibroblast growth factor (FGF), 1325b Fibroblast growth factor 23 (FGF23), in skeletal disease, 990b Fibrolamellar hepatocellular carcinoma,

Fibromuscular dysplasia, renal artery stenosis and, 406 Fibromyalgia (FM), 1018–1019, 1018f–1019f investigations of, 1019b spectrum of symptoms in, 1018b Fibrosis cystic, 580–581, 580f, 581b, 842,

contraception and, 1297 fertility and child-bearing potential in, 1297 transition medicine and, 1297 hepatic, 894 cirrhosis and, 866, 866f congenital, 868f, 902 non-invasive markers of, 855 pathogenic mechanisms in, 849f idiopathic pulmonary, 605–608, 607f of liver, 894 cirrhosis and, 866, 866f congenital, 868f, 902 non-invasive markers of, 855 pathogenic mechanisms in, 849f nephrogenic sclerosing, 390b pulmonary, 547f in dermatomyositis, 610b idiopathic, 605–608, 607f in respiratory function abnormalities, 555b in rheumatoid arthritis, 610b, 1024 in sarcoidosis, 609b in sclerosis, 610b in systemic lupus erythematosus, 610b retroperitoneal, 434 drug-induced, 427b Fibrous and fibrocartilaginous joints, 986 Fidaxomicin, 124 Fifth disease, 237b ‘Fight or flight’ response, 1213–1214 Filaggrin, 1212 Filariases, 233b Finasteride, 659b for alopecia, 1259 Fine needle aspiration cytology, 643 Fingers clubbing, 546f, 559, 559b, 559f asbestosis, 618 in lung cancer, 600 trigger, 1060 Finkelstein’s sign, 998 First aid, for envenomed patient, 156–157 First-pass metabolism, 17 Fish minerals in, 717b venom, 154b vitamins in, 711b Fish eye disease, 375, 375b Fish oils, 697, 711b Fissure anal, 836 skin, definition of, 1244b Fistulae, 836 inflammatory bowel disease and, 823 tracheo-oesophageal, 625 see also different types Fitz-Hugh-Curtis syndrome, 836 Flapping tremor, hepatic encephalopathy and, 864–865 Flares, of gout, 1015 Flavonoids, 716 Fleas, 231b bartonellosis, 272b plague, 259 typhus, 271, 271b Flecainide, 470–473, 476b Flora, normal microbial, 102–103, 103f Flow cytometry, 105 Flucloxacillin, 117b, 120b cerebral abscess, 1124b hepatotoxicity, 894 for impetigo, 1236 for infective endocarditis, 223 for pneumonia, 585b for septic arthritis, 1020, 1020b for staphylococcal infections, 251 for staphylococcal scalded skin syndrome, 1236 Fluconazole, 125b, 126 acute leukaemia patients, 957 candidiasis, 336 HIV/AIDS patients, 316 cryptococcal meningitis, HIV-related, 315b, 321 for cutaneous leishmaniasis, 286 for paracoccidioidomycosis, 304 in pregnancy, 120b prophylaxis, 315b for skin disease, 1239–1240 Flucytosine, as antifungal agents, 126 Fludarabine for chronic lymphocytic leukaemia,

for Waldenström macroglobulinaemia,

Fludrocortisone for adrenal insufficiency, 673, 673b postural hypotension, 1308–1309 Fluid, loss of, in diabetic ketoacidosis, 736, 736b Fluid balance for community-acquired pneumonia,

for heat exhaustion, 167 for renal failure, chronic kidney disease, 418 Fluid overload, in hypertension, 193 Fluid replacement for acute diarrhoea, 229–230, 229b for cholera, 265 for decompression illness, 171 for diabetic ketoacidosis, 737 for diving-related illness, 171 for food poisoning, 150 for heat exhaustion, 167 intensive care unit, 208 intravenous, for decompression illness, 171 Fluid therapy assessment, in hospitalised patients, 353b intravenous, for hypovolaemia, 353 for shocked patients, 206 Fluke, liver, 1320b Flumazenil, 142 Fluocinolone acetonide, 1226b Fluorescent in situ hybridisation (FISH) techniques, 1322 Fluoride, 718 dietary sources of, 717b and osteomalacia, 1053 poisoning, 718 reference nutrient intake of, 717b Fluorimetry, 348b 5-Fluorocytosine, 125b, 126 Fluoroquinolones, 122–123, 123b for leprosy, 269 for plague, 259 skin reactions, 1173b tuberculosis, 593 Fluorosis, 149 5-Fluorouracil (5-FU), 804 for basal cell carcinoma, 1230, 1230b for colorectal cancer, 832 for gastric cancer, 804 Fluoxetine, 1199b for bulimia nervosa, 1204 for fibromyalgia, 1018–1019 Flupentixol, 1198b Flutamide, 659b Fluvoxamine, 139 FMF see Familial Mediterranean fever Foamy macrophages, 430, 809 Focal hypermelanosis, 1258 Focal nodular hyperplasia, 893 Focal segmental glomerulosclerosis (FSGS), 400 Focal seizures, 1099, 1099b Folate (folic acid), 715, 945 absorption, 945 biochemical assessment of status, 712b deficiency, 715, 945 causes of, 945b investigation of, 945b management of, 945 dietary sources of, 711b for neural tube defects, 712b, 715 reference nutrient intake of, 711b reference range of, 1362b supplements, 715 Folate antagonists, 123 Folate synthesis inhibitors, 128 Folinic acid for colorectal cancer, 832 for toxoplasmosis, 281 Follicle-stimulating hormone (FSH) puberty and, 1290 reference range of, 1359b Follicular carcinoma, 636b, 649 Folliculitis, 1236–1237 deep, 1237f pruritic, 1220b superficial, 1236–1237 Fomepizole, 147 Fondaparinux, 938–939, 938b Fonsecaea compacta, 300–301 Fonsecaea pedrosoi, 300–301 Food allergy, 812 Food hygiene, 323 Food intolerance, 812 irritable bowel syndrome of, 825 Food poisoning Bacillus cereus, 262, 262f Clostridium perfringens, 262 non-infectious causes of, 230 staphylococcal, 262 Food-related poisoning, 149–150 Foot drop, 1087, 1309b Foot/feet diabetic, 759f, 761–762 aetiology of, 761 clinical features of, 761b management of, 761–762, 762b, 762f examination of diabetes mellitus, 721b musculoskeletal system, 982f non-freezing cold injury (trench or immersion foot), 167 Foot pain, 999 Foot ulcer, 761–762 Forced expiratory volume (FEV1), 554f in COPD, 574b in old age, 550b Forced vital capacity (FVC), 550b Foreign body, inhaled, 179, 179f Fortification spectra, 1088 Foscarnet for CMV infection, 243 for herpesvirus infection, 127, 127b Fosfomycin, 124 Fournier’s gangrene, 227 Fractures, 994–995 associated with osteoporosis, 1044, 1045f bone mineral density and, 1046f fragility, 995b high-energy, 995b hip, 1308, 1308f investigation of, 994–995, 995b osteoporotic, 1308 pathological, 995b

1384 • INDEX prevention of, 1308–1309, 1309b repair, 1002b stress, 995b vertebral, 995b Fragile site mental retardation 2 (FRAXE), 43b Fragility fracture, 995b Frailty, 1306, 1306b Frameshift mutation, 42 Francisella tularensis, 261 FRAXE see Fragile site mental retardation 2 FRC see Functional residual capacity Freckle, 1234 Free fatty acids, 697 Free intravascular haemoglobin, 917 Free radicals, 713, 881 Freezing cold injury, 166–167 Frequency of micturition, 396 Fresh frozen plasma, 931b Fried Frailty score, 1306b Froin’s syndrome, 1136–1137 Frontal lobes, 1066 functions of, 1066b effects of damage, 1066b Fronto-temporal dementia, 1193–1194, 1193f Frontostriatal reward circuits, high-risk behaviour and, 1295 Frostbite, 166–167, 167f Frozen shoulder, 997–998 Fructose, 695–697, 696b FSH see Follicle-stimulating hormone 5-FU see 5-Fluorouracil Full blood count (FBC), 919–920 see also Blood count Fulminant liver failure, hepatitis B and,

Functional disorders, 802–803, 1094–1095, 1095b ‘Functional’ gonadotrophin deficiency,

Functional IgG antibody deficiency, 79 Functional residual capacity (FRC),

Functional somatic syndromes, 1187, 1187b Fundus angiography, of visual disorders,

Fungal infections, 300–304, 300f after HSCT, 937b antifungal agents, 125–126, 125b, 1239–1240 skin, 1239–1240, 1240f subcutaneous, 300–301 superficial, 300 systemic, 301–304 Fungal keratitis, 1173 Fungal meningitis, 1121 Fungi, 101–102 respiratory diseases caused by, 596–598, 596b ‘Funny turns’, 1080 Furosemide adverse reactions of, 22b ascites and, 864 for heart failure, 465 for hyperkalaemia, 363b for hypertension, 513 for oedema, 396 route of administration, 30b for skin disease, 1221b Furuncles, 1237 Fusariosis, 302–303, 303f Fusidic acid, 124 for impetigo, 1236 Fusobacterium necrophorum, 586 Fusobacterium spp., 103f, 117b Fusobacterium ulcerans, 234b Futility, 213 FVC see Forced vital capacity G G-CSF see Granulocyte-colonystimulating factor G6PD see Glucose-6-phosphate dehydrogenase (G6PD) deficiency GABA hepatic encephalopathy and, 865 role in epilepsy, 1097–1098 Gabapentin for abdominal pain, 789 adjuvant analgesics, 1352b for chronic pain, 1345b for epilepsy, 1102b for fibromyalgia, 1018–1019 multiple sclerosis, 1110b for neuropathic pain, 1084, 1350b for post-herpetic neuralgia, 240 for somatoform pain disorder, 1202 GAD see Glutamic acid decarboxylase Gain-of-function mutations, 45 Gait abnormal, 1086–1087 assessment of, 983f examination of, 1063b in older people, 1309b stamping, 1087 waddling, 1063b Galactorrhoea, 684 Galactosaemia, 370 Galactose, 370, 768 Galactose-1-phosphate uridyl transferase gene (GALT), 370 Gallbladder, 849–850 adenomyomatosis of, 909 cancer of, 904 in old age, 909b carcinoma of, 907 cholesterolosis of, 909 disease of, in old age, 909b strawberry, 909 tumours of, 907–908 benign, 908 Gallstone dyspepsia, 904 Gallstones, 903–905, 904f biliary sludge and, 904 cholesterol, 903, 903b clinical features of, 904, 904b in old age, 909b pigment stones and, 903–904, 903b pregnancy and, 900 treatment of, 905b ultrasound for, 853–854, 854f GALT, 370 Gambiense infections, 279 Gametogenesis, 41f Gamma-glutamyl transferase (GGT), liver blood biochemistry test and, 852, 853b Gamma hydroxybutyrate, misuse of,

Gamma ray-emitting radiopharmaceuticals, 390 Gamma rays, 164, 164f Gammopathy, 966 Ganciclovir for CMV infection, 224 HIV-related, 322 transplant patients, 89, 937b for herpesvirus infection, 126, 127b ‘Gas-bloat syndrome’, 794 Gas exchange, in lungs, 549–550, 549f Gas gangrene, 227 prophylaxis for, 119b Gastrectomy sleeve, 703b under-nutrition and, 706 Gastric acid, 791 Gastric aspiration, 136 Gastric banding, 703b Gastric bypass, 703b Gastric carcinogenesis, 803f risk factors for, 804b Gastric emptying, defective, 791 Gastric emptying study, 778b Gastric inhibitory polypeptide (GIP), 723–724, 772b Gastric lavage, 136, 136b Gastric outlet obstruction, 801–802, 801b Gastric secretion, 767, 767f Gastric varices, 865–866, 865f Gastric volvulus, 793 Gastrin, 767, 772b reference range of, 1359b Gastritis, 797–798 acute, 797 causes of, 798b chronic autoimmune, 797 due to Helicobacter pylori infection, 797, 798f Gastro-oesophageal reflux disease, 791–794, 791f, 794f asthma and, 791–792 in old age, 794b Gastroenteritis eosinophilic, 811–812 infective causes of, 228b foods associated with, 228b in old age, 228b Gastroenterology, 763–844 functional anatomy of, 766–772 histology of, 776, 777b Gastroenteropancreatic neuro-endocrine tumours, 678–679, 678b, 679f Gastroenteropathy, allergic, 812 Gastroenterostomy, 801–802 Gastrointestinal bleeding, 780–783 acute upper gastrointestinal haemorrhage in, 780–782 management of, 781–782 endoscopic therapy, 780 lower gastrointestinal tract, 782–783, 782b severe, 782–783 subacute or chronic, 783 occult, 783 of unknown cause, 783, 783f upper, risk stratification in, 781b Gastrointestinal decontamination, in poisoning, 135–136, 136b Gastrointestinal disease, 785 contrast radiology in, 773b HIV-related, 316–317 ophthalmic features of, 1166b during pregnancy, 1277–1278 transition medicine and, 1299–1300 inflammatory bowel disease in, 1299–1300 Gastrointestinal haemorrhage, upper, causes of, 781f Gastrointestinal obstruction, in palliative care, 1354 Gastrointestinal polyposis syndromes, 828b Gastrointestinal stromal cell tumours (GISTs), 805 Gastrointestinal system, pregnancy and,

Gastrointestinal tract absorption from, 17 clinical examination of, 764–766, 764f, 765b diseases/disorders classification of, 677b functional, 802–803 gut hormones, 772 investigation of, 772–778 presenting problems in, 778–789 function, control of, 771–772 HIV/AIDS and, 826 obstruction, 788 Gastrointestinal tuberculosis, 590, 591f Gastroparesis, 760, 803 Gastropathy, congestive, ‘portal hypertensive’, 871 Gastrostomy feeding, 707, 707b, 708f Gaucher’s disease, 371b GCA see Giant cell arteritis GCS see Glasgow Coma Scale Gefitinib, 1332 Gegenhalten, 1094 Gels, 1225b Gemcitabine, for pancreatic cancer, 842–844 Gender, alcoholic liver disease and, 880 Gene panels, 54b Gene promoter, 39, 39f Gene sequencing, 52–56, 54f–55f challenges of NGS technologies in, 53–54 methods for, 55b NGS capture in, 53 third-generation, 56 uses of, 54–56 Gene therapy, for genetic disease, 58 General anaesthetics, 14 General assessment of locomotor system (GALS), 983, 983f General sales list (GSL), 27 Generalised anxiety disorder, 1200 Generalised lymphadenopathy, 927 Generalised pain, causes of, 995b Generalised seizures, 1099–1100 Generic virus life cycle, 101f Genes amplification of, 52, 53f packaging of, 38, 38f Genetic disease(s) constitutional, 46–50 inheritance patterns of, 46–50 renal, 403–406 skin, 1264 somatic, 50–51 treatment of, 58 Genetic factors adverse drug reactions and, 29 of ageing, 1304–1305 alcoholic liver disease and, 880, 881f of cancer, 1316 of inflammatory bowel disease,

of osteoarthritis, 1007–1008 of osteoporosis, 1044 of Parkinson’s disease, 1112 psychiatric disorders and, 1183 Genetic testing, 1077 for Peutz-Jeghers syndrome, 829 Genetic variant classes of, 42–44, 42b consequences of, 44–45 in evolutionary selection, 45–46 normal, 45–46 Genital herpes, 334b, 336b Genital itch/rash, 333, 334b Genital lumps in men, 334 in women, 336 Genital ulcers in Behçet’s disease, 1043–1044 in men, 333–334, 334f in women, 336 Genital warts, 1238 Genitalia, in endocrine disease, 630f Genitourinary disease, in tuberculosis,

Genitourinary system, pregnancy and,

Genome editing, for genetic disease,

Genome-wide association studies (GWAS), 45 Genomics clinical practice and, 56–59 common disease and, 56 ethics and, 59 fundamental principles of, 38–41 health and disease, 42–51 health care and, 56–58 in infectious disease, 58 obstetrics and, 56 oncology and, 56–58 in rare neurodevelopmental disorders,

technologies for, 51–56 Gentamicin, 429 for brucellosis, 255b for cerebral abscess, 1124b dosing of, 122, 122f drug concentration, 36b for infective endocarditis, 223 for liver abscess, 880 for meningitis, 1120b for neutropenic sepsis, 957 for plague, 259 prophylactic, 119b renal or hepatic disease, 32b for septic arthritis, 1020 for tularemia, 261 for urinary tract infection, 429b Fractures (Continued)

INDEX • 1385 Geriatric medicine assessment, 1306 presenting problems in, 1307–1311 see also Age/ageing; Older people Gerstmann-Sträussler-Scheinker syndrome, 1127b Gestational diabetes, 1278, 1278b diagnosis of, 1278 management of, 1278 screening for, 1278 Get up and go test, 1303b GFR see Glomerular filtration rate GGT see γ-Glutamyl transferase GH see Growth hormone Ghrelin, 767, 772b Giant cell arteritis (GCA), 1042–1043,

emergency management of, 1043b Giardia lamblia, 287 Giardiasis, 287 clinical features and investigations of,

management of, 287 Gilbert’s syndrome, 860, 860b, 897 Gingivitis, 316 GIP see Gastric inhibitory polypeptide GISTs see Gastrointestinal stromal cell tumours Gitelman’s syndrome, 361 Glanzmann’s thrombasthenia, 971 Glasgow Coma Scale (GCS), 134, 185, 186f, 194, 194b Glasgow criteria, for prognosis in acute pancreatitis, 837b Glasgow score, for alcoholic liver disease, 882, 882b Glatiramer acetate, 1109, 1109b Glioblastoma multiforme, 1129 Gliomas, 1130–1131 Glitazones, for non-alcoholic fatty liver,

Global burden of disease (GBD) causes of death and disability, 92–93, 92b underlying risk factors of, 93b Global warming, 94 Glomerular diseases, 397–401, 397b histopathology of, 399f inherited, 403–404 pregnancy and, 1282 Glomerular filtration rate (GFR), 386–387, 387f diabetes mellitus and, 417f estimation of, 386b limitations of, 387b pregnancy and, 1272 renal failure, chronic, 415 renal haemodynamics and, 413f Glomerulonephritis, 397–401 antibody production, associated with, 397f categorised, 398b–399b causes of, 401b drug-induced, 427b infection-related, 398b–399b, 401 mesangiocapillary, 398b–399b, 401 nephrotic syndrome, 392b, 395, 395b rapidly progressive, 397 in systemic lupus erythematosus,

terminology used in, 400b Glomerulosclerosis, nodular, diabetic, 757, 758f Glomerulus, 384 Glossitis, atrophic, 764f Glossopharyngeal (9th cranial), tests of, 1063b Gloves and socks syndrome, 237b Glucagon famine, 704–705 secretion, regulation, 724 Glucagon-like peptide-1 (GLP-1), 723–724, 772b Glucagon-like peptide-1 (GLP-1) receptor agonists, for hyperglycaemia, 747–748 Glucocorticoid-induced osteoporosis,

Glucocorticoids, 665 for acute exacerbations of COPD,

for adrenal insufficiency, 672–673 adverse effects of, 670–671 advice to patients on, 671b for alcoholic hepatitis, 882 for allergy, 86 anabolic, cholestatic hepatitis and,

for ankylosing spondylitis, 1031 for antineutrophil cytoplasmic antibody-associated vasculitis,

for autoimmune hepatitis, 886–887 in bone remodelling, 986b for Duchenne muscular dystrophy,

for Graves’ ophthalmopathy, 646 growth retardation and, 1290, 1299 for inflammatory bowel disease, 821b,

for musculoskeletal disease, 1005–1006 in old age, 673b osteoporosis induced by, transition medicine, 1300 for polymyositis and dermatomyositis,

for primary biliary cholangitis, 888 pruritus, 1220b for psoriatic arthritis, 1033–1034 for reactive arthritis, 1032 for rheumatic fever, 517 sodium content of, 864b therapeutic use of, 670–671, 670b topical, 1226, 1226b, 1226f for tuberculosis, 593 for ulcerative colitis, 1299–1300 for warm autoimmune haemolysis,

weight gain, 700b withdrawal of, management of, 671, 671b see also Corticosteroids; Cortisol; Hydrocortisone; Mineralocorticoids; Prednisolone Gluconeogenesis, 850 Glucosamine sulphate, for osteoarthritis,

Glucose acute kidney injury and, 416b blood diabetes and, 724–726 impaired fasting glucose, 726b,

normal metabolism of, 724, 725f cerebrospinal fluid, 1361b control of, in intensive care, 210–211 filtration and reabsorption by nephron, 748f impaired tolerance, 374, 1360b interstitial, diabetes and, 726 intravenous, porphyria, 379 metabolism of, pregnancy and, 1272–1273 reference range of, venous blood, 1360b urine, diabetes and, 725 values of, in gestational diabetes,

Glucose-6-phosphate dehydrogenase (G6PD) deficiency, 948–949, 949b Glucose tolerance, impaired, 726b,

Glucose tolerance test, oral, 726b Glue sniffing, 1196 Glutamate, 698b Glutamic acid decarboxylase (GAD), 1111b Glutaminase, 364 γ-Glutamyl transferase (GGT) in alcohol misuse, 1184 reference range of, venous blood, 1360b Glutathione, 712b Gluten-free diet, 807 Gluteus medius enthesitis, 999b Glycaemic control, in diabetes, 756–757, 756f in adolescence, 753b in old age, 757b self-assessment of, 742 ‘Glycaemic index,’ of foods, 695–697 Glycated haemoglobin (HbA1C), 726–727, 727b, 1360b Glycation, 726–727 Glyceryl trinitrate (GTN) for anal fissure, 836 angina, 489, 490b duration of action, 490b intravenous, accelerated hypertension, 514 for pulmonary oedema, 465b route of administration, 30b sublingual, 489, 500 Glycine, 698b Glycogen, 694 Glycogen storage diseases (GSDs), 370, 370b Glycopeptide-resistant enterococci (GRE), 117b Glycopeptides, 123 mechanism of action, 116b in pregnancy, 120b Glycoprotein intrinsic factor, 767 Glycosidases, 987 Glycosuria, 725, 729–730 diabetes mellitus, 409, 729–730 Fanconi’s syndrome, 410b hypernatraemia and, 359b ‘lag storage’, 638b leg ulcers and, 1224 in old people, 732b pregnancy and, 1272 renal, 405, 725 Glycosylphosphatidylinositol (GPI), 950–951 Glycylcyclines, 120b, 124 GM2-gangliosidosis, 371b Gnathostomiasis, 294 Goitre endemic, 717 multinodular, 648–649, 648f simple diffuse, 648, 648f thyrotoxicosis, 635–636, 636b Gold (myocrisin) adverse effects on kidney, 427b adverse reactions of, 926b for musculoskeletal disease, 1004b,

Golfer’s elbow, 998 Golgi apparatus, 40 Golimumab, for musculoskeletal disease, 1007b Gonadotrophin-releasing hormone (GnRH), 633f for infertility, 656–657 puberty and, 1290 Gonadotrophin-releasing hormone analogues, 379 Gonococcal infection, disseminated (DGI), 340 Gonococcal ophthalmia neonatorum, 340f Gonococcal urethritis, 333, 333f Gonorrhoea, 339–340 arthritis, 340 complications of delayed therapy in, 340b incubation period, 111b, 339 pharyngeal, 340 treatment of uncomplicated, 340b urethritis, 333 Goodpasture’s disease, 612 Gorlin’s syndrome, 57b Goserelin, 1332 Got transition, 1290 Gottron’s papules, 1039 Gout, 1012–1016 causes of, 1013b clinical features of, 1014, 1014f–1015f epidemiology of, 1012–1013 investigations for, 1014–1015 management of, 1015–1016 in old age, 1014b pathophysiology of, 1013–1014, 1013f tophaceous, 1014–1015, 1015f Graft-versus-host disease (GVHD), 937,

Graham Steell murmur, 526 Granulocyte-colony-stimulating factor (G-CSF), 1327–1328 Granulocytes, 917 count, 1362b Granuloma annulare, 1263 Granuloma inguinale, 341b Granulomas, 71 Granulomatosis with polyangiitis, 612,

Granulomatous disease, 1263 Granzymes, 67 Graves’ disease, 643–646 ophthalmopathy, 631b, 645–646, 645f thyrotoxicosis and, 635–636, 636b, 643–646, 643f management of, 644–645, 644b Graves’ thyrotoxicosis, 643–645, 643f Gravitational eczema, 1247 Grays (Gy), 164 Grenz (Bucky) ray therapy, for skin disease, 1228–1229 ‘Grey baby’ syndrome, 120b Grey Turner’s sign, 837–838 Grief reactions, 1201 Griseofulvin, as antifungal agents, 126 Group A streptococci (GAS), 252 Group B streptococcal infection, in pregnancy, 235b Growth, analytes affected by, 1363b Growth factors, 914, 915f asthma, 568 cancer, 1317, 1317f haematopoiesis, 914 Growth failure, 823 Growth hormone (GH), 632, 633f reference range of, 1359b Growth hormone-releasing hormone (GHRH), 633f Growth hormone replacement, for Hypopituitarism, 682 Growth hormone secretion, tests of, 682b Growth retardation congenital heart disease and, 533 eating disorders, 1204b GSDs see Glycogen storage diseases GTN see Glyceryl trinitrate Guanine, 38 Guillain-Barré syndrome, 1140 Guinea worm (dracunculiasis), 293 Gumma, 338 Gums, 696b Kaposi’s sarcoma, 316f scurvy, 716b Gut hormones, 772, 772b testing, 778 GVHD see Graft-versus-host disease Gynaecomastia, 657, 657b, 867 in hypogonadism, 653 H HACE see High-altitude cerebral oedema HACEK group bacteria, endocarditis, 528, 528b HAE see Hereditary angioedema Haem, biosynthetic pathway, 378f Haemagglutination testing, 261 Haemagogus spp., yellow fever and,

Haemangioblastomas, 1132 Haemangiomas, 1234 liver, 893, 893f Haemarthrosis, 992–993 Haematemesis, 780 Haematocrit (Hct), 919–920, 1362b Haematological abnormalities, HIV-related, 322 Haematological disorders see Blood diseases Haematological investigations, in older people, 923b

1386 • INDEX Haematological malignancies, 954–968, 955b chemotherapy in, 936 in old age, 968b Haematological practice, treatments for emergencies in, 939b Haematological system, pregnancy and,

Haematological tests, for hepatobiliary disease, 853 Haematological values, 1362b Haematology, 388 in coeliac disease, 807 in musculoskeletal disease, 990 transfusion medicine and, 911–979 Haematoma extradural, 1133 intracerebral, 1133 muscle, haemophilia, 973f in stroke patients, 1157–1158, 1158b subdural, 1133 subungual, 1260, 1260f Haematopoiesis, 914–915, 914f Haematopoietic stem cell transplantation (HSCT), 936–938 for acute leukaemia, 958 allogeneic, 936–937, 936b–937b for aplastic anaemia, 969 autologous, 936–938 for beta-thalassaemia, 954b for chronic myeloid leukaemia, 959 fever after, 224–225 for high-grade NHL, 966 infections during recovery from, 937b for myelofibrosis, 969 for myeloma, 968 Haematuria, 391–392, 392f investigation of, 393f loin pain, 396 non-visible, 392b Haemochromatosis, 717, 895–896, 896f causes of, 895b hereditary, 895–896 liver function test (LFT) abnormality in, 854b rheumatological manifestations of,

secondary, 896 Haemoconcentration, hypothermia and,

Haemodiafiltration, 423 Haemodialysis, 136, 421–423 access, 423f in acute kidney injury, 422 in CKD, 422–423 peritoneal dialysis vs., 420b problems with, 424b Haemofiltration, 423 continuous venovenous, 423 Haemoglobin, 915–916, 917f abnormal, 951 glycated, 726–727, 727b, 1360b mean cell (MCH), 1362b pregnancy and, 1273 reference range of, 1362b Haemoglobin A, 915–916 Haemoglobin C, 951–952 Haemoglobin C (HbC) disease, 953 Haemoglobin F, 915–916 Haemoglobin H, 954 Haemoglobin-oxygen dissociation curve, 190, 191f Haemoglobin S, 951–952 Haemoglobin SC disease, 953 Haemoglobinopathies, 951–954, 951f Haemoglobinuria, 338, 392b march, 950 paroxysmal cold, 950 paroxysmal nocturnal, 950–951 Haemolysis, 945 active, investigation results indicating, 946b causes and classification of, 946f extravascular, 946–947 intravascular, 946b, 947 Haemolytic anaemias, 923, 945–951 alloimmune, 950 autoimmune, 949–950 causes of, 946f, 947 microangiopathic, 950 non-immune, 950 Haemolytic crisis, 947 Haemolytic disease of newborn (HDN), 933, 933b Haemolytic uraemic syndrome (HUS), 104b, 388, 408–409 pregnancy and, 1285 Haemophilia, rheumatological manifestations of, 1058 Haemophilia A, 971–973 clinical features of, 972, 972b, 973f coagulation factor therapy for, complications of, 973 genetics in, 971–972 management of, 972–973 Haemophilia B, 973–974 Haemophilus ducreyi, 341b Haemophilus influenzae, 117b bacterial meningitis, 1119b–1120b immunisation for, 115b pneumonia, 319, 583 Haemophilus spp., 103f Haemoptysis in lung cancer, 599–600 in respiratory disease, 559–560, 559b, 560f Haemorrhage during dialysis, 424b intracerebral, 1154–1155, 1155f causes of, 1155b major, transfusion in, 931b, 934–936, 936b obstetric, circulatory collapse and,

retinal, 169 splinter, 994b, 1260 subarachnoid, 1160–1162 clinical features of, 1161, 1162f investigations of, 1161 management of, 1162 see also stroke Haemorrhagic fevers, viral, 245–247, 245b Haemorrhagic toxins, 155–156 Haemorrhoids, 835–836 Haemosiderin, 851 Haemosiderosis, 716 idiopathic pulmonary, 613b Haemostasis, 917–919, 918f–919f in old age, 978b Haemostasis system toxins, 155, 156f Hair abnormalities, 1224 disorders, 1258–1260 follicles, 1212–1213 loss, 1266b Hairy cell leukaemia, 960 Hairy leucoplakia, 316 Hallpike manoeuvre, 1104, 1104f Hallucinations, 1181, 1184 in alcohol misuse, 1194 hypnagogic, 1184 hypnopompic, 1184 in schizophrenia, 1196–1197 Hallucinogens, misuse of, 143–144,

Hallucinosis, alcoholic, 1194 Hallux valgus, 999 Haloperidol adverse reactions of, 22b agitation, 1354 for delirium, 209 for disturbed behaviour, 1188–1189 poisoning, 141 schizophrenia, 1198b Halothane, 82–83, 857f Hamartoma, 603b small intestine and, 813 Hands in endocrine disease, 630f examination of blood disease, 912f cancer, 1314f cardiology, 442f diabetes mellitus, 721b endocrine disease, 630f gastrointestinal disease, 764f liver and biliary disease, 846f musculoskeletal system, 982f renal/urinary tract disease, 382f respiratory system, 546f skin disease, 1210f foot and mouth disease, 248 gastrointestinal disease, 764f hygiene, infection control, 112–113, 113f liver and biliary disease and, 846f osteoarthritis, 1009f pain, 998 rheumatoid arthritis in, 1023f washing, 113f Hantavirus infection, 258 Haploinsufficiency, 659 Haptoglobin, 947, 1362b in acute phase response, 70 Hard metal disease, 616 Hartmann’s procedure, 788 Hartmann’s solution, 353b Hartnup’s disease, 714 Hasenclever index, in Hodgkin lymphoma, 964, 964b Hashimoto’s thyroiditis, 646 Haversian system, 984f Hay fever, 85, 622 Hayflick limit, 41 Head and neck examination of diabetes mellitus, 720f endocrine disease, 630f gastrointestinal disease, 764f imaging of, 1073–1074, 1074f injury, 1133 tumours in, 1335–1336, 1335b investigations of, 1335 management of, 1335–1336 pathogenesis of, 1335 Head lice, 1241 Head-up tilt-table testing, 183 Headache, 185–186, 1080, 1095–1097 analgesic for, 1096 associated with specific activities,

benign paroxysmal, 1097, 1097b brain tumours causing, 1129 clinical assessment of, 185, 186f cluster, 1096 exertion, 1097 fever and, 217b heat stroke and, 167 investigations of, 185–186 medication overuse, 1096 migraine and, 1095–1096 morning, 558 pregnancy and, 1275 presentation of, 185, 185b raised ICP, 1128b ‘red flag’ symptoms in, 185b sexual activity and, 1097 stroke and, 1153 subarachnoid haemorrhage and,

tension-type, 1095 Health, social determinants of, 93–94 Health care, genomics and, 56–58 Health care-associated infection, 111–113, 112f–113f MRSA, 100 predisposing factors, 112f Health data/informatics, 97–98 Hearing disturbance, 1093 Heart anatomy of, 444–446, 444f–445f auscultation of, 443b blood flow through, 444f catheterisation, 453–454, 453f chamber, 445f dilation of, 450 conduction system, 445, 445f coronary circulation in, 444–445 endothelium and, 447 inflammatory arthritis in, 994b nerve supply of, 445–446 physiology of, 446–448 Starling’s law, 461, 461f Heart beats ectopic atrial, 469–470, 470f ventricular, 474–475, 475f see also Palpitation Heart block atrioventricular, 477–478, 477f–478f, 478b bifascicular, 478–479 bundle branch, 478–479, 478b, 478f hemiblock, 478–479 Heart disease congenital, 531–538, 531b, 532f HIV-related, 322 pregnancy, 1282 rheumatic, 515–517 rheumatoid arthritis and, 1024 Heart failure, 461–468 in acute coronary syndrome, 496 acute left, 463 biventricular, 461 chronic, 463–464, 463b, 463f clinical assessment for, 463–464, 463b complications of, 464 congestive, in old age, 466b high-output, 463 investigations for, 464, 464f left, 461 management of, 464–468, 465b drug treatment for, 465–467, 466f mechanisms of, 462b, 462f right, 461 Heart murmur, 459b Heart rate effects of respiration on, 447b pregnancy and, 1272 Heart sounds, 460f abnormal, 457–461, 459b normal, 459b Heart valves, diseases of, 514–531, 515b Heartburn, 779 Heat cramps, 167 Heat exhaustion, 167 Heat-related illness, 167–168 Heat stroke, 167–168 Heat syncope, 167 Heberden’s nodes, 1009f Height, in endocrine disease, 630f Heinz bodies, 950 Helicobacter pylori eradication therapy, 800, 800b gastric lymphoma, 805 peptic ulcer and, 798–799, 799f, 800b Helium dilution technique, 575 Heller’s operation, 795 HELLP syndrome, pregnancy and,

Helminthiases, soil-transmitted, 233b Helminths, 101–102 drugs used against, 129 Hemicellulose, 696b Hemicrania, chronic paroxysmal, 1097b Hemidiaphragm, elevation of, 627, 627b Hemifacial spasm, 1116 Hemiparesis, 1083, 1123 Hemiplegic gait, 1309b Henderson-Hasselbalch equation, 364 Henoch-Schönlein purpura, 398b–399b, 401, 1043 Heparin, 938–939 for acute limb ischaemia, 503 for angina, 491 indications for, 938b low-molecular-weight, in thrombosis,

monitoring, 922 for stroke, 1160 Heparin-induced thrombocytopenia (HIT), 939 Hepatic acinus, 848, 848f Hepatic adenomas, 893 Hepatic artery aneurysms, 898 Hepatic decompensation, 867 Hepatic disease, prescribing for patients with, 32, 32b

INDEX • 1387 Hepatic encephalopathy, 847b, 864–865 acute liver failure and, 856–857 clinical grade of, assessment for, 857b differential diagnosis of, 865b factors precipitating, 865b Hepatic fibrosis, 894 cirrhosis and, 866, 866f congenital, 868f, 902 non-invasive markers of, 855 pathogenic mechanisms in, 849f Hepatic hydrothorax, 863 Hepatic Iron Index (HII), 895 Hepatic-renal disease, 409–410 Hepatic venous disease, 898 Hepatic venous pressure, 868 Hepatitis acute kidney injury and, 416b alcoholic, 881 autoimmune, 886–887 conditions associated with, 886b liver function test (LFT) abnormality in, 854b interface, 886 viral, 343–344, 871–878 causes of, 871b chronic, HIV-related, 317–318 features of, 872b investigations for, 872 management of, 872 non-A, non-B, non-C (NANBNC),

pregnancy and, 1284 sexual, 343–344 Wilson’s disease and, 896 Hepatitis A virus (HAV), 872–873, 872b acute liver failure and, 873 antigen for, 872 immunisation, 115b incubation period of, 111b in old age, 901b pregnancy and, 900 transmission, sexual, 343 Hepatitis B core antigen (HBcAg), 873–874 Hepatitis B core IgM antibody, screening for, in acute liver failure, 858 Hepatitis B e antigen (HBeAg), 874–875 Hepatitis B surface antigen (HBsAg),

recombinant hepatitis B vaccine with,

Hepatitis B virus (HBV), 872b, 873–877 acute, management of, 875 chronic HBeAg-negative, 875 liver function test (LFT) abnormality in, 854b management of, 875–876 natural history of, 874f phases of, 874b risk of, 873b source of, 873b cirrhosis and, 876 co-infection with HIV, 876–877 HIV-related, 317–318 incubation period of, 111b investigations of, 873–875 in pregnancy, 235b, 900 prevention of, 876, 876b schematic diagram of, 873f serology for, 873–875, 875b, 875f transmission, sexual, 343 vertical transmission of, 873 viral load and, 875, 875f Hepatitis C virus (HCV), 872b, 877–878 antigens for, 877 chronic, risk factors for, 877b cirrhosis and, 877 HIV-related, 318 liver function test for, 877 abnormality in, 854b liver histology for, 878 molecular analysis for, 877 pregnancy and, 900 transmission, sexual, 343 Hepatitis D virus, 872b, 877 Delta antigen for, 877 vertical transmission of, 877 Hepatitis E, 872b, 878 in pregnancy, 235b pregnancy and, 900 Hepatitis viruses, 249 Hepatobiliary disease, HIV-related, 317–318 Hepatocellular carcinoma, 890–892, 891f chemotherapy for, 892 cirrhosis and, 890 fibrolamellar, 892 hepatic resection for, 891 hepatitis B and, 873 liver biopsy for, 891 liver transplantation for, 891 management of, 892f in old age, 901b percutaneous therapy for, 891 screening for, 890–891 trans-arterial chemo-embolisation for,

Hepatocellular jaundice, 860–861 Hepatocytes, 848, 849f necrosis of, 894 Hepatology, 845–909 Hepatomegaly, 862 acute liver failure and, 857–858 Budd-Chiari syndrome and, 899 cirrhosis and, 866–867 Hepatopulmonary syndrome, 898 Hepatorenal syndrome ascites and, 864 type 1, 864 type 2, 864 Hepatosplenic candidiasis, 302 Hepcidin, 716–717, 943 HER2 receptor, as tumour markers, 1322, 1324b Herbal medicines, for pain, 1348 Herd immunity, 115 Hereditary angioedema (HAE), 88 Hereditary coproporphyria (HCP), 379b Hereditary elliptocytosis, 947–948 Hereditary haemorrhagic telangiectasia (HHT), 970 Hereditary hypophosphataemic rickets, 405, 1052–1053 Hereditary nephrotic syndrome, 404 Hereditary neuropathy, 1140 Hereditary spherocytosis, 947 investigations of, 947, 948f management of, 947, 948b Hernia diaphragmatic, 627 hiatus, 791, 791b, 792f lumbar disc, 1135, 1135f Heroin, misuse, 142 Herpangina, 248 Herpes simplex keratitis, 1173 Herpes simplex virus (HSV), 238b after HSCT, 937b genital, 341–342 HIV-related, 314f, 315, 315b HSV-1, 247–248, 247f HSV-2, 247–248, 247f in pregnancy, 235b, 332b viral hepatitis and, 878 Herpes zoster, 239–240, 1123 clinical features of, 239 facial pain from, 1080 HIV-related, 315 management of, 240 Herpesvirus infections, skin, 1238 Herring worm, 294 Heterochromatin, 38–39 Hiatus hernia, 627, 791, 791b, 792f ‘Hibernating’ myocardium, 452 Hibernian fever, 81 Hierarchy of systems, 93, 93b, 93f High altitude, 168–169 illnesses at, 168–169 cerebral oedema (HACE), 168 pulmonary oedema (HAPE), 168–169 physiological effects of, 168, 168f High-altitude cerebral oedema (HACE),

High-density lipoproteins (HDL), 1360b High-energy fracture, 995b High-flow nasal cannulae (HFNCs), 202 High-grade tumours, 961 High haemoglobin, 925, 925b High-risk behaviour, transition medicine and, 1295 history-taking in, 1295b personality and, 1295 protective factors in, 1295 theories in, 1295 Highly polyunsaturated long-chain n-3 fatty acids, 377 Hip osteoarthritis, 1010, 1010f pain, 998, 999b, 999f Hippocampus, 1066 Hirschsprung’s disease, 834–835 Hirsutism, 657–658, 658b, 1259–1260 His bundle, 445 Histamine, 767 Histidine, 698b Histones, 38 Histopathology, in respiratory disease,

Histoplasma capsulatum, 303 Histoplasmosis, 303–304 in HIV infection/AIDS, 314f HIV infection/AIDS, 312 antiretroviral therapy for, 324–327, 324b asymptomatic, 312, 312f CD4 counts in, 311 chemoprophylaxis for, 323–324 clinical examination of, 306f clinical manifestations of, 311–312 counselling for, 311b diagnosis of, 310–311, 310b epidemiology of, 308 global and regional epidemics of, 308, 308b hepatitis B and acute, 875 co-infection with, 876–877 immunisation for, 324 immunology of, 309–310 investigations of, 310–311, 311b life cycle of, 309f liver and, 879 liver blood tests in, abnormal, 879b modes of transmission of, 308, 308b–309b musculoskeletal manifestations of, 1021b in old age, 326b pregnancy and, 1280 presenting problems of, 312–322, 313b cancers, 322, 323b cardiac disease, 322 fever, 313–314, 313f–314f gastrointestinal disease, 316–317 haematological abnormalities, 322 hepatobiliary disease, 317–318 lymphadenopathy, 313 mucocutaneous disease, 314–316, 314b nervous system and eye disease, 319–321, 319f renal diseases, 322 respiratory disease, 318–319, 318b rheumatological diseases, 321–322 weight loss, 313, 313f prevention of, 323–324, 327b primary, 311–312, 312b prophylaxis for, 119b pruritus and, 1219b staging classifications of, 307b testing of, 330 tuberculosis and, 595 viral load in, 311 virology of, 309–310 HIV serology, acute kidney injury and, 416b Hives, 1252 HLA antigen, transplant rejection, 88–89 HNF1-beta mutations, 406 Hoarseness, psychogenic, 624 Hodgkin lymphoma (HL), 961–964, 962f classification of, 962b clinical features of, 962 epidemiology of, 961, 962b investigations of, 962, 963f management of, 962–964 prognosis of, 964, 964b stages of, 962b Holmes-Adie syndrome, 1092b Home ventilation, for chronic respiratory failure, 567 Homocystinuria, 369–370 Honeycomb lung, 608f Hookworm ancylostomiasis, 288–289, 288f dog, 294 Hookworm infestation, 233b Hoover’s sign, 1081–1082 Hormone replacement therapy amenorrhoea, 655 cancer, 1332 for osteoporosis, 1048b, 1049 Hormones gastrointestinal tract, 772 production, ectopic, 1325b in venous blood, 1359b Horner’s syndrome, 1091b–1092b, 1091f Hospital, under-nutrition in, 693f, 705–708, 706b Host-pathogen interactions, 104 House dust mite, 570 Howell-Jolly bodies, 921f Human albumin, 930 Human albumin solution (HAS), ascites and, 864 Human chorionic gonadotrophin (hCG) secretion of, pregnancy and, 1272 as tumour markers, 1322, 1324b Human herpesvirus 6 (HHV-6), 238, 238b Human herpesvirus 7 (HHV-7), 238, 238b Human herpesvirus 8 (HHV-8), 238b,

Human leucocyte antigen (HLA) molecules, 67 antigen processing and presentation and, 70 Human papillomavirus (HPV), 342–343 in pregnancy, 332b vaccines, 115 Human parvovirus arthropathy, 1020–1021 Human T-cell lymphotrophic virus type 1, 250 Humanitarian crisis, 171–172, 172b Humidifier fever, 616b, 617 Humoral immunity, 68 Hunter’s syndrome, 371b Huntington’s disease, 1115 genetic testing of, 1077 Hurler’s syndrome, 371b Hutchinson’s sign, 1233 Hyaluronic acid, intra-articular injections of, 1012 Hydatid cyst, liver and, 880 Hydatid disease, 298–299, 299f Hydralazine, 467 lupus syndrome, 1057b malignant hypertension, 514 pharmacokinetic, 20b skin reactions, 1266b Hydration for stroke patients, 1159b see also Fluid replacement Hydroa vacciniforme, 1221b Hydrocephalus, 1132–1133, 1132f causes of, 1132b, 1133f dementia and, 1191b management of, 1133 normal pressure, 1132–1133 obstructive, 1092b, 1121 Hydrocortisone ACTH deficiency, 682 adrenal insufficiency, 673 anaphylaxis, 76b asthma, 573

1388 • INDEX eczema, 1244 equivalent dose, 670b for inflammatory bowel disease, 820, 821b laryngeal obstruction, 625 potency and strength, 1226b topical, 1226b see also Cortisol Hydrocortisone sodium succinate, 625 Hydrogen ions acid-base balance, 364 in arterial blood, 565b, 1358b Hydromorphone, 1352 Hydronephrosis, 413 Hydrophobia, 1122 Hydrops fetalis, 237b Hydrotherapy, for musculoskeletal disease, 1001 Hydrothorax, hepatic, 863 Hydroxyapatite crystals, 985 Hydroxycarbamide essential thrombocythaemia, 970 leukaemia, 959 for myelofibrosis, 969 sickle-cell disease, 953 for skin disease, 1227–1228 Hydroxychloroquine (HCQ) for musculoskeletal disease, 1004b,

for rheumatoid arthritis, 1026b for Sjögren’s syndrome, 1039 skin reactions, 1266b for systemic lupus erythematosus,

for Whipple’s disease, 809 1α-Hydroxycholecalciferol (alfacalcidol), for hypoparathyroidism, 665 Hydroxycobalamin see Vitamin B12 5-Hydroxyindole-3-acetic acid (5-HIAA), 1361b 11-Hydroxylase deficiency, 509b 17α-Hydroxylase deficiency, 509b 21-Hydroxylase deficiency, 676 11β-Hydroxysteroid dehydrogenase, 665, 665b deficiency, 509b 25-Hydroxyvitamin D (25(OH)D), for skeletal disease, 990b Hyfrecation, 343 Hygiene, hand-washing, 113f Hygiene hypothesis, 84–85 Hyoscine butylbromide, 1350b, 1354 Hyper IgD syndrome (HIDS), 81 Hyperacusis, 1083 Hyperacute rejection, 89 Hyperaesthesia dengue fever, 243b diabetic neuropathy, 758–759 herpes simplex, 247 Hyperaldosteronism glucocorticoid suppressible, 509b,

primary, 674–675, 674b secondary, 674b in type 1 diabetes, 729–730 Hyperalgesia, fibromyalgia, 1018 Hyperalphalipoproteinaemia, 374 Hyperbilirubinaemia non-haemolytic, 860, 860b see also Jaundice Hypercalcaemia, 661–662 cancer and, 1327, 1327b causes of, 662, 662b clinical assessment of, 662 familial hypocalciuric, 662, 664 hypoparathyroidism, 664–665 investigations of, 662 malignant, 662 management of, 662 multiple myeloma and, 410b, 967f sarcoidosis, 609–610 Hypercapnia, ventilator-induced lung injury and, 204 Hypercarotenosis, 713 Hypercholesterolaemia, 373–374, 376–377 atherosclerosis risk, 486 familial, 374, 374b management of, 376–377 nephrotic syndrome and, 395b polygenic, 373–374 primary biliary cholangitis and, 887–888 secondary, 373b Hypercoagulability, nephrotic syndrome and, 395b Hypercortisolism, 667b Hyperemesis gravidarum, pregnancy and, 1277–1278, 1278b Hyperglycaemia in acute medical illness, 754 in diabetes, 734–735, 734f clinical assessment of, 734–735 drugs to reduce, 745–748 symptoms of, 735, 735b type 1, 729–730 type 2, 732 diabetic ketoacidosis, 735 maternal, diabetes and, 1278–1279 pancreatitis, 838b stress, 728 Hyperglycaemic hyperosmolar state (HHS), 738, 739b Hypergonadotrophic hypogonadism, 653b, 654 Hyperinsulinaemia, 740 Hyperkalaemia, 362–363, 464 acute kidney injury and, 413 causes of, 362b chronic kidney disease, 417 heart failure, 464 periodic paralysis, 1145b treatment of, 363b Hyperkeratosis, subungual, 1031 Hyperketonaemia, 725 Hyperlactataemia, 196, 197f Hyperlipidaemia check for signs of, 347f classification of, 374b drug treatment of, 376f familial combined, 374, 374b mixed, 375, 377–378 in old age, 377b rare forms of, 375b remnant, 375 secondary, 373b treatment of, 376f Hypermagnesaemia, 368 Hypermelanosis, focal, 1258 Hypermobile Ehlers-Danlos syndrome (hEDS), 1059 Hypermobility syndromes, 1059 Hypernatraemia, 358–360 causes of, 359b in old age, 360b Hyperostosis, diffuse idiopathic skeletal, 1058–1059, 1058f Hyperparasitaemia, malaria, 276b Hyperparathyroidism chronic kidney disease and, 418–419 in old age, 665b pain, 663 primary, pregnancy and, 1280 Hyperphosphataemia, chronic kidney disease and, 419 Hyperpigmentation, photo-exposed site,

Hyperprolactinaemia, 684, 684b disconnection, 667 Hyperpyrexia, 276b Hypersensitive carotid sinus syndrome,

Hypersensitivity, 71 allergic rhinitis, 622 drug response, 20b Gell and Coombs classification of, 83, 83b patch tests, 1215 prick tests, 1215 type I, 83–84, 85f type II, 83 type III, 83 type IV, 83 Hypersensitivity pneumonitis, 616–617, 617b, 617f Hypersensitivity rashes, 326 Hypersensitivity reaction, definition of,

Hypersomnolence, 1105, 1105b Hypersplenism leucopenia and, 853 portal hypertension, 868b and thrombocytopenia, 869 Hypertension, 193–194, 396, 508–514, 509b–511b, 509f, 511f–512f accelerated, 514 assessment and management of, 193–194 cocaine, 143 definition, 509b essential, 509 gestational, 1276, 1276b history, 510 idiopathic intracranial, 1133 investigations, 510 management antihypertensive drugs, 513 British Hypertension Society guidelines, 512f intervention thresholds, 511–512 non-drug therapy, 513 treatment targets, 512–513, 513b in old age, 512b pathogenesis, 509 pathophysiology of, 193 portal, 868–871, 898 ascites and, 869 cirrhosis and, 868 classification of, 868f clinical features of, 868–869 complications of, 868b extrahepatic portal vein obstruction,

investigations for, 869 management of, 869–871 pathophysiology of, 869 portopulmonary, 898 pre-eclampsia, 1276–1277 during pregnancy, 1276–1277 classification of, 1276b pre-eclampsia and eclampsia in, 1276–1277, 1276b, 1277f pre-existing, 1276 pulmonary, 550, 621–622, 621b, 622f congenital heart disease and, 533 systemic sclerosis and, 1038 renal artery stenosis and, 406 renal disease, 396 AKI, 411–412 chronic, 415 polycystic, 405 reflux nephropathy, 430 secondary, 509b in systemic sclerosis, 1038 target organ damage, 510 venous, 1223 white coat, 510, 1276b Hypertensive renal crisis, systemic sclerosis and, 1038 Hyperthermia, malignant, 1145b Hyperthyroidism, pregnancy and, 1279 Hypertrichosis, 1259 drug-induced, 1266b Hypertriglyceridaemia, 374 familial, 374, 374b management of, 377–378 secondary, 373b Hypertrophic cardiomyopathy, 539–540, 540b Hypertrophic obstructive cardiomyopathy, transition medicine and, 1297–1298 Hypertrophic pulmonary osteoarthropathy (HPOA), in lung cancer, 600–601 Hyperuricaemia, 1012–1013 causes of, 1013b chronic, 1014 gout, 1013b Hyperventilation in panic disorder, 1200 psychogenic, 1202 and respiratory alkalosis, 367 Hyperviscosity syndrome, 966 Hypervolaemia, 353–355 clinical features of, 352b hypernatraemia with, 359b hyponatraemia with, 357 Hypnic jerks, 1086 Hypnotics dosage regimens of, 31b in old age, 32b Hypoadrenalism, tuberculosis, 595 Hypoalbuminaemia, nephrotic syndrome and, 395b Hypobetalipoproteinaemia, 375 Hypocalcaemia, 662–663 aetiology of, 662–663 clinical assessment of, 663 differential diagnosis of, 662b ethylene glycol poisoning, 147 hypomagnesaemia and, 368 kidney failure and acute, 414 chronic, 418–419 kidney injury acute, 414 chronic, 418–419 management of, 663, 663b pancreatitis, 838b Hypochlorhydria, 798–799, 944 Hypochlorous acid, 64 Hypochondriacal disorder, 1202 Hypofibrinogenaemia, 922b, 972b Hypogammaglobulinaemia, in vitamin B12 deficiency, 944 Hypoglossal (12th cranial) nerve, tests of, 1063b Hypoglycaemia, 738–741 acute treatment of, 740 awareness of, 740 causes of, 740b diabetes, 738–741 drug-induced, 747 emergency treatment of, 741b exercise-induced, 740 malaria, 276b nocturnal, 740 prevention of, 740–741, 741b risk factors for, 740b spontaneous, 676–678, 677f, 738 in old age, 678b symptoms of, 739, 739b Hypogonadism hypergonadotrophic, 653b, 654 hypogonadotrophic, 653, 653b male, 655, 656b, 660b Hypogonadotrophic hypogonadism, 653, 653b Hypokalaemia, 361–362, 464 causes of, 361b chloroquine poisoning, 141b heart failure, 464 hyperaldosteronism, 674 mineralocorticoid excess, 675 periodic paralysis, 1145b Hypomagnesaemia, 368 causes of, 368b management, 368 Hypomania, 1199–1200 Hypomimia, 1113b Hyponatraemia, 357–358, 464, 852–853 adrenal insufficiency, 671–672 algorithm for diagnosis of, 359f brain and, 358f causes of, 357b depletional, 672b dilutional, 414 ecstasy/amphetamine misuse, 143 with euvolaemia, 357 heart failure, 464 with hypervolaemia, 357 hypopituitarism, 681–682 with hypovolaemia, 357 in old age, 360b symptoms and severity of, 358b Hypoparathyroidism, 664–665 Hypophosphataemia, 368–369, 369b Hypophosphataemic rickets biochemical abnormalities in, 990b transition medicine and, 1300 Hypophosphatasia, 1053 Hydrocortisone (Continued)

INDEX • 1389 Hypopigmentation, 1257–1258 Hypopituitarism, 681–682, 681b–682b, 681f clinical assessment, 681–682, 681f investigations, 682, 682b management, 682 Hyposmia, 1088 Hypotension, 193 assessment and management of, 193, 193b during dialysis, 424b pathophysiology of, 193, 193b poisoning, 137b postural, 181, 1308–1309 glucocorticoid insufficiency, 672b in old age, 32b renal disease, 411–412 shock, 196b treatment of, 1308–1309 Hypothalamus, 679–688, 1066–1067 disease classification of, 680b presenting problems in, 681–684 functional anatomy, physiology and investigations of, 679f in old age, 688b therapeutic modalities, 683b thermoregulation and, 165 tumours, 1066–1067 Hypothermia, 165–166, 165f–166f cold water immersion, 166 in old age, 166b Hypothyroidism, 639–642 autoimmune, 637b, 639b causes, 639b clinical assessment of, 639–640, 640f clinical features of, 637b congenital, 639b, 650 iatrogenic, 639b investigations of, 640 laboratory abnormalities, 638b management of, 640–641, 641b with normal thyroid function tests, 641–642 obesity, 654–655 in old age, 650b in pregnancy, 641, 651b, 1279 radiotherapy and, 1298 rheumatological manifestations of,

secondary, 639b spontaneous atrophic, 639b subclinical, 642 transient, 640 transient thyroiditis, 639b Hypoventilation, alveolar, 567, 621b Hypovolaemia, 352–353 causes of, 352b clinical features of, 352b hypernatraemia with, 359b hyponatraemia with, 357 Hypovolaemic shock, description of, 206b Hypoxaemia, 168f acute mountain sickness and, 168 assessment and management of, 191, 191b causes of, 192b cirrhosis, 866–867 high-altitude pulmonary oedema, 168–169 mechanisms of, 192f near drowning accidents and, 169–170 pathophysiology of, 190–191, 191f pulmonary hypertension, 621b Hypoxia altitude illness and, 168 cytopathic, 197f, 198 pancreatitis, 838b respiratory failure, 565b Hypromellose, 1039 Hysterectomy, cancer treatment, 1335 Hysteria, 1126 I Ibandronate, for osteoporosis, 1048b Ibuprofen, 1003b adverse reactions of, 22b Ice cream headache, 1097b Ice pick headache, 1097b Ichthyosis, 1212 Idarucizumab, 940 Idiopathic interstitial pneumonias, 605–608, 606b Idiopathic intracranial hypertension, pregnancy and, 1284 Idiopathic osteoporosis, 1044 Idiopathic Parkinson’s disease, 1112–1114 causes of, 1112b clinical features of, 1112–1113, 1113b non-motor symptoms of, 1112–1113 investigations of, 1113, 1113f management of, 1113–1114 drug therapy, 1113–1114 surgery, 1114 pathophysiology of, 1112, 1112f Idiopathic pulmonary fibrosis, 605–608, 607f Idiopathic pulmonary haemosiderosis, 613b Idiopathic thrombocytopenic purpura (ITP), 971 pregnancy and, 1285 If channel antagonists, angina, 491 Ifosfamide, 365b Ileal resection, 810f under-nutrition and, 706 Ileus meconium, 842 paralytic, 837–838 Illusions, 1181 Iloprost, 622 Imaging for epilepsy, 1101b in gastroenterology, 774b, 774f of gastrointestinal tract, 772–776 for hepatobiliary disease, 853–855 for lung cancer, 601, 601f for musculoskeletal disease, 988–990 neuroimaging, 1151, 1151f, 1157–1158 of renal tract, 389–390 of respiratory system, 551–553 vascular, 1151, 1152f Imatinib, 1332 acute leukaemia, 957b chronic myeloid leukaemia, 958 for GIST, 805 Imidazoles, 125b, 126 Imipenem, 120b nocardiosis, 261 Imipramine, 611b irritable bowel syndrome, 825 neurogenic bladder, 1094b Imiprothrin, 148b Imiquimod for lentigo maligna, 1233 for molluscum contagiosum,

for skin cancer, 1230, 1230b for viral warts, 1239 Imiquimod cream, for anogenital warts,

Immersion foot, 167 Immotile cilia syndrome, 578b Immune deficiency, 77–81 autoimmune lymphoproliferative syndrome and, 80 common variable, 79 complement pathway deficiencies in,

consequences of, 77 investigations of initial, 74b specialist, 74b primary, warning signs of, 73b primary antibody deficiencies in, 78–79, 78f, 79b primary phagocyte deficiencies in, 77–78, 77f primary T-lymphocyte deficiencies and, 79–80, 80f secondary, 80–81, 80b Immune disorders anaphylaxis and, 75–76 common causes of, 75b intermittent fever and, 74 presenting problems of, 73–76 recurrent infections and, 73 Immune reconstitution inflammatory syndrome (IRIS), 104, 325–326 Immune response modifiers, 1226 Immune responses, in lower airway defences, 550 Immune senescence, 80–81, 81b Immune serum globulin, for hepatitis A, 872–873 Immune system adaptive, 67–70 cellular immunity and, 69–70, 69f immunoglobulins and, 68–69, 68b, 68f lymphoid organs and, 67 innate, 62–67 complement and, 66 cytokines and, 64–66, 65b, 65f dendritic cells in, 64 integrins and, 66 mast cells and basophils, 66–67 natural killer cells and, 67 phagocytes in, 63–64, 63f physical barriers in, 62–67 regulation of, 851 Immunisation, 114–115, 115b for chickenpox, 239 for cholera, 265 for diphtheria, 266 Haemophilus influenzae, 115b for hepatitis A, 872–873 for hepatitis B, 876, 876b for HIV infection/AIDS, 324 for human papillomavirus, 343 for influenza, 241 for meningococcal infection, 1120 for mumps, 240 for plague, 259 for pneumococcal infection, 266 for poliomyelitis, 1123 primary antibody deficiencies and,

for rabies, 1122 for rubella, 266 for tetanus, 1126 for tuberculosis, 595 for typhoid fever, 261 for whooping cough, 582 whooping cough (pertussis), 115b for yellow fever, 245 see also Vaccines/vaccination Immunity adaptive humoral immunity and, 67–68 cellular, 67, 69–70, 69f humoral, 67–68 Immunoblot (Western blot), 107 innate, 769 Immunoblot (Western blot), 107 Immunobullous disease, drug-induced, 1266b Immunochromatographic rapid diagnostic tests (RDTs), 276 Immunochromatographic tests, 108 Immunocompromised host, fever in, 223–224 Immunocompromised patient, pneumonia in, 587 Immunodiffusion, 108 Immunofluorescence assays, 107 anti-endomysial antibodies of, 807 Immunoglobulin(s), 68–69, 68b, 68f,

for idiopathic thrombocytopenic purpura, 971 intravenous Guillain-Barré syndrome, 1140 myasthenia gravis, 1142b myositis, 1040 thrombocytopenia, 971 toxic shock syndrome, 252 prophylactic, 115b reference range of, venous blood, 1360b Immunoglobulin A (IgA), 68b deficiency, selective, 78–79 linear IgA disease, 1255b, 1256–1257 nephropathy, 398b–399b, 400 reference range of, venous blood, 1360b Immunoglobulin D (IgD), 68b hyper-IgD syndrome, 81 Immunoglobulin E (IgE), 68b, 1215 reference range of, venous blood, 1360b serum total, for allergy, 86 specific tests, for allergy, 86 Immunoglobulin G (IgG), 68b anti-HBc, 875b antibody, functional deficiency in, 79 cerebrospinal fluid, 1361b reference range of, 1360b rubella-specific, 236 Immunoglobulin M (IgM), 68b anti-HBc, 875b cold agglutinin disease, 950 reference range of, venous blood, 1360b Immunoglobulin replacement therapy, for primary antibody deficiencies,

Immunohistochemistry, tumour identification, 1322 Immunological memory, 69 Immunological tests, 1077 antibody-independent specific, 109 for hepatobiliary disease, 853 for respiratory disease, 554 Immunoproliferative small intestinal disease (IPSID), 813 Immunosuppressants for skin disease, 1227–1228 for systemic lupus erythematosus,

Immunosuppression liver transplantation and, 901 myasthenia gravis, 1142b in transplant complications of, 89–90 drugs used in, 89b Immunosuppressive agent, for autoimmune hepatitis, 886 Immunotherapy antigen-specific, for allergy, 86 cancer, 1332 myasthenia gravis, 1142b Impaired glucose tolerance, 374, 1360b Impetigo, 1235–1236 non-bullous, 1235f Implantable cardiac defibrillators, 467, 483–484, 483b for acute coronary syndrome, 501 Impotence see Erectile dysfunction Imprinting, 49–50, 51b Incidence of disease, microbiological sampling, 105b Incident pain, 1350b Incidental adrenal mass, 673–674 Incidental pancreatic mass, 844 ‘Incidentalomas’, 633b Inclusion body myositis, 1059 Incontinence continual, 437 faecal, 1094 overflow, 437, 1093 stress, 436 of stroke patients, 1159b urge, 436–437, 1093 urinary, 397, 436–437 older people, 436b, 1309–1310, 1310f Increased intra-abdominal pressure, 791 Incremental cost-effectiveness ratio (ICER), 28 ‘Incretin’ effect, 723–724, 724f Indirect antiglobulin tests, 948f Indocyanine angiography, of visual disorders, 1169 Indometacin, 1003b for paroxysmal headache prevention,

for pericarditis, 542 for persistent ductus arteriosus, 534

1390 • INDEX Inductively coupled plasma/mass spectroscopy, 348b Infection(s), 215–304, 930 in adolescence, 234, 235b agents of, 100–102, 100b bacterial, 250–273 after HSCT, 937b chlamydial, 272–273, 272b gastrointestinal, 262–265 with neurological involvement, 267 respiratory, 265–267 rickettsial, 270–272, 271b of skin, 1235–1238 soft tissues and bones, 250–254 systemic, 254–262 caused by helminths, 288–299, 288b central venous catheter, 225–226 chain of, 100f chlamydial, 340–341 in men, 340 in reactive arthritis, 1031 treatment of, 341b urethritis, 333 in women, 340–341 clinical examination of, 216–218, 216f, 217b common infecting organisms, 117b constitutive barriers to, 63 control, 111–115, 112b cytomegalovirus, 238b, 242–243 after HSCT, 937b clinical features of, 242–243 encephalitis, 320 investigations of, 243 liver transplantation and, 901 management of, 243 polyradiculitis, 321 in pregnancy, 235b viral hepatitis and, 878 definition of, 100 deliberate release, 111 emerging and re-emerging disease, 110, 110f endemic disease, 110 epidemiology of, 110–111 Epstein-Barr virus, 238b, 241–242 clinical features of, 241–242 complications of, 241–242, 242b investigations of, 242 management of, 242 Escherichia coli, 263–264 entero-aggregative, 263–264 entero-invasive, 263 enterohaemorrhagic, 263–264 enteropathogenic, 263 verocytotoxigenic, 263f fungal, 300–304, 300f after HSCT, 937b skin, 1239–1240, 1240f subcutaneous, 300–301 superficial, 300 systemic, 301–304 gastrointestinal tract function of, 777–778, 777b oral cancer, 790 test of, 777 geographical and temporal patterns of, 110 history-taking in, 217b HIV/AIDS, 305–327 antiretroviral therapy for, 324–327, 324b asymptomatic, 312, 312f CD4 counts in, 311 chemoprophylaxis for, 323–324 clinical examination of, 306f clinical manifestations of, 311–312 counselling for, 311b diagnosis of, 310–311, 310b epidemiology of, 308 global and regional epidemics of, 308, 308b immunisation for, 324 immunology of, 309–310 investigations of, 310–311, 311b life cycle of, 309f liver and, 879 liver blood tests in, abnormal, 879b modes of transmission of, 308, 308b–309b musculoskeletal manifestations of, 1021b in old age, 326b pregnancy and, 1280 presenting problems of, 312–322, 313b prevention of, 323–324, 327b primary, 311–312, 312b pruritus and, 1219b staging classifications of, 307b testing of, 330 tuberculosis and, 595 viral load in, 311 virology of, 309–310 host-pathogen interaction of, 104 incubation periods of, 111b investigation of, 105–109, 105b culture, 106 direct detection of pathogens, 105–106 joints, 1019–1021 in old age, 1020b of liver, 871–880 liver transplantation and, 901 microbiological sampling, 105b mycobacterial, 267–270 nematode, 233b intestinal, 288–290 tissue-dwelling, 290–293, 290b zoonotic, 293–294 in non-immune haemolytic anaemia,

normal microbial flora, 102–103, 103f of oesophagitis, 794 outbreaks of, 114 reporting, 114b terminology, 114b parvovirus B19, 237 clinical features of, 237, 237b, 237f diagnosis of, 237 management of, 237 in pregnancy, 235b periods of infectivity, 111b in pregnancy, 234, 235b presenting problems in, 218–234 prevention, 111–115, 112b protozoal, 273–288 gastrointestinal, 286–288 leishmaniasis, 281–286 systemic, 273–281 recurrent, 73 reservoirs of, 110 animal, 110 environmental, 110 human, 110 respiratory, 581–598 in old age, 586b pneumonia, 582–587 pregnancy and, 1277 tuberculosis (TB), 588–595 upper respiratory tract infection, 581–587 rubella clinical features of, 236 congenital malformation and, 237b diagnosis of, 236 in pregnancy, 235b prevention of, 236–237 sexually transmitted, 329–344 approach to patients, 332–333, 332b in children, 332–333 contact tracing for, 333 HIV testing for, 330 management goals of, 331b in men, 330, 330b, 330f men who have sex with men, 330b, 334–335 during pregnancy, 332 presenting problems of, men, 333–336, 333f–334f prevention of, 336–337 those at particular risk, 331b viral, 341–344 in women, 331, 331b, 331f skin, 1235–1241 bacterial, 1235–1238 fungal, 1239–1240, 1240f mycobacterial, 1237–1238 tropical, 234, 234b, 235f viral, 1238–1239 of small intestine, 812–813 soft tissue, 226–227 necrotising, 227b staphylococcal, 250–252, 251f cannula-related, 251–252, 251b methicillin-resistant Staphylococcus aureus, 252 skin, 251 staphylococcal toxic shock syndrome, 252, 252f wound, 251, 251f starvation-associated, 705b supportive therapy for, 957 transmission of, 100f, 111 tropical, 230–234, 230b urinary tract, 426–431 antibiotic regimens for, 429b investigation of, 428b in old age, 428b persistent or recurrent, 429, 429b risk factors for, 428b in stroke patients, 1159f viral, 236–250 gastrointestinal, 249 with neurological involvement, 249–250 respiratory, 249 with rheumatological involvement,

sexually transmitted, 341–344 of skin, 247–249, 1238–1239 Infection-related glomerulonephritis, 398b–399b, 401 Infectious conditions, in ophthalmological conditions, 1173–1174 Infectious disease genomics in, 58 pathogenesis of, 104, 108f periods of infectivity in, 111b principles of, 99–129 treatment of, 116–129, 119b Infectious keratitis/corneal ulceration, 1173, 1174f common causes of, 1173b Infectious mononucleosis, 241–242 causes of, 241b clinical features of, 241–242, 242f investigations of, 242 management of, 242 Infective endocarditis, 527–531, 528b, 531b acute, 529 antimicrobial treatment of, 530b in old age, 527b post-operative, 529 prevention of, 531 subacute, 528–529, 529b, 529f Inferior petrosal sinus sampling, bilateral, 670f Inferior vena cava, 384, 444f Infertility, 656–657, 656b cytotoxic medications and, 1298 in polycystic ovarian syndrome, 659 Infestations, skin, 1241 Inflammation acute, 70–71, 71f cancer, 1319–1320 chronic, 71 laboratory features of, 71–72 resolution, 71 systemic, 196–198 Inflammatory bowel disease (IBD), 813–824 childhood, 823 clinical features of, 816–817 complications of, 818, 818f differential diagnosis of, 817, 817b disease distribution in, 815f investigations of, 818–820, 819f management of, 820–823 metabolic bone disease and, 824 microscopic colitis and, 824 monitoring of, 822b pathogenesis of, 815f pathophysiology of, 814–816, 814b in pregnancy, 823–824, 824b, 1278 systemic complications of, 819f transition medicine and, 1299–1300 treatment of, 821b Inflammatory molecules, 64 Inflammatory myopathy, 1042b Inflammatory response, 70–72 acute inflammation and, 70–71, 71f acute phase response in, 70 resolution of, 71 septic shock and, 70–71 chronic inflammation and, 71 laboratory features of, 71–72 C-reactive protein as, 72 erythrocyte sedimentation rate and,

plasma viscosity as, 72 Inflammatory rheumatic diseases biologics for, 1006, 1006f, 1007b in pregnancy, 1280–1281 anti-phospholipid syndrome as,

rheumatoid arthritis as, 1280 systemic lupus erythematosus as, 1281, 1281b systemic sclerosis as, 1280–1281, 1281b Infliximab for inflammatory bowel disease, 821b,

for musculoskeletal disease, 1007b in pregnancy, 1278 Influenza, 240–241 avian, 241 clinical features of, 241 diagnosis of, 241 epidemic, 104 immunisation for, 115b incubation period of, 111b management and prevention of, 241 prophylaxis for, 119b swine, 241 Infraorbital artery, 1168 Infrapatellar bursitis, 999b Inhalation (‘humidifier’) fever, 616b,

Inhalational administration, 17–18 Inheritance autosomal dominant, 46–47 autosomal recessive, 48 mitochondrial, 49 pedigrees, 46f X-linked, 48–49 Inherited cancer predisposition syndromes, 56–57, 57b Inherited metabolic myopathies, 1144, 1144b Inherited thrombophilia, 977–979 Inherited tubulo-interstitial diseases, 404, 404b Inhibin, 633f Inhibitor of kappa B kinase (IKK), 64–66 Innate immune system, 62–67 complement and, 66 cytokines and, 64–66, 65b, 65f dendritic cells in, 64 integrins and, 66 mast cells and basophils, 66–67 natural killer cells and, 67 phagocytes in, 63–64, 63f physical barriers in, 62–67 Inorganic micronutrients, 716–718 Insect bites, 230 Insect stings, allergic reactions, 75b Insect venom allergy, 85 Insecticides carbamate, 146–147 organophosphorus, 145–146, 145b, 145f pyrethroid, 148b Insertions, 42 Insight, lack of, 1183 Insomnia fatal familial, 1127b sporadic fatal, 1127b

INDEX • 1391 Inspiration, of lungs, 548 Insulin adverse reactions of, 22b amino acid structure of, 748–749, 749f manufacture and formulation of, 748–749 metabolic actions of, 723b puberty and, 1290 reference range of, 1359b resistance to, pregnancy and, 1272–1273 secretion of, 724f regulation of, 723–724 synthesis of, 724, 724f Insulin-like growth factor (IGF), 633f, 849f Insulin-like growth factor binding protein (IGF-BP3), 633f Insulin pump, 751, 751f Insulin resistance polycystic ovarian syndrome, 658b in type 2 diabetes, 730–731 Insulin therapy closed loop, 751, 752f for diabetes mellitus, 748–751 dosing regimens in, 750, 750f, 751b subcutaneous, 749–750, 749b for diabetic ketoacidosis, 737 injection sites of, 721b preparations for, duration of action of, 748–749, 749b side-effects of, 750b Insulin tolerance test, for Hypopituitarism, 682b Insulitis, 728, 729f Integrade inhibitors, 324b Integrase, 309–310 Integrins, 66 Intensive care clinical management in, 208–211 blood transfusion in, 211 clinical review in, 208–209 delirium in, 209 extubation in, 210 glucose control in, 210–211 nutrition in, 210 peptic ulcer prophylaxis in, 211 sedation and analgesia in, 209, 209b thromboprophylaxis in, 210 tracheostomy in, 210, 210b weaning from respiratory support in, 209–210 discharge from, 213, 214b withdrawal of active treatment and death in, 213 Intention tremor, 1069 Intercellular adhesion molecule type 1(ICAM-1), 447 Intercostal tube drainage, 626–627, 627f Interferon pegylated, 877 warts, 1239 Interferon-α, 65b Interferon-alfa for hepatitis B, 876 pegylated, for hepatitis C, 878 polycythaemia rubra vera, 970 Interferon-gamma (IFN-γ), 65b in coeliac disease, 806f Interferon-gamma release assays (IGRAs), 594, 594f Interleukin, immune response, 65b Intermediate-density lipoproteins, 371–372 Intermediate syndrome, from OP poisoning, 146 Intermittent claudication, 502 Intermittent positive pressure ventilation, 203–204 International Autoimmune Hepatitis Group (IAIHG) criteria, 886 International normalised ratio (INR), 850,

International Prostate Symptom Score (IPSS), 438b International staging system (ISS), for multiple myeloma, 968 International system of units (SI units),

Interpersonal psychotherapy, 1191 Interphalangeal joints, osteoarthritis in, 1009f Interstitial and infiltrative pulmonary diseases, 605–613 diffuse parenchymal lung disease (DPLD), 605–610, 605b, 606f, 607b due to irradiation and drugs, 612–613 due to systemic inflammatory disease, 610–611 in old age, 613b pulmonary eosinophilia and vasculitides, 611–612, 611b rare interstitial lung diseases, 613b Interstitial cells of Cajal, 772 Interstitial lung disease, systemic sclerosis and, 1038 Interstitial nephritis acute, 402, 402b, 402f chronic, 402–403, 403b drug-induced, 427b Interstitial pneumonia acute, 606b desquamative, 606b lymphocytic, 606b usual, 608f Interstitial pneumonitis lymphoid, 319 usual, 608f Intertrigo, 300, 1240 Intervertebral disc, 986 prolapse of, 996–997 Intervertebral discs intra-articular, 987 Intestinal defence mechanisms, 770f Intestinal failure (IF), 708–710 causes of, 708–709 classification of, 708–709 management of, 709–710, 709b in jejunostomy patients, 709 in jejunum-colon patients, 709 in small bowel and multivisceral transplantation, 710, 710b Intestinal microbiota, 771 Intestinal tapeworm, 298 Intra-aortic balloon pump, 207 Intra-articular discs, 987 Intra-articular glucocorticoids, for musculoskeletal disease, 1005–1006 Intra-articular injections, for osteoarthritis, 1012 Intracellular fluid (ICF), 349 Intracerebral haemorrhage, 1154–1155, 1155f causes of, 1155b Intracranial hypertension, idiopathic,

Intracranial mass lesions, 1127–1133 Intracranial pressure (ICP) measurement of, 208 raised, 1127–1129, 1128b, 1128f Intramuscular administration, 17 Intramuscular androgen replacement therapy, 656b Intramuscular glucocorticoids, for musculoskeletal disease, 1005–1006 Intranasal administration, 17 Intraretinal microvascular abnormalities (IRMAs), 1175 Intravascular haemolysis, 946b, 947 Intravenous administration, 17 Intravenous fluid therapy, 353 Intravenous urography (IVU), 389 for retroperitoneal fibrosis, 434 Intrinsic factor, glycoprotein, 767 Introns, 39f Intubation, 203–204 endotracheal, critically ill patients, 190b, 208 nasogastric, 805b safety during, 203b ventilator modes in, 203, 203f Invasive pulmonary aspergillosis (IPA), 597–598, 598b Involuntary movements, 1069 Iodide, 634 Iodine, 647, 717 deficiency, 639b, 647, 717 pregnancy and, 651b, 1279 dietary sources of, 717b radioactive for fetal hypothyroidism, 1279 for Graves’ thyrotoxicosis, 644b,

reference nutrient intake of, 717b for thyroid neoplasia, 649 Iodine-associated thyroid disease, 647–648 Iodine-induced thyroid dysfunction, 647 Iodine therapy, for differentiated carcinoma, 649–650 Iodoquinol, 129 Ion channels, drugs acting on, 15b Ion-selective electrodes, 348b Ionising radiation, 164, 164f Ipratropium bromide, asthma, 572 Irbesartan, 513 Irinotecan, 832, 842–844 Iris, of eye, 1167 Iron, 716–717 absorption/uptake, 716–717 deficiency, 717 dietary sources of, 717b overload, 717 haemochromatosis, 717 poisoning from, 140 reference nutrient intake of, 717b reference range of, 1362b supplements congestive gastropathy, 871 constipation and, 786b in pregnancy, 941b Iron deficiency anaemia, 923, 940–943 alimentary tract disorders, 793 blood loss in, 940–941 confirmation of, 941–942, 942b investigations in, 941–942 of cause, 942 malabsorption in, 941, 942f management of, 943 physiological demands in, 941, 941b pregnancy and, 1284 Iron oxide, 615b Irritable bowel syndrome (IBS), 824–826 clinical features of, 825, 825b complementary and alternative therapies for, 826b investigations of, 825, 825b management of, 825–826, 826f dietary, 825b pathophysiology of, 824–825 behavioural and psychosocial factors, 824 luminal factors, 825 physiological factors, 824 Irritant eczema, 1247 Ischaemia cerebral, 967f critical limb, 502–503 liver, 898 lower limb, 504b Ischaemic gut injury, 827 Ischaemic heart disease hierarchy of systems applied to, 93b levothyroxine replacement in, 641 Ischaemic nephropathy, 406–407 Ischaemic pain, 1350b Ischaemic penumbra, 1154 Ischiogluteal bursitis, 999b Islet autoantibodies, 727 Islet cell antibodies, in type 1 diabetes, 728 transplantation of, 752, 753f Isocyanates, 614b Isolated gonadotrophin deficiency, 653 Isolation precaution, types of, 113b Isoleucine, 698b Isoniazid as antimycobacterial agents, 125 hepatotoxicity, 120b, 894b poisoning, 141b polyneuropathy and, 1139b prophylactic, 119b and pyridoxine deficiency, 715 resistance, 118 skin reactions, 1266b tuberculosis HIV/AIDS patients, 324, 324b treatment, 592–593, 593b Isoprenaline, 476–477 AV block, 478 Isosorbide dinitrate, 490b Isosorbide mononitrate, 490b Isotretinoin, 1227 Ispaghula husk, 834 Itch, 1219–1220 ITGB2 gene, loss-of-function mutations in, leucocyte adhesion deficiencies and, 77 Itraconazole, 125b, 126 acute leukaemia patients, 957 allergic bronchopulmonary aspergillosis, 596 chromoblastomycosis, 301 cutaneous leishmaniasis, 286 fungal skin infections, 1239–1240 histoplasmosis, 304 mycetoma, 301 P. marneffei infection, 303 prophylactic, 119b sporotrichosis, 301 ITU, referral to, in community-acquired pneumonia, 584b Ivabradine angina, 491 for heart failure, 467 Ivermectin for helminthic infections, 129 filariasis, 291 for scabies, 1241 for strongyloidiasis, 289 J Jaccoud’s arthropathy, 1035 JAK proteins, 64–66 Janus-activated kinase (JAK) inhibitors, for musculoskeletal disease,

Japanese B encephalitis, 249–250 Jarisch-Herxheimer reaction, 339 Jaundice, 860–862, 860b acute liver failure and, 857–858 alcoholic hepatitis and, 881, 881b cholecystitis and, 905 cholestatic, 860b–862b, 861–862 cirrhosis and, 866–867 hepatocellular, 860–861 investigation of, 861f obstructive, 861–862 pre-hepatic, 860 primary biliary cholangitis and, 887 JC virus, 319–320 Jejunal mucosa, 807f Jejunostomy patients, intestinal failure and, 709 Jejunum coeliac disease see Coeliac disease hormones, 772b short bowel syndrome, 709b Jejunum-colon patients, intestinal failure and, 709 Jellyfish, 154b Jiggers, 299–300 Jod-Basedow effect, 647 Joint capsule, 987 Joint disease crystal-associated, 1012–1018, 1013b, 1013f in tuberculosis, 591 Joint hypermobility syndrome, 1349 Joints, 986–987 aspiration, 988, 988f, 1015, 1017,

fibrous and fibrocartilaginous, 986 haemophilia, 1058 hypermobility, 1059b infection, 1019–1021 neuropathic (Charcot), 1057, 1058f in old age, 1020b protection, 1001

1392 • INDEX replacement arthroplasty, 1002b for osteoarthritis, 1012 synovial, 987, 987f tumours, 1056–1057 types of, 986b Jugular venous pressure, effects of respiration on, 447b Jugular venous pulse examination of, 443b respiratory system, 546f tricuspid regurgitation, 526 Junin and Machupo viruses, 245b Juvenile absence epilepsy, 1100b Juvenile dermatomyositis (JDM), 1040 Juvenile idiopathic arthritis (JIA), 1026–1027 in adolescence, 1027b clinical features of, 1027b oligoarticular, 1300 transition medicine and, 1300 Juvenile myoclonic epilepsy, 1100b Juvenile polyposis, 829 K Kala-azar (visceral leishmaniasis), 282–284, 282f clinical features of, 282 differential diagnosis of, 283 HIV co-infection, 283–284 investigations of, 282–283, 282f management of, 283 post-kala-azar, dermal leishmaniasis, 284, 284f Kallmann’s syndrome, 653 Kaposi’s sarcoma, HIV-related, 315, 316f Kartagener’s syndrome, 550 Karyotype, 38f Kashin-Beck disease, 1011 Katayama syndrome, 295 Kawasaki disease, 1041–1042 Kayser-Fleischer rings, 896–897 in Wilson’s disease, 1174f Kco (transfer coefficient for carbon monoxide), 555b Kearns-Sayre syndrome, 1144b Keloid scar, definition of, 1226 Kennedy’s disease, 1093b Keratan sulphate, 987 Keratin, 1212 Keratinocytes, 1212 Keratoacanthoma, 1234, 1234f Keratoconjunctivitis sicca rheumatoid arthritis, 1024 Sjögren’s syndrome and, 1038 Keratoderma blennorrhagica, 1031 Keratolysis, pitted, 1238 Keratomalacia, 713 Keratosis, actinic, 1230b Kerion, 1240 Kernig’s sign, 1118 Kerosene, poisoning, 148b Keshan’s disease, 718 Ketamine, 1345b Ketoacidosis, diabetic, 729–730, 735–738 in adolescence, 753b clinical features of, 736, 736b investigations of, 736 management of, 736–738, 737b bicarbonate in, 738 fluid replacement in, 737 insulin in, 737 ongoing, 738 phosphate in, 738 potassium in, 738 pathogenesis of, 735–736, 736b severe, indications of, 736b Ketoconazole, 125b, 126 Cushing’s syndrome, 669 cutaneous leishmaniasis, 286 fungal skin infections, 1239–1240 mycetoma, 301 paracoccidioidomycosis, 304 shampoos, 1240 Ketogenesis, 725f Ketone bodies, 725, 725f Ketones blood, 726, 726b urine, 726 Ketonuria, 726 Ketoprofen, 1003b Kidney acid-base balance control, 364 clinical examination of, 382–384, 382f–383f cystic diseases of, 405–406 drugs and, 426 duplex, 434 functional anatomy and physiology of, 384–386, 385f imaging of, 389–390, 389f MRI images of, 406f single, 433 sodium handling, 349 stones, 431b systemic lupus erythematosus in,

transplantation, 424 tumours of, 434–436 Kidney disease in adolescence, 426b chronic, 415–420, 417b causes of, 415b haemodialysis in, 422–423 indications for dialysis for, 422b osteodystrophy and, 419f physical signs of, 416f pregnancy and, 1282, 1283f pruritus, 415 stages of, 388b staging of, in children over 2 years of age, 1298b transition medicine and, 1298–1299 medullary sponge, 433 Kidney injury, acute, 411–415 causes of, 411f clinical features of, 411–413 dialysis for, indications for, 422b haemodialysis in, 422 investigations of, 412b management of, 413–414, 413b in old age, 414b pathophysiology of, 411 post-renal, 412b, 413 pre-renal, 411–412, 412b pregnancy and, 1282, 1283b recovery from, 414–415, 414f renal, 412–413, 412b renal replacement therapy, 414 Kimmelstiel-Wilson nodule, 758f Kinase inhibitors, for low-grade NHL,

Kinases, cyclin-dependent, 1317 Klebsiella granulomatis, 341b Klebsiella oxytoca, 230 Klebsiella pneumoniae, 116 Klebsiella spp., 103f Klinefelter’s syndrome, 44b, 660–661 Knee osteoarthritis, 1009–1010, 1010f pain, 998–999, 999b rheumatoid arthritis, 1023 Knee height, measurement of, 693b Knudson hypothesis, 56–57 Köbner phenomenon, 1252 Koch’s postulates, 100b Koilonychia, 1261, 1261f Koplik’s spots, 236, 236f Korsakoff’s psychosis, 714 Korsakoff’s syndrome, 1081 Krebs (citric acid) cycle, 49, 714 Krukenberg tumour, 804 Kupffer cells, 64, 848, 850f Kuru, 1127b Kussmaul breathing, 415 Kussmaul’s sign, 544b Kwashiorkor, 704 Kyasanur fever, 245b Kyphoplasty, 1002b for osteoporosis, 1049 Kyphoscoliosis, 546f thoracic, 628 Kyphosis, 591f, 1302f ankylosing spondylitis, 1030 L L-dopa see Levodopa Labetalol aortic dissection, 508 hypertension, 513 accelerated, 514 Laboratory investigations, biochemical, 348–349, 348b Laboratory reference ranges, 1357–1364 of adolescence, 1363 of adults, 1358 of childhood, 1363 in pregnancy, 1364 Labyrinthitis, 1104 Lacrimal gland/lacrimal drainage, 1164 Lactase deficiency, 812 Lactate reference range of, venous blood, 1360b sepsis and, 196, 197f Lactate dehydrogenase (LDH) acute kidney injury, 412b empyema, 564 megaloblastic anaemia, 943, 944b pancreatitis and, 837b pleural effusion, 610 reference range of, venous blood, 1360b Lactation, nutrition in, 712b Lactic acidosis, 365 Lactitol, 834b Lactobacillus spp., 103f Lactoferrin, 62–63, 992 in acute phase response, 70 Lactose, refeeding diet, 705b Lactose hydrogen breath test, 812 Lactose intolerance, 812 Lactulose for hepatic encephalopathy, 865 for variceal bleeding, 869b Lacunar infarctions, 1153 Lacunar syndrome (LACS), 1156f Lambert-Eaton myasthenic syndrome (LEMS), 1142f, 1143, 1325–1326 Lamina densa, 1212 Lamina lucida, 1212 Laminin, 1212 Lamivudine, 324b for hepatitis B, 876 co-infection with HIV, 877 resistance, 325 Lamotrigine, 1102b–1103b Langerhans cell histiocytosis (histiocytosis X), 613b Langerhans’ cells, 1212 Language disorders, 1089b spoken, 1070f Lanreotide, 686–687 Laparoscopy for ascites, 863 for infertility, 656 for lower abdominal pain, 336 for pyrexia of unknown origin, 219–222 Large-bowel diarrhoea, HIV-related, 317 Large rectal adenomatous polyp, 828f Laron dwarfism, 680b Larva currens, 289 Larva migrans cutaneous, 294, 294f visceral, 233–234 Laryngeal disorders, 624–625 Laryngeal obstruction, 624–625, 624b Laryngeal paralysis, 624 Laryngoscopy, 553 Lasègue’s sign, 1135 Laser therapy for bleeding control, 775f for colorectal cancer, 832 for hereditary haemorrhagic telangiectasia, 970 for hypertrichosis, 1259 for lung cancer, 603 for oesophageal carcinoma, 797 for proliferative diabetic retinopathy,

for rosacea, 1244 for skin disease, 1228 Lassa fever, 245b incubation period of, 111b Latent autoimmune diabetes of adulthood (LADA), 730 Latent tuberculosis, 1172 detection of, 594, 594f Lateral film, of chest X-ray, 551 Lateral humeral epicondylitis, 998b Latex agglutination test, 301 Lavage bronchoalveolar, 609–610 gastric, 136, 136b Law, psychiatry and, 1207 Lawrence-Moon-Biedl syndromes, 700 Laxative misuse syndromes, 834 Laxatives, 834b Lead poisoning, 148b reference range of, venous blood, 1360b Lead pipe rigidity, 1069 Leão, spreading depression of, 1095 Learning difficulties, congenital heart disease and, 533 Leber’s hereditary optic neuropathy, 1089b Lecithin cholesterol acyl transferase (LCAT), 375 deficiency, 375, 375b Lectin mannose-binding deficiency, 78 Lectin pathway, for complement, 66 Leflunomide, for musculoskeletal disease, 1004b, 1005 Left anterior descending artery (LAD) and coronary arteries with a stenosis, 453f in coronary circulation, 444–445, 445f Left atrial dilatation, 450 Left bundle branch block, 478–479, 479f Left main coronary artery, 444–445, 445f occlusion, 445 Left ventricular dilatation, 450 Left ventricular hypertrophy, 523f Legal considerations, in artificial nutritional support, 710b Legionella pneumophila infection, 106, 117b Legionella spp., 114b, 119b Legs examination of, 982f–983f cardiology, 442f diabetes mellitus, 720f endocrine disease, 630f febrile injecting drug user, 222f HIV/AIDS, 306f liver and biliary disease, 846f liver and biliary disease and, 846f oedema and, 395–396 examination of, respiratory system, 546f ulcers, 1223–1224 causes of, 1223b, 1223f clinical assessment of, 1223–1224 due to arterial disease, 1223–1224 due to neuropathy, 1224 due to vasculitis, 1224 due to venous disease, 1223, 1223f investigations in, 1224 management of, 1224 Leigh’s syndrome, 49 Leishman-Donovan body (amastigotes), 282f Leishmania, 281 life cycle of, 281–282, 282f Viannia subgenus, 285 Leishmania aethiopica, 284 Leishmania amazonensis, 285 Leishmania brasiliensis, 285 Leishmania chagasi, 282, 282f Leishmania donovani, 282, 282f Leishmania guyanensis, 285 Leishmania infantum, 282, 282f Joints (Continued)

INDEX • 1393 Leishmania major, 284 Leishmania mexicana, 285 Leishmania tropica, 284 Leishmaniasis, 281–286, 1238 cutaneous, 284–285, 285b, 285f incubation period of, 111b dermal, post-kala-azar, 284, 284f epidemiology and transmission of, 281–282, 281f–282f mucosal, 285 prevention and control of, 284 visceral, 282–284, 282f clinical features of, 282 differential diagnosis of, 283 HIV co-infection, 283–284 incubation period of, 111b investigations of, 282–283, 282f management of, 283 Lemierre’s syndrome, 586–587 Lenalidomide, for multiple myeloma,

Lens, of eye, 1168 Lentigo, 1234 Leprosy, 267–270, 267f borderline cases of, 269 clinical features of, 268–269, 268b, 269f epidemiology and transmission of,

granulomas in, 71 incubation period of, 111b investigations of, 269 management of, 269–270, 269b–270b pathogenesis of, 267–268 patient education of, 270 prevention and control of, 270 prognosis of, 270 reactions, 268–269, 268b tuberculoid, 267–268 Leptin, 694 Leptosphaera senegalensis, 301 Leptospira interrogans, 257 Leptospirosis, 257–259, 880 aseptic meningitis, 257 bacteraemic, 257 clinical features of, 257–258, 258f diagnosis of, 258 icteric, 258 management and prevention of, 258–259 microbiology and epidemiology of,

Lesch-Nyhan syndrome, 1014 Leucine, 698b Leucocyte adhesion deficiencies, 77 Leucocytes, 917 Leucocytosis, 926–927 cholecystitis and, 905 choledocholithiasis and, 906 hepatobiliary disease and, 853 in inflammation, 71–72 pyogenic liver abscess and, 880 Leucoencephalopathy, progressive multifocal, 1123 HIV-associated, 319–320, 320f Leucoerythroblastic anaemia, 969 Leuconychia, striate, 1260 Leucopenia, 925–926 hepatobiliary disease and, 853 Leukaemias, 954–961 acute, 955–958 haematopoietic stem cell transplantation for, 958 investigations of, 955–956, 956f management of, 956–958 outcome of, 958b prognosis of, 958 specific therapy for, 956–957, 956b–957b supportive therapy for, 957–958 WHO classification of, 955b in children, 1298 chronic lymphocytic, 959–960 clinical features of, 959 investigations of, 959–960 management of, 960 prognosis of, 960 staging of, 960b chronic myeloid, 958–959 accelerated phase, management of, 959 blast crisis, management of, 959 characteristics of, 958 chronic phase, management of, 959, 959b clinical features of, 958 investigations of, 959 management of, 959 natural history of, 958 epidemiology and aetiology of, 954–955 hairy cell, 960 prolymphocytic, 960 risk factors for, 955b terminology and classification of, 955, 955b Leukoplakia, hairy, 316 Leukotriene receptor antagonists, asthma, 571f, 572 Leukotrienes, 66–67 Levator palpebrae superioris, 1164 Levetiracetam, 1100b in pregnancy, 1103b Levodopa adverse reactions, chorea, 1085 for Parkinson’s disease, 1113–1114 Levofloxacin, 117b, 123b plague, 259 Levothyroxine hypothyroidism management, 640–641, 641b in ischaemic heart disease, 641 Lewy body dementia, 1194 Leydig cell tumours, 439 LH see Luteinising hormone Li-Fraumeni syndrome, 1321b Libman-Sacks endocarditis, 1035 Lice body, 1241 head, 1241 pubic (crab), 1241 relapsing fever, 256b, 257, 257f Lichen planus, 1252 clinical features of, 1252, 1252f investigations of, 1252 management of, 1252 in nails, 1261 pathogenesis of, 1252 rash, 334b rash in, 1217b vulval pain/itch, 336b Lichen sclerosus, 334b, 336b Lichen simplex, 1247 Lichenoid eruptions, drug-induced, 1252, 1266b Liddle’s syndrome, 361 Lidocaine arrhythmias, 480, 480b effect in old age, 32b in renal/hepatic disease, 32b Life course, 93 Life expectancy, 92, 1304, 1304b Life support advanced, 457, 458f basic, 456–457, 457f Lifestyle advice, for obesity, 701 Lifestyle changes for chronic kidney disease, 420 for dyslipidaemia, 375 Lifestyle factors ageing, 1305 cancer, 1316 diabetes mellitus, 743–745 weight management, 744 Lifestyle interventions, for musculoskeletal disease, 1000–1001 in gout, 1016 in osteoarthritis, 1012 Ligaments, 987 Ligand assay, 348b Likelihood ratios (LR), 3, 3f Limb girdle dystrophy, 1143b Limbic encephalitis, 1111b Limbic (emotional) influences, in control of breathing, 549 Limbic system, 1066 Limbs lower see Legs upper see Arms Linagliptin, 747 Lincomycin, 29 Lincosamides, 122 antibiotics, 121–122 mechanism of action, 116b Lindane, 148b Linear accelerators, 1331 Linear IgA disease, 1255b, 1256–1257 Linezolid, 117b, 124 in pneumonia, 587 in pregnancy, 120b Linitis plastica, 804 Linoleic acid, 697 Linolenic acid, 697 Lipase, 770b Lipid emulsion therapy, 136–137 Lipid-lowering therapy for acute coronary syndrome, 501 chronic kidney disease, 420 for dyslipidaemia, 375 Lipid peroxidation, 1305 Lipids, 370–378 acute kidney injury and, 416b cardiovascular disease and, 373 dietary, 371 endogenous, 372f measurement, 373 metabolism, 370–378, 850 disorders of, 370 effects of insulin in, 723b presenting problems in, 373–375 transport, 372f see also Fats Lipodermatosclerosis, 1223 Lipodystrophy, 326, 326f Lipohypertrophy, 721b Lipolysis, 694 Lipomas skin, 1235 small intestine and, 813 Lipopeptides, 123 Lipoprotein lipase, 371–372 deficiency, 374b Lipoproteins high-density (HDL), 1360b intermediate-density, 371–372 low-density, 371–372 metabolism, 370–378 structure of, 371f very low-density, 371–372 Liquorice, excessive intake of, 361 Liraglutide, for obesity, 702–703, 702f Lisch nodule, 1132b Lisinopril heart failure, 466b hypertension, 513 Listeria monocytogenes bacterial meningitis from, 1119 listeriosis from, 259 Listeriosis, 259–260 in pregnancy, 235b Lisuride, for Parkinson’s disease, 1114b Lithium for cluster headache, 1096 drug interactions of, 24, 24b hypothyroidism and, 639b nephrotoxicity, 427b plasma interactions of, 36b poisoning from, 139 prescribing, 32b skin reactions, 1266b teratogenesis, 1200 Lithium carbonate, for bipolar disorder,

Livedo reticularis, 1035, 1036f Liver abscess, 879–880, 893 amoebic, 880 in old age, 901b pyogenic, 879–880, 880b biopsy of, 855, 855b for hepatocellular carcinoma, 891 for non-alcoholic fatty liver, 884 blood supply to, 848–849, 848f cells see Hepatocytes drugs and, 893–895 fatty alcoholic, 881, 881b non-alcoholic, 882–885, 883f, 885f fibrosis of, 894 cirrhosis and, 866, 866f congenital, 868f, 902 non-invasive markers of, 855 pathogenic mechanisms in, 849f function of, 850–851, 850f functional anatomy and physiology of, 848–851 HIV infection and, 879 infections of, 871–880 injury to drug-induced, 894–895, 894b types of, 894–895 ischaemia, 898 nodular regenerative hyperplasia of,

size of assessment for, 847b change in, causes of, 862b structure of, 848–849, 848f transplantation of, 900–901 for acute liver failure, 858–859 for alcoholic liver disease, 882 for Budd-Chiari syndrome, 899 for cirrhosis, 867 complications of, 901 for hepatic encephalopathy, 865 for hepatitis B, 876 for hepatitis C, 878 for hepatocellular carcinoma, 891 indications and contraindications for, 900–901, 900b, 901f living donor, 901 orthotopic, 890 for primary biliary cholangitis, 888 for primary sclerosing cholangitis,

prognosis for, 901 split liver, 901 for Wilson’s disease, 897 tumours, metastatic, 1328–1329 Liver capsule pain, 1350b Liver disease abdominal signs in, history and significance of, 847 alcoholic, 880–882 fatty, 881 liver function test (LFT) abnormality in, 854b in old age, 901b risk factors for, 880 autoimmune, 885–890 bleeding, 975 chronic, 853b hepatitis B and, 873 cirrhosis see Cirrhosis clinical examination for, 846f clinical features of, 847b cystic, 893, 893f decompensated, 867 drug-induced, liver function test (LFT) abnormality in, 854b HIV-related, 317–318 hydatid cyst and, 880 inherited, 895–897 haemochromatosis as, 895–896 investigation of, 852–855, 852b in old age, 901b pregnancy and, 899–900, 1283–1284 acute fatty liver as, 1283, 1283b obstetric cholestasis as, 1284 viral hepatitis as, 1284 prescribing in, 32, 32b presentation of, 856b presenting problems of, 855–866, 856f pruritus and, 1219b silent presentation of, 847b tumours as, 890–893 benign, 893 primary malignant, 890–892 secondary malignant, 892–893, 893f vascular, 898–899 Wilson’s disease and, 896

1394 • INDEX Liver failure acute, 856–859 adverse prognostic criteria in, 858b causes of, 856f–857f classification of, 857b clinical assessment of, 857–858 complications of, 858b hepatic encephalopathy and, 857b hepatitis A and, 873 investigations for, 858, 858b management of, 858–859, 858b pathophysiology of, 857 chronic causes of, 856f, 867b cirrhosis and, 867 fulminant, hepatitis B and, 875 hepatic encephalopathy, 856–857 Liver flukes, 233b, 297, 297b Liver function tests, 852 abnormal, 859–860, 859b asymptomatic, 859f HIV infection and, 879b identifying the cause of, 854b in pregnancy, 900b cholestatic/obstructive, 853b for gastrointestinal bleeding, 781 hepatitic, 853b for hepatitis C, 877 Loa loa, 233b, 290b, 292 Loading dose, 19 Local glucocorticoid injections, for ankylosing spondylitis, 1031 Localised lymphadenopathy, 927 ‘Locked-in’ syndrome, 211 Lockjaw, 1126 Lofexidine, 1196 Löfgren’s syndrome, 608–609 Loiasis, 233b, 292 Loin pain, 396 Long QT syndrome, 476 Long-term domiciliary oxygen therapy (LTOT), for chronic obstructive pulmonary disease (COPD), 577 Loop diuretics, for hypervolaemia, 354–355 Loop of Henle, 350, 384–386 Looser’s zones, 1052 Loperamide for faecal incontinence, 835 for inflammatory bowel disease, 821b intussusception and, 230 for irritable bowel syndrome, 826f for radiation enteritis, 810 for short bowel syndrome, 808–809 for small bowel bacterial overgrowth, 808–809 Lopinavir, 324b Loratadine, 622, 1254 Lorazepam disturbed behaviour, 1189f palliative care, 1353 status epilepticus, 1081b Loricrin, 1212 Losartan, 58 Loss-of-function mutations, 44 Loss of vision, of ophthalmic disease, 1170–1171, 1170b Lotions, 1225b Louse-borne relapsing fever, 256b, 257, 257f Low back pain assessment of, 988–989 causes of, 996b mechanical, features of, 996b radicular, 997b Low birth weight, and disease susceptibility, 93 Low-density lipoproteins, 371–372 Low-dose dexamethasone suppression test (LDDST), in Cushing’s syndrome, 668 Low-grade tumours, 961 Low-molecular-weight heparins (LMWHs), 922, 938–939, 938b for venous thromboembolism, 975 Low mood, 1185–1186 alcohol misuse and, 1194 Lower airway defences, 550 Lower limbs examination, diabetes mellitus, 721b ischaemia, 504b see also Foot/feet; Legs Lower oesophageal sphincter, abnormalities of, 791 Lubiprostone, 825 Lumbar canal stenosis, 1135–1136 Lumbar disc herniation, 1135, 1135f Lumbar nerve root compression, 1135f Lumbar puncture, 1077–1078 for meningitis, 1118 for stroke, 1152 for viral encephalitis, 1118 Lumbar spondylosis, 1135–1136 Lumbosacral plexopathy, 1141 Lumefantrine, for malaria, 128 Lumps, skin, 1216 Lung(s) abscess, 170f, 219f, 251f biopsy in interstitial pneumonias, 607 pleural effusion, 563–564 cavitation of, 551b collapse by bronchial obstruction, 552f upper lobe, 547f consolidation of, 551b defences, 550, 550f fibrosis see Pulmonary fibrosis functional anatomy and physiology of, 548–550, 548f–549f gas exchange in, 549–550, 549f inflammatory arthritis in, 994b innate response of, 550 irradiation and, 612–613 mechanics, 549 near drowning accidents and, 169 near-drowning victims, 169 shrinking, 610b, 611 systemic lupus erythematosus in,

transplantation, 567, 567b tumours of, 598–605 metastatic, 1328 primary, 599–603 secondary, 603 volumes, 555 Lung cancer, 599–603, 599f burden of, 598b cell types in, 599b clinical features of, 599–601 investigations of, 601–602 management of, 602–603 non-metastatic extrapulmonary manifestations of, 601b occupational, 618 pathology of, 599, 599f prognosis for, 603, 603b Lung disease alveolar microlithiasis, 613b proteinosis, 613b diffuse parenchymal, 605–610 drug-induced, 612–613, 612b due to organic dusts, 616–617, 616b due to systemic inflammatory disease, 610–611 dust exposure and, 614–615, 615b HIV-related, 318–319, 318b infection, 581–598 interstitial, 605–613 investigation of, 550–556 obstructive, 573–578 in old age, 578b occupational, 613–619 presenting problems of, 556–567 radiotherapy-induced, 612 rheumatoid arthritis, 1024 tumours, 598–605 secondary, 603 vascular, 619–622 Lung flukes, 233b Lung injury, ventilator-induced, 204 Lupus anticoagulant, 920–921 Lupus erythematosus, 1221b, 1262 bullous, 1255b drug-induced, 1266b systemic, 410–411, 1034–1037 classification of, criteria for, 1036b clinical features of, 1035–1036 investigations of, 1036 management of, 1036–1037 pathophysiology of, 1034 pregnancy and, 1281, 1281b respiratory involvement in, 611 Lupus nephritis, 392b Lupus pernio, 609f, 610 Luteinising hormone (LH) deficiency, 680b puberty and, 1290 reference range of, 1359b Lyme disease, 255–256, 256b, 256f,

myopericarditis, 538 Lymecycline, 1243 Lymph node biopsy, in Hodgkin lymphoma, 962, 963f Lymph nodes, 67 diphtheria, 266 of envenomed patient, 152f examination of, cancer, 1314, 1315b normal architecture of, 961, 961f trypanosomiasis, 279 tuberculosis and, 590 Lymphadenitis, 590 Lymphadenopathy, 913b, 927, 927b HIV-related, 313 persistent generalised, 313 rheumatoid arthritis, 1024–1025 Lymphangiectasia, intestinal, 811 Lymphangioleiomyomatosis, 613b Lymphangitic carcinomatosis, 603 Lymphatic filariasis, 290–292 Lymphatics, 67 Lymphocytes, 917, 926b, 926f count, 1362b older people, 923b see also B lymphocytes; T lymphocytes Lymphocytic interstitial pneumonia, 606b Lymphocytosis, 926b, 927 infectious mononucleosis, 241 Lymphogranuloma venereum (LGV), 341b Lymphoid interstitial pneumonitis, 319 Lymphoid organs, 67 Lymphoid tissue gastrointestinal mucosa-associated, 769–770 mucosa-associated, 67 Lymphomas, 650, 961–966, 961f B-cell, 805 cutaneous, 1232 gastric, 805 gastrointestinal tract and, 813 Hodgkin, 961–964, 962f classification of, 962b clinical features of, 962 epidemiology of, 961, 962b investigations of, 962, 963f management of, 962–964 prognosis of, 964, 964b stages of, 962b MALT, 769–770 non-Hodgkin, 964–966, 965f clinical features of, 964, 965f epidemiology of, 964, 964b high-grade management of, 966 investigations of, 964–965 low-grade management of, 965 management of, 965–966 prognosis of, 966 primary CNS, 320, 320f T-cell cutaneous, 1224 enteropathy-associated, 813 thyroid, 646 Lymphopenia, 925–926, 926b HIV infection, 311–312 sarcoidosis and, 609–610 Lymphoproliferative syndrome, autoimmune, 80 Lynch’s syndrome, 46 d-Lysergic acid diethylamide, 144, 144f Lysine, 698b Lysolecithin, 905 Lysosomal storage diseases, 370, 371b Lysosomes, 370 Lysozyme, 62–63 M Machado-Joseph disease, genetics, 43b Machupo virus, 245b Macrocytic anaemia, 925 Macrocytosis, 853, 921f, 941f Macroglobulinaemia, Waldenström, 966 Macrolides, 117b, 121–122 mechanism of action, 116b Macronutrients (energy-yielding nutrients), 695–697 dietary recommendations for, 697, 698b Macrophage colony stimulating factor (M-CSF), 1022–1023, 1022f Macrophages, 64, 550 alveolar, 303, 615 foamy, 430, 809 functions of, 64b in gastrointestinal tract, 769–770 Macroprolactin, 684 Macroprolactinaemia, 684, 684b Macroprolactinomas, pregnancy and,

Macules café au lait, 1131f definition of, 1211f Maculopathy, diabetic, 721 Maddrey score, 882 Madopar, 1113 Madura foot, 301 Madurella grisea, 301 Madurella mycetomatis, 301 Magic (hallucinogenic) mushrooms, 143,

Magnesium, 718 dietary sources of, 717b homeostasis, 367–368 intravenous acute severe asthma, 573 arrhythmias, 140 tetany, 663b torsades de pointes, 476–477 metabolism, disorders of, 367–368 refeeding diet, 705b reference nutrient intake of, 717b reference range of, venous blood, 1360b Magnesium ammonium phosphate stones, 431b Magnesium chloride, 368 Magnesium salts, 368 Magnesium sulphate asthma, 573f hypomagnesaemia, 368 pre-eclampsia, 1276 ventricular tachycardia, 137b Magnetic resonance angiography (MRA) in nervous system, 1072 renal artery stenosis, 407, 407f stroke, 1157b urinary tract disease, 389 Magnetic stimulation, 1077 Magnifying glass, 1214 Main d’accoucheur, 663 Main en lorgnette, 1033 Major haemorrhage, transfusion in, 931b Major histocompatibility complex (MHC), 851, 1028–1029, 1248 Malabsorption, 783–785, 784f, 785b, 942f after gastric resection, 783–785 after ileal resection, 706 biliary cirrhosis, 888 of chronic pancreatitis, 841 cystic fibrosis, 581 disorders causing, 805–810 investigations of, 785, 785b, 785f iron deficiency anaemia, 941, 942f in old age, 808b pathophysiology of, 784–785 primary biliary cholangitis and, 888 Maladie de Roger, 535–536

INDEX • 1395 Malar flush, 442f Malar rash, of systemic lupus erythematosus, 1035f Malaria, 273–277 algid, 276b cerebral, 276b chemoprophylaxis of, 277, 278b clinical features of, 274b, 275–276, 275f complicated, 277 control in endemic areas, 277 distribution of, 273f exchange transfusion, 277 haemolysis, 274–275 incubation period, 111b, 274b investigations of, 276 management of, 277, 277b mild, 277 non-falciparum, 277 pathogenesis of, 273–275 pathology of, 274–275 in pregnancy, 235b prevention of, 277 sickle-cell anaemia, 951 treatment of, 128 vector control, 323 Malarial parasite, life cycle of, 273–274, 274f Malarone, 278b Malassezia, 103f, 1240 Malassezia furfur, 1240 Malathion louse infestation, 1241 scabies, 1241 Male hypogonadism in, 655, 656b, 660b reproductive system of, 651, 651f Malignancy, pruritus and, 1219b Malignant disease, rheumatological manifestations of, 1057, 1057b Malignant hyperpyrexia, 195 Malignant plasma cells, 967 Malingering, 1206 Mallory-Denk bodies, 884 Mallory-Weiss syndrome, 177b Mallory-Weiss tears, 781f Mallory’s hyaline, 884 Malnutrition in dementia, 711, 711f risk of, screening for, 693f see also Under-nutrition MALT (mucosa-associated lymphoid tissue), 769–770 MALT lymphomas, 964 Malt worker’s lung, 616b Mammary artery grafts, 491–492 Mammography, 1333 Manganese, 718 Mania, 1186 Mannitol, 355 Mannose-binding lectin deficiency, 78 Mansonella perstans infection, 233b,

Mansonella streptocerca, 290b Mantle cell lymphoma, 964 MAOI-B inhibitors, for Parkinson’s disease, 1114 Maple bark stripper’s lung, 616b Marasmus, 704 Maraviroc, 324b Marburg fever, 230, 245b March haemoglobinuria, 950 Marche à petits pas, 1087 Marcus Gunn pupil, 1092b Marfan’s syndrome, 508 cardiovascular system aortic aneurysm, 505, 506f aortic dissection, 506, 507b mitral valve prolapse, 520 congenital defects, 531–532 mutation, 508 Marine poisonous animals, envenomation of, 162 Marine venomous animals, envenomation of, 162 Marjolin’s ulcer, 1021, 1223 Mass spectroscopy (MS), 348b inductively coupled, 348b Massive small bowel resection, under-nutrition and, 706 Mast cell tryptase, 86 Mast cells, 66–67 degranulation of, clinical features of, 75b Mastectomy, 1334 Maternal medicine, 1269–1285 adrenal disease in, 1280 cardiac disease in, 1282 clinical evaluation in, 1271, 1271f clinical examination in, 1270, 1270f–1271f diabetes in, 1278–1279 gestational, 1278, 1278b endocrine disease in, 1279–1280 functional anatomy and physiology in, 1272–1273 bone metabolism and, 1272 cardiovascular system and, 1272 endocrine system and, 1272 gastrointestinal system and, 1272 genitourinary system and, 1272 glucose metabolism in, 1272–1273 haematological system and, 1273 respiratory system and, 1273 gastrointestinal disease in, 1277–1278 haematological disease in, 1284–1285 human immunodeficiency virus infection in, 1280 hypertension in, 1276–1277 imaging and, 1274 inflammatory rheumatic disease in, 1280–1281 investigations in, 1274, 1274b liver disease and, 1283–1284 medical disorders in pregnancy and, 1276–1285 neurological disease in, 1284 parathyroid disease in, 1280 pituitary disease in, 1280 planning pregnancy in, for patients with medical conditions, 1272 presenting problems in pregnancy and, 1274–1276 breathlessness as, 1274–1275 chest pain as, 1275 circulatory collapse as, 1275 headache as, 1275 nausea and vomiting as, 1275, 1275b oedema as, 1275 seizures as, 1275–1276, 1276b psychiatric disorders in, 1284 renal disease in, 1282–1283 respiratory disease in, 1277 thyroid disease in, 1279 Matrix metalloproteinases, 485–486 Mayaro viruses, 250, 1020–1021 McArdle’s disease, 1144b McCune-Albright syndrome, 50–51, 1055, 1056f Meal bolus calculation, 751b Mean arterial pressure (MAP), calculation of, 193b Mean cell haemoglobin (MCH), 919–920, 1362b Mean cell volume (MCV), 853, 919–920 in alcohol misuse, 1184 in anaemias, 940 reference range of, 1362b Measles, 236 clinical features of, 236, 236f management of, 236 in pregnancy, 235b prevention of, 236 rash, 236f subacute sclerosing panencephalitis,

Mebendazole, for helminthic infections,

Mechanical heart valves, 950 pregnancy and, 1282 Meckel’s diverticulum, 778, 812 bleeding from, 782b Meckel’s scan, 778b Meconium ileus, 842 Medial collateral ligament lesions, 998b–999b Medial fibroplasia, 407 Medial humeral epicondylitis, 998b Medial longitudinal fasciculus (MLF), 1069–1070 Median nerve entrapment, 1139b palsy, 760 Mediastinal spread, in lung cancer, 600 Mediastinoscopy, 604 Mediastinum divisions of, 604f tumours of, 603–605, 603b–604b, 604f Medical emergency team, deterioration and, 188, 189b Medical interview, 231b Medical ophthalmology, 1163–1178 functional anatomy and physiology of, 1164–1168 ophthalmic disease, presenting problems in, 1169–1171 specialist ophthalmological conditions in, 1171–1178 visual disorders, investigation of, 1168–1169 Medical psychiatry, 1179–1207 Medically unexplained somatic symptoms, 1187, 1187b, 1205f general management principles for, 1202, 1203b in old age, 1189b Medication, of stroke patients, 1159b Medication errors, 24–26 causes of, 25, 25b, 25f response to, 26 types of, 25b Medication overuse headache, 1096 migraine and, 1095 Medicines management, 26 Medroxyprogesterone, 655 Medullary carcinoma, 650 Medullary cystic kidney disease, 404 Medullary sponge kidney disease, 433 Medulloblastoma, 1129 Mefenamic acid, overdose, 138 Mefloquine, for malaria, 278b Megacolon acquired, 835 toxic, 818 Megakaryoblasts, 915f, 918 Megakaryocytes, 918 Megaloblastic anaemia, 940, 943–945 clinical features of, 943b investigations in, 944b management of, 945 Megaloblastic crisis, 947 Megaureter, 434 Megestrol, 1332 Meglitinides, 746b, 747 Meglumine antimoniate, 128 Meiosis, 40–41, 41f Meissner’s plexus, 771–772 Melaena, 780 Melanocortin-4 receptor (MC4R) mutations, 700 Melanocytes, 1212 Melanocytic naevi, 1216, 1234–1235, 1235f Melanoma, 1232–1234 ABCDE rule of, 1216, 1216b acral lentiginous, 1233 amelanotic, 1322 clinical features of, 1232–1233 cutaneous, 1232b diagnosis and management of, 1233 lentigo maligna, 1233 malignant, 1216 nodular, 1233, 1233f pathophysiology of, 1232 prognosis of, 1233–1234 subungual, 1233 superficial spreading, 1232–1233, 1233f Melanoptysis, 615 Melanosis coli, 834 Melarsoprol, for trypanosomiasis, 128 MELAS, 1116b, 1144b Melasma, 1258 MELD score, for liver transplantation, 900–901 Meleney’s gangrene, 227b Melioidosis, 261 Melphalan, 968, 1320b Memantine, 1193 Membrane attack complex (MAC), 66 Membranoproliferative glomerulonephritis, 401 Membranous nephropathy, 398b–399b, 401, 427b Memory, 1066 Alzheimer’s disease, 1192–1193 disorders of, 1066b long-term, 1065, 1192–1193 loss, 1081 short-term, 1081, 1192–1193 Memory cells, 68 Ménétrier’s disease, 797–798 Ménière’s disease, 1104–1105 MENIN, 688 Meningioma, 1130–1131 Meningism, 1118 Meningitis, 1118–1121 aseptic, 257 bacterial, 1118–1120 cerebrospinal fluid in, 1119 headache and, 185, 185b management of, 1120, 1120b causes of, 1118b Coccidioides, 304 cryptococcal, HIV-related, 321 fungal, 1121 HIV-related, 321 malignant, 1121 in mumps, 240 protozoa, 1121 recurrent aseptic, 1121 tuberculous, 1120–1121, 1121b viral, 1118 cerebrospinal fluid in, 1118 Meningococcaemia, chronic, 1119 Meningococcal infection chemoprophylaxis following, 1121b meningitis, 1118–1119, 1119b prevention of, 1120 rash, 1120 Meningococcal sepsis, 1119b Meningoencephalitis, 279 Menopause, 652 male, 660b premature, 654 Menorrhagia, 923 Menstrual cycle, normal, 652f Menstrual irregularity, in polycystic ovarian syndrome, 659 Menstruation, 1290, 1291f Mental state examination, 1181–1183 Mental test, older people, 184 Menthol, topical, 1220 Mepacrine, hyperpigmentation from, 1258b Meptazinol, 1002 Meralgia paraesthetica, 1139b Mercaptopurine for acute leukaemia, 957b for inflammatory bowel disease, 821b Mercury poisoning, 365b Merkel cells, 1212 Meropenem, 117b, 120b melioidosis, 261 neutropenic fever, 1327–1328 nocardiosis, 261 pneumonia, 586 in pregnancy, 120b MERRF (myoclonic epilepsy with ragged red fibres), 1116b, 1144b Mesalazine, for inflammatory bowel disease, 818, 820, 821b Mesangiocapillary glomerulonephritis (MCGN), 398b–399b, 401 Mesenteric ischaemia, chronic, 827 Mesna, 1036 Mesothelioma, 618 Meta-iodobenzyl guanidine (MIBG) scintigraphy, 675

1396 • INDEX Metabolic acidosis, 364–366 acute mountain sickness, 168 causes of, 365b diabetic ketoacidosis, 735 hypothermia and, 166 kidney failure/renal failure acute, 413 chronic, 415 malaria, 276b near-drowning, 170 poisoning, 139b, 141b starvation, 704–705 Metabolic alkalosis, 366–367, 367f Metabolic disorders, 785 clinical examination of, 346–348, 346f supportive therapy for, 957–958 Metabolic medicine, 345–380 Metabolic myopathies, 1144 Metabolic syndrome, 730–731 liver transplantation and, 901 Metabolism first-pass, 17 interactions, 24 phase I, 18 phase II, 18 Metadrenalines, 1361b Metalloproteinases, 485–486 Metamyelocytes, 917 Metaphase, 40 Metapneumovirus, 249 Metastatic bone disease, 1057 Metastatic spread, in lung cancer, 600 Metatarsophalangeal joints, polyarthritis in, 994f Metavir system, for hepatitis C, 878 Metered-dose inhaler, for asthma, 571f Metformin, 746, 746b acidosis, 135b, 141 for hyperglycaemia, 746 mechanism of action, 746 overdose, 135b, 141 polycystic ovarian syndrome, 659 in pregnancy, 1278 renal/hepatic disease, 32b Methadone misuse, 142, 142b withdrawal, 16b Methaemoglobin, 277, 947 Methaemoglobinaemia, 120b, 135f, 1227–1228 Methanol, poisoning from, 147, 147f Methicillin-resistant Staphylococcus aureus (MRSA), 252 Methimazole, 644 Methionine, 138 Methotrexate (MTX) acute leukaemia, 957, 957b drug interaction, 24b eczema, 1227–1228 hepatic fibrosis and, 895–897 hepatotoxicity of, 894b for inflammatory bowel disease, 821b, 822, 1299 for musculoskeletal disease, 1004, 1004b antineutrophil cytoplasmic antibody-associated vasculitis,

juvenile dermatomyositis, 1040 juvenile idiopathic arthritis, 1027 polymyositis and dermatomyositis,

psoriatic arthritis, 1033–1034 systemic lupus erythematosus,

pregnancy and, 1226b, 1278 psoriasis, 1227–1228, 1250 renal disease, 32b and respiratory disease, 612b sarcoidosis, 610 Methyl-phenyl-tetrahydropyridine (MPTP), 1112b Methylbenzethonium chloride, 286 Methylcellulose, 646, 834b Methyldopa, for pre-existing hypertension, pregnancy and,

Methylphenidate, 1105 Methylprednisolone for acute disseminated encephalomyelitis, 1110 antineutrophil cytoplasmic antibody-associated vasculitis (AAV), 1041 Grave’s ophthalmopathy, 646 histoplasmosis, 304 for inflammatory bowel disease, 820 for juvenile dermatomyositis, 1040 liver transplant patients, 901 for polymyositis and dermatomyositis,

rheumatic disease, 1005–1006 for systemic lupus erythematosus,

for transverse myelitis, 1110 Methysergide, and respiratory disease, 612b Meticillin, 120b Metoclopramide chronic intestinal pseudo-obstruction,

and hyperprolactinaemia, 684b nausea and vomiting, 803, 1351b poisoning, 137b sodium content of, 864b Metoprolol, 466b, 480b angina, 500 arrhythmias, 481 hypertension, 513 Metronidazole, 117b for amoebiasis, 287 for balanitis, 334b for cerebral abscess, 1124b for cholecystitis, 905 for choledocholithiasis, 906 for Clostridium difficile infection, 264 for gas gangrene, 227 for giardiasis, 287 for Helicobacter pylori eradication,

for inflammatory bowel disease, 823 for liver abscess, 880 for neutropenic fever, 1327–1328 for PID, 336 for pneumonia, 587 polyneuropathy and, 1139b in pregnancy, 120b prophylactic, 119b for rosacea, 1244 for small bowel bacterial overgrowth, 808–809 for tetanus, 1126b for tropical ulcer, 254 Metyrapone, 669, 671b Mevalonate kinase deficiency, 81 Mexiletine, 480, 480b Mezavant, for inflammatory bowel disease, 821b Micafungin, 125b Micelles, mixed, 768 Miconazole, 125b, 1239–1240 erythrasma, 1238 Microalbuminuria, 394 in diabetic nephropathy, 757, 758b in diabetic neuropathy, 727 Microaneurysms, 509–510 Microangiopathic haemolytic anaemia (MAHA), 408, 950 Microangiopathy, diabetic, 756 Microarrays, 51 Microbial flora, normal, 102–103, 103f Microbiological investigations, for respiratory disease, 554 Microbiome, 63, 103 Microcytic anaemia, 925 in rheumatoid arthritis, 1024–1025 Microcytosis, 921f, 941f Microdeletion syndromes, 44 Microglia, 1106 Microlithiasis, alveolar, 613b Micronutrients, 711–718 Microorganisms culture, 106 detection of components, 106 detection of whole organisms, 105 host response, 105–109 MicroRNA (miRNA), 40 Microsatellite repeats, 43 Microscopy bright field, 105 dark field, 105 electron, 105 epiluminescence, 1214 Microsomal ethanol-oxidising system (MEOS) pathway, 881 Microsporidiosis, HIV-related, 317b Microsporum audouinii, 1240 Microsporum canis, 1240, 1240f Micturating cystourethrography, reflux nephropathy, 431f Micturition cycle, 386 disorders of, benign prostatic hyperplasia, 437 frequency of, 396 Mid-axillary line, 626–627 Midazolam, 1189f Middle East respiratory syndrome coronavirus (MERS-CoV), 249 Midges, filariases, 293 Miglitol, 747 Migraine, 1095–1096 pregnancy and, 1284 stroke risk in, 1095 in visual disturbance, 1088 Migrainous neuralgia, 1096 Migrating motor complexes (MMC), 772 Miliary tuberculosis (TB), 588–589 Milk, cow’s, type 1 diabetes and, 729 Milk alkali syndrome, 716 Milk intolerance, 812 Millard-Gubler syndrome, 1072b Miller Fisher syndrome, 1140 Miltefosine, 283 Milwaukee shoulder syndrome, 1017–1018 Mineralocorticoid receptor, 355 Mineralocorticoid receptor antagonists for acute coronary syndrome, 501 for primary hyperaldosteronism, 675 Mineralocorticoid replacement, for adrenal insufficiency, 673 Mineralocorticoids, 666, 666f in adrenal insufficiency, 672 excess in, causes of, 674b Minerals, storage of, liver and, 851 Mini-Mental State Examination (MMSE), 1181–1183 Minimal change nephropathy, 398–400, 398b–399b Minimally conscious state, 211, 212b Minimum bactericidal concentration (MBC), 109 Minimum inhibitory concentration (MIC),

Minocycline for acne, 1243 hyperpigmentation from, 1243, 1258b for leprosy, 269 skin reactions, 1266b Minoxidil alopecia, 1259 hypertension, 513 skin reactions, 1266b Mirizzi’s syndrome, 904–905 Misoprostol, 1003 Missense mutation, 42, 42f Mites house dust, 568, 570, 1215, 1245 typhus, 270 Mitochondria, 49, 50f Mitochondrial disorders, 49, 1144 Mitochondrial DNA, 1305 Mitochondrial inheritance, 49, 49b Mitochondrial syndromes, 1144b Mitomycin C, 436, 612b Mitosis, phases of, 40 Mitotane, 669–670 Mitotic spindle poisons, 1317f Mitoxantrone, 936b acute leukaemia, 957b Mitral regurgitation, 519–521, 519b, 520f clinical features of, 521b, 521f investigation of, 521b management of, 521 Mitral stenosis, 517–519, 518b, 518f investigations in, 518f, 519b chest X-ray for, 451f pregnancy and, 1282 Mitral valve balloon valvuloplasty, 519, 519b, 519f disease of, 517–521 endocarditis, 200f prolapse, 520 pain, 177 repair, 521 replacement, 526–527 Mixed connective tissue disease (MCTD), 1038 Mixed venous oxygen saturation, 198b Mobilisation, of stroke patients, 1159b Mobitz type I second-degree AV block, 477, 477f Mobitz type II second-degree AV block, 477, 477f Moclobemide, 1199b Modafinil, 1105, 1110b Modified Beighton score, for joint hypermobility, 1059, 1059b Modified Dukes classification, survival in colorectal cancer and, 832f Mohs’ micrographic surgery, 1228 Molecular adsorbent recirculating system (MARS), for pruritus, primary biliary cholangitis and,

Molecular diagnostics, 348b Molecular mimicry, 82 Moles, 1234–1235, 1235f Mollaret’s syndrome, 1121 Molluscum contagiosum, 248f, 343, 343f, 1239, 1239f HIV disease and, 306f, 314b Mometasone, 1226b Monday fever, 614 Monge’s disease, 169 Monitoring in critical care/critical illness, 175–176, 175b, 175f Monitoring drug therapy, 34–36 Monkeypox, 248–249 Monoamine oxidase inhibitors, 1199, 1199b drug interactions, 24b Monoarthritis acute, 992–993, 993b chronic inflammatory, 992 Monobactams, 120b, 121 Monoclonal antibody therapy for allergy, 86 for asthma, 572 for haemolytic uraemic syndrome,

for high-grade NHL, 966 for low-grade NHL, 965 for osteoporosis, 1048 Monoclonal gammopathy of uncertain significance (MGUS), 966 Monoclonal immunoglobulin deposition disease, multiple myeloma and, 410b Monocytes, 64, 917, 926b, 926f count, 1362b Monocytosis, 926b Monofilament testing, 721b Monoiodotyrosine (MIT), 635f Mononeuritis multiplex, 1140 Mononeuropathy diabetic, 760 multifocal, 1140b Monosodium urate monohydrate crystals, 988f, 1015 Monospot test, 242 Montelukast, asthma, 572 Montreal Cognitive Assessment (MoCA), 1181–1183, 1182f Mood, 1071 assessment of, in psychiatric interview, 1181 Mood disorders, 1198–1200 bipolar, 1199–1200 organic, 1185b Mood-stabilising drugs, 1190b Moraxella catarrhalis, 103f

INDEX • 1397 Morphine adverse reactions of, 22b COPD, 577 intensive care, 209b misuse, 142b palliative care, 1351 pharmacogenetics, 20b renal colic, 432 renal or hepatic disease, 32b rout of administration, 30b Morphoea, 1262–1263 Morquio’s syndrome, 371b Mortality ratios, standardised (SMRs),

Morton’s neuroma, 999 Mosaic warts, 1238 Mosquitoes, 231b filariasis, 290 malaria, 273–274 virus transmission of, 111 Motilin, 772b Motility disorders, in vitamin B12 deficiency, 944 Motor cortex, 1063f Motor neuron disease, 1111b, 1116–1117, 1117b, 1117f Motor neurons lower, 1068 upper, 1068–1069 Motor neuropathy, 503b Motor system, 1068–1069, 1068f Mountain sickness acute, 168 chronic, 169 Mouth disease of, 790 of envenomed patient, 152f examination of cardiology, 442f respiratory system, 546f oral allergy syndrome, 812 ulcers in Behçet’s disease, 1043–1044, 1043f Mouth ulcers, for systemic lupus erythematosus, 1036 Movement disorders, 1112–1115 involuntary movements, 1069 see also names of specific disorders Moxifloxacin, 123b meningitis, 1120b MRCP (magnetic resonance cholangiopancreatography), 776, 854–855 for cholangiocarcinoma, 855f for choledocholithiasis, 906 for gallstones, 904–905, 904f MRI (magnetic resonance imaging) of aldosterone-producing adenoma,

for cancer, 1323 for cardiovascular system, 452–453, 453f of gastrointestinal tract, 774 for haemangiomas, 893f for hepatobiliary disease, 854 for hepatocellular carcinoma, 891 for musculoskeletal disease, 989, 989b, 989f for neurological disease, 1072, 1073b epilepsy, 1101b stroke, 1151, 1157–1158, 1158b viral encephalitis, 1122 of osteonecrosis, 1055 for pain, 1342 pregnancy and, 1274 for renal disease, 389 for respiratory disease, 553 for sacroiliitis, 1029–1030, 1029f MRSA (meticillin-resistant Staphylococcus aureus), 117b Mucociliary escalator, 550f Mucocutaneous disease, HIV-related, 314–316, 314b Mucopolysaccharidosis, 371b Mucor spp., 303 Mucormycosis, 303, 598 Mucosa-associated lymphoid tissue (MALT), 67 Mucosal leishmaniasis, 285 Mucous membranes inflammatory arthritis in, 994b as physical barrier, 62–63 Mucous patches, syphilis, 337 Multi-organ failure, causes of, 201 Multidisciplinary team, 1303b, 1311,

Multifocal encephalomyelitis, 1111b Multifocal neuropathy, 1140, 1140b Multimorbidity, 1306 Multinodular goitre, 648–649, 648f Multiple endocrine neoplasia (MEN), 688–689, 689b Multiple myeloma, 409, 410b, 966–968 classification of, 967b clinical features and investigations of, 967, 967f management of, 967–968 bisphosphonates for, 968 chemotherapy for, 968 immediate support for, 967–968 radiotherapy for, 968 prognosis of, 968 Multiple organ failure, 411 Multiple sclerosis, 1106–1110 cerebrospinal fluid in, 1108 clinical features of, 1106–1108, 1108b investigation of, 1108, 1108f–1109f Macdonald criteria for, 1107b management of, 1109–1110 acute episode, 1109 disease-modifying treatments, 1109, 1109b symptoms, complications and disability, 1109–1110, 1110b pathophysiology of, 1106, 1107f–1108f in pregnancy, 1110b Multiple systems atrophy (MSA), 1114 Multivisceral transplantation, 710 complications of, 710b Mumps, 240 clinical features of, 240, 240f diagnosis of, 240 incubation period, 111b, 232b, 240 management and prevention of, 240 periods of infectivity, 111b testicular swelling, 216f Münchausen’s syndrome, 1206 Murmur aortic regurgitation, 524, 524b, 525f aortic stenosis, 522, 522b, 522f atrial septal defect, 535, 535f ausculatory evaluation, 443b Austin Flint, 524 benign, 459, 459b–460b cardiac, 459b, 460f carditis, 515–516 Carey Coombs, 515–516 coarctation of aorta, 534 continuous, 461 diastolic, 460 Graham Steell, 526 mitral regurgitation, 520, 520f, 521b mitral stenosis, 518–519, 518f persistent ductus arteriosus, 533 pulmonary regurgitation, 526 pulmonary stenosis, 526 systolic, 459–460, 460b tetralogy of Fallot, 537 timing and pattern, 460f tricuspid stenosis, 526 ventricular septal defect, 460b, 535–536 Murphy’s sign, cholecystitis and, 905 Muscle biopsy, 992 in polymyositis and dermatomyositis, 1039, 1040f contraction, 1068 of envenomed patient, 152f pain, 1000, 1000b skeletal, 987–988 Muscle disease, 1143–1144 acquired, 1144, 1145f Muscle fibre, 446f Muscle haematomas, in haemophilia A,

Muscle spindles, in control of breathing,

Muscle weakness/wasting, 1000, 1000b diabetes, 759 osteoarthritis, 1010 systemic sclerosis and, 1037 Muscular atrophy, spinal, 1117 Muscular dystrophies, 1143–1144, 1143b inheritance, 1143 transition medicine and, 1297 Musculoskeletal disease anatomy and physiology of, 984–988, 984f investigation of, 988–992 management of, 1000–1007, 1001b X-rays for, 988, 988b bony metastases, 662 Charcot’s joint, 1058f chondrocalcinosis, 1016f CPPD crystal deposition disease,

fracture, 994–995 osteoarthritis, 1009f–1011f osteomalacia, 1052, 1052f osteonecrosis, 1055 osteosarcoma, 1056–1057 reactive arthritis, 1032 rheumatoid arthritis, 1025 supraspinatus tendon calcification, 1017f Musculoskeletal system anatomy and physiology of, 984–988, 984f clinical examination of, 982–983, 982f drug-induced effects on, 1057b presenting problems in, 992–1000 primary tumours of, 1056b Mushrooms magic (hallucinogenic), 143, 1196 poisoning, 857 Mutation(s) de novo, 47 domain negative, 45 frameshift, 42 gain-of-function, 45 loss-of-function, 44 missense, 42 nonsense, 42, 42f point, 42 simple tandem repeat, 43, 43b splice site, 43f tandem repeat, 43, 43b Myalgia drug-induced, 1057b fever and, 217b infections, 223 Myasthenia gravis, 1111b, 1141–1143, 1142b, 1142f diplopia, 1141 drug-induced, 1057b weakness, 1093 Myasthenic crisis, 1142–1143 Mycetoma, 301 intracavitary, 559 Mycobacteria, 100–101 opportunistic infection, 595, 595b Mycobacterial infections, skin, 1237–1238 Mycobacterium abscessus, 580–581 Mycobacterium avium complex, HIV-related disseminated, 315b prophylaxis for, 324 Mycobacterium chelonei, 595b Mycobacterium fortuitum, 595b Mycobacterium genavense, 595b Mycobacterium haemophilum, 595b Mycobacterium kansaii, 595, 595b Mycobacterium leprae, 100, 106, 595b Mycobacterium malmoense, 595, 595b Mycobacterium marinum, 595b Mycobacterium tuberculosis (MTB), 106, 588 Mycobacterium ulcerans, 254, 595b Mycobacterium xenopi, 595, 595b Mycology, 1215 Mycophenolate mofetil (MMF) for autoimmune hepatitis, 886–887 liver transplantation and, 901 for musculoskeletal disease, 1004b,

for polymyositis and dermatomyositis,

for systemic lupus erythematosus,

Mycoplasma pneumoniae, 583 cold agglutination, 950 Mycoplasma spp., 121 Mycoses, superficial, 300 Mycosis fungoides (cutaneous T-cell lymphoma), 1232 Myelin sheaths, 358, 1106 Myelinolysis, 358 Myelitis, transverse, 1110 Myeloablative conditioning, 937 Myelocytes, 917 Myelodysplasia, 124 Myelodysplastic syndromes (MDSs), 960–961, 961b Myelofibrosis, 969 Myelography, spine, 996–997 Myeloma AKI, 412b multiple, 409, 410b, 966–968 Myelopathy, 1111b cervical, 1134–1135 HIV-related, 321 vacuolar, 321 Myeloperoxidase, 64 Myeloproliferative neoplasms, 969–970 Myelosuppression, drug-induced, 1330 Myiasis, 300 Myocardial contraction, 446, 446f Myocardial infarction, 199–200, 199b acute, 493b diagnosis of, 493 electrocardiogram (ECG) for, 448 investigation of, 496 ECG, 496–497 management of late, 498, 498b in old age, 500b pregnancy and, 1282 rehabilitation, 501 time course, 495f Myocardial ischaemia electrocardiogram (ECG) for, 448 myocardial infarction, 498 Myocardial stunning, 199–200 Myocarditis, 538, 538b acute, 538 chronic, 538 fulminant, 538 Myocardium disease of, 538–542 hibernating, 452 Myoclonic seizures, 1099–1100 Myoclonus, 1086 Myocytes, 446, 446f Myofibrils, 987 Myoglobinuria, 392b Myonecrosis, clostridial, 227 Myopathic gait, 1087 Myopathy, critical illness, 212 Myophosphorylase deficiency (McArdle’s disease), 1144b Myosin, 446, 987 Myositis drug-induced, 1057b inclusion body, 1059 systemic sclerosis, 1037 Myotonia, potassium-aggravated, 1145b Myotonia congenita, 1145b Myotonic dystrophy, 1143b genetics/inheritance, 43b Myotoxicity, 155 Myxoedema, Graves’ disease, 643 Myxoedema coma, 641 Myxoma, atrial, 541–542 N N-Acetylcysteine therapy, for acute liver failure, 858–859 NADH dehydrogenase, 49b

1398 • INDEX Nadolol arrhythmias, 481 thyrotoxicosis, 637–638 variceal bleeding, 869 Naevi blue, 1235 melanocytic, 1216, 1234–1235, 1235f spider, 846f autoimmune hepatitis and, 886 Nafcillin, 120b Nails, 1214 abnormalities, 1224 in congenital disease, 1261 disorders, 1260–1261 HIV-related, 316 inflammatory arthritis in, 994b involvement in skin diseases, 1260–1261 normal variants of, 1260 plate and bed, 1260f in systemic disease, 1261, 1261f trauma, 1260 Na,K-activated adenosine triphosphatase (ATPase), 349 Nalidixic acid, 123b skin reactions, 1266b Naloxone adverse reactions of, 23 drug interactions of, 24b Naltrexone, for pruritus, primary biliary cholangitis and, 888 Naproxen, 1003b Narcolepsy, 1105, 1105b Narcotics, cirrhosis and, 894b Nasal cannulae, high-flow, 202 Nasogastric tube, 805b Nasogastric tube feeding, 707, 707b Nasopharynx, disease of, 622 Natalizumab, 66, 1109b Nateglinide, 747 National Institute for Health and Clinical Excellence (NICE), 11 Natural killer cells, 67 Nausea and vomiting palliative care and, 1353–1354, 1353f pregnancy and, 1275, 1275b Near-drowning, 169–170, 170f Necator americanus, 288 Neck Casal’s necklace, 714, 715f examination of endocrine disease, 630f neurological disease, 1062f stiffness, 321 Neck pain, 997, 997b Necrobiosis lipoidica, 1263, 1263f Necrosis, 41, 1316–1317 Necrotising enteritis, 262 Necrotising fasciitis, 226–227, 227f Necrotising pancreatitis, 839 Necrotising scleritis, 1172 Necrotising soft tissue infections, 227b skin, 1238 Nefopam, 1002 Negative visual phenomena, 1171 Neisseria gonorrhoeae, 117b, 339 in pregnancy, 235b, 332b Neisseria spp., 103f Nelson’s syndrome, 669 Nematode infections, 233b intestinal, 288–290 tissue-dwelling, 290–293, 290b zoonotic, 293–294 Neoadjuvant chemotherapy, 1330 Neomycin allergy, 1247b for vitamin B12 deficiency, 715 Neostigmine, 835 Nephelometry, 348b Nephrectomy, 431, 435 Nephritic syndrome, 392, 392b, 393f Nephritis crescentic, 398b–399b, 410 drug-induced, 427b interstitial acute, 402, 402b chronic, 402–403, 403b drug-induced, 427b lupus, 392b post-streptococcal, 401 Nephrocalcinosis, drug-induced, 427b,

Nephrogenic sclerosing fibrosis, 390b Nephrology, 381–440 Nephron, 349–350, 350f, 384 segments of, 351f Nephronophthis, 404 Nephropathy analgesic, 426 Balkan, 403 diabetic, 757–758 diagnosis and screening for, 757 management of, 757–758 natural history of, 757, 758f HIV-associated, 322 IgA, 398b–399b, 400 ischaemic, 406–407 membranous, 398b–399b, 401 minimal change, 398–400, 398b–399b multiple myeloma and, 410b pregnancy and, 1279 reflux, 430–431 salt-losing, 403 sickle-cell, 411 Nephrotic syndrome, 392b, 395, 395b diseases typically presenting with, 398–400 Neprilysin inhibitors, for heart failure, 466–467 Nerve, disorder of, 1089b Nerve agents, organophosphorus insecticides and, 145–146 Nerve biopsy, 1078 Nerve blocks and nerve ablation, for pain, 1348 for pain, 1342–1343 Nerve conduction studies, 1076, 1076f for pain, 1342 Nerve entrapment, in lung cancer, 600 Nerve fibre, 1338 types of, 1338b Nerve root decompression, 1002b Nerve root lesions, 1083 Nerve root pain, 997b Nervous impulse, 1065, 1065f Nervous system anatomy and physiology of, 1064–1072 functional, 1065–1071, 1065f cells of, 1064–1065, 1064f clinical examination of, 1062–1064, 1062f in old age, 1079b in gastrointestinal function, 771–772 Nervous system disease cerebrovascular disease see specific conditions clinical examination of, 1062–1064, 1062f cranial nerves, 1063b emergencies, 1064b HIV-related, 319–321, 319f infections, 1117–1127, 1118b intracranial mass lesions/raised intracranial pressure, 1127–1133, 1128b investigation of, 1072–1078 lesion localisation in, 1071–1072 neuromuscular junction, 1141–1143 paraneoplastic, 1110–1111, 1111b,

paraneoplastic syndromes, 1325–1326 peripheral nerves, 1138–1141, 1139b presenting problems in, 1078–1094, 1079b–1080b spine/spinal cord, 1134–1137 Neural tube defects, prevention with folic acid, 712b, 945 Neuralgia migrainous, 1096 post-herpetic, 239, 1080 trigeminal, 1080, 1096–1097 Neuralgic amyotrophy, 1141 Neuro-endocrine tumours (NETs), 603b, 678–679, 678b, 679f, 813 Neuro-inflammatory diseases, 1106–1110 Neuroacanthocytosis, 1085b Neurocognitive disorders, HIVassociated, 319 Neurodegenerative diseases, 1111–1117 Neurodestructive interventions, for cancer pain, 1352 Neurodevelopmental disorders, rare, genomics in, 56 Neurofibroma, 1129b, 1137f Neurofibromatosis, 613b, 1131–1132, 1131f, 1132b, 1264 and cancer predisposition, 1321b inheritance, 1131–1132 Neurogenic shock, description of, 206b Neuroglycopenia, 739 Neuroimaging, 1072–1074, 1073b, 1151, 1151f, 1157–1158 Neuroleptic malignant syndrome, 1197–1198 Neurological disease in pregnancy, 1284 epilepsy as, 1284 idiopathic intracranial hypertension as, 1284 migraine as, 1284 stroke as, 1284 rheumatological manifestations of, 1058, 1058f in systemic lupus erythematosus,

transition medicine and, 1296–1297 cerebral palsy in, 1296 epilepsy in, 1296 muscular dystrophy in, 1297 Neurological support, in intensive care,

Neurology, 1061–1146 Neuroma acoustic, 1131 Morton’s, 999 Neuromuscular junction, diseases of, 1141–1143 Neuromyelitis optica, 1110 Neuromyotonia, 1111b Neuronectomy, multiple sclerosis, 1110b Neuropathic pain, 1084, 1348, 1348b, 1348f Neuropathy ataxia and retinitis pigmentosa (NARP), 1144b autonomic, 760, 760b critical illness, 211 diabetic, 758–761 classification of, 759b clinical features of, 758–761 management of, 761, 761b risk factors for, 757b entrapment, 1139–1140, 1139b hereditary, 1140 leg ulcers due to, 1224 motor, 503b, 1111b multifocal, 1140, 1140b peripheral, 1325 cancer-related, 1325 diabetic, 755, 756b drug-induced, 321 HIV-related, 321 leprosy, 268 in rheumatoid arthritis, 1024 sensorimotor, 321 peripheral, cancer-related, 1325 sensory, 503b, 1111b Neuropeptides, 1338–1339, 1340b Neurosensory retina, 1167 Neurosyphilis, 338, 1125, 1125b Neurotoxic flaccid paralysis, 155 Neurotoxins, hepatic encephalopathy and, 865 Neurotransmission/neurotransmitters, 1065f in pain processing, 1340b Neutral variants, 44 Neutrons, 164, 164f Neutropenia, 925 drug-induced, 926b fever in, 224, 1327–1328 HIV-related, 322 Neutropenic fever, cancer and, 1327–1328 Neutrophil chemotactic factor, 75b Neutrophil extracellular trap (NET) formation, 64 Neutrophil granulocytes, 1362b Neutrophilia, 926, 926b asthma, 568–569 Neutrophilic dermatoses, 1262 Neutrophils, 64, 917, 926b, 926f asthma, 568–569 count, 1362b toxic granulation, 64 Nevirapine, in pregnancy, 326–327 Newborn, haemolytic disease of, 933, 933b Next-generation sequencing (NGS), 52–53 capture, 53 challenges of, 53–54 methods of, 55b uses of, 54–56 Niacin (vitamin B3), 714–715 biochemical assessment of, 712b deficiency, 714, 715f dietary sources of, 711b reference nutrient intake of, 711b toxicity, 715 Nicardipine, angina, 491b Nickel hypersensitivity, 83b, 1247b Niclosamide, 129 Nicorandil, 790b Nicotinamide, for pellagra, 714 Nicotinamide adenine dinucleotide (NAD), 881 Nicotinamide adenine dinucleotide phosphate (NADPH)-oxidase enzyme complex, 64 Nicotine replacement therapy, 4 Nicotinic acid, 377 Niemann-Pick disease, 371b Nifedipine altitude illness, 169 angina, 490–491, 491b unstable, 500 for high-altitude pulmonary oedema,

hypertension, 513 and neutropenia, 926b for oesophageal disorders, 795 older people, 32b Raynaud’s syndrome, 504–505 sphincter of Oddi dysfunction, 909 Nifurtimox, for trypanosomiasis, 128 Night blindness, 713 Night sweats, 217b Night terrors, 1094 Nightmares, 1094 Nikolsky sign, 1254–1255 Nimodipine, for subarachnoid haemorrhage, 1162 Nipah virus encephalitis, 250 Nitazoxanide, 129 Nitrates angina, 489–490 duration of action, 490b heart failure, 467 for oesophageal disorders, 795 Nitric oxide (NO), 386, 447 anal fissure, 836 hepatopulmonary syndrome and, 898 Nitrites, 428 Nitrofurantoin, 124 and pulmonary eosinophilia, 611b–612b urinary tract infection, 428, 429b Nitrogen narcosis, 170 Nitroimidazoles, 124 mechanism of action, 116b Nitroprusside reaction, 726 Nitrosamines, type 1 diabetes and, 729 ‘Nits’, 1241 Nocardia, 587 pneumonia, 319 Nocardiosis, 261

INDEX • 1399 Nociceptive pain, 1084 Nocturia, 397 Nodal osteoarthritis, generalised, 1009, 1009b, 1009f Nodular lymphocyte-predominant HL, 961–962 Nodular regenerative hyperplasia, of the liver, 899 Nodules definition of, 1211f pulmonary, 560–562, 560b–561b, 560f–562f cryptococcosis, 302 lung metastases, 1328 rheumatoid, 1023–1024, 1024f skin, definition, 1211f thyroid, 630f, 635 Non-alcoholic fatty liver disease (NAFLD), 850, 882–885, 883f, 885f biochemical tests for, 884, 884b clinical features of, 884 imaging for, 884 investigations for, 884 liver biopsy for, 884 liver function test (LFT) abnormality in, 854b management of, 884–885 pathophysiology of, 883 Non-alcoholic steatohepatitis (NASH), 882–883, 883f Non-antivenom treatments, 159–160 Non-cardiac surgery, with heart disease, 501–502, 501b Non-compliance, 30–31 Non-disjunction, 44 Non-epileptic attack disorder (‘dissociative attacks’), 1103–1104 Non-freezing cold injury, 167 Non-Hodgkin lymphoma, 964–966, 965f clinical features of, 964, 965f epidemiology of, 964, 964b investigations of, 964–965 management of, 965–966 high-grade, 966 low-grade, 965 prognosis of, 966 Non-immune haemolytic anaemia, 950 Non-invasive prenatal diagnosis (NIPD),

Non-invasive prenatal testing (NIPT), 56 Non-invasive ventilation, for acute exacerbations of COPD, 578 Non-metastatic extrapulmonary effects, of lung cancer, 601 Non-necrotising scleritis, 1172 Non-nucleoside reverse transcriptase inhibitors (NNRTIs), 324b Non-opioid analgesics, for pain, 1345–1346 Non-specific interstitial pneumonia, 608 Non-specific urethritis (NSU), 333 Non-starch polysaccharides (NSPs; dietary fibre), 697 Non-steroidal anti-inflammatory drugs see NSAIDs Non-thrombocytopenic purpura, 928b Non-thyroidal illness, 642 Nonsense mutation, 42, 42f Noradrenaline (norepinephrine), for refractory hypotension, 198, 198b Noradrenaline (norepinephrine) re-uptake inhibitors, 1199, 1199b poisoning from, 139 Norfloxacin for spontaneous bacterial peritonitis,

urinary tract infection, 428 Normal distribution/range, 3, 4f Normetadrenaline, 1361b Normoblasts, 915, 916f Normocytic anaemia, 925 Norovirus, 249 Nortriptyline, pharmacokinetics, 20b Norwalk agent, 249 Nosocomial (health care-acquired) infections Clostridium difficile, 211 MRSA, 111–112 pneumonia, 585 Notification food poisoning, 262 partner, STIs, 333, 339 Novel therapies, for cystic fibrosis, 581 NSAIDs adverse reactions of, 22b associated with small intestinal toxicity, 811 for back pain, 997 in blood loss, 940–941 for cholecystitis, 905 cirrhosis and, 894b for CPPD crystal deposition disease,

for gout, 1015 hepatotoxicity of, 894b for intermittent fever, 74 mechanism of action of, 1003f for musculoskeletal disease, 1002–1003 in old age, 1004b for osteoarthritis, 1012 for pain, 1345 for pancreatitis, 841 for peptic ulcer, 799 poisoning from, 138 for psoriatic arthritis, 1033–1034 for reactive arthritis, 1032 recommendations for the use, 1003b renal disease and, 426 risk of, in gastrointestinal bleeding and perforation, 1003b for systemic lupus erythematosus,

topical, 1003–1004 ulcers induced by, risk factors for, 1003b Nuclear antigens, extractable, antibodies to, 389 Nuclear factor kappa B (NFκB) pathway, 64–66 Nucleic acid amplification test (NAAT), 106, 333 Nucleoside reverse transcriptase inhibitors (NRTIs), 324b Nucleosome, 38 Nucleotide substitutions, 42, 42f Numbness, 1083–1084 ‘Nutcracker’ oesophagus, 795 Nutraceuticals, for osteoarthritis, 1012 Nutrients, energy-yielding (macronutrients), 694–697 Nutrition, 694, 694f for alcoholic liver disease, 882 alcoholic liver disease and, 880–881 artificial, 710–711 dementia and, 711, 711f in hospital patients, 706 in intensive care, 210 in lactation, 712b parenteral, 707–708, 708b physiology of, 694–697 in pregnancy, 712b of stroke patients, 1159b under-nutrition and, 704–711 Nutritional disorders, clinical examination in, 692, 692f Nutritional factors, in disease, 691–718 Nutritional status, clinical assessment and investigation of, 693b, 693f Nutritional supplements, oral, 706 Nutritional support, artificial, ethical and legal considerations in management of, 710–711, 710b Nystagmus, 1069, 1090 balance disorders and, 1104f gaze-evoked, 1090 Nystatin, 125b candidiasis, 126, 790 O Obesity, 94, 698–704 aetiology of, 699–700, 699b body fat distribution in, 699 clinical assessment for, 693b clinical features of, 700, 700b complications of, 698–699, 698f investigations of, 700 management of, 700–704, 701f drugs in, 702–703, 702f lifestyle advice in, 701 surgery in, 702f–703f, 703–704, 703b weight loss diets in, 701–702, 701b in musculoskeletal disease, 1001–1002 non-alcoholic fatty liver disease and, 882–883 reversible causes of, 700 susceptibility to, 699–700 type 2 diabetes and, 732 Obesogenic environment, 699b Obeticholic acid (OCA), for primary biliary cholangitis, 888 Obidoxime, 146 Obinutuzumab, for chronic lymphocytic leukaemia, 960 Obliterative cardiomyopathy, 541 Obsessive-compulsive disorder (OCD),

Obstetric cholestasis, pregnancy and,

Obstetric haemorrhage, circulatory collapse and, 1275 Obstetrics, genomics and, 56 Obstructive pulmonary diseases, 567–581 asthma, 567–573 bronchiectasis, 578–579 chronic, 573–578 cystic fibrosis, 580–581 Obstructive shock, description of, 206b Occipital lobes, 1066 disorders of, 1089b functions of, 1066b effects of damage, 1066b Occupational airway disease, 613–614 Occupational and environmental lung disease, 613–619 asbestos-related, 617–618 due to organic dusts, 616–617, 616b occupational airway disease, 613–614 pneumoconiosis, 614–616, 615b Occupational asthma, 613–614, 614b, 614f Occupational lung cancer, 618 Occupational pneumonia, 618–619 Occupational therapist, 1303b Occupational therapy for musculoskeletal disease, 1001 rheumatoid arthritis, 1026 for Parkinson’s disease, 1114 Ochrobactrum spp., 617 Octopus, blue-ringed, 154b Octreotide acromegaly, 686–687 gastrointestinal obstruction, 1354 scintigraphy, 679f short bowel syndrome, 709b for Zollinger-Ellison syndrome, 802 Ocular abnormalities, 1088–1093 Ocular dysmetria, 1090 Ocular imaging, 1169f Ocular inflammation, 1171–1173 Ocular pain, 1080 Ocular ultrasound, for visual disorders,

Oculomotor (3rd cranial) nerve palsies, 1121b, 1144b tests of, 1063b Oculopharyngeal dystrophy, 1143b Odds ratio, drug therapy, 28f Odynophagia, 316, 1324b Oedema, 395–396 ascites, 395–396 causes of, 396b cerebral see Cerebral oedema famine, 704 generalised, 282 legs, 395–396 mechanisms of, 186b nephrotic syndrome, 395–396, 395b peripheral differential diagnosis, 463b heart failure, 463b hypervolaemia, 354 pitting, 395 pregnancy and, 1275 pulmonary see Pulmonary oedema Oesophageal candidiasis, in HIV/AIDS patients, 316, 317f Oesophageal diseases, HIV-related, 315b, 316, 317f Oesophageal dysmotility, secondary causes of, 795 Oesophageal motility, 778 Oesophageal transection, for variceal bleeding, 871 Oesophageal variceal bleeding, 869 management of, 870f Oesophageal varices, 865–866, 865f management of, 870f Oesophagitis, 792 eosinophilic, 794 herpes simplex, in HIV infection/AIDS,

reflux, 792, 792f systemic sclerosis, 1037–1038 Oesophagus Barrett’s, 792–793, 793f carcinoma and, 796 carcinoma of, 796–797 diseases of, 791–797 achalasia of, 794–795, 795f motility disorders, 794–796 reflux, 791–794 functional anatomy of, 766–767, 766f lower, adenocarcinoma of, 796f ‘nutcracker’, 795 perforation of, 797 tumours of, 796–797 benign, 796 17β−Oestradiol, 1359b Oestradiol, pregnancy and, 1272 Oestrogen in bone remodelling, 986b for delayed puberty, 654 hepatotoxicity, 894b Oestrogen deficiency, 654b Oestrogen receptors, as tumour markers, 1322, 1324b Oestrogen replacement therapy delayed puberty, 655 Turner’s syndrome, 660 Ofloxacin leprosy, 270b for PID, 336 for STIs, chlamydial infection, 341b Ogilvie’s syndrome, 835 Ointments, 1225b Older people acute illness, 1308, 1308b acute kidney injury in, 414b adrenal glands, 673b antimicrobial therapy in, 120b blackouts, 1308 cancer in, 1325b comorbidities in, 1307 critical illness in, 212, 213b delirium, 1309 demography of, 1304, 1304f deprescribing in, 1310–1311 diabetes mellitus in, 732b management of, 757b dizziness, 1309 endoscopy in, 776b energy balance in, 710b epilepsy in, 1103b examination, 1303b falls, 1308–1309, 1308b, 1308f frailty, 1306, 1306b gait and balance, 1303b gastrointestinal disorders, acute abdominal pain in, 788b geriatric assessment, 1302, 1302f gout in, 1014b haematological investigations in, 923b history, 1303b hypernatraemia in, 360b hyponatraemia in, 360b

1400 • INDEX incontinence, 436b, 1309–1310, 1310f investigation, 1306–1307 Comprehensive Geriatric Assessment, 1306 decisions on, 1306–1307 medical psychiatry in, 1189b neurological examination in, 1079b NSAIDs in, 1004b ophthalmological findings of, 1175b oral health in, 791b osteoarthritis in, 1011b osteoporosis in, 1049b polypharmacy in, 1310b prescribing in, 1310–1311 presenting problems in, 1307–1311, 1311b rehabilitation, 1311–1312 renal replacement therapy in, 422b respiratory disease in infection, 586b interstitial lung disease, 613b obstructive pulmonary disease, 578b pleural disease, 626b respiratory function in, 550b urinary tract infection in, 428b vitamin deficiency in, 712b Oleander, poisoning from, 140 Olecranon bursitis, 998b, 1024f Olfactory loss, 1088 Olfactory (1st cranial) nerve, tests of, 1063b Oligoarthritis, 1027 asymmetrical inflammatory, 1032 Oligoclonal bands, 1077 Oligodendrocytes, 1064–1065 Oligodendroglioma, 1129b Oligopeptides, 768 Oliguria, 391 critically ill patients, 195 Olsalazine, for inflammatory bowel disease, 821b Omalizumab, for allergy, 86 Omeprazole drug interactions of, 24b for H. pylori eradication, 800 Onchocerca volvulus, 292, 292f Onchocerciasis, 233b, 292–293 Oncogenes, 51 Oncogenesis, 1318f Oncology, 1313–1336 genomics and, 56–58 transition medicine and, 1298 Onychogryphosis, 1260 Onychomycosis, 1240 Oophoritis, mumps, 240 Open reading frame (ORF), 40 Ophthalmia neonatorum, 341 Ophthalmic disease, presenting problems of, 1169–1171 Ophthalmology, 1164 medical, 1163–1178 Ophthalmopathy, Graves’, 645–646, 645f examination of, 631b Opiates/opioids adverse reactions of, 22b for cholecystitis, 905 misuse of, 142, 142b, 1195 for osteoarthritis, 1012 for pain, 1346–1347, 1346b–1347b adverse effects of, 1351–1352, 1351b Opisthorchiasis, 297b Opisthotonus, 1126 Opportunistic mycobacterial infection, 595, 595b Opsoclonus-myoclonus, 1111b Opsonins, 63 complement fragments as, 66 Opsonisation, 63, 63f Optic atrophy, 1091–1093, 1092f Optic chiasm, disorder of, 1089b Optic disc disorders, 1089b Optic disc swelling, of ophthalmic disease, 1171 Optic (2nd cranial) nerve, tests of, 1063b Optic neuritis, 1089b, 1111b multiple sclerosis, 1108b onchocerciasis, 293 swelling, 1092b and transverse myelitis (neuromyelitis optica), 1110 Optic neuropathy, Leber hereditary,

Optic tract, disorders of, 1089b Optical coherence tomography, 1169 OptiMAL®, 276 Oral administration, 17 Oral allergy syndrome, 812 Oral androgen replacement therapy, 656b Oral cancer, 790, 790b Oral cavity, organisms in, 103f Oral contraception/contraceptives acne treatment, 1243 migraine and, 1095 skin reactions, 1266b venous thtombosis and, 975b, 1162b Oral contraceptive pill (OCP) cystic fibrosis and, 1297 epilepsy and, 1296 porphyria and, 379 Oral diseases, HIV-related, 316 Oral glucocorticoids, for chronic obstructive pulmonary disease (COPD), 576–577 Oral glucose tolerance test (OGTT), 726b Oral hairy leukoplakia, 316 Oral health, in old age, 791b Oral rehydration solution (ORS), 229b Oral ulcers, in Behçet’s disease, 1043–1044, 1043f Orbit, 1164 blood supply of, 1168 imaging of, 1073–1074, 1074f Orbital septum, 1164 Orchitis, mumps, 240 Orf, 1239 Organ donation, 90 after brain death, 213 after cardiac death, 213 altruistic living, 90 cadaveric, 90 Organelles, intracellular, 1154f Organic solvents, misuse of, 1196 Organisms detection of components of, 106 whole, detection of, 105 Organophosphate-induced delayed polyneuropathy, 146 Organophosphorus compound, 145–146, 145b, 145f Oriental spotted fever, 271b Orientation, assessment, 1181 Orlistat, for obesity, 702, 702f Ornidazole, 287 Oropharynx, examination HIV disease, 306f infectious disease, 216f Oroya fever, 272 Orphenadrine, for Parkinson’s disease,

Orthopnoea, 557, 611 Orthoses, for musculoskeletal disease,

Oscillopsia, 1090 Oseltamivir, 119b, 127 Osgood-Schlatter disease, 999b Osmolality, 1360b presenting problems of, 356–360 Osmolarity, 1360b Osmotic agents, 14 Osmotic diuretics, for hypervolaemia,

Osteitis fibrosa cystica, 418–419 Osteoarthritis (OA), 1007–1012 clinical features of, 1008–1011, 1009b early-onset, 1011, 1011b epidemiology of, 1007 erosive, 1011 generalised nodal, 1009, 1009b, 1009f hip, 1010, 1010f investigations for, 1011 knee, 1009–1010, 1010f management of, 1011–1012 in older people, 1011b pathophysiology of, 1007–1008, 1008f risk factors for, 1008b spine, 1011, 1011f Osteoarthropathy, hypertrophic pulmonary, 600–601 Osteoblasts, 984 in bone remodelling, 985f Osteochondritis dissecans, 998–999 of patella ligament, 998b Osteoclasts, 984 in bone remodelling, 985f Osteocytes, 985 Osteogenesis imperfecta (OI), 1055–1056 transition medicine and, 1300 Osteoid, 985f Osteoid osteoma, 1056b Osteomalacia, 1051–1052 causes of, 1050b chronic kidney disease and, 418–419 clinical features of, 1052 investigations in, 1052, 1052f management of, 1052 pathogenesis of, 1051–1052 tumour-induced, 1053 vitamin D-deficient, biochemical abnormalities in, 990b Osteomyelitis, 1021 Osteonecrosis, 1055 drug-induced, 1057b pain, 1055 Osteopenia biliary cirrhosis, 888 fracture and, 994 hyperparathyroidism, 663 radiographic, 989–990 Osteopetrosis, 1056 Osteophytes, 988, 1134 Osteoporosis, 1044–1049 biochemical abnormalities in, 990b clinical features of, 1045 coeliac disease and, 807 fractures associated with, 1044, 1045f bone mineral density and, 1046f glucocorticoid-induced, 1045 transition medicine and, 1300 idiopathic, 1044 investigations of, 1046, 1047b, 1047f management of, 1046–1049 non-pharmacological interventions for,

in old age, 1049b pathophysiology of, 1044–1045, 1045f pharmacological interventions for, 1047–1049, 1048b pregnancy-associated, 1045 risk factors for, 1046b secondary, 1044–1045 surgery for, 1049 treatment of, 1309 Osteoprotegerin, in bone remodelling, 986b Osteosarcoma, 1056–1057 Osteosclerosis osteoarthritis and, 1007, 1011f Paget’s disease and, 1054 Osteotomy, 1002b, 1012 Ostium primum defects, 534 Otitis media, 236, 253b, 266, 1119 Ovarian cancer, 1334 investigations of, 1334 management of, 1334 pathogenesis of, 1334 Ovarian failure, chemotherapy-induced,

Ovaries, polycystic, 658–659, 659f Over-nutrition, responses to, 694–695 Overflow incontinence, 437, 1093 in older people, 1310 Overnight dexamethasone suppression test (ONDST), in Cushing’s syndrome, 668 Ovulation, 656–657 Oxacillin, 120b Oxalate, 1361b Oxazolidinones, 124 Oxcarbazepine, 1102b Oxidative killing, 64 Oxidative stress, 881f, 883 Oximes, 146 Oximetry, 555–556 asthma, 573 Oxygen arterial blood (PaO2), 1358b content and delivery of, in shock, 193, 193b for gastrointestinal haemorrhage, 782 Oxygen dissociation curve, in haemoglobin, 915–916, 917f Oxygen saturation, 1358b Oxygen therapy for acute exacerbations of COPD,

for air passengers, 169 for chronic obstructive pulmonary disease (COPD), 577, 577b for community-acquired pneumonia,

for critical illness, 191, 191b for diving-related illness, 171 for high-altitude pulmonary oedema,

Oxyhaemoglobin dissociation curve, 190, 191f Oxytetracycline, acne, 1243 P P gene, 1258 Pabrinex, 1195 Pachyonychia congenita, 1261 Pacing AV block, 482, 483f dual-chamber, 714 tachyarrhythmias, 469 transcutaneous, 482–483 Packed cell volume (PCV), 1362b Paclitaxel, 1334 Paediatric disease, in systemic lupus erythematosus, 1036 Paediatric health services, transition to adult health services from, 1288–1290 Paget’s disease biochemical abnormalities in, 990b of bone, 1053–1054 clinical features of, 1054 investigations in, 1054, 1054f management of, 1054, 1054b pathophysiology of, 1053–1054 Pain, 1070, 1338–1349 abdominal, 787–789 acute, 787–789, 787b acute pancreatitis, 837–839, 837b assessment of, 787, 788f chronic or recurrent, 789, 789b chronic pancreatitis, 839–841 constant, 789 diabetic ketoacidosis and, 736, 736b investigations of, 787 irritable bowel syndrome and, 824 large bowel obstruction of, 789 liver abscess and, 880 in lower abdomen, 336 management of, 787–789 in old age, 788b peptic ulcer, perforated, 789 ankle, 999 back, 995–997 red flags for, 996b triage assessment of, 996f biliary, gallstones and, 904 biopsychosocial model of, 1338f in cancer, 1350, 1350b central processing of, 1339–1340 challenges in, 1344b Older people (Continued)

INDEX • 1401 chest, 176–179, 454–455 associated features of, 177–178, 178f characteristics of, 177 clinical assessment of, 178 differential diagnosis of, 177b investigations of, 178–179, 179b ischaemic, 454f onset of, 177 pregnancy and, 1275 in respiratory disease, 558 site and radiation of, 177 elbow, 998, 998b facial, 1080 foot, 999 functional anatomy and physiology of, 1338–1341 hand, 998 in headache, 1080 hip, 998, 999b, 999f osteoarthritis and, 1010 instruments for assessment of, 1343b interventions for, 1344–1348 complementary and alternative therapies for, 1348 nerve blocks and nerve ablation in,

pharmacological therapies in, 1344–1347, 1345b–1347b physical therapies in, 1344, 1344b psychological therapies in, 1347 stimulation therapies in, 1347, 1347f supported self-management in,

investigations of, 1342–1343 knee, 998–999, 999b loin, 396 low back assessment of, 988–989 causes of, 996b mechanical, features of, 996b radicular, 997b muscle, 1000, 1000b musculoskeletal, regional, 997–999 neck, 997, 997b neuropathic, 1084, 1348, 1348b, 1348f ocular, 1080 of ophthalmic disease, 1170 osteoarthritis and, 1007–1008 hip, 1010 knee, 1009–1010 palliative care for, 1349–1354, 1349f perception of, 1338f principles of management of, 1343 radicular, 997b shoulder, 997–998, 998b, 998f somatoform disorder, 1202 wrist, 998 Pain relief, for pancreatitis, 841 Pain scoring system, 1343 Painful vaso-occlusive crisis, 952 Palliation, for cancer, 1330 Palliative care, 1349–1354, 1349f for chronic obstructive pulmonary disease (COPD), 577 presenting problems of, 1350–1354 anxiety and depression in, 1354 cough in, 1353 dehydration in, 1354 delirium and agitation in, 1354 gastrointestinal obstruction in,

nausea and vomiting in, 1353–1354, 1353f weight loss in, 1354 Palliative chemotherapy, 1329 Palmar erythema, 630f, 635–636, 846f, 866–867 Palmoplantar pustulosis, 1249 Palpable mass, cancer and, 1323 Palpable purpura, 1042, 1042f Palpation of abdomen, 765b of precordium, 443b in respiratory system, examination of, 546f Palpitation, 455–456, 455b, 456f Pamidronate bone metastases, 1329 hypercalcaemia, 1329 for Paget’s disease, 1054, 1054b Pancoast’s syndrome, 600 Pancolitis, 815–816 Pancreas, 770, 770f annular, 842 artificial, 751, 751f carcinoma of, 843f congenital abnormalities affecting,

diseases of, 837–844 divisum, 842 endocrine, 676–679 pre-diabetic, 728 structure and endocrine function of, 723f tumours of, 842–844 Pancreatic cancer, 843f Pancreatic β-cell failure, in type 2 diabetes, 731 Pancreatic disease, 733 Pancreatic enzymes, 770b Pancreatic necrosis, 839f Pancreatic pseudocyst, 838f ‘Pancreatic rests’, 805 Pancreatitis acute, 837–839, 837b causes of, 838b complications of, 838b management of, 839 pathophysiology of, 837, 838f autoimmune, 841 chronic, 839–841, 840b complications of, 840b investigations of, 840, 841b, 841f management of complications of,

pathophysiology of, 840f hereditary, 840b, 842 necrotising, 839 Pancreolauryl test, 777b Pancytopenia, 930, 930b Panic disorder, 1200 Pannus, 1022–1023 Panton-Valentine leukocidin, 586, 1237 Papilla of Vater, 861 Papillary carcinoma, 649 Papillary muscle rupture, in acute coronary syndrome, 496 Papillary necrosis, 403 Papillary renal cell cancer syndrome, 1321b Papilloedema, 1090–1091, 1092b, 1092f haemorrhagic, 1062f Papilloma, basal cell, 1234, 1234f Papillomaviruses, 1238–1239 Papular pruritic eruption, HIV-related,

Papule, definition of, 1211f Papulosquamous eruptions, 1251 Para-aminosalicylic acid (PAS), skin reactions, 1266b Parabens, 1247b Paracentesis, for ascites, 863–864 Paracetamol adverse reactions, 22b for chronic pain, 1345b for fever, 218 for headache, 1096 hepatoxicity of, 857, 857f for musculoskeletal disease, 1002 osteoarthritis, 1012 for pain, 1345 poisoning, 134b poisoning from, 137–138, 138f acute liver disease and, 857–858, 858b Paracoccidioides brasiliensis, 304 Paracoccidioidomycosis, 304 Paraesthesia, 1083–1084 Paraganglioma, 675–676 Paragonimiasis, 233–234 Paragonimus spp., 129 Paragonimus westermani, 233b Parainfluenza viruses, 249 Paraldehyde disturbed behaviour, 1189f poisoning, 135b Paralysis, ventilator-induced lung injury and, 204 Paralysis ticks, envenomation of, 161 Paralytic ileus, 837–838 Paralytic shellfish poisoning, 149 Paramyotonia congenita, 1145b Paraneoplastic disease, neurological, 1110–1111, 1111b Paraneoplastic syndromes, neurological, 1325–1326 Paraparesis, 1086–1087 Paraphasia, 1088 Paraphenylenediamine, 1247b Paraplegia, hereditary spastic, 1138b Parapneumonic effusion, 564 Paraproteinaemias, 966–968 Paraproteins, 965–966 Paraquat, poisoning from, 147 Parasitic infections and cancer, 1320b eosinophilia, 233b Parasitosis, delusional, 1202 Parasomnias, 1105–1106 non-REM, 1105 Parathyroid disease, pregnancy in,

familial hypocalciuric hypercalcaemia as, 1280 primary hyperparathyroidism as, 1280 Parathyroid glands, 661–665 disease of classification of, 661b presenting problems in, 661–663 familial hypocalciuric hypercalcaemia and, 664 functional anatomy, physiology and investigations of, 661 hypoparathyroidism and, 664–665 in old age, 665b primary hyperparathyroidism and, 663–664, 663b, 664f Parathyroid hormone (PTH), 661 acute kidney injury and, 416b in bone remodelling, 986b osteomalacia and rickets, 1051–1052 osteoporosis, 1047b reference range of, 1359b in skeletal disease, 990b Parathyroid hormone-related protein (PTHrP), ectopic production, 1325b Parathyroidectomy, 419 Paratyphoid fever, 260 Parenchymal bacterial infections, 1124–1125 Parenchymal viral infections, 1121–1123 Parenteral administration, 17 Parenteral nutrition, 707–708, 708b Parietal lobes, 1066 disorders of, 1089b functions of, 1066b effects of damage, 1066b Parinaud syndrome, 1072b Parkinsonian syndromes, 1114–1115 Parkinsonism, 1084–1085, 1085b, 1112 drug-induced, 1112b Parkinson’s disease, idiopathic, 1112–1114 causes of, 1112b clinical features of, 1112–1113, 1113b non-motor symptoms of, 1112–1113 investigations of, 1113, 1113f management of, 1113–1114 drug therapy, 1113–1114 surgery, 1114 pathophysiology of, 1112, 1112f Paromomycin, 129 for leishmaniasis, 283 Parotitis, 790, 790b Paroxysmal atrial fibrillation, 471–472 Paroxysmal cold haemoglobinuria, 950 Paroxysmal nocturnal haemoglobinuria (PNH), 950–951 Partial agonists, 14 Partial anterior circulation syndrome (PACS), 1156f Partial thromboplastin time with kaolin (PTTK), 920–921 Parvovirus B19 infection, 237 clinical features of, 237, 237b, 237f diagnosis of, 237 management of, 237 in pregnancy, 235b Past-pointing, 1069 Pastes, 1225b Pastia’s sign, 252, 253f Patau’s syndrome (trisomy 13), 44b Patch testing, for skin disease, 1215 Patella ligament enthesopathy, 999b Paterson-Kelly syndrome, 795–796 Pathergy test, 1044 Pathogen-associated molecular patterns (PAMPs), 63 ‘Pathogenicity,’ in host-pathogen interactions, 104 Pathogens direct detection of, 105–106 host-pathogen interactions, 104 indirect detection of, 106–109 successful, 104 Pathological fracture, 995b Pathway medicine, for genetic disease,

Patient-centred evidence-based medicine, 10, 11f, 12 Patient factors, of gastro-oesophageal reflux disease, 791 Patients, autonomy, 1288–1289 Pattern recognition receptors (PRRs),

Paul-Bunnell test, 242 PCSK9 inhibitors, 377 Peak expiratory flow (PEF) asthma, 569f, 573f home monitoring, 555 morning dipping, 569f Peak flow meters, 555, 569 Peanut allergy, 85 PECAM-1, 447 Pectins, 696b Pectus carinatum, 628 Pectus excavatum, 628 Pediculus humanus, 257 Pediculus humanus capitis, 1241 Pedigree, construction of, 46, 46f Pegloticase, for gout, 1016 Pegvisomant, 686–687 Pellagra, 714, 715f, 1221b Pelvi-ureteric junction obstruction (PUJO), 434 Pelvic floor exercises, faecal incontinence, 835 Pelvic inflammatory disease (PID), 336 Pemphigoid, bullous, 1255–1256, 1255b, 1256f Pemphigoid gestationis, 1220b, 1255b Pemphigus, 1256, 1326 Pemphigus foliaceus, 1255b Pemphigus vulgaris, 1255b Penciclovir, as anti-herpesvirus agent, 126, 127b Pendred’s syndrome, 635f, 650 Pendrin, 635f Penetrance, genetic, 47 Penicillamine for musculoskeletal disease, 1004b,

nephrotoxicity, 427b for oral ulceration, 790b for primary biliary cholangitis, 888 for pyridoxine deficiency, 715 for Wilson’s disease, 897 Penicillin(s), 117b, 121 adverse reactions, 21, 22b allergy, 75b anthrax, 267 diphtheria, 266 endocarditis, 528 leptospirosis, 258–259 listeriosis, 260 meningitis, 1120 nephrotoxicity, 427b

1402 • INDEX for neurosyphilis, 1125 penicillinase-resistant, 121 in pregnancy, 120b prophylactic, 78, 119b resistance, 116 rheumatic fever, 517 syphilis, 337 for syphilis, 339 tetanus, 1126b tropical ulcer, 254 urinary tract infection, 428 Penicillium marneffei infection, 303 Penile erection, 440 Penis, 386 Pentamidine, prophylactic, 119b Pentamidine isethionate for leishmaniasis, 283 for Pneumocystis jirovecii pneumonia,

Pentasa, for inflammatory bowel disease, 821b Pentavalent antimonials, 128, 283 Pentoxifylline for alcoholic hepatitis, 882 for frostbite, 166–167 Pepsinogen, 767 Peptic ulcer complications of, 801–802 indications for, 800b in old age, 801b perforation, 789, 801 prophylaxis for, in intensive care,

Zollinger-Ellison syndrome, 802 Peptic ulcer disease, 798–802 Peptide YY, 772b Peptides, antimicrobial, 62–63 Peptostreptococcus spp., 253b Perceptions abnormal, 1086, 1181 delusional, 1196–1197 Percussion abdomen, 765b in respiratory system, examination of, 546f Percutaneous coronary intervention (PCI) angina, 491–493, 491f–492f myocardial infarction, 493b vs. CABG, 493b Percutaneous endoscopic gastrostomy (PEG), 707, 708f Percutaneous therapy, for hepatocellular carcinoma, 891 Percutaneous transhepatic cholangiography (PTC), 854–855 Perforating dermatosis, acquired reactive, 1265 Perforin, 67 Perfusion, in respiratory system, 549–550 Perianal disease, inflammatory bowel disease and, 823 Pericardial disease, in tuberculosis (TB),

Pericardial effusion, 542b, 543, 543f, 1315b Pericarditis acute, 542, 542b, 542f in acute coronary syndrome, 496 chronic constrictive, 543–544, 543b, 544f tuberculous, 543 Pericardium, diseases of, 542–544 Perimetry, 1168 Perimysium, 987–988 Periodic fever syndromes, 81, 1059 Periodic limb movements, and sleep,

Periodic paralysis hyperkalaemic, 1145b hypokalaemic, 1145b Periostitis, 337, 600–601 Peripartum cardiomyopathy, pregnancy and, 1282 Peripheral arterial disease, 502–505, 502b Peripheral nerves, 1338 disease of, 1138–1141, 1139b HIV-related, 321 endings, 1338 lesions, 1083 Peripheral nervous system motor, 1068 sensory, 1068 Peripheral neuropathy, 1325 cancer-related, 1325 diabetic, 755, 756b drug-induced, 321 HIV-related, 321 leprosy, 268 in rheumatoid arthritis, 1024 sensorimotor, 321 Peripheral sensitisation, 1340, 1341f Peripheral ulcerative keratitis, 1171–1172 Peripheral vascular disease, in diabetes, 503b Perisinusoidal fibrosis, 884 Peristalsis, 772 Peritoneal cavity, disease of, 836–837 Peritoneal dialysis, 424 automated, 424 continuous ambulatory, 424 haemodialysis vs., 420b problems with, 425b Peritonitis, 836 spontaneous bacterial, 864 Permanent pacemakers, for arrhythmias, 483, 483b Pernicious anaemia, 944 Persistent atrial fibrillation, 472–473 Persistent ductus arteriosus, 532f–533f, 533–534 Personality, 1071 change, 1094 high-risk behaviour and, 1295 psychiatric disorders and, 1183 Personality disorders, 1204–1205 prevalence of, 1180b Pes cavus, 1140 Pesticides, 144–149 Petechiae, definition of, 1211f Petechial purpura, 928–929, 928f Petit mal, 1097 Pets allergic rhinitis and, 622 asthma and, 568 HIV infection/AIDS and, 323 Peutz-Jeghers syndrome, 829, 829f Peyer’s patches, 67, 769–770 Phaeochromocytoma, 675–676, 675b, 676f Phaeohyphomycoses, 301 Phagocytes, 63–64, 63f deficiency in, 73b primary, 77–78, 77f Phagocytosis, 63, 63f Phagolysosome, 64 Phantom limb pain, 1349 Pharmacist, 21b Pharmacodynamics, 14–16, 14f dose-response relationship in, 14–16, 15f drug targets in, 14, 15b mechanisms of action of, 14 Pharmacogenomics, for genetic disease, 58 Pharmacokinetics, 17–19, 17f absorption in, 17–18 distribution in, 18 elimination in, 18–19 patient-specific factors in, 20b repeated dose regimens in, 19 Pharmacological therapies, for pain, 1344–1347, 1345b Pharmacovigilance, 23, 23b Pharmacy, 27 Pharyngeal pouch, 794 Phenelzine, 1199b Phenobarbital epilepsy, 1102b in old age, 32b poisoning, 136b status epilepticus, 1081b Phenothiazines, for schizophrenia, 1198b Phenoxymethylpenicillin, 120b prophylactic, 119b Phentermine, for obesity, 702–703 Phenylketonuria, 369 Phenytoin ataxia, 1115b drug interactions, 24b epilepsy, 1102b multiple sclerosis, 1110b pharmacokinetics of, 19 plasma concentration, 36b poisoning, 141b renal or hepatic disease, 32b sodium content of, 864b status epilepticus, 1081b Phobia, 1200 Phobic anxiety disorder, 1200 Phosphate acute kidney injury and, 416b in diabetic ketoacidosis, 738 enema, 869b homeostasis, 368–369 reference range of urine, 1361b venous blood, 1360b in skeletal disease, 990b Phosphenes, 1088 Phosphodiesterase type 5 inhibitors, erectile dysfunction, 440 Phospholipids, 126, 370 Phosphorus, 716 deficiency, 716 dietary sources of, 717b excess, 716 reference nutrient intake of, 717b Photo-exposed site hyperpigmentation,

Photoallergy, 1221b Photochemotherapy, 1227 Photodynamic therapy (PDT) for oral cancer, 790 for skin disease, 1228 Photophobia/glare, of ophthalmic disease, 1170 Photopsia, of ophthalmic disease, 1170 Photosensitivity, 1220–1223, 1221b clinical assessment of, 1221 drug-induced, 1266b investigations and management of, 1221–1223 Phototesting, for skin disease, 1215 Phototherapy, 1227 Phototoxicity, 1221b Physical activity, energy expenditure and, 694, 695f Physical therapies for musculoskeletal disease, 1001 rheumatoid arthritis, 1026 for pain, 1344, 1344b Physiological anaemia of pregnancy,

Physiological breathlessness, of pregnancy, 1274–1275 Physiotherapy for bronchiectasis, 579 for cancer pain, 1352 for cervical spondylosis, 1134 for community-acquired pneumonia,

for fracture, 995 for Parkinson’s disease, 1114 for stroke, 1159f Phytoestrogens, 716 Pick’s disease, 1193–1194 Pigment stones, 903–904, 903b Pigmentation drug-induced, 1258, 1258b, 1266b endocrine, 1258 Pigmented villonodular synovitis, 1059 Pinta, 254, 254b Piperacillin, 120b for spontaneous bacterial peritonitis,

for variceal bleeding, 869 Piperacillin-tazobactam, 117b for necrotising fasciitis, 227 for neutropenic fever, 224 Piperazine, 129 Piroxicam, 1003b Pitted keratolysis, 1238 Pituitary disease investigation of patients with, 680, 680b pregnancy and, 1280 diabetes insipidus as, 1280 prolactinoma as, 1280 Sheehan’s syndrome as, 1280 Pituitary hormones, 632 Pituitary tumours, 683–684, 1129 Pityriasis lichenoides chronica, 1251 Pityriasis rosea, 1217b, 1251 Pityriasis versicolor, 1240 rash in, 1217b Placental alkaline phosphatase (PLAP), as tumour markers, 1322, 1324b Plague, 259, 259f Plain chest X-ray for gastrointestinal disease, 772, 773f contrast studies of, 773 normal, 551f for respiratory disease, 551, 551b, 551f abnormalities, 552b aspergillosis, 597f asthma, 569 bronchiectasis, 579 COPD, 575 empyema, 564f haemoptysis, 560 interstitial, 605, 605f lobar collapse, 552f lung cancer, 599, 599f mediastinal tumours, 604, 604f pleural effusion, 563 pleural plaques, 617f pneumonia, 585 pneumothorax, 626 pulmonary embolism, 619–620, 619b, 619f pulmonary hypertension, 622f sarcoidosis, 609b silicosis, 615f tuberculosis, 590f Plane warts, 1238 Plant poisoning, 150, 150b Plantar warts, 1238 Plaques amyloid in, 1192 definition of, 1211f Plasma derivatives, 930 Plasma exchange (PE) for Guillain-Barré syndrome, 1140 pre-renal transplant, 424 Plasma iron, 942 Plasma viscosity, inflammation and, 72 Plasmapheresis, for pruritus, primary biliary cholangitis and, 888 Plasmodium falciparum infection, 274f, 275, 276b Plasmodium falciparum malaria, 950 Plasmodium knowlesi infection, 276 Plasmodium malariae infection, 276 Plasmodium ovale infection, 275 Plasmodium vivax infection, 275 Platelet-derived growth factor (PDGF),

Platelet-endothelial cell adhesion molecule type 1 (PECAM-1), 447 Platelet function disorders, 970–971 Platelets, 918, 920f concentrate, 931b count in coagulation screening tests, 922b high, 929–930 low, 929 function, assessing, 921 reference range of, 1362b Plethysmography (SpO2), 175b Pleural disease, 625–627 Pleural effusion, 562–565, 1329, 1329b cardiac failure in, 563b causes of, 563b clinical assessment of, 563 investigations of, 563–564 large right, 547f Penicillin(s) (Continued)

INDEX • 1403 malignant, 563b management of, 564 obstruction of thoracic duct in, 563b oedema, 395–396 pancreatitis in, 563b pulmonary infarction in, 563b rheumatoid disease in, 563b, 610–611 in systemic lupus erythematosus,

systemic lupus erythematosus in, 563b tuberculosis in, 563b, 589f–590f Pleural pain in community-acquired pneumonia, treatment of, 584 in lung cancer, 600 Pleural plaques, 617–618, 617f Pleural rub, 457–459 Plexopathy, 1138 brachial, 1141 lumbosacral, 1141 Plumboporphyria, 379b Plummer-Vinson syndrome, 795–796 Pluripotent stem cells, induced, for genetic disease, 58 Pneumatosis cystoides intestinalis, 837 Pneumococcal infection, 266 Pneumoconiosis, 614–616, 615b Pneumocystis jirovecii infection, after HSCT, 937b Pneumocystis jirovecii pneumonia, HIV-related, 315b, 318, 318b, 318f Pneumocytes, 548–549 Pneumonia, 582–587 bacterial, HIV-related, 319f community-acquired, 582–585, 582f clinical features of, 582–583 discharge and follow-up of, 585 investigations of, 583, 584b management of, 583–584 organisms causing, 582b prognosis for, 585 complications of, 585b differential diagnosis of, 583b factors predispose to, 582b hospital-acquired, 585–586, 585b in immunocompromised patient, 587 necrotising, 104b occupational, 618–619 pregnancy and, 1277 causes of, 1277b viral, 1277 right middle lobe, 547f, 584f suppurative pneumonia, aspiration pneumonia and pulmonary abscess, 586–587 Pneumonic plague, 259 Pneumothorax, 547f, 625–627, 625f age distribution of, 625f air travel after, 169 classification of, 625b clinical features of, 626 investigations of, 626 management of, 626–627, 627f spontaneous recurrent, 627 types of, 626f tension, 566 Podocytes, 384 Podophyllotoxin, 343 Point mutations, 42 Point-of-care testing (POCT), 348 Poiseuille’s Law, 447 Poisoning, 131–150 acute, 134 assessment and investigation for, 134–135, 135b from chemicals and pesticides, 144–149 chemicals less commonly taken in, 148, 148b clinical signs of, 133f decontamination and enhanced elimination for, 133f drugs of misuse and, 141–144 environmental, 149 evaluation for, 132–134, 132b, 132f food-related, 149–150 management of, 135–137 antidotes for, 137, 137b gastrointestinal decontamination for, 135–136, 136b haemodialysis and haemoperfusion for, 136, 136b lipid emulsion therapy for, 136–137 supportive care for, 137, 137b urinary alkalinisation for, 136 in old age, 134b by pharmaceutical agents, 137–141 less commonly taken in, 141, 141b plant, 150, 150b poisoned patient, general approach to, 134–137 psychiatric assessment for, 135 substances involved in, 134b substances of very low toxicity and, 134b triage and resuscitation, 134 Poliomyelitis, 1123, 1123f immunisation for, 1123 incubation period of, 1123 Pollution, atmospheric, 94 PolyA tail, 39f, 40 Polyadenylation signal, 38 Polyarteritis nodosa, 1042 Polyarthritis, 993–994, 993b, 1020–1021 inflammatory arthritis and, extra-articular features of, 994b joint involvement in, 994f symmetrical, 1032 Polycystic ovarian syndrome, 658–659, 659f features of, 658b hirsutism and, 658b, 659 Polycythaemia, 384–386, 925 Polycythaemia rubra vera (PRV), 925,

Polydipsia, 357, 634b Polyenes, 126 Polyethylene glycol, 842 Polymerase chain reaction (PCR), 106 for genetic diseases, 52, 53f for hepatitis B, 873 for herpes simplex virus, 333, 1077 for Whipple’s disease, 809 Polymorphic eruption of pregnancy, 1220b Polymorphic light eruption, 1221b Polymorphisms, 45 single nucleotide, 45 Polymorphonuclear cells, 1122 Polymorphonuclear leucocytes, 64 Polymyalgia rheumatica (PMR), 1042–1043 mimic, 1042b Polymyositis (PM) see Dermatomyositis/ polymyositis Polymyxins, 123 Polyneuropathy, 1139b chronic, 1140–1141 critical illness, 211–212 Polyostotic fibrous dysplasia, 1055 Polypeptides, 768 Polyposis syndromes, 827–829, 827b juvenile, 829 Polyps, 827–829, 827b Polyuria, 396–397, 396b, 634b Pompe’s disease, 1144b Pompholyx, 1247 Popliteal cyst, 998b–999b Population health, 91–98 Porphyria cutanea tarda (PCT), 379b, 1257, 1263–1264, 1264f Porphyrias, 378–380, 1221b, 1263–1264 acute intermittent, 379b congenital erythropoietic, 379b cutaneous, 1263–1264 erythropoietic protoporphyria, 379b hepatic, exacerbation of, 1266b hereditary coproporphyria, 379b plumboporphyria, 379b variegate, 379b ‘Portal’ circulation, 384, 385f Portal hypertension, 868–871, 898 ascites and, 869 cirrhosis and, 868 classification of, 868f clinical features of, 868–869 complications of, 868b extrahepatic portal vein obstruction,

investigations for, 869 management of, 869–871 pathophysiology of, 869 Portal vein thrombosis, 898 Portal venous disease, 898 Portal venous pressure, pharmacological reduction of,

Portopulmonary hypertension, 898 Portosystemic shunt fetor hepaticus from, 868 portal hypertension and, 869 for variceal bleeding, 871 Posaconazole, 126 Positron emission tomography (PET) for cancer, 1323, 1323f of gastrointestinal tract, 778b for Hodgkin lymphoma, 962, 963f of nervous system, 1072 for oesophageal carcinoma, 796f for respiratory disease, 553, 553f Post-cholecystectomy syndrome, 908, 908b Post-exposure prophylaxis, for HIV infection/AIDS, 327 Post-micturition dribble, 437 Post-partum blues, 1206 Post-partum haemorrhage primary, 1275 secondary, 1275 Post-partum thyroiditis, 647, 651b in pregnancy, 651b, 1279 Post-pyloric feeding, 707 Post-transplant lymphoproliferative disorders (PTLDs), 1299 Post-traumatic stress disorder, 1201–1202 Posterior circulation stroke (POCS), 1156f Posterior descending artery, 444 Posterior scleritis, 1170 Posterior uveitis, 1172 Posteroanterior (PA) film, of chest X-ray,

Postmortem examination, 213 Postural hypotension, renal dysfunction, 395–396 Posture, examination of, 1063b Potassium, 349b, 718 and diabetic ketoacidosis, 738 dietary sources of, 717b foods high in, 418b homeostasis, 360–363 presenting problems in, 361–363 intake, chronic renal failure, 418 plasma concentration control and, 360f reference nutrient intake of, 717b reference range of urine, 1361b venous blood, 1358b renal handling, 360, 360f ROMK channel, 360 supplements, 367 Potassium chloride, hypokalaemia, 362 Potassium phosphate, 369 Potassium-sparing diuretics, for hypervolaemia, 355 Potency, 16 Poverty, health consequences of, 94 Poxviruses, 248–249 Practolol, nephrotoxicity, 427b Praziquantel, 129 Pre-eclampsia, hypertension and, 1276–1277, 1276b, 1277f Pre-exposure prophylaxis, for HIV infection/AIDS, 327 Pre-implantation genetic diagnosis (PGD), 56 Pre-patellar bursitis, 999b Pre-symptomatic/predictive testing, 59 Pre-test probability, in clinical decision-making, 11 Pre-transfusion testing, 934 Precocious puberty (PP), 654 Prednisolone for alcoholic hepatitis, 882 for autoimmune hepatitis, 886–887 for eosinophilic gastroenteritis, 811–812 for gout, 1015 for inflammatory bowel disease, 821b liver transplantation and, 901 for respiratory disease aspergillosis, 596 asthma, 572 chronic eosinophilic pneumonia, 611–612 COPD, 578 hypersensitivity pneumonitis, 617 rheumatoid disease, 610 sarcoidosis, 610 for syphilis, 339 for systemic lupus erythematosus,

for type II thyrotoxicosis, 648 for warm autoimmune haemolysis,

Prefrontal cortex (PFC), high-risk behaviour and, 1295 Pregabalin, 1102b Pregnancy abnormal liver function tests in, 900b adolescent, rates of, 1296b adrenal disease in, 1280 air travel and, 169 analytes affected by, 1364b antimicrobial agents in, 120b biliary obstruction and, 900 cardiac disease in, 1282 cholecystitis and, 900 congenital heart disease in, 533, 533b diabetes in, 1278–1279 diabetes mellitus in, 752–753 dyslipidaemia in, 377b ectopic, 336 endocrine disease in, 1279–1280 functional anatomy and physiology in, 1272–1273 bone metabolism and, 1272 cardiovascular system and, 1272 endocrine system and, 1272 gastrointestinal system and, 1272 genitourinary system and, 1272 glucose metabolism in, 1272–1273 haematological system and, 1273 respiratory system and, 1273 gallstones and, 900 gastrointestinal disease in, 1277–1278 haematological disease in, 1284–1285 anaemia as, 1284, 1285b Rhesus disease as, 1285 thrombocytopenia as, 1285, 1285b venous thromboembolism as,

haematological physiology in, 941b hepatitis A and, 900 hepatitis B and, 900 hepatitis C and, 900 hepatitis E and, 900 hormonal changes in, 1273f human immunodeficiency virus infection in, 1280 hypertension in, 1276–1277 hypothyroidism in, 641, 651b immunological diseases during, 88b inflammatory bowel disease in, 823–824, 824b inflammatory rheumatic disease in, 1280–1281 iodine deficiency in, 651b ketoacidosis and, 1279 laboratory reference range in, 1364 liver disease and, 899–900, 1283–1284 medical disorders in, 1276–1285

1404 • INDEX neurological disease during epilepsy, 1103, 1103b multiple sclerosis, 1110b neurological disease in, 1284 neutrophilia during, 926 nutrition in, 712b osteoporosis in, 1045 parathyroid disease in, 1280 physiological anaemia of, 1273 pituitary disease in, 1280 diabetes insipidus as, 1280 prolactinoma as, 1280 Sheehan’s syndrome as, 1280 planning of, in patients with medical conditions, 1272 post-partum thyroiditis in, 651b prescribing in, 32–33, 32b presenting problems of, 1274–1276 breathlessness as, 1274–1275 chest pain as, 1275 circulatory collapse as, 1275 headache as, 1275 nausea and vomiting as, 1275, 1275b oedema as, 1275 seizures as, 1275–1276, 1276b prolactinoma in, 685 psychiatric disorders during, 1206–1207, 1206b, 1284 renal disease in, 426, 426b, 1282–1283 respiratory disease in, 1277 Rhesus D blood groups in, 933b rheumatoid arthritis in, 1026b safety of antirheumatic drugs during, 1281b sickle-cell disease in, 953, 953b STI during, 332, 332b swollen legs in, 187, 188b syphilis in, 339 thyroid disease in, 651b, 1279 thyrotoxicosis in, 645, 651b unplanned, transition medicine and, 1295–1296 visual disorders and, 1175b Prenatal genetic testing, 56, 59 Prescribing, 13–36, 14b choice of drug, 29 decision-making in, 28–31 for elderly patients, 32, 32b high-risk moments, 33b in hospitals, 33 monitoring treatment effects, 31 patient involvement, 30–31, 31b for patients with hepatic disease, 32, 32b for patients with renal disease, 31–32 in practice, 28–36 for pregnancy and breastfeeding, 32–33, 32b in primary care, 33–34 principles of, during transition, 1289, 1289b repeat, 34 in special circumstances, 31–33 steps in, 14b writing, 31, 33–34, 34f–35f Prescription-only medicine (PoM), 27 Pressure areas, of stroke patients, 1159b Pressure sores, 1262 in stroke patients, 1159f Presyncope, 181–183, 455 clinical assessment of, 182–183 congenital heart disease and, 533 differential diagnosis of, 182f features of, 181b gastrointestinal haemorrhage, 780 heat, 167 investigations of, 183 in older people, 1308 presentation of, 181–182 seizures versus, 182b Pretibial myxoedema, 646 Prevalence, of disease, 95 Preventive medicine, 93–94 alcohol, 94 atmospheric pollution, 94 obesity, 94 poverty and affluence, 94 smoking, 94 Prevotella spp., 103f Prick tests, 1215 Primary afferent neurons, 1338 Primary biliary cholangitis, 887–888 AMA-negative, 888 associated diseases with, 887 autoimmune hepatitis and, 888 bone disease and, 888 clinical features of, 887 diagnosis and investigations for, 887–888 epidemiology of, 887 fatigue and, 888 liver function test (LFT) abnormality in, 854b management of, 888 natural history of, 887f in old age, 901b overlap syndromes, 888 pathophysiology of, 887 primary sclerosing cholangitis and, 902b pruritus and, 888 Primary CNS lymphoma, 320, 320f Primary disease, in endocrinology, 632–633 Primary eosinophilias, 927 Primary granules, 64 Primary haemostasis, disorders of, 970–971 Primary headache syndromes, 185b Primary hyperaldosteronism, 674–675, 674b, 675f Primary hyperparathyroidism, 663–664, 663b, 664f biochemical abnormalities in, 990b pregnancy and, 1280 Primary idiopathic acquired aplastic anaemia, 968–969, 968b Primary immune deficiency, warning signs of, 73b Primary sclerosing cholangitis, 888–890, 889f diagnostic criteria for, 888 diseases associated with, 889b liver function test (LFT) abnormality in, 854b magnetic resonance cholangiopancreatogram of, 889, 889f primary biliary cholangitis and, 902b Primary Sjögren’s syndrome (PSS), 1038–1039 Primidone, 1102b Prion diseases, 250, 1126–1127, 1127b, 1191b Prions, 102 Pro-carboxypeptidases, 770b Pro-elastase, 770b Probenecid, for neurosyphilis, 1125 Problem-solving therapy, 1191, 1191b Procaine penicillin for neurosyphilis, 1125 for syphilis, 339 Procaine reaction, 339 Procarboxypeptidases, 768 Prochlorperazine, 803, 1104 Proctocolitis, radiation, 809–810, 810b Proctoscopy, 339 Procyclidine, 1188–1189 Progeric syndromes, 41 Progesterone pregnancy and, 1272 reference range of, 1359b Progesterone receptors, as tumour markers, 1322, 1324b Progestogens, in cancer treatment,

Progressive multifocal leucoencephalopathy, 1123 Progressive pulmonary hypertension, in systemic sclerosis, 1038 Progressive supranuclear palsy, 1114–1115 Proguanil, 128 for malaria, 278b Prokaryotes, 100–101 Prolactin (PRL), reference range of, 1359b Prolactinoma, 684–685, 685b, 685f pregnancy and, 1280 Prolymphocytic leukaemia (PLL), 960 Prone positioning, as advanced respiratory support, 204 Propantheline, 1142–1143 Prophase, 40 Prophylactic gonadectomy, for Turner’s syndrome, 660 Propionibacterium spp., 103f Propranolol for anxiety disorder, 1201 for congestive ‘portal hypertensive’ gastropathy, 871 for variceal bleeding, 869 Proptosis, of ophthalmic disease, 1171 Propylthiouracil (PTU) for Graves’ thyrotoxicosis, 644 for thyrotoxicosis, in pregnancy, 1279 Prosody, 1070 Prostacyclin, 447 for acute kidney injury, 422 Prostaglandin E1, erectile dysfunction,

Prostaglandin E2, febrile response, 104 Prostate benign hyperplasia, 437 cancer, 438–439 Prostate gland, 386 Prostate-specific antigen (PSA), 439b as tumour markers, 1322, 1324b Prostatic acid phosphatase (PAP), as tumour markers, 1322, 1324b Prostatitis, 437 Prosthetic valve dysfunction, 527 Prosthetic valves, 526–527 Protease inhibitors (PIs), 324b Proteases, 768 Protein C deficiency, 977 Protein-losing enteropathy, 811b Protein S deficiency, 977 Proteins, 697, 697b, 1305 Bence Jones, 394–395 biliary transport, 851f cerebrospinal fluid, 1361b cholesterol ester, 373 digestion of, 768, 769f IGF-BP3, 633f metabolism of, effects of insulin in, 723b plasma, 850 production of, 39f, 40 reference range of urine, 1361b venous blood, 1360b restriction in, for hepatic encephalopathy, 865 Tamm-Horsfall, 392 urine, 727 Proteinuria, 392–395, 394b in diabetic neuropathy, 727 investigation of, 394f orthostatic, 394 overt (dipstick-positive, 394–395 pregnancy and, 1282 reduction of, 417 tubular, 394 Proteoglycans, 987 Proteosome inhibitor, for multiple myeloma, 968 Proteus spp., 103f Prothrombin G20210A, 977 Prothrombin time (PT), 920–921 in coagulation screening tests, 922b for gastrointestinal bleeding, 781 for liver disease, 850, 853 acute liver failure and, 858 alcoholic hepatitis and, 882 reference range of, 1362b Prothrombotic states, 977–979 Proto-oncogenes, 56–57 ‘Proton pump’, 767 Proton pump inhibitor, for variceal bleeding, 869b Protozoa, 101–102 Protozoal infections, 273–288 gastrointestinal, 286–288 leishmaniasis, 281–286 systemic, 273–281 Prozone phenomenon, 338–339 Prurigo gestationis, 1220b Pruritic folliculitis, 1220b Pruritus, 1219–1220, 1326 clinical assessment of, 1219–1220 investigations and management of, 1220, 1220f of ophthalmic disease, 1170 in pregnancy, 1220b primary biliary cholangitis and, 887 treatment for, 888 primary causes of, 1219b secondary causes of, 1219b Pruritus ani, 836, 836b Pseudo-hallucinations, 1184 Pseudo precocious puberty, 654 Pseudocyst, pancreatic, 838f Pseudohypoparathyroidism, 664–665 Pseudomonas aeruginosa, 117b Pseudomonas fluorescens, 225 Pseudoporphyria, 1221b, 1257, 1266b Psoralens, for skin disease, 1227 Psoriasiform, drug-induced, 1266b Psoriasis, 1247–1251 arthropathy and, 1249 clinical features of, 1249, 1249f erythrodermic, 1249 guttate, 1249 investigations of, 1250 management of, 1250–1251, 1250f–1251f pathogenesis of, 1248, 1248b, 1248f plaque, 1249 pustular, 1249 rash in, 1217b Psoriatic arthritis (PsA), 1032–1034 CASPAR criteria for, 1032b clinical features of, 1032–1033, 1033f investigations for, 1033 management for, 1033–1034 pathophysiology of, 1032 Psoriatic spondylitis, 1032 Psychiatric assessment, poisoning and,

Psychiatric disorders, 1094, 1191–1207 classification of risk factors for, 1183, 1183b clinical examination of, 1180–1183 mental state examination, 1181–1183 psychiatric interview, 1181, 1181b emergencies for, 1189b functional anatomy and physiology in, 1183–1184 biological factors, 1183 psychological and behavioural factors, 1183 social and environmental factors,

HIV-related, 321 law and, 1207 management of, 1189–1191 electroconvulsive therapy, 1190 pharmacological treatment, 1190 psychological therapies, 1190–1191 social interventions, 1191 surgery, 1190 in old age, 1189b organic, 1189b in pregnancy, 1284 presenting problems of, 1184–1189 prevalence of, 1180b psychological factors affecting medical conditions, 1186–1187, 1186b puerperal, 1206–1207 WHO classification of, 1180, 1180b Psychodynamic psychotherapy, 1191 Psychogenic attacks, 1099 Psychogenic pruritus, 1219b Psychological elements, in back pain, 995–996 Pregnancy (Continued)

INDEX • 1405 Psychological factors affecting medical conditions, 1186–1187, 1186b of migraine, 1095 Psychological therapies/psychotherapy, 1190–1191 for alcohol misuse, 1195 general, 1190 interpersonal, 1191 for pain, 1347 psychodynamic, 1191 Psychosis affective, 1200 organic, 1197 puerperal, 1206 toxic, 1195–1196 Psychotropic drugs, 1190b Pthirus pubis, 334b Ptosis causes of, 1091b unilateral, 1091f Puberty analytes affected by, 1363b delayed, 653–654, 653b, 1290 hormonal events of, 1291f initiation of, 1290 onset of, 1290 Pubic (crab) lice, 1241 Pubic symphysitis, 999b Puerperal psychiatric disorders, 1206–1207 Pulmonary abscess, 586–587 Pulmonary artery catheter, 206, 207f Pulmonary artery wedge pressure, portopulmonary hypertension and, 898 Pulmonary circulation, 549–550 Pulmonary embolism, 619–621 acute massive, 200 clinical features of, 619, 619b investigations of, 619–620, 619f–620f management of, 620–621 in pregnancy, 620b prognosis for, 621 in stroke patients, 1159f Pulmonary eosinophilia and vasculitides, 611–612, 611b Pulmonary fibrosis, 547f in dermatomyositis, 610b idiopathic, 605–608, 607f in respiratory function abnormalities, 555b in rheumatoid arthritis, 610b, 1024 in sarcoidosis, 609b in sclerosis, 610b in systemic lupus erythematosus, 610b Pulmonary hypertension, 550, 621–622, 621b, 622f congenital heart disease and, 533 systemic sclerosis and, 1038 Pulmonary nodules cryptococcosis, 302 lung metastases, 1328 in respiratory disease, 560–562, 560b–561b, 560f–562f Pulmonary oedema, 413–414, 413f high-altitude, 168–169 renal artery stenosis, 407 sputum in, 546f Pulmonary regurgitation, 526, 527b Pulmonary rehabilitation, for chronic obstructive pulmonary disease (COPD), 577 Pulmonary stenosis, 526 Pulmonary syndrome, 258 Pulmonary tuberculosis clinical presentations of, 590b HIV-related, 318–319, 319f major manifestations and differential diagnosis of, 590f post-primary, 589 primary, 588, 589b, 589f Pulmonary tuberous sclerosis, 613b Pulmonary valve disease, 526 Pulmonary vascular disease, 619–622 pulmonary embolism, 619–621 pulmonary hypertension, 621–622, 621b, 622f Pulse, in endocrine disease, 630f Pulsus paradoxus, 447–448 Pupillary abnormalities, 1090, 1091f, 1092b Purkinje fibres, 445 Purpura definition of, 1226 drug-induced, 1266b Henoch-Schönlein, 398b–399b, 401,

idiopathic thrombocytopenic, 971 non-thrombocytopenic, 928b petechial, 928–929, 928f pinch, 1264 senile, 978b thrombotic thrombocytopenic, 388, 409, 979 Pustule, definition of, 1211f Pustuloderma, drug-induced, 1266b Pustulosis acute generalised exanthematous, 1266b palmoplantar, 1249 PUVA, 1215, 1227 atopic eczema, 1246 granuloma annulare, 1263 lichen planus, 1252 necrobiosis lipoidica, 1263 psoriasis, 1250 vitiligo, 1257–1258 Pyelography, 390 retrograde, 390f Pyelonephritis acute, 402f, 430 chronic, 430 emphysematous, 430 pregnancy and, 1282 Pyeloplasty, 434 Pyloroplasty, 782 Pyoderma gangrenosum, 1261–1262, 1262f Pyonephrosis, 432 Pyopneumothorax, 564 Pyramidal gait, 1086–1087 Pyrantel pamoate, 129 Pyrazinamide as antimycobacterial agents, 125 for tuberculous meningitis, 1121 Pyrexia of unknown origin, 218–222 aetiology of, 220b clinical assessment of, 218–219 investigations of, 219–222, 221b prognosis of, 222 Pyridostigmine, 1142–1143 Pyridoxal, 715 Pyridoxamine, 715 Pyridoxine (vitamin B6), 715 biochemical assessment of, 712b deficiency, 715 dietary sources of, 711b reference nutrient intake of, 711b supplements, 715 Pyrimethamine malaria, 273 toxoplasmosis, 281 HIV-related, 320 Pyrimidine 5’ nucleotidase deficiency,

Pyrin, 81 Pyrophosphate arthritis, 993b Pyruvate kinase deficiency, 949 Pyuria, sterile, 430 Q Q fever, 231b, 272 endocarditis, 272, 528 Qualitative abnormalities, 951 Quality-adjusted life years (QALYs), 28, 28b Quality of life, 202b Quantitative abnormalities, 951 Quantitative sensory testing, for pain, 1342, 1342f Questions, medical interview, 231b Quetiapine bipolar disorder, 1200 delirium, 209 Quinagolide, prolactinoma, 685 Quincke’s sign, 524b Quinidine arrhythmias, 480 malaria, 277b and neutropenia, 926b poisoning, 137b Quinine babesiosis, 278 lichenoid eruptions, 1252 for malaria, 128 poisoning, 141b Quinolones, 122–123, 123b adverse effects of, 123 drug eruptions, 1266b mechanism of action, 116b in old age, 120b pharmacokinetics of, 122 in pregnancy, 120b prophylactic, spontaneous bacterial peritonitis, 864 for spontaneous bacterial peritonitis,

see also Fluoroquinolones R R protein, 944 RA see Rheumatoid arthritis Rabies, 1122–1123 incubation period, 111b, 232b prophylaxis for post-exposure, 1122–1123 pre-exposure, 1122 vaccination, 115b, 1122–1123 Radial nerve, entrapment, 1139b Radial pulse, 534 examination of, in respiratory system, 546f Radiation(s), 164–165 dosage and exposure of, 164 effects of exposure to, 164–165 enteritis and proctocolitis, 809–810, 810b infrared, 1222f ionising, 164, 164f management of exposure to, 165 mutagenic effects, 1320b natural background, 164 non-ionising, 164 pneumonitis, 612 proctocolitis, 809–810, 810b ultraviolet see Ultraviolet radiation Radicular pain, 997b, 998f Radiculography, 1073b Radiculopathy, 256, 1138, 1141 cervical, 1134, 1134f HIV-related, 321 Radio-femoral delay, 442f Radio-iodine therapy, for thyrotoxicosis, 637–638, 645b Radioactive iodine, for Graves’ thyrotoxicosis, 644b, 645 Radioallergosorbent test (RAST), 86 Radiofrequency ablation arrhythmias, 481b, 484f cardiovascular disease, 484 GORD, 792–793 for hepatocellular carcinoma, 891 liver metastases, 1328–1329 renal cell cancer, 435 Radiography see X-rays Radioiodine multinodular goitre, 649 thyrotoxicosis, 637, 644b Radioisotope imaging see Radionuclide (radioisotope) imaging Radioisotope tests, gastroenterology,

Radioisotopes cancer treatment, 1331 exposure to, 165 intravenous injection of, 1331 Radiology see CT; MRI; X-rays Radionuclide (radioisotope) imaging of bone, 988–989 of cardiovascular system, 454 of nervous system, 1073b Paget’s disease, 1054f renal disease, 390, 390f Radionuclide studies, renal disease, 390, 390f Radionuclide ventilation/perfusion (Vࡆ/Qࡆ) scanning, pregnancy and, 1274 Radiotherapy, 1331–1332 for acromegaly, 686 adverse effects, 1331f, 1332 blood disorders chronic lymphocytic leukaemia, 960 Hodgkin lymphoma, 962 multiple myeloma, 968 non-Hodgkin lymphoma, 965 for brain tumours, 1130–1131 breast cancer, 1334 for cancer pain, 1352 colorectal cancer, 832 conformal, 1331 fractionation, 1331 for high-grade NHL, 966 hypothyroidism and, 1298 late effects, 689, 955b for low-grade NHL, 965 lung cancer, 602 for lung cancer, 602 lung damage, 612 lung disease due to, 612 mesothelioma, 618 for multiple myeloma, 968 oesophageal cancer, 797 for oral cancer, 790 pain management, 1344 palliative, 1352 pituitary tumours, 683–684 for prolactinoma, 685 prostate cancer, 439 for skin disease, 1228–1229 Radon, lung cancer and, 561b Raloxifene, for osteoporosis, 1048b,

Raltegravir, 119b Ramadan, diabetes during, 745, 745b Ramipril heart failure, 466b hypertension, 513 myocardial infarction, 500–501 Ramsay Hunt syndrome, 239 Randomised controlled clinical trials, 27–28, 28f Ranitidine and neutropenia, 926b urticaria, 1254 RANK (receptor activator of nuclear κB),

RANKL (Receptor activator of nuclear factor kappa B ligand), in bone remodelling, 986b Rapid diagnostic tests (RDTs), immunochromatographic, 276 Rapid immunochromatographic tests,

Rapid plasma reagin (RPR), 338–339 Rapidly progressive glomerulonephritis,

diseases typically presenting with,

Rare inherited bleeding disorders, 974 Rare interstitial lung diseases, 613b Rasagiline, for Parkinson’s disease,

Rashes, 1216–1218, 1217b atopic eczema, 1217b, 1246b butterfly (malar), 982f in chickenpox, 238 clinical features, 1217b dengue, 243–244 dermatitis herpetiformis, 807 dermatomyositis, 1039 distribution, 1217b drug eruption, 316, 1217b, 1267f erythema migrans, 256f erythematous, 1255 in fever, 218 genital, 333, 334b haemorrhagic, 271b hand, foot and mouth disease, 248 herpes simplex, 247f HIV-related, 316 infectious mononucleosis, 242f lichen planus, 334b, 1217b Lyme borreliosis (disease), 256f macular/maculopapular, 271b

1406 • INDEX morbiliform, 271b parvovirus B19, 237f petechiae, 928–929, 928f photosensitivity, 1221f pityriasis rosea, 1217b pityriasis versicolor, 1217b post-kala-azar dermal leishmaniasis, 284f psoriasiform, 1266b psoriasis, 1217b purpura see Purpura rheumatic fever, 515 in rubella infection, 234b scaly, 1217b scarlet fever, 253f shingles, 238f syphillis, 1217b of systemic lupus erythematosus, 1035f tinea corporis, 1217b toxic shock syndrome, 1236 tropical diseases, 234b typhoid, 260 typhus, 271 urticarial, 1253f vesicular, 315 RAST (radioallergosorbent test), 86 Rat bite fever, 235f Raynaud’s phenomenon in systemic lupus erythematosus, 1035, 1035f in systemic sclerosis, 1037–1038 Raynaud’s syndrome, 504–505 RB-ILD see Respiratory bronchiolitisinterstitial lung disease RBBB see Right bundle branch block RCA see Right coronary artery Re-entry, 468 Reactive airways dysfunction syndrome,

Reactive arthritis, 1031–1032 Reactive disorders, 1264–1265 ‘Ready Steady Go’ programme,

Reassurance, somatoform disorders and, 1203 Receiver operating characteristic (ROC) curve, 5f Receptor activator of nuclear factor kappa B ligand (RANKL), in bone remodelling, 986b Receptor activator of nuclear factor κB ligand see RANKL Receptor activator of nuclear κB see RANK Receptors B-cell, 68, 68f drugs acting on, 15b in pain processing, 1340b Recombinant human DNAase (rhDNAase), cystic fibrosis, 581b Recombinant human erythropoietin, chronic renal failure, 419 Recombinant tissue plasminogen activator (rt-PA), stroke, 1158f, 1159–1160 Recombination, 41 Recompression, for diving-related illness, 171 Rectal administration, 17 Rectal examination, 765b gastrointestinal disease, 787 prostate, 427, 437–438 Rectal varices, portal hypertension and,

Rectum, 771f disorders of, 827–836 dysfunction of, 1094 tumours of, 827–833 see also Colorectal cancer Recurrent occult upper gastrointestinal bleeding, systemic sclerosis and, 1037–1038 Red cell enzymopathies, 948–949 Red cell membrane defect, 947–948 structure, 915, 916f Red cells, 915–917, 916f agglutination, cold, 950 anaemia, 941f aplasia, 947 appearance of, 921b, 921f blood film examination, 921f concentrate, 931b count, 1362b destruction of, 917 effects of malaria, 273–274 enzymopathies, 948–949 formation, 915, 916f fragments, 921f haemoglobin and, 915–916, 917f haemolytic anaemia, 945, 946b, 946f incompatibility, in blood transfusion, 931–933 lifespan, 1362b membrane defects, 947–948 nucleated, 921f sickled see Sickle-cell anaemia/ disease structure and functions, 915–917, 916f transfusion, (in)compatibility, 932–933 Red eye, 1170 Red hepatisation, 583 ‘Red man’ reaction, 123 Reduced-intensity conditioning, 937 5α-Reductase inhibitors, 438 Reduviid bugs, 280 Reed-Sternberg cells, 961 Refeeding diets, WHO recommended, 705, 705b Refeeding syndrome, 706 Reference nutrient intake (RNI), 711–712 of minerals, 717b of vitamins, 711b Reference range, 3, 4f Reflex(es) cough, 556 diabetes, 759 stretch, 1068 tendon, root values of, 1063b Reflex sympathetic dystrophy (RSD), 1348–1349 Reflux bile, 801 duodenogastro-oesophageal, 792 gastro-oesophageal, 791–794, 791f Reflux nephropathy, 430–431 Refractory cough, 169 Refractory hypertension, 514 Regenerative medicine, for genetic disease, 58 Regurgitation, 779 aortic, 443b, 524–525, 524b, 525f causes, 524b chest X-ray for, 451f clinical features, 524–525, 524b clinical features of, 524–525, 524b, 525f investigations, 525, 525b investigations of, 525, 525b mitral, 519–521, 519b, 520f clinical features of, 521b, 521f investigation of, 521b management of, 521 pulmonary, 526, 527b tricuspid, 526, 526b Rehabilitation for acute coronary syndrome, 501 myocardial infarction, 501 in older people, 1311–1312 schizophrenia, 1198 for somatoform disorders, 1203 stroke, 1158 Rehydration see Fluid replacement Reiter’s disease/syndrome see Reactive arthritis Relapsing fevers louse-borne, 256b, 257, 257f tick-borne, 256b, 257 Relapsing polychondritis, 1044 Relative erythrocytosis, 925, 925b REM sleep behaviour disorder, 1105 Remission consolidation, in acute leukaemia, 956 Remission induction, in acute leukaemia, 956 Remission maintenance, in acute leukaemia, 956 Renal see Kidney Renal allograft dysfunction, common causes of, 425b Renal arteriography/venography, 389 Renal artery stenosis, 406–408, 407b, 407f Renal biopsy, 391, 391b Renal cell cancer, 434–435, 435f Renal colic, 396 Renal dialysis see Dialysis, renal Renal disease in adolescence, 426, 426b atheroembolic, 390b, 410 chronic, 415–420 pruritus, 415 stages, 388b in connective tissue disease Henoch-Schönlein purpura, 1043 SLE, 1036 systemic sclerosis, 1038 cystic, 405–406 adult polycystic kidney, 405–406 medullary, 404 diabetics see Diabetic nephropathy drug-induced, 426, 427b genetic, 403–406 glomerular, 397–401 HIV-related, 322 infections, 426–431 investigation of, 386–391 in pregnancy, 426, 426b, 1282–1283 acute kidney injury as, 1282, 1283b chronic kidney disease as, 1282, 1283f glomerular disease and, 1282 renal replacement therapy for, 1282–1283 renal tract infection as, 1282 for prescribing patients with, 31–32,

presenting problems in, 391–397 signs, 416f transition medicine and, 1298–1299 tuberculosis, 591 tubulo-interstitial, 401–403 tumours/cancer, 1316f vascular, 406–409 see also Nephropathy Renal failure acute see Acute kidney injury ascites, 864 bleeding, 975 chronic, 415–420, 417b causes of, 415b haemodialysis in, 422–423 indications for dialysis for, 422b osteodystrophy and, 419f physical signs of, 416f pregnancy and, 1282, 1283f staging of, in children over 2 years of age, 1298b transition medicine and, 1298–1299 cystic disease see Renal disease, cystic diabetics, 757 end-stage, 415b heart failure, 464 heart failure causing, 464 pruritus and, 1219b pyelonephritis see Pyelonephritis Renal function tests, 962 Renal impairment, causes of, in childhood and adolescence, 1298b Renal infarction, acute, 408 Renal lesion, systemic lupus erythematosus and, 1035 Renal osteodystrophy, biochemical abnormalities in, 990b Renal pelvis, 386 obstruction, 389f pyelonephritis, 430 stone in, 431 tumours, 435 Renal replacement therapy (RRT), 208, 420–426, 421f for acute kidney injury, 414 for chronic kidney disease, 414 continuous, 424b in old age, 422b percentage survival in, 422f pregnancy and, 1282–1283 preparing for, 420 Renal stones, 431 composition of, 431b investigations for, 432b Renal support, in intensive care, 208 Renal tract infection, pregnancy and,

Renal tract obstruction, acute kidney injury and, 414 Renal transplantation in diabetic nephropathy, 758 recipients of, pregnancy and, 1283 Renal tubular acidosis, 365, 365b, 405 Renal tubules, 384–386 collecting ducts, 350–351, 384–386 distal, 350 loop of Henle, 350, 384–386 proximal, 350 Renal ultrasound, acute kidney injury and, 416b Renin, 351–352 Renin activity, 666 Renin-angiotensin-aldosterone system,

hypertension, 509 hypokalaemia, 362 Renin-angiotensin blockade, for acute coronary syndrome, 500–501 Renin concentration, reference range of, 1359b Repaglinide, 747 Repeat prescriptions, 34 Repeated dose regimens, 19 Reperfusion therapy, for acute coronary syndrome, 499–500 Replacement therapy, for amenorrhoea,

Replicative immortality, 1318 Reproductive disease classification of, 652b presenting problems in, 653–658 Reproductive system, 651–661 classification of diseases of, 652b female, 652, 652f functional anatomy, physiology and investigations of, 651–652, 651f–652f Klinefelter’s syndrome in, 660–661 male, 651, 651f polycystic ovarian syndrome in, 658–659, 659f Turner’s syndrome in, 659–660, 660f Resection hepatic, for hepatocellular carcinoma,

ileal, under-nutrition and, 706 massive small bowel, under-nutrition and, 706 pancreatic, under-nutrition and, 706 Residual volume (RV), 555b Resin bile acid-sequestering, 376–377 ion-exchange, 363, 363b Resistin, 699 Respiration haemodynamic effects of, 447–448, 447b Kussmaul, 415 see also Breathing Respiratory acidosis, 367 Respiratory alkalosis, 367 Respiratory bronchiolitis-interstitial lung disease (RB-ILD), 606b Respiratory burst, 64 Respiratory chain complexes, 49b Respiratory disease, 556–567 air travel and, 169 breathlessness in, 557–558, 557f, 558b Rashes (Continued)

INDEX • 1407 caused by fungi, 596–598, 596b chest pain in, 558 cough in, 556, 556b drug-induced, 612–613, 612b finger clubbing in, 559, 559b, 559f haemoptysis in, 559–560, 559b, 560f HIV-related, 318–319, 318b investigation of, 550–556 ophthalmic features of, 1165b pleural effusion in, 562–565, 563b–564b pregnancy and, 1277 pulmonary nodule in, 560–562, 560b–561b, 560f–562f respiratory failure in, 565–567, 565b transition medicine and, 1297 cystic fibrosis in, 1297 tumours, 598–605 Respiratory distress syndrome, acute see Acute respiratory distress syndrome Respiratory failure, 565–567 acute, management of, 565–566 chronic and ‘acute on chronic’ type II, 566–567 management of, 566–567, 566b pathophysiology of, 565, 565b Respiratory function in old age, 550b testing, 554–556, 554f airway obstruction, measurement of, 555 arterial blood gases and oximetry, 555–556, 555f in asthma, 555b in chronic bronchitis, 555b in emphysema, 555b exercise tests, 556 lung volumes, 555 in pulmonary fibrosis, 555b transfer factor, 555 Respiratory infections, 581–598 cystic fibrosis, 580–581 fungal, 596–598 in old age, 586b pneumonia, 582–587 pregnancy and, 1277 bacterial, 1277 viral, 1277 tuberculosis (TB), 588–595 upper respiratory tract infection, 581–587 Respiratory medicine, 545–628 Respiratory support, in intensive care, 202–204 advanced, 204 extracorporeal, 204 intubation and intermittent positive pressure ventilation, 203–204 non-invasive, 202 weaning from, 209–210 Respiratory syncytial virus (RSV), 249 Respiratory system clinical examination of, 546–548, 546f–547f functional anatomy and physiology of, 548–550, 548f–549f infections see Respiratory infections in old age, 550b pregnancy and, 1273 tumours, 598–605 Response evaluation criteria in solid tumours (RECIST), 1333b Restless legs syndrome, 1105–1106, 1106b Restraint, for aggressive behaviour, 1188–1189 Restrictive cardiomyopathy, 540 Resuscitation drowning and, 170 for gastrointestinal haemorrhage, 782 hypothermia and, 166 initial, 204–206, 206b for poisoning, 134 in sepsis, 196–197, 197b Resynchronisation devices, 467, 467f Resynchronisation therapy, cardiac, 467f, 484 Reteplase, 500 Reticular formation, brainstem, 1067f Reticulocytes, 915 reference range of, 1362b Retina detachment, 1088 of eye, 1167 visual field loss in, 1089b Retinal artery occlusion, in ophthalmological conditions, 1178, 1178f Retinal haemorrhage high-altitude, 169 see also Diabetic retinopathy Retinal pigment epithelium, congenital hypertrophy, 829 Retinal vascular occlusion, in ophthalmological conditions, 1177–1178 Retinal vein occlusion (thrombosis), 1177–1178, 1177f Retinitis cytomegalovirus, 216f HIV-related, 321 Retinitis pigmentosa, 810 Retinoblastoma, 1321b Retinochoroiditis, due to toxoplasmosis, 280, 281f Retinoic acid, 713 all-trans-Retinoic acid, 958 Retinoids, 713 hyperlipidaemia, 373b hypertriglyceridaemia, 374 phototherapy and photochemotherapy, 1227 for skin disease, 1227 squamous cell carcinoma, 1231 warts, 1239 Retinol (vitamin A), 712–713 deficiency, 713, 713f dietary sources of, 711b reference nutrient intake of, 711b Retinopathy, 1325 HIV-related, 321 hypertensive, 509–510, 510b pregnancy and, 1279 Retroperitoneal fibrosis, 434 drug-induced, 427b Retroviruses, 100 Return of spontaneous circulation (ROSC), in post cardiac arrest, 200–201, 201b Reverse transcriptase, 309–310 Reverse transcriptase inhibitors non-nucleoside, 316, 324b nucleoside, 324b Reversibility test, 569f Revised International Prognostic Scoring System (IPSS-R), in myelodysplasia, 961, 961b Reye’s syndrome, acute liver failure and, 857–858 Rhabdomyolysis, 363 diagnosis and management of, 195 Rhesus D blood group, 933, 933b Rhesus disease, pregnancy and, 1285 Rheumatic fever, 515–517, 516f investigations in, 517b Jones criteria for, 516b prophylactic, 119b Rheumatic heart disease, 515–517 chronic, 517 Rheumatoid arthritis (RA), 1021–1026 clinical features of, 1023–1025, 1023f cardiac involvement in, 1024 extra-articular, 1024b nodules in, 1023–1024, 1024f ocular involvement in, 1024 peripheral neuropathy in, 1024 pulmonary involvement in, 1024 serositis in, 1024 spinal cord compression in, 1024, 1025f systemic, 1023 vasculitis in, 1024 criteria for diagnosis of, 1023b investigations in, 1025, 1025b, 1026f management of, 1025–1026 algorithm for, 1026f biologic therapy for, 1026 DMARD therapy for, 1025–1026 non-pharmacological therapy for,

surgery for, 1026 pathophysiology of, 1022–1023, 1022f in pregnancy, 1026b, 1280 Rheumatoid disease pleural effusion, 563b, 610–611 respiratory involvement in, 610–611, 611f Rheumatoid factor (RF), in musculoskeletal disease, 991, 991b Rheumatoid nodules, 1023–1024, 1024f Rheumatological/musculoskeletal disease HIV-related, 321–322 ophthalmic features of, 1166b Rheumatology, 981–1060 see also Musculoskeletal disease Rheumatology and bone disease, transition medicine and, 1300 glucocorticoid-induced osteoporosis in, 1300 hypophosphataemic rickets in, 1300 juvenile idiopathic arthritis in, 1300 osteogenesis imperfecta in, 1300 Rhinitis, allergic, 622 Rhinocladiella mackenziei, 301 Rhinosinusitis, 582 Rhinoviruses, 249 Rhizomucor spp., 303 Rhizopus spp., 303 Rhodesiense infections, 278 Rhodesiense trypanosomiasis, 278–279 Rhodococcus equi, 319 Rib fracture, 626b Ribavirin, 128 for hepatitis C, 878 viral haemorrhagic fevers, 246 Riboflavin (vitamin B2), 714 biochemical assessment of, 712b deficiency, 714 dietary sources of, 711b reference nutrient intake of, 711b Ribonucleic acid (RNA) degradation of, 40 editing of, 40 messenger ribonucleic acid (mRNA),

microRNA (miRNA), 40 non-coding, 40 ribosomal RNA (rRNA), 40 splicing of, 40 synthesis of, 39f transfer RNA (tRNA), 40 Ribosomes, 39f Ribozymes, 40 Richmond Agitation Sedation Scale (RASS), 209, 209b Richter’s transformation, 960 Rickets, 1051–1052 causes of, 1050b hypophosphataemic, 990b hereditary, 1052–1053 hypophosphataemic, transition medicine and, 1300 vitamin D-resistant, 1052 Rickettsial fevers, 270–272, 271b Rickety rosary, 1052 Riedel’s thyroiditis, 650 Rifampicin, 117b as antimycobacterial agents, 125 drug interactions of, 24 hepatotoxicity of, 894b infective endocarditis, 530b for leprosy, 269 meningitis, 1120b pneumonia, 585b prophylactic, 119b for pruritus, primary biliary cholangitis and, 888 Q fever, 272 for tuberculosis, 593 Rifamycin, mechanism of action, 116b Rifaximin, for hepatic encephalopathy,

RIFLE criteria, 411 Rift Valley fever, 245b Right atrial pressure, in critically ill patients, 207f Right bundle branch block (RBBB), 478f Right coronary artery (RCA), 444, 445f Right ventricle, 444f Right ventricular cardiomyopathy, arrhythmogenic, 453, 539f Right ventricular dilatation, 450 Rigidity cogwheel, 1069 lead pipe, 1069 Parkinson’s disease, 1084–1085, 1113b tetanus, 1126 tetanus and, 1126 Rigors, 217b Riluzole, amyotrophic lateral sclerosis,

Rimantadine, 127 Rimonabant, 702 Ringer-lactate, 265 Ringworm, 1239 Risedronate for osteoporosis, 1048b for Paget’s disease, 1054, 1054b Risk attributable, 95b global burden of disease and underlying factors, 92–93 relative, 95b Risperidone bipolar disorder, 1200 schizophrenia, 1198b Risus sardonicus, 1126 Rituximab, for musculoskeletal disease, 1006, 1007b polymyositis and dermatomyositis,

systemic lupus erythematosus, 1037 Rivaroxaban, for venous thromboembolism, 975 Rivastigmine, for Parkinson’s disease,

River blindness, 292–293 RNA degradation of, 40 editing of, 40 messenger (mRNA), 38 messenger ribonucleic acid (mRNA),

microRNA (miRNA), 40 non-coding, 40 ribosomal RNA (rRNA), 40 splicing, editing and degradation, 40 splicing of, 40 synthesis, 39f synthesis of, 39f transfer, 40 transfer RNA (tRNA), 40 RNA polymerase, 38 RNI see Reference nutrient intake Robertsonian translocation, 45f Rocky Mountain spotted fever, 270, 271b Rodent ulcer, 1229 Rodenticide poisoning, 148 Rokitansky-Aschoff sinuses, 909 Romaña’s sign, 279 Romberg’s test, 1062f Romosozumab, for osteoporosis, 1049 Ropinirole, Parkinson’s disease, 1114b Rosacea, 1221b, 1243–1244, 1243f Roseola infantum, 238 Rosiglitazone, 747 Ross River virus, 250, 1020–1021 Rotator cuff lesions, 997–998, 998b Rotavirus, 249 Rotigotine, Parkinson’s disease, 1114b Rotor’s syndrome, 860b Roundworm (Ascaris lumbricoides), 289–290, 906 Roux-en-Y gastric bypass, 703b RPGN see Rapidly progressive glomerulonephritis RSV see Respiratory syncytial virus RT see Reverse transcriptase rt-PA see Recombinant tissue plasminogen activator

1408 • INDEX RTA see Renal tubular acidosis Rubber allergy, 1247b Rubella infection clinical features of, 236 congenital malformation and, 237b diagnosis of, 236 in pregnancy, 235b prevention of, 236–237 Russell’s sign, 1204 Ruxolitinib, for myelofibrosis, 969 RV see Residual volume Ryanodine receptor channelopathies, 1145b S SA node see Sinoatrial (SA) node Sabin-Feldman dye test, 281 Saccades, 1090 Sacroiliitis, 1029f and ankylosing spondylitis, 1030 and axial spondyloarthropathies, 1028, 1028b and brucellosis, 255f and inflammatory bowel disease, 819f polyarthritis and, 994f and Whipple’s disease, 809b Salbutamol asthma, 572 drug interactions, 24b scombrotoxic fish poisoning, 150 Salicylates (aspirin) overdose, 138 poisoning from, 136, 138 Salicylic acid actinic keratosis, 1230b molluscum contagiosum, 1239 warts, 1239 Saline, 353b abdominal compartment syndrome,

genital itch/rash, 333 heat cramps, 167 hyperkalaemia, 363 hyponatraemia, 358 hypophosphataemia, 369 hypovolaemia, 353 metabolic alkalosis, 367 Salivary glands disease of, 790 enlargement, 1039b Salmonella food poisoning/gastroenteritis, 263 HIV/AIDS patients, 323 Salmonella enteritidis, 262–263 Salmonella paratyphi, 227–228 Salmonella spp. infection, 262–263 Salmonella typhi, 117b Salmonella typhimurium, 262–263 Salmonellosis, 231b Salofalk, for inflammatory bowel disease, 821b Salt in diabetic diet, 744 see also Sodium Salt-losing nephropathy, 403 Salt-wasting disease, 418 Sand flea, 299–300 Sandflies, 282 bartonellosis, 272 leishmaniasis, 282 Sandhoff’s disease, 371b Sanfilippo’s syndrome, 371b Sanger, Fred, 52–53 Sanger sequencing, 52–53, 54f Saphenous vein grafts, 492f SARA see Sexually acquired reactive arthritis Sarcoidosis, 410, 608–610, 608f,

clinical features of, 608–609, 609b, 609f investigations of, 609–610, 609b management of, 610 Sarcoma Ewing’s, 1057 osteogenic, 1056–1057 see also Kaposi’s sarcoma Sarcomere, cardiac, 446 Sarcoptes scabiei, 1241 SARS see Severe acute respiratory syndrome Sausage digit, 1032 Saxagliptin, 747 Saxophone player’s lung, 616b SBAR system, of communication, 10, 10b SBP see Spontaneous bacterial peritonitis Scabies, 1241, 1241f ecthyma, 1236 HIV/AIDS, 330f–331f Norwegian, 1241 pruritus, 1219b Scaling, 1216 Scalp fungal infections, 300–304 head lice, 1241 psoriasis, 1247–1251 tinea capitis, 1240, 1240f Scapula, winging, 1062f Scarlet fever incubation period, 111b period of infectivity, 111b streptococcal, 252, 253f Scars, definition, 1226 Scedosporium apiospermum, 301 SCF see Stem cell factor ‘Schatzki ring’, 795–796 Scheuermann’s osteochondritis, 1055 Schilling test, 944 Schirmer tear test, 1038–1039 Schistosoma, life cycle of, 294, 295f Schistosoma haematobium, 295–296, 296f Schistosoma intercalatum, 296 Schistosoma japonicum, 296 Schistosoma mansoni, 296, 296f Schistosoma mekongi, 296 Schistosomiasis, 233b, 294–297 clinical features of, 295–296, 295b investigations of, 296 management of, 296 pathology of, 294 prevention of, 296–297 Schizoaffective disorder, 1200 Schizophrenia, 1196–1198 acute, 1196–1197 clinical features of, 1196–1197 diagnosis of, 1197 differential diagnosis of, 1197b investigations of, 1197 management of, 1197–1198 pathogenesis of, 1196 prevalence of, 1180b prognosis of, 1198 symptoms of, 1197b auditory hallucinations as, 1185 thought disorder as, 1181 Schmidt’s syndrome, 689 Schöber’s test, 983, 983f Schumm’s test, 947 Schwann cells, 1064–1065 Sciatica, 1135 Scintigraphy bone, in musculoskeletal disease, 988–989, 989b meta-iodobenzyl guanidine, 675 octreotide, 679f of thyroid gland, 638f, 642 see also Radionuclide (radioisotope) imaging SCLE see Subacute cutaneous lupus erythematosus Sclera, of eye, 1166–1167 Scleritis, 1172 posterior, 1170 Sclerodactyly, 1037 Scleroderma see Systemic sclerosis Scleromalacia, rheumatoid arthritis,

Sclerosing bone dysplasias, 1056 Sclerosing cholangitis primary, 888–890, 889f diagnostic criteria for, 888 diseases associated with, 889b liver function test (LFT) abnormality in, 854b magnetic resonance cholangiopancreatogram of, 889, 889f primary biliary cholangitis and, 902b secondary, 888, 889b Sclerosis, systemic see Systemic sclerosis Sclerostin, in bone remodelling, 986b Sclerotherapy, for variceal bleeding, 870 Sclerotic bodies, 301 Scoliosis, 1059 Scombrotoxic fish poisoning, 150 Scorpions, envenomation of, 161 Scotoma, 1095–1096 Screening aortic aneurysm, 505 breast cancer, 1325b for chronic liver disease, 853b ciliary dysfunction syndromes, 579 coagulation, 922b colorectal cancer, 832–833 cystic fibrosis, 580 diabetes mellitus, 1278 diabetic nephropathy, 757 genetic, 58 gestational diabetes, 1278 hepatitis B core IgM antibody, 858 hepatocellular carcinoma, 890–891 for hepatocellular carcinoma, 890–891 malnutrition, 693f microalbuminuria, 394 principles of, 94–95 Scrub typhus fever, 270–271, 271b Scurvy, 715–716, 716b, 716f, 970 Sebaceous glands, 1213 Sebocytes, 1213 Seborrhoeic dermatitis, HIV-related,

Seborrhoeic eczema, 1246 Seborrhoeic warts, 1234 Sebum, 1213 acne vulgaris, 1242 Secondary aplastic anaemia, 969, 969b Secondary disease, in endocrinology, 632–633 Secondary granules, 64 Secondary headache syndromes, 185b Secondary osteoporosis, 1044–1045 Secretin, 772b Secukinumab, for musculoskeletal disease, 1007, 1007b Sedation for aggressive behaviour, 1188–1189 in intensive care, 209, 209b Sedatives, misuse of, 1195 75SeHCAT test, 777b 75SeHCAT test, 777b Seizures brain tumour and, 1129 pregnancy and, 1275–1276, 1276b in stroke patients, 1153, 1159f syncope versus, 182b types of, 1098–1100, 1098b absence, 1099 atonic, 1100 clonic, 1100 focal, 1099, 1099b generalised, 1099–1100 myoclonic, 1099–1100 tonic, 1100 tonic-clonic, 1099, 1099b Selective noradrenaline reuptake inhibitors (SNRIs), poisoning, 139 Selective serotonin re-uptake inhibitors (SSRIs), 1199, 1199b poisoning from, 139 Selectivity, 14 Selegiline, for Parkinson’s disease, 1114 Selenium, 634, 718 deficiency, 718 dietary sources of, 717b excess, 718 for Graves’ ophthalmopathy, 646 reference nutrient intake of, 717b Selenium sulphide shampoo, 314 Selenosis, 716 Self-harm in old age, 1189b patient assessment of, 1187b, 1188f Self-help and coping strategies, for musculoskeletal disease, 1001, 1001b Seminoma, 439 Senescence immune, 80–81, 81b see also Age/ageing; Older people Sengstaken-Blakemore tube, for variceal bleeding, 870, 870f Senna, 761b, 834b Sensitisation, 1340 Sensorimotor polyneuropathy, 1111b Sensory ataxia, 1125b Sensory cortex, 1063f Sensory disturbances, 1083–1084 diabetes see Diabetic neuropathy Sensory loss, pattern of, 1084f Sensory neurons, 1338 Sensory neuropathy, 1111b Sensory system examination, 1062f Sentinel lymph node biopsy, 1233 Sentinel pile, 836 Sepsis, 196–198, 226–227, 226b acute kidney injury and, 411–412 cardiomyopathy and, 198 coagulation system and, activation of,

definition of, 196b during dialysis, 424b lactate and, 196 meningococcal, 1119b mimics of, 198b organ damage from, 196, 197f resuscitation in, 196–197, 197b skin and soft tissue infections causing, 226–227 Sepsis syndrome, 550 Septic arthritis, 1019–1020 emergency management of, 1020b synovial fluid in, 1020 Septic shock, 70–71, 196b, 206b Septicaemic plague, 259 Sequestration crisis, 952 ‘Seroconversion’, 106 Serological tests, for respiratory disease,

Serology for gastrointestinal infection, 777 for Helicobacter pylori infection, 777 for hepatitis B, 873–875, 875b for hepatitis C, 877 Seronegative spondyloarthropathies, 1166b Serositis, in rheumatoid arthritis, 1024 Serotonin (5-hydroxytryptamine, 5-HT), 1345b, 1353f excess in irritable bowel syndrome,

Serotonin agonists, irritable bowel syndrome, 824 Serotonin-noradrenaline reuptake inhibitors (SNRIs), 139 Serotonin selective (specific) re-uptake inhibitors (SSRIs), 1199, 1199b Serotonin syndrome, 1199 Serratia spp., 102f Sertraline, 1199b Serum- ascites albumin gradient (SAAG), 863 Serum ferritin, 941 Serum sickness antivenom, 159 diphtheria antitoxin, 266 schistosomiasis, 295b Severe acute respiratory syndrome (SARS), 249 Severe combined immune deficiency, 79–80 X-linked, 79–80 Severe idiopathic constipation, 834 Sex, HIV infection/AIDS and, 323 Sex chromosomes, 38 see also X chromosome; Y chromosome

INDEX • 1409 Sex hormone replacement therapy for hypopituitarism, 682 see also Hormone replacement therapy Sex hormones see individual hormones Sexual activity, headache and, 1097 Sexual disturbance, 1093–1094 Sexual dysfunction, 1109–1110 see also Erectile dysfunction Sexually acquired reactive arthritis (SARA), 1031 Sexually acquired reactive arthropathy,

Sexually transmitted infections (STIs), 329–344 approach to patients, 332–333, 332b in children, 332–333 clinical examination of in men, 330, 330f in women, 331, 331f contact tracing for, 333 HIV testing for, 330 investigations of in men, 330b in women, 331b management goals of, 331b men who have sex with men, 330b, 334–335 during pregnancy, 332 presenting problems of, men, 333–336, 333f–334f prevention of, 336–337 those at particular risk, 331b viral, 341–344 Sézary’s syndrome, 1224, 1232 SGLT2 inhibitors, for hyperglycaemia, 748, 748f SH (self-harm) see Self-harm Shagreen patches, 1264 Shampoo ketoconazole, 1240, 1246 selenium sulphide, 314 Shared decision-making, 10, 11f, 12 Shave excision, for skin disease,

Sheehan’s syndrome, pregnancy and,

Shellfish poisoning, paralytic, 149 Sheltered employment, 1198 Shiga-like toxin, 408–409 Shigella diarrhoea, 227–228, 232 dysentery/shigellosis, 265 reactive arthritis, 1031 Shigellosis, 265 Shingles see Herpes zoster Shivering, 165b, 165f Shock anaphylactic, 204, 206b cardiogenic, 199–200, 206b causes of, 200f downward spiral of, 199, 200f clinical features of, 180b hypotension and, 193, 193b hypovolaemic, 206b neurogenic, 206b obstructive, 206b septic, 70–71, 196b, 206b Short bowel syndrome, 708–710 Short stature in Turner’s syndrome, 659 see also Dwarfism; Growth retardation Shoulder frozen, 997–998 pain, 997–998, 998b, 998f painful, in stroke patients, 1159f Shrinking lungs, 610b, 611 Shuffling gait, 1087b Shunts Blalock-Taussig, 537 intracardiac, 454, 459 left-to-right, 450 persistent ductus arteriosus, 533 portosystemic fetor hepaticus from, 868 portal hypertension and, 869 for variceal bleeding, 871 TIPSS for ascites, 864 for variceal bleeding, 871, 871f transjugular intrahepatic portosystemic stent for ascites, 864 for variceal bleeding, 871, 871f SI units, 1358 SIADH see Syndrome of inappropriate secretion of ADH Siberian tick typhus, 271b Sibutramine, 702 Sick euthyroidism, 642 Sick sinus syndrome, 469, 469b, 469f Sickle-cell anaemia/disease, 923, 951–953 clinical features of, 952–953, 952f epidemiology of, 951, 951f investigations of, 953 management of, 953 pathogenesis of, 951–952 in pregnancy, 953b prognosis of, 953 rheumatological manifestations of,

Sickle-cell nephropathy, 411 Sickle-cell trait, 951 Sickle chest syndrome, 952 Side-effect, definition of, 21 Siderosis, 614–616, 615b Sieverts (Sv), 164 Sigmoidoscopy, 776 amoebiasis, 287 Clostridium difficile infection, 264 constipation, 787 familial adenomatous polyposis, 829 inflammatory bowel disease, 824b for inflammatory bowel disease, 817b radiation enteritis and proctocolitis,

schistosomiasis, 296 ulcerative colitis, 817b Sildenafil, 440 Silicosis, 615–616, 615f Silicotuberculosis, 615–616 Simple aspergilloma, 596–597, 597f Simple diffuse goitre, 648, 648f Simple tandem repeat mutations, 43, 43b Simulium spp., onchocerciasis, 292 Simvastatin for stroke prevention, 1161f timing, 31b Sinemet, 1113 Single-layered retinal pigment epithelium, 1167 Single nucleotide polymorphisms (SNPs; snips), 42 Single photon emission tomography (SPECT), 1072 Sinoatrial disease, 469b, 469f, 471b Sinoatrial (SA) node, 445, 445f Sinus arrhythmia, 469 Sinus bradycardia, 469 Sinus tachycardia, 469, 469b Sinusitis see Rhinosinusitis Sinusoidal obstruction syndrome, 899 Sipple’s syndrome, 689b SIRS (systemic inflammatory response syndrome), pancreatitis, 838b Sister Joseph’s nodule, 804 Sitagliptin, 747 Sitosterolaemia, 375, 375b Sixth disease, 238 Sjögren’s syndrome, 1038–1039, 1039b, 1171 Skeletal muscle, 987–988 Skin blood vessels and nerves in, 1214 changes in old age, 1215b of envenomed patient, 152f epidermal appendages of, 1212–1214 examination of cancer, 1315b endocrine disease, 630f gastrointestinal disease, 764f function of, 1214, 1214b functional anatomy and physiology of, 1212–1214 imaging, 1216 immunobullous disease of, 1255–1257, 1255b infestations, 1235–1241 inflammatory arthritis in, 994b lichenoid eruptions in, 1252 microbiology of, 1215 as physical barrier, 62–63 systemic lupus erythematosus in, 1035f systemic sclerosis in, 1037, 1037f Skin cancer, 1229 non-melanoma, 1228, 1230b pathogenesis, 1229 see also names of specific tumours Skin disease abnormal pigmentations in, 1224 acute skin failure in, 1224–1225 clinical examination in, 1210, 1210f in general medicine, 1261–1267, 1261b investigation of, 1214–1216 management of, 1225–1229 nail involvement in, 1260–1261 ophthalmic features of, 1166b phototherapy and photochemotherapy for, 1227 pigmentation disorders as, 1257–1258 presenting problems in, 1216–1225 terminology in, 1211f treatment of non-surgical, 1228–1229 surgery for, 1228 systemic, 1227–1228 topical, 1225–1227, 1225b Skin grafts, vitiligo, 1257–1258 Skin infections, 1235–1241 bacterial, 1235–1238 fungal, 1239–1240, 1240f mycobacterial, 1237–1238 tropical, 234, 234b, 235f viral, 1238–1239 Skin lesions, benign, 1234–1235 Skin-prick tests, for allergy, 86 Skin snips, 234b Skin tags See Acrochordon Skin test asthma, 613–614 patch tests, 1215 prick tests, 86, 1215 tuberculin, 594, 594f Skin tumours, 1229–1235 malignant, 1229–1234 pathogenesis of, 1229 Skinfold thickness, 693f Slapped cheek syndrome, 237, 237f SLE see Systemic lupus erythematosus Sleep, 1071 Sleep apnoea/hypopnoea syndrome, 622–624 aetiology of, 623 clinical features of, 623 investigations of, 623, 623b–624b, 623f management of, 623–624 Sleep-disordered breathing, 622–624 Sleep disorders, 1105–1106 Sleep disturbance, 1094 Sleep paralysis, 1094 Sleepiness Epworth scale, 623b, 1105 persistent, differential diagnosis, 624b see also Hypersomnolence Sleeping sickness, 278–279, 278f Sleeve gastrectomy, 703b Small bowel bacterial overgrowth, causes of, 808b Small-bowel diarrhoea, HIV-related, 317, 317b, 317f Small bowel surgery, proximal, under-nutrition and, 706 Small bowel transplantation, 710 complications of, 710b indications for, 710b Small interfering RNA (siRNA), 27b Small intestine bacterial overgrowth, 808–809 diseases/disorders of, 805–813 functional anatomy of, 767–770, 767f infections of, 812–813 miscellaneous disorders of, 811–812 motility disorders, 810–811 protective function of, 769–770 tumours of, 813 ulceration of, 811, 811b Small-vessel vasculitis, 409 Smallpox (variola), 248 Smell, disturbance of, 1088 Smith-Magenis syndrome, genetics, 44b Smoking and autoimmune disease, 82–83 cannabis, 143 and cardiovascular risk, 420 cocaine, 143 effects on health, 94 familial hypercholesterolaemia, 374b freezing cold injury, 166 heart failure and, 465b lung cancer and, 1320–1321 in older people, 1305 peptic ulcer and, 799 urinary incontinence, 436 Smoking cessation acute coronary syndrome and, 501 in Graves’ ophthalmopathy, 646 Smooth muscle atrophy, systemic sclerosis and, 1037–1038 Snail track ulcers, 337 Snake bites, 134 Snakes, geographical distribution of,

Snakeskin gastropathy, 871 Snoring, 623 SNPs see Single nucleotide polymorphisms Social isolation, psychiatric disorders and, 1184 Social worker, 1303b Sodium, 349b, 718 depletion, 349 dietary sources of, 717b excess, 354b, 354f homeostasis, 349–355 intake, chronic renal failure, 418 presenting problems of, 352–355 in primary hyperaldosteronism, 674 reabsorption, 384 reference nutrient intake of, 717b reference range of urine, 1361b venous blood, 1358b restriction of, for ascites, 863 retention of, 395, 864b transport, 351–352, 352f see also Hypernatraemia; Hyponatraemia Sodium aurothiomalate (gold), 1005 Sodium bicarbonate chronic kidney disease, 418 drug interactions, 24b salicylate poisoning, 138 in urinary alkalinisation, 136 Sodium calcium edetate, 137b Sodium chloride dietary, 718 see also Saline Sodium cromoglicate for allergy, 86 for food allergy, 812 Sodium-dependent glucose transporter inhibitors, for hypervolaemia, 354 Sodium ipodate, 639 Sodium nitroprusside aortic dissection, 508 hypertension, 514 phaeochromocytoma, 676 Sodium phosphate, 368 Sodium-potassium pump, 349 Sodium stibogluconate, 128 Sodium valproate bipolar disorder, 1200 cluster headache, 1096 epilepsy, 1102b, 1284 pregnancy, 1103, 1103b

1410 • INDEX for epilepsy, 1100b neutropenia, 926b poisoning, 141b sodium retention and, 864b status epilepticus, 1081b steatosis, 894 SOFA score, 214b Soft tissue infections, 226–227 necrotising, 227b Soft tissue release, 1002b Solar urticaria, 1221b Solitary rectal ulcer syndrome, 836 Solvent inhalation, 1196 Somatic hypermutation, 68, 68f Somatic mutations, 50–51 Somatic symptoms, medically unexplained, 1187, 1187b, 1189b, 1203b, 1205f Somatic syndromes, functional, 1187b Somatisation disorder, 1202 Somatoform autonomic dysfunction,

Somatoform disorders, 1202–1203 advice for, 1203 prevalence of, 1180b Somatoform pain disorder, 1202 Somatosensory system, 1070–1071, 1071f–1072f Somatostatin, 767, 772b Somatostatin analogues, for neuro-endocrine tumours (NETs),

Somatostatin receptor scintigraphy (SRS), 778b Somatostatinoma, 678b Somnolence daytime, 1105–1106 idiopathic hypersomnolence, 623 Sorafenib, for hepatocellular carcinoma,

Sorbitol, 812 Sotalol, 140 South American botfly, 300 Space-occupying lesions, HIV-related, 320–321 Space of Disse, 849 cirrhosis and, 866 Sparganosis, 299 Spastic catch, 1068–1069 Spastic paraplegia, hereditary, 1138b Spasticity, 1068–1069 Specialised receptors, 1338 Specialist nurse, 1109–1110 Spectinomycin, 117b, 122 Spectrophotometry, 348b Spectroscopy (ICP-MS), 348b Speech disturbance, stroke and,

Speech/speech disorders, 1070, 1070f, 1087–1088, 1088f assessment of, in psychiatric interview, 1181 Speech therapy, for Parkinson’s disease, 1114 Spermatogenesis, 651f Spherocytes, 915, 921b, 921f Spherocytosis, hereditary, 947 investigations of, 947, 948f management of, 947, 948b Sphincter anal, 437 bladder, 386 control, 1070–1071 urethral, 103, 436 Sphincter of Oddi, 849–850 dysfunction of, 908–909 classification of, 908b pancreatic, criteria for, 908b Sphincterotomy biliary, 906 endoscopic, in old age, 909b Sphygmomanometry, 510 Spider bites, 161 Spider naevi, 846f autoimmune hepatitis and, 886 Spider telangiectasia, 866–867 Spiders, envenomation of, 161 Spina bifida, 715, 1138b Spinal cord, 1067, 1338–1339 compression, 1136–1137, 1136b, 1137f cancer and, 1326, 1326b in rheumatoid arthritis, 1024, 1025f disorders of, 1134–1137 intrinsic diseases of, 1137, 1137f, 1138b lesions, sensory loss, 1083 Spinal cord syndrome, 1136b Spinal epidural abscess, 1125 Spinal muscular atrophy, 1117 Spinal root lesions, 1141 Spinal stenosis, 1135–1136 Spine assessment of, 983f bamboo, 1030–1031, 1031f cervical imaging of, 1074, 1075f myelopathy, 1134–1135 radiculopathy, 1134, 1134f spondylosis, 1134–1135, 1134f subluxation of, 1024, 1025f disorders of, 1134–1137 lumbar, imaging of, 1074, 1075f osteoarthritis, 1011, 1011f thoracic, imaging of, 1074, 1075f Spinobulbar muscular atrophy, 43b Spinocerebellar ataxia, 43b, 1116b Spiramycin, 281 Spirillum minus, 234b Spirometry asthma, 569 COPD, 575 Spironolactone ascites, 864 ascites and, 864 gynaecomastia, 657b heart failure, 465 Splanchnic vasodilatation, for ascites, 862–863 Spleen, 67 enlarged see Splenomegaly examination of, 913b Splenectomy for chronic lymphocytic leukaemia,

for idiopathic thrombocytopenic purpura, 971 for myelofibrosis, 969 Splenomegaly, 927, 928b cirrhosis and, 867 portal hypertension and, 868 Splice site mutations, 43f Splicing, 40 Splinter haemorrhages, 994b, 1260 Splints, for musculoskeletal disease,

Spondylitis, psoriatic, 1032 Spondyloarthritis, axial, 1028b, 1029–1030, 1029f Spondyloarthropathies (SPAs), 1027–1034, 1028b seronegative, 1166b Spondylolisthesis, 996–997, 1059–1060 Spondylolysis, 1059–1060 Spondylosis cervical, 1134–1135, 1134f lumbar, 1135–1136 Spondylotic myelopathy, cervical, 1082b Spongiosis, 1244 Spontaneous bacterial peritonitis, 864 Spontaneous breathing trials, respiratory support and, 210 Spontaneous hypoglycaemia, 676–678 cause of, 677–678 clinical assessment of, 677 differential diagnosis of, 677f investigations of, 677–678 management of, 678 in old age, 678b Sporadic fatal insomnia, 1127b Sporothrix schenckii, 301 Sporotrichosis, 301 Sporozoites, malaria, 273–274 Spreading depression of Leão, 1095 Sprue, tropical, 233 Spurious full blood count results, from autoanalysers, 919–920, 920b Sputum, 546f cough, 556 cytology, 554 haemoptysis, 559 investigations, 554 Pneumocystis jirovecii pneumonia,

in pulmonary oedema, 546f pulmonary tuberculosis, 318 Squamous carcinoma, 796b Squamous cell carcinoma, skin, 1230–1231, 1230b, 1231f SRS see Somatostatin receptor scintigraphy SSPE see Subacute sclerosing panencephalitis SSSS see Staphylococcal scalded skin syndrome St John’s wort, drug interactions, 24b St Vitus dance, 516 Stable angina advice to patients with, 489b risk stratification in, 488b Staging, in lung cancer, 602, 602f Stamping gait, 1087 Stannosis, 614–615 Staphylococcal food poisoning, 262 Staphylococcal infections, 250–252, 251f cannula-related, 251–252, 251b methicillin-resistant Staphylococcus aureus, 252 skin, 251 staphylococcal toxic shock syndrome, 252, 252f wound, 251, 251f Staphylococcal scalded skin syndrome, 1236, 1236f Staphylococcal toxic shock syndrome, 252, 252f Staphylococcus aureus, 104b, 117b,

acute leukaemia, 957 atopic eczema, 1246b bacteraemia, 225 blood-stream infection, 225b bronchiectasis, 579 cerebral venous sinus thrombosis,

chronic granulomatous disease, 77 fever, 223, 223f folliculitis from, 1236–1237 impetigo from, 1235–1236 infections caused by, 251f infectious keratitis, 1173b infective endocarditis, 527 meningitis, 1119b pneumonia bacterial, 319 community-acquired, 582b, 584b in septic arthritis, 1020 skin infections, 251f vancomycin-resistant, 252 Staphylococcus epidermis, 251 Staphylococcus intermedius, 251 Staphylococcus saprophyticus, 251 Starches dietary, 695–697 hydrolysis, 768 polysaccharides, 696b resistant, 265 Starling’s law, 461, 461f Starvation, 704–705 infections associated with, 705b STAT proteins, 64–66 Statins, 376 for acute coronary syndrome prevention, 498b hepatotoxicity of, 894b for hypertension, 513 for non-alcoholic fatty liver disease,

for stroke prevention, 1161f Statistics, 10 Status epilepticus, 1080, 1081b,

Steady state, 19 Steatohepatitis, non-alcoholic, 882–883, 883f Steatorrhoea bile acid diarrhoea, 809 cystic fibrosis, 842 malabsorption, 783–784, 784b small bowel disorders, 808 Steatorrhoea, pancreatitis, 840 Steatosis, 882–883, 894 Stellate cells, 772 Stem cell factor, 914 Stem-cell plasticity, 914–915 Stem cells, 914–915, 915f plasticity, 914–915 pluripotent, 954 Stenosis aortic, 443b, 521–524, 522b, 522f causes of, 521b Doppler echocardiography for, 451f investigations of, 522–524, 523b, 523f in old age, 524b lumbar canal, 1135–1136 mitral, 517–519, 518b, 518f chest X-ray for, 451f investigations in, 518f, 519b pregnancy and, 1282 pulmonary, 526 renal artery, 406–408, 407b, 407f spinal, 1135–1136 tricuspid, 525–526 Stents/stenting aortic dissection, 508 carotid, 1160 cholecystitis, 905 colonic, 833f coronary, 491, 491f graft, 507f liver arterial disease, 898 for lung cancer, 603 myocardial infarction, 1282 pregnancy and, 1282 renal artery, 389 superior vena cava obstruction, 1327 thrombosis, 493b ureteric, 414 Stercobilin, 851 Stercobilinogen, 851 Sterile pyuria, 430 Steroid hormones, pathways of synthesis of, 667f Steroids anabolic, 88 synthesis, 667f see also Corticosteroids Stevens-Johnson syndrome, 316, 1224, 1254–1255 Stiff person syndrome, 1111b Still’s disease adult, 895, 1040 see also Juvenile idiopathic arthritis Stimulant, misuse of, 1195–1196 Stimulation therapies for cancer pain, 1353 for pain, 1347, 1347f Stings insect, 75b scorpion, 159 see also Envenomation Stockings, compression, 396 ‘Stokes-Adams’ attacks, 477–478 Stomach emptying, 778 erosions, 781f functional anatomy of, 766–767, 766f outlet obstruction, 801–802, 801b tumours of, 803–805 ulcer, 798–802 Stomatitis angular, 764f, 817 herpetic, 247f Stones see Calculi (stones) Stool cultures, 777 Stop codons, 40 Storage disorders, 929b Stratum corneum, 1212 Strawberry gallbladder, 909 Strawberry tongue, 252, 253f Streptococcal infections, 252–253, 253b acute rheumatic fever, 515, 517b bone and joint, 1020 Sodium valproate (Continued)

INDEX • 1411 in pregnancy, 235b tics, 1086 Streptococcal toxic shock syndrome, 217f, 253 Streptococci, 102f alpha-haemolytic, 102f beta-haemolytic, 102f group A, 252 group B, 252 Streptococcus anginosus, 103f Streptococcus constellatus, 103f Streptococcus intermedius, 103f Streptococcus mitis, 528 Streptococcus pneumoniae, 67, 73b, 117b, 266, 1277b in community-acquired pneumonia, 582, 582f meningitis, 1119b–1120b peritonitis, 836 sepsis, 226b Streptococcus pyogenes, 103f, 117b Streptococcus suis, 1119 bacterial meningitis, 1120b Streptococcus viridans endocarditis,

Streptokinase, Budd-Chiari syndrome and, 899 Streptomyces, 1238 Streptomycin adverse reactions, 593b as antimycobacterial agents, 125 mycetoma, 301 plague, 259 tuberculosis, 97f for tuberculosis, 593 Stress acute reaction, 1201 oxidative, 881f, 883 post-traumatic stress disorder, 1201–1202 Stress echocardiography, 452 Stress electrocardiography, 449–450 Stress fracture, 995b Stress incontinence, 436 in older people, 1309–1310 Stress-related disorders, 1201–1202 Stressors, psychiatric disorders and,

Stretch reflex, 1068 Striae, definition of, 1226f Strictures, endoscopic techniques for management see Endoscopy Stridor aortic aneurysm, 505 bronchial obstruction, 600 connective tissue disorders, 610b hypocalcaemia, 663 inspiratory, 566 laryngeal disorders, 624 tracheal disorders, 625 String test, 287 Stroke, 952, 1153–1160 anatomy and physiology of, 1150–1151, 1150f classification of, 1150f clinical examination of, 1148, 1148f clinical features of, 1150f, 1155–1157, 1155b, 1156f completed, 1157 complications of, 1159f differential diagnosis of, 1155b general examination of, 1149b heat, 167–168 HIV-related, 321 investigations of, 1151–1152, 1157–1158, 1157b blood tests, 1151–1152 cardiac, 1158 cardiovascular, 1152 lumbar puncture, 1152 neuroimaging, 1151, 1151f, 1157–1158 vascular imaging, 1151, 1152f,

management of, 1158–1160, 1158f aspirin, 1160 carotid endarterectomy and angioplasty, 1160 coagulation abnormalities, 1160 heparin, 1160 reperfusion (thrombolysis and thrombectomy), 1159–1160 supportive care, 1158–1159, 1159b unusual causes, 1160 medicine for, 1147–1162 migraine and, 1095 pathophysiology of, 1153–1155 cerebral infarction, 1153–1154, 1153f–1154f intracerebral haemorrhage, 1154–1155, 1155b, 1155f pregnancy and, 1284 presenting problems of, 1152–1153 ataxia, 1153 coma, 1153 headache, 1153 seizure, 1153 speech disturbance, 1152 visual deficit, 1152 visuo-spatial dysfunction, 1152 progressive (in evolution), 1157 rapid assessment of, 1149b risk factors for, 1153b analysis, 1157, 1157b management, 1160 secondary prevention of, 1161f Stroke mimics, 1155b Stroke units, 1158 Stroke volume, 446 pregnancy and, 1272 Strongyloides hyperinfection syndrome, 226b, 289 Strongyloides stercoralis, 231b, 233b, 289, 612 Strongyloidiasis, 233b, 289, 289b Subacute cutaneous lupus erythematosus (SCLE), 1262 Subacute invasive aspergillosis (SIA),

Subacute sclerosing panencephalitis (SSPE), 236, 1123 Subacute (de Quervain’s) thyroiditis, 646–647 Subarachnoid haemorrhage, 1160–1162 clinical features of, 1161, 1162f investigations of, 1161 management of, 1162 see also stroke Subclavian steal, 504 Subclinical hypothyroidism, 642 Subclinical thyrotoxicosis, 636b, 638,

Subclinical urethritis, 334b Subcutaneous administration, 17 Subcutaneous androgen replacement therapy, 656b Subdural empyema, 1125 Subdural haematoma, 864–865 Sublingual administration, 17 Substance misuse, 1184, 1184b prevalence of, 1180b Substance misuse disorder, 1195–1196 Substance P, 1003–1004 Subtotal thyroidectomy, for Graves’ thyrotoxicosis, 644b, 645 Subtotal villous atrophy, important causes of, 806b Subungual haematoma, in nails, 1260f Succinate dehydrogenase, 49b Sucralfate, 801 Sudden death due to heart failure, 464 in raised ICP, 1128 Sugars dietary, 696b recommended intake, 698b Suicide anorexia nervosa, 1204 attempted, 1187 bipolar disorder, 1200 depression, 1198 low mood, 1185 old age, 1189b risk factors for, 1187b schizophrenia, 1198 see also Self-harm Sulfadiazine prophylactic, 119b rheumatic fever, 517 toxoplasmosis, 281, 320 Sulfadoxine, and neutropenia, 926b Sulfamethoxazole, melioidosis, 261 Sulfasalazine (SSZ) in haemolysis, 950 for inflammatory bowel disease, 821b for musculoskeletal disease, 1004–1005, 1004b prophylactic, 119b Sulfinpyrazone, gout, 1016 Sulindac, 829 Sulphonamides mechanism of action, 116b in pregnancy, 120b Sulphonylureas effect of hepatic impairment, 32b effect of renal insufficiency, 32b for hyperglycaemia, 746–747 weight gain and, 700b Sulphur, 718 Sulpiride, 1115 Sumatriptan, for migraine, 1096 Sunbed exposure, cancer and, 1229 Sunburn, 1221f SUNCT, 1097, 1097b Sunflower cataract, in Wilson’s disease, 1174f Sunitinib, 435 Sunlight melanoma and, 1232 sensitivity to, 1036b Sunscreens, 1222–1223 albinism and, 1258 melanoma and, 1233 photosensitivity, 1221b protection levels, 1222–1223 vitiligo and, 1257–1258 Superficial bursitis, 999b Superior vena cava, 444f Superior vena cava obstruction (SVCO), 1314f, 1315b cancer and, 1326–1327, 1327b Superior vena cava syndrome, 505 Superoxide dismutase, 1116 Supported self-management, for pain,

Suppurative pneumonia, 586–587, 587b Supranuclear palsy, progressive, 1114–1115 Supraventricular tachycardia, 473, 473f Suramin, for trypanosomiasis, 128 Surfactant, 548–549 Surgery for acromegaly, 686 bariatric, 702f–703f, 703–704, 703b for brain tumours, 1130 for cholecystitis, 905 for chronic obstructive pulmonary disease (COPD), 577 for epilepsy, 1102 gastrointestinal achalasia, 795 haemorrhage, 782 prophylactic, 119b for lung cancer, 602 for musculoskeletal disease, 1002, 1002b osteoarthritis, 1012 osteoporosis, 1049 rheumatoid arthritis, 1026 for obesity, 702f–703f, 703–704, 703b for Parkinson’s disease, 1114 for primary hyperparathyroidism, 664 for prolactinoma, 685 for psychiatric disorders, 1190 Surrogate endpoints, 35–36 Sustained virological response (SVR),

Suxamethonium allergy, 75b pharmacokinetics, 20b Swallowing, difficulty in see Dysphagia Swan-Ganz catheter, 206, 207f Swan neck deformity of fingers, 1023, 1023f Sweat glands, 1213–1214 Sweating, excessive, 217b Sydenham’s chorea, 516 Symmetrical polyarthritis, 1032 Symmetrical sensory polyneuropathy, diabetic, 758–759 Sympathetic nervous system, sodium transport regulation in, 352 Synaptic transmission, 1065 Syncope, 181–183, 455 clinical assessment of, 182–183 congenital heart disease and, 533 differential diagnosis of, 182f features of, 181b gastrointestinal haemorrhage, 780 heat, 167 investigations of, 183 in older people, 1308 presentation of, 181–182 seizures versus, 182b Syndesmophytes, 988 Syndrome of inappropriate secretion of ADH (SIADH), 357b Synergistic gangrene, 227, 227b Synovectomy, 1002b for rheumatoid arthritis, 1026 Synovial biopsy, 992 Synovial fluid, 987, 988f in septic arthritis, 1020 Synovial joints, 987 structure of, 987f Synovial membrane, 987 Synoviocytes, 987 Synovitis, pigmented villonodular, 1059 Synovitis-acne-pustulosis-hyperostosisosteitis (SAPHO) syndrome,

Synovium, 987 loose bodies within, 988 needle trauma to, 988 in osteoarthritis, 1008 Synthetic cannabinoid receptor agonist, misuse of, 143 Syphilis, 253, 337–339 acquired, 337–338 benign tertiary, 338 cardiovascular, 338 classification of, 337b congenital, 338–339, 338b dementia and, 339 early, 337–338 investigations of, 338–339 late, 338 latent, 337–338 management of, 339 neurosyphilis, 338, 1125, 1125b in pregnancy, 235b, 339 primary, 337, 337f secondary, 337 rash in, 1217b serological tests for, 339b treatment reactions of, 339 Syringomyelia, 1083 Systemic disease, 785 Systemic glucocorticoids, for musculoskeletal disease, 1005 Systemic inflammatory response, 196–198 initiation of, 196 propagation of, 196 see also Sepsis Systemic juvenile idiopathic arthritis,

Systemic lupus erythematosus (SLE), 410–411, 1034–1037 classification of, criteria for, 1036b clinical features of, 1035–1036 investigations of, 1036 management of, 1036–1037 pathophysiology of, 1034 pregnancy and, 1281, 1281b respiratory involvement in, 611 Systemic sclerosis (SScl), 410, 1037–1038, 1037f, 1262 pregnancy and, 1280–1281, 1281b respiratory involvement in, 611 Systemic vasculitis, 410 Systolic dysfunction, 450 Systolic murmurs, 459–460, 460b

1412 • INDEX T T-helper lymphocytes, HIV infection/ AIDS and, 310 T lymphocytes (T cells), 69–70, 69f, 917 CD4+, 70 CD8+, 70 deficiency in, 73b primary, 79–80, 80f liver and, 849f lymphoma cutaneous, 1224 enteropathy-associated, 813 multiple sclerosis, 1106 skin, 1212 psoriasis, 1248f T-regulatory cells (T regs), 70 Tabes dorsalis, 1125b Tachycardia, 191–193 assessment and management of, 192–193 pathophysiology of, 191–192 sinus, 469, 469b supraventricular, 473, 473f ventricular, 475–476, 475b, 475f–476f poisoning, 137b pulseless, 457 Tachyphylaxis, 16 Tachypnoea, 190, 191f assessment and management of, 190, 191f pathophysiology of, 190 Tacrolimus, 1281b liver transplantation and, 901 nephrotoxicity, 427b thrombocytopenia, 971 vitiligo, 1257–1258 Tactoids, 951–952 Taenia asiatica, 298 Taenia echinococcus, 298–299 Taenia saginata, 298 Taenia solium, 297f, 298 Takayasu arteritis, 1041 Takotsubo cardiomyopathy, 541, 541f Tamm-Horsfall protein, 392 Tamoxifen breast cancer, 1334 desmoid tumours, 829 gynaecomastia, 657 Tamponade balloon, for variceal bleeding, 870–871, 870f cardiac, 447–448 Tamsulosin, 438 Tandem repeat mutations, 43, 43b Tangent/Goldmann kinetic perimetry,

Tangier disease, 375, 375b Tanner staging, 1290, 1292f Tapeworms, 297–299 Tarsal tunnel syndrome, 1024 Tarui disease, 370b Tay-Sachs disease, 371b Tazobactam for spontaneous bacterial peritonitis,

for variceal bleeding, 869 TB see Tuberculosis TBG see Thyroxine-binding globulin TBW see Total body water 99mTc-sestamibi scintigraphy, for primary hyperparathyroidism, 663–664, 664f TCAs see Tricyclic antidepressants Team communication, effective, for clinical decision-making, 10, 10b Teardrop poikilocytes, 969 Teduglutide, for intestinal failure, 710 Teenagers, adherence in, 1294–1295 Teichopsia, 1088 Teicoplanin, 117b, 123 adverse effects of, 123 Telangiectasia definition of, 1226 hereditary haemorrhagic, 970 spider, liver disease and, 866–867 Telaprevir, 878b Teletherapy, 1331 Telomerase, 1318 Telomeres, 1304–1305 Telophase, 40 Temperature, 94 abnormal, 165f body, 165 cold injury and, 166–167 elevated body, 167b extremes of, 165–168 heat-related illness and, 167–168 hypothermia and, 165–166, 165f–166f of stroke patients, 1159b thermoregulation and, 165, 165b Temporal artery biopsy, 992 Temporal coning, 1128, 1128f Temporal lobes, 1066 disorders of, 1089b functions of, 1066b effects of damage, 1066b Temporary pacemakers, for arrhythmias, 482–483, 483f Tendinitis adductor, 999b bicipital, 998b, 998f Tendon, xanthomas, 375 Tendon reflexes, root values of, 1063b Tendon repairs and transfers, 1002b Tenecteplase (TNK), 500 Tennis elbow, 998b Tenofovir, 119b, 324b for hepatitis B, 876 Tenosynovectomy, 1002 Tenosynovitis, 998 Tension-type headache, 1095 Teratogen, 22–23 Terbinafine, 125b, 126 chromoblastomycosis, 301 fungal infections, 1239–1240 sporotrichosis, 301 Terbutaline, asthma, 571 Teriparatide, for osteoporosis, 1048–1049, 1048b Terlipressin, 864 for variceal bleeding, 869b, 870 Terminal illness see Palliative care Terrorism see Bioterrorism Testicular tumours, 439–440 Testis epididymo-orchitis, 240 undescended, 653 Testosterone for delayed puberty, 654 puberty and, 1290 reference range of, 1359b Tetanus, 104b, 1125–1126 prevention of, 1126 treatment of, 1126b Tetany, 663 Tetrabenazine, 1115 Tetracycline(s), 117b, 124 acne, 1243 adverse effects of, 124 bartonellosis, 272 brucellosis, 254 bullous pemphigoid, 1256 cholera, 265 drug interactions, 24b mechanism of action, 116b pharmacokinetics of, 124 plague, 259 in pregnancy, 120b pyoderma gangrenosum, 1261–1262 relapsing fever, 257 rickettsial fevers, 271–272 rosacea, 1244 steatosis, 894 timing, 31b trachoma, 273 tropical sprue, 808 Tetralogy of Fallot, 536–537, 536f Th1 (T helper) cells, 70 Th2 cells, 70 Th17 cells, 70 Thalamus, 1066–1067 Thalassaemias, 951, 953–954 alpha, 954 beta, 953–954 rheumatological manifestations of,

Thalidomide for Behçet’s disease, 1044 for multiple myeloma, 968 sarcoidosis, 610 Theophylline asthma, 1277 plasma concentration, 36b poisoning, 137b, 141b tremor, 1116b Therapeutic approach, 29, 29b Therapeutic drug monitoring, 119 Therapeutic efficacy, 16 Therapeutic goal, 29 Therapeutic index, 15f, 16 Thermal injury, 950 Thermodilution, for measurement, of cardiac output, 454 Thermogenesis, diet-induced, 694, 695f Thermoregulation, 165, 165b in old age, 166b Thiabendazole, 129 Thiamin (vitamin B1), 714 biochemical assessment of, 712b deficiency, 714 dietary sources of, 711b reference nutrient intake of, 711b Thiamin pyrophosphate (TPP), 714 Thiazides adverse effects, 355b for hypertension, 513 for hypervolaemia, 355, 355b and hyponatraemia, 357b Thiazolidinediones, for hyperglycaemia,

Thienobenzodiazepines, 1198b Thin glomerular basement membrane disease, 404 Thiopurines, for inflammatory bowel disease, 821b Thioxanthenes, 1198b Thirst diabetes insipidus, 687 water homeostasis, 356 Thomsen’s disease, 1145b Thoracic kyphoscoliosis, 628 Thoracic outlet syndrome, 1141b Thoracoscopy, 553 Thorax, examination of, in respiratory system, 546f Thought assessment of, 1181 passivity of, 1196–1197 Thought, passivity of, 1196–1197 Threadworm (Enterobius vermicularis),

Threonine, 697b Thrombasthenia, Glanzmann’s, 970–971 Thrombin, 918f–919f Thromboangiitis obliterans, 504 Thrombocythaemia, essential, 969–970 Thrombocytopenia, 929, 929b, 971 hepatobiliary disease and, 853 HIV-related, 322 pregnancy and, 1285, 1285b Thrombocytopenic purpura (TTP), pregnancy and, 1285 Thrombocytosis, 929–930, 929b Thromboembolism in cancer patients, 1324–1325 Heart failure causing, 464 venous, 975–977 causes and consequences of, 975, 976f factors predisposing to, 975b management of, 975–976 pregnancy and, 1285 prophylaxis of, 976–977, 977b Thrombolytic therapy for acute coronary syndrome, 500, 500b for pulmonary embolism, 621 Thrombophilia, 977–979 acquired, 977–979 investigation of, 922–923, 923b testing in, indications for, 922–923, 923b Thrombopoietin receptor agonists (TPO-RA), for idiopathic thrombocytopenic purpura, 971 Thromboprophylaxis, 472–473, 473b in intensive care, 210 Thrombosed prolapsed haemorrhoids, 836f Thrombosis deep vein air travel and, 169 investigation of, 187, 187f pre-test probability of, 187b pregnancy and, 1285 presentation of, 186 in stroke patients, 1159f warfarin for, 939 hepatic artery, 898 in old age, 978b Thrombospondin (TSP)-1, 1318 Thrombotic disorders, 922–923, 923b, 975–979 Thrombotic microangiopathies, 408–409, 408b Thrombotic thrombocytopenic purpura (TTP), 388, 409, 979 Thrush, 300 oral, 790 Thumb, Z deformity, 1023 Thymectomy, myasthenia gravis, 1142b Thymine, 38 Thymus, 67 Thyroglobulin (Tg), 634, 635f as tumour markers, 1324b Thyroid autoantibodies, 637b Thyroid disease autoimmune, 639b, 643–646 classification of, 634b clinical features of, 637b congenital, 650–651 investigations of, 634–635 iodine-associated, 647–648 during pregnancy, 651b, 1279 hyperthyroidism as, 1279 hypothyroidism as, 1279 iodine deficiency as, 1279 post-partum thyroiditis as, 1279 presenting problems of, 635–643 Thyroid function tests asymptomatic abnormal, 642 hypothyroidism, 636b interpretation of, 636b for obesity, 700 thyrotoxicosis, 636b Thyroid gland, 634–651 enlargement of, 642–643, 642b examination of, 631b functional anatomy, physiology and investigations of, 634–635, 635f, 636b in old age, 650b scintigraphy, 638f, 642 ultrasound, 643 Thyroid hormone, 634, 635f in bone remodelling, 986b replacement, for hypopituitarism, 682 resistance, 651 Thyroid lump or swelling, 642–643, 642b Thyroid neoplasia, 649–650, 649b Thyroid nodule, solitary, 642 Thyroid peroxidase antibodies, 640 Thyroid-stimulating hormone (TSH; thyrotrophin), 632, 634 and free T4, relationship of, 634, 635f receptor antibodies (TRAb), 643 reference range of, 1359b Thyroid-stimulating immunoglobulins,

Thyroid storm, 639 Thyroiditis Hashimoto’s, 646 post-partum, pregnancy and, 1279 Riedel’s, 650 subacute (de Quervain’s), 646–647 transient, 646–647, 646f Thyrotoxic crisis, 639 Thyrotoxicosis, 635–639 in adolescence, 645, 645b amiodarone and, 636b, 638f, 647–648 atrial fibrillation in, 638 causes of, 636b

INDEX • 1413 clinical assessment of, 635–636, 637b differential diagnosis of, 638f factitious, 637 goitre and, 635–636, 636b Graves’ disease and, 635–636, 636b, 643–646, 643f management of, 644–645, 644b investigations of, 636–637, 637b–638b iodide-induced, 636b laboratory abnormalities, 638b low-uptake, 637 management of, 637–639 in pregnancy, 645, 651b subclinical, 636b, 638, 642 T4 : T3 ratio in, 637 toxic adenoma in, 638f, 649 type I, 647–648 type II, 648 Thyrotrophin-releasing hormone (TRH), 633f, 634 Thyroxine (T4), 633f, 634, 635f reference range of, 1359b thyroid-stimulating hormone (TSH) and, relationship of, 634, 635f Thyroxine-binding globulin (TBG), 634 Tiagabine, 1102b Tibial compartment syndrome, anterior,

Tibolone, for osteoporosis, 1048b, 1049 Tic douloureux, 1096–1097 Ticarcillin, 120b Tick-borne diseases, 256b babesiosis, 278 Lyme disease, 255 rickettsial fevers, 270 tularaemia, 261 viral haemorrhagic fevers, 246 Tick-borne relapsing fever, 256b, 257 Tics, 1086 Tidal volume (TV), pregnancy and, 1273 Tietze’s syndrome, 177b Tigecycline, 117b, 124 Tiludronate, for Paget’s disease, 1054b Tin oxide, 615b Tinea capitis, 1240, 1240f Tinea corporis, 1240 rash in, 1217b Tinea cruris, 1240, 1240f Tinea incognito, 1240 Tinea pedis, 1240 Tinidazole, 287, 808–809 Tirofiban, 500, 918 Tissue biopsy, in musculoskeletal disease, 992 Tissue factor pathway, assessing, 920–921 Tissue plasminogen activator, 447 Tizanidine, 1110b TNF inhibitors, pregnancy and, 1278,

TNF receptor-associated periodic syndrome, 81 TNF receptor-associated proteins (TRAPs), 64–66 TNFRSF1A gene, TNF receptorassociated periodic syndrome and, 81 TNM classification, 1322b Tobramycin cystic fibrosis, 581b dosing interval, 122f Tocilizumab, 1027 for musculoskeletal disease, 1007, 1007b α-Tocopherol see Vitamin E Toe cock-up deformities, 1023 ingrowing toenails, 1260 Tofacitinib, for musculoskeletal disease, 1004b Tolcapone, for Parkinson’s disease,

Tolerance, 16 Toll-like receptors, 63 Tolterodine, 1094b, 1310f Tongue biting, 1102b strawberry, 252, 253f Tonic-clonic seizures, 1099, 1099b Tonic seizures, 1100 Tonsillar coning, 1128, 1129f Tonsillitis, 242–243 membranous, 266b streptococcal, 252, 253b Tonsils, 67, 912f Tophi, 1014, 1015f Topical administration, 17–18 Topical agents, for musculoskeletal disease, 1003–1004 Topical analgesics, for pain, 1345 Topiramate, for obesity, 702–703 Topoisomerase II inhibitors, 936b Topotecan, ovarian cancer, 1334 Torsades de pointes, 476–477, 476b, 476f Torticollis, 997b, 1116 Total anterior circulation syndrome (TACS), 1156f Total body water (TBW), 349 Total iron binding capacity (TIBC), 942 Total lung capacity, 555b Total parenteral nutrition candidiasis, 302 gastroparesis, 803 Total thyroidectomy, for medullary carcinoma, 650 Tourette’s syndrome, 1086 Toxic adenoma, 638f, 649 Toxic epidermal necrolysis, 1254–1255, 1254b, 1254f, 1266b Toxic megacolon, 818 Toxic pustuloderma, drug-induced, 1266b Toxic shock syndrome (TSS), 1236 staphylococcal, 252, 252f streptococcal, 217f, 253 Toxins bacterial, 1125–1126 food-related poisoning, 149–150 ciguatera poisoning, 149–150 paralytic shellfish poisoning, 149 scombrotoxic fish poisoning, 150 gastrointestinal decontamination for, 135–136 plant, 150, 150b venom, 154, 154b Toxocara canis, 233b Toxocariasis, 233b Toxoplasma gondii, 280 life cycle of, 280f Toxoplasmosis, 280–281 clinical features of, 280, 281f congenital, 280 investigations of, 281 management of, 281 in pregnancy, 235b Trace elements, absorption, 769 Tracheal disorders, 625 Tracheal obstruction, 625 Tracheo-oesophageal fistula, 625 Tracheostomy, in intensive care, 210, 210b Trachoma, 273, 273f Trachyonychia, 1261 Tramadol, 1002 Tranexamic acid, 560, 597 Tranquillisers, effect of old age, 32b Trans-arterial chemo-embolisation, for hepatocellular carcinoma, 892 Transcatheter aortic valve implantation, 527, 527f Transcobalamin II, 943–944 Transcription, of DNA, 38–40 Transcription factors, 39 Transcutaneous electrical nerve stimulation (TENS), 1012 for osteoarthritis, 1012 Transdermal administration, 17 Transdermal androgen replacement therapy, 656b Transference, 1191 Transferrin, 1362b saturation of, 1362b Transforming growth factor beta (TGF-β1), 849f Transfusion-associated graft-versushost disease (TA GVHD), 933 Transfusion medicine haematology and, 911–979 key points in, 936b Transfusion-transmitted infection, 933 Transient ischaemic attack (TIA), 1156–1157 causing sensory loss, 1083 causing visual loss, 1088 Transient ocular ischaemia, 1171 Transient thyroiditis, 646–647, 646f Transition medicine, adolescent and, 1287–1300 clinical assessment in, 1293 features of, 1293b clinical presentations in, 1296–1300 diabetes and, 1299 functional anatomy and physiology in, 1290–1292 cognitive and behavioural changes in, 1292 endocrine changes in, 1290, 1291f physical changes in, 1290 gastrointestinal disease and, 1299–1300 inflammatory bowel disease and, 1299–1300 investigations in, 1293, 1293b neurological disease and, 1296–1297 cerebral palsy in, 1296 epilepsy in, 1296 muscular dystrophy in, 1297 oncology and, 1298 organ transplantation and, 1299 presenting problems in, 1294–1296 adherence as, 1294–1295 high-risk behaviour as, 1295 unplanned pregnancy as, 1295–1296 renal disease and, 1298–1299 respiratory disease and, 1297 cystic fibrosis in, 1297 rheumatology and bone disease and,

glucocorticoid-induced osteoporosis in, 1300 hypophosphataemic rickets in,

juvenile idiopathic arthritis in, 1300 osteogenesis imperfecta in, 1300 transition from paediatric to adult health services in, 1288–1290 principles of prescribing during, 1289, 1289b readiness for, key features in, 1289b timing of, 1290, 1290f transition planning in effectiveness of, 1288 general principles of, 1288–1289, 1288f reasons to consider, 1288f systematic approach to, 1289–1290 transition referral letter in, 1293 Transition planning effectiveness of, 1288 general principles of, 1288–1289, 1288f impact of, on outcome in diabetes, 1299b reasons to consider, 1288f systematic approach to, 1289–1290 Transjugular intrahepatic portosystemic stent shunt (TIPSS) for ascites, 864 for variceal bleeding, 871, 871f Translation, 39f, 40 Transoesophageal echocardiography (TOE), 452 Transplantation cardiac, 467–468 in diabetes mellitus, 752 graft rejection and, 88–90 investigations in, 89 haematopoietic stem cell, 936–938 for acute leukaemia, 958 allogeneic, 936–937, 936b–937b autologous, 936–938 fever after, 224–225 for high-grade NHL, 966 infections during recovery from, 937b immunosuppression in complications of, 89–90 drugs used in, 89b of islet cell, 752, 753f of kidney, 424 of liver, 900–901 for acute liver failure, 858–859 for alcoholic liver disease, 882 complications of, 901 for hepatic encephalopathy, 865 for hepatitis B, 876 for hepatitis C, 878 for hepatocellular carcinoma, 891 indications and contraindications for, 900–901, 900b, 901f living donor, 901 for primary biliary cholangitis, 888 prognosis for, 901 split liver, 901 for Wilson’s disease, 897 for low-grade NHL, 965 lungs, 567, 567b multivisceral, 710 complications of, 710b organ donation and, 90 pre-implantation testing in, 89 renal, 424–426 in diabetic nephropathy, 758 recipients of, pregnancy and, 1283 small bowel, 710 complications of, 710b indications for, 710b transition medicine and, 1299 transplant rejection and, 88–89 classification of, 88b Transportation, for envenomed patient,

Transposition of great arteries, 531b Transrectal ultrasound scan (TRUS) of prostate, 437–438 Transverse myelitis, 1110 Tranylcypromine, 1199b TRAPS see TNF receptor-associated periodic syndrome Trastuzumab, 1332 Trauma head, 1133 nails, 1260 Travellers eosinophilia, 233 fever in, 231b, 231f health needs, 230b incubation times and illnesses, 232b rash, 234b Traveller’s diarrhoea, 232b Treadmill, for exercise electrocardiography, 449–450 Trefoil factor family (TFF) peptides, 767 Trematodes, 294–297 Tremor, 1085, 1115 causes and characteristics of, 1085b drug-induced, 1116b dystonic, 1085b essential, 1085b, 1115 flapping, hepatic encephalopathy and, 864–865 functional, 1085b intention, 1069 Parkinson’s disease causing, 1085b resting, 1081 Trench fever, 272 Trench foot, 167 Trephine biopsy, 920, 922f Treponema pallidum, 117b, 333, 336 in pregnancy, 332b Treponema pertenue, 253 Treponema vincentii, 254 Treponemal (specific) antibody tests,

Treponematoses, 253–254 endemic, 253–254 see also Syphilis Triamcinolone, 790 Triamterene, 355 Triazoles, 125b, 126 Tricarboxylic acid (Krebs) cycle, 714

1414 • INDEX Triceps skinfold thickness, 693b Trichiasis, 273 Trichinella spiralis, 293 Trichinellosis, 293–294 Trichinosis, 293–294 Trichloroacetic acid, 1239 Trichomonas vaginalis, 333 Trichomoniasis, genital, 335 Trichophyton rubrum, 1240 Trichophyton verrucosum, 1240 Trichuris trichiura (whipworm), 290 Triclabendazole, 297b Tricuspid regurgitation, 526, 526b Tricuspid stenosis, 525–526 Tricuspid valve, disease of, 525–526 Tricyclic antidepressants, 1199, 1199b poisoning from, 138–139, 139b, 139f Trientine dihydrochloride, Wilson’s disease, 897 Trigeminal (5th cranial) nerve, tests of, 1063b Trigeminal neuralgia, 1080, 1096–1097 Trigger finger, 1060 Triglycerides measurement, 373 reference range of, venous blood, 1360b Trihexyphenidyl, for Parkinson’s disease,

Triiodothyronine (T3), 633f, 635f reference range of, 1359b Trimethoprim acne vulgaris, 1243 brucellosis, 255b listeriosis, 260 mechanism of action, 116b melioidosis, 261 in pregnancy, 120b urinary tract infection, 428 Triple X syndrome, 44b Triptans, 17, 1096 Trismus, 1126 Trisomy 13 (Patau’s syndrome), 44b Trisomy 18 (Edwards’ syndrome), 44b Trisomy 21 (Down’s syndrome), genetics, 44b Trochanteric bursitis, 999b Trochlear (4th cranial) nerve, tests of, 1063b Troisier’s sign, 804 Tropheryma whipplei, 100, 106, 809 Tropical diseases diarrhoea, 232–233 eosinophilia, 233–234 fever, 230–232 skin, 234 Tropical fever, 230–232 causes of, 231b clinical assessment of, 230–232, 232b history taking in, 231b investigations of, 232, 232b management of, 231f, 232 Tropical pulmonary eosinophilia, 612 Tropical sprue, 233, 807–808 Tropical ulcer, 254, 254b Tropomyosin, 446 Troponins cardiac, 450 reference range of, venous blood, 1360b Trousseau’s sign, 367 ‘True’ polycythaemia, 925 Truncus arteriosus, 531–532 Trunk, examination of, in musculoskeletal system, 982f Trypanosoma brucei gambiense infection, incubation period of, 111b Trypanosoma cruzi, 794–795 Trypanosomiasis African (sleeping sickness), 278–279, 278f American (Chagas’ disease), 279–280 drugs for, 128 Trypsin, 768 Trypsinogen, 770b Tryptamines, misuse of, 143 Tryptase, 1360b Tryptophan, 697b Tube drainage, intercostal, 626–627 Tube feeding, nasogastric, 707, 707b Tuberculin skin test, 594, 594f Tuberculoma, 320–321 Tuberculosis (TB), 267, 430, 588–595,

abdominal, 812–813 bone and joint disease in, 591 central nervous system disease in,

chronic pulmonary, complications of, 590b control and prevention of, 594–595 cryptic, 589b diagnosis of, 592b epidemiology of, 588, 588f gastrointestinal, 590, 591f genitourinary disease in, 591 granulomas in, 71 HIV-related prevention of, 323 therapy for, 324, 324b investigations of, 591–592, 592f lymphadenitis and, 590 management of, 592–594, 593b miliary, 588–589 pathology and pathogenesis of, 588, 588f pericardial disease in, 590 pregnancy and, 1277 prognosis for, 595 pulmonary clinical presentations of, 590b major manifestations and differential diagnosis of, 590f post-primary, 589 primary, 588, 589b, 589f risk of, factors increasing, 589b Tuberculous granuloma, 588f Tuberculous meningitis, 1120–1121, 1121b HIV-related, 321 Tuberculous pericarditis, 543 Tuberous sclerosis, 1264 Tubular obstruction, drug-induced, 427b Tubulo-interstitial diseases, 401–403 inherited, 404, 404b Tularaemia, 261 Tumbu fly, African, 300 Tumour-induced osteomalacia, 1053 Tumour lysis syndrome, 369 cancer and, 1328 Tumour markers, 1322, 1324b Tumour necrosis factor (TNF), 64–66 Tumour suppressor genes, 51 Tumours, 836–837 adrenal, management of, 669–670 bone, 1056–1057 metastatic, 1329 brain, 1129–1132, 1129b, 1129f clinical features of, 1129 investigations of, 1130, 1130f management of, 1130–1131 metastatic, 1328, 1328b prognosis of, 1131 of bronchus, 598–605 of gallbladder and bile duct, 907–908 benign, 908 gastroenteropancreatic neuroendocrine, 678–679, 678b, 679f gastrointestinal stromal cell, 805 head and neck, 1335–1336, 1335b investigations of, 1335 management of, 1335–1336 pathogenesis of, 1335 immunology of, 90 of liver, 890–893 benign, 893 primary malignant, 890–892 secondary malignant, 892–893, 893f of lungs, 598–605 metastatic, 1328 primary, 599–603 secondary, 603 vascular, 619–622 of mediastinum, 603–605, 603b–604b, 604f neuro-endocrine, 603b, 678–679, 678b, 679f, 813 of oesophagus, 796–797 benign, 796 of pancreas, 842–844 pituitary, 683–684, 1129 of rectum, 827–833 of respiratory system, 598–605 skin, 1229–1235 malignant, 1229–1234 pathogenesis of, 1229 of small intestine, 813 of stomach, 803–805 of urinary tract, 434–436 urothelial, 435–436 Tunga penetrans, 299–300 Tungiasis, 299–300 Turbidimetry, 348b Turcot’s syndrome, 829 Turner’s syndrome, 659–660, 660f genetics of, 44b Type A (‘augmented’) ADRs, 22 Type B (‘bizarre’) ADRs, 22 Type C (‘chronic/continuous’) ADRs, 22 Type D (‘delayed’) ADRs, 22 Type E (‘end-of-treatment’), 22 Typhoid fever, 260, 260b Typhus fever endemic, 271, 271b epidemic, 271, 271b scrub typhus, 270–271 Tyrosine, 635f Tyrosine kinase inhibitors, 959 in chronic myeloid leukaemia, 959b TZD drugs see Thiazolidinediones U UDCA see Ursodeoxycholic acid UIP see Usual interstitial pneumonia UK Faculty of Public Health, 92 UK NHS Pregnancy and Newborn Screening Programmes, 96f UK Prospective Diabetes Study, 746 Ulceration aphthous, 790, 790b of small intestine, 811, 811b Ulcerative colitis active left-sided or extensive, 820 cancer, 1320b childhood, 823 clinical features of, 816, 817b comparison with Crohn’s disease, 814b complications, 818 differential diagnosis, 817b histology of, 816f investigations, 818–820 management of, 820, 1299–1300 medical, 822b surgical, 823, 823b pathophysiology of, 815–816 pregnancy, 823–824 primary sclerosing cholangitis and,

pseudopolyposis in, 815f severe, 820 treatment of, medical, 820 Ulcers amoebic, 287 Buruli, 254 Chiclero, 285 dendritic, 248 digital, 1038 foot, 761–762 genital in men, 333–334, 334f in women, 336 legs, 1223–1224 causes of, 1223b, 1223f clinical assessment of, 1223–1224 due to arterial disease, 1223–1224 due to neuropathy, 1224 due to vasculitis, 1224 due to venous disease, 1223, 1223f investigations in, 1224 management of, 1224 leishmaniasis, 285f leprosy, 268 Marjolin’s, 1021 mouth, 1036 neuropathic, 759f, 1224 oesophageal, 794 oral, 1043–1044, 1043f peptic complications of, 801–802 indications for, 800b in old age, 801b perforation, 789, 801 prophylaxis for, in intensive care,

rodent, 1229 skin, definition, 1216 small intestine, 811, 811b solitary rectal ulcer syndrome, 836 tropical, 254 Ulnar nerve entrapment, 1002b palsy, 760 Ultrafiltration, 349–350, 384 failure, 425b Ultrasound for ascites, 863 for cancer, 1323 Doppler see Doppler ultrasound echocardiography see Echocardiography endocrine disease polycystic ovary, 659f thyroid, 643 endoscopic, 774 for choledocholithiasis, 906f for hepatobiliary disease, 855 of gastrointestinal tract, 774 oesophageal cancer, 797f pancreatitis, 839 for hepatobiliary disease, 853–854 gallstones and, 853–854, 854f for hepatocellular carcinoma, 891 for musculoskeletal disease, 989 rheumatoid arthritis, 1025 synovitis, 989f for nervous system, 1073b for non-alcoholic fatty liver disease,

for portal hypertension, 869 renal, 389, 389f for renal artery stenosis, 407 for respiratory disease, 553 for splenomegaly, 927 for tachypnoea, 190, 191f of thyroid gland, 643 Ultraviolet radiation, 1229 photosensitivity, 1220–1223 psoriasis, 1250f skin cancer, 1320b ultraviolet A, 1227 ultraviolet B, 1227 Wood’s light, 1214 Under-nutrition, 704–711 causes of, 704b classification of, 704b clinical assessment for, 693 clinical features of, 704, 704b in hospital, 705–708, 706b responses to, 694–695 Under water, 169–171 Undifferentiated autoimmune connective tissue disease, 1040 Unfractionated heparin (UFH), 938–939 Unilateral leg swelling, 186–187, 186b clinical assessment of, 186–187 investigations of, 187, 187b–188b, 187f presentation of, 186, 187b United Kingdom End-stage Liver Disease (UKELD) score, for liver transplantation, 900–901 Upper airway defences, 550 disease of, 622–625 Upper respiratory tract infection, 581–587 Uracil, 39 Uraemia haemolytic uraemic syndrome, 388 see also Renal failure

INDEX • 1415 Urate, reference range of urine, 1361b venous blood, 1360b Urate-lowering drugs, indications for, 1015b Urea, 349b acute kidney injury and, 416b reference range of urine, 1361b venous blood, 1358b Urea breath test, 778b Ureidopenicillins, 121 Ureterocele, 434 Ureteropyelogram, retrograde, 436 Ureterovaginal fistula, 437 Ureters, 386 colic, 431–432 diseases of, 433–434 ectopic, 434 megaureter, 434 obstruction, 434 Urethral discharge, 333 Urethral syndrome, 427–428 Urethritis chlamydial, 333 gonococcal, 333, 333f non-specific, 333 subclinical, 334b Urge incontinence, 436–437, 1093 in older people, 1309 Uric acid crystals, 431b in gout, 1013–1014 lowering, 1015 metabolism of, 1013f pool, 1013f reference values, urine, 1361b Uricosuric drugs, for gout, 1016 Urinalysis acute kidney injury, 412b reference range, 1361b Urinary diversion, 436 Urinary incontinence, 397, 436–437 older people, 436b, 1309–1310, 1310f Urinary tract, 383f calculi, 431 clinical examination of, 382–384, 382f–383f collecting system diseases of, 433–434 imaging, 389f congenital abnormalities of, 433–434, 434f stones, removal of, 433b, 433f tumours of, 434–436 Urinary tract disease investigation of, 386–391 presenting problems in, 391–397 Urinary tract infection, 426–431 antibiotic regimens for, 429b clinical features, 427–428 investigation of, 428b management, 428–429 in old age, 428b pathophysiology, 427 persistent or recurrent, 429, 429b prophylaxis, 429b risk factors for, 428b in stroke patients, 1159f vesico-ureteric reflux, 428b Urine alkalinisation, 136 black, 947 investigation of, 387–388 microscopy, 387, 388f retention acute, 437–438 benign prostatic hyperplasia, 437–438 chronic, 438 volume, 391 see also Anuria; Oliguria Urine output, decreased, 195 assessment of, 195 diagnosis and management of, 195 Urine testing diabetes, 725 glycaemic control, 742 Urobilin, 851 Urobilinogen, 851 Urography, intravenous see Intravenous urography Urokinase, 1319f Urolithiasis, 431–433 Urology, 381–440 Urothelial tumours, 435–436 Ursodeoxycholic acid (UDCA) gallstones, 905b for primary biliary cholangitis, 888 Urticaria, 1252–1254 causes of, 1253b clinical features of, 1252–1253, 1253f drug-induced, 1266b investigations of, 1253–1254 management of, 1254 papular, 292 pathogenesis of, 1253f solar, 1221b Ustekinumab for Crohn’s disease, 822 for inflammatory rheumatic disease, 1007, 1007b for psoriatic arthritis, 1033–1034 Usual interstitial pneumonia, 608f Uterine tumours, 1316f UTI see Urinary tract infection Uveal tract, of eye, 1167 Uveitis, 1031, 1172–1173 acute anterior, ankylosing spondylitis,

aetiology of, 1172b brucellosis, 255f HTLV-1, 250 immune recovery, 321 treatment, 258–259 Weil’s disease, 258 UVR see Ultraviolet radiation V Vaccines/vaccination, 114–115, 115b anthrax, 115b BCG, 595 chickenpox, 239 cholera, 115b diphtheria, 266 guidelines for, 115b Haemophilus influenzae type B, 115b for hepatitis B, 876b HIV, 327 for human papillomavirus, 343 influenza, 241 Japanese B encephalitis, 250 leprosy, 270 malaria, 277 meningococcal infection, 1120 MMR, 240 mumps, 240 plague, 259 pneumococcal pneumonia, 266 for poliomyelitis, 1123 primary antibody deficiencies and, 79 for rabies, 1122 rotavirus, 249 rubella, 236–237 tetanus, 1126 tick-borne encephalitis, 230b for tuberculosis, 595 types of, 114–115 typhoid, 261 use of, 115, 115b varicella zoster virus (VZV), 115b, 239, 240b whooping cough, 115b yellow fever, 245 see also Immunisation Vaccinia virus, 249 Vacuolating cytotoxin (vacA), 798f VAD see Ventricular assist devices Vagina, discharge, 335, 335b, 335f Vaginosis, bacterial, 335, 335b, 335f Vagotomy, complication of, in peptic ulcer, 801 Vagus (10th cranial) nerve, tests of, 1063b Valaciclovir as anti-herpesvirus agent, 126, 127b for herpes virus infection, genital, 342 Valganciclovir for CMV infection, 224 herpesvirus infection, 127b Valine, 697b Valproate see Sodium valproate Valsartan heart failure, 466b hypertension, 513 myocardial infarction, 500–501 Valves of Heister, 850 Valvular heart disease causes of, 515b infective endocarditis, 527–531 prevention, 531 pregnancy and, 1282 rheumatic, 515–517 risks of non-cardiac surgery, 501b,

valve replacement, 526–527 Valvuloplasty aortic, 524 mitral, 519 Van Buchem’s disease, 1056 Vancomycin, 117b, 123 acute leukaemia, 957 adverse effects, 123 Clostridium difficile infection, 264 drug eruptions, 1266b for infective endocarditis, 223 meningitis, 1120b pharmacokinetics, 123 respiratory disease, 586 for septic arthritis, 1020 therapeutic monitoring, 36b toxic shock syndrome, 252 Vancomycin-resistant Staphylococcus aureus (VRSA), 252 Vandetanib, for medullary carcinoma,

Vanishing bile duct syndrome, 889, 902 Variant Creutzfeldt-Jakob disease (vCJD), 933, 1127, 1127f Variceal band ligation, 869b Variceal bleeding, 865–866, 865f cirrhosis, 866–867 management of, 869–871, 869b, 870f–871f portal hypertension and, 869 prevention of primary, 869 secondary, 871 Variceal ligation, 775f for variceal bleeding, 870 Varicella, pneumonia, 582b Varicella zoster virus (VZV), 238b after HSCT, 937b HIV infection, 321 immunisation, 115b, 240b infection from, pregnancy and, 1277 management and prevention of, 239, 239b in pneumonia, 582b in pregnancy, 235b, 1277 stem cell transplantation, 937b Varicella zoster virus immunoglobulin (VZIG), 239, 240b Varices gastric, 865–866, 865f oesophageal, 865–866, 865f rectal, portal hypertension and, 868 Varicose veins, 1223 Variegate porphyria, 379b Variola, 248 Vascular dementia, 1191b Vascular disease atherosclerotic see Atherosclerosis diabetes, 503b, 756 diffuse, 1191 liver, 898–899 peripheral, 502–505 pulmonary, 619–622 pulmonary embolism, 619–621 pulmonary hypertension, 621–622, 621b, 622f renal, 406–409 Vascular endothelial growth factor, 1318 Vascular imaging, 1151, 1152f, 1158 Vascular malformations, jejunal bleeding, 775f Vascular resistance portal hypertension, 869 pulmonary, 461, 467, 532f systemic, 447 Vasculitides, 611–612 Vasculitis, 1040–1044, 1040f, 1261 antineutrophil cytoplasmic antibody, 1041, 1041f cerebral, 1093b, 1108 cryoglobulinaemic, 1043 cutaneous, 581b drug-induced, 1266b leg ulcers due to, 1224 renal artery stenosis, 407 in rheumatoid arthritis, 1024 small-vessel, 409 systemic, 410, 1041b, 1042f urticarial, 1253b Vaso-occlusive crisis, 952 Vasoactive agents, actions of, 206b Vasoactive intestinal peptide (VIP), 772b Vasodilatation, 206b splanchnic, for ascites, 862–863 Vasodilators angina, 487 for heart failure, 467 for hypertension, 513 myocardial infarction, 199b valvular heart disease, 521 Vasomotor rhinitis, 622 Vasopressin for refractory hypotension, 198 see also Antidiuretic hormone Vasopressin receptor agonist desmopressin, in haemophilia A,

Vasopressinase, pregnancy and, 1280 Vasopressors, 206 for variceal bleeding, 869b VDRL see Venereal Diseases Research Laboratory (VDRL) test VDRR see Vitamin D-resistant rickets Vedolizumab, for inflammatory bowel disease, 821b Vegan, 697 vitamin B12 deficiency, 944 Velocardiofacial syndrome, 44b Venae cavae, 444, 444f see also Inferior vena cava; Superior vena cava Venereal Diseases Research Laboratory (VDRL) test, 338–339 Venesection haemochromatosis, 895–896 for polycythaemia rubra vera, 970 Venlafaxine, 1199b Veno-occlusive disease, 899 Venography cerebral, 1162 hepatic portal, 854, 899 venous thrombosis, 1162 Venom, 154, 154b of animals, 156b–158b clinical effects of, 155–156 insect, allergy to, 85 local effects of, 155, 155b scorpions, 156b–157b snakes, 154b, 156b–157b spiders, 157b Venomous animals, 154–155 Venomous hymenopterans, envenomation of, 161–162 Venomous insects, envenomation of, 161–162 Venomous lepidopterans, envenomation of, 161 Venomous snakes envenomation of, 160–161 geographical distribution of, 153, 153f Venous disease cerebral, 1162 causes of, 1162b clinical features of, 1162, 1162b investigations and management of,

leg ulcers due to, 1223, 1223f Venous hypertension, 1223

1416 • INDEX Venous pulse distinguishing arterial and, 443b jugular, 443b Venous thromboembolism/thrombosis, 169, 975–977 air travellers, 169 causes and consequences of, 975, 976f clinical features, 619, 619b factors predisposing to, 975b at high altitude, 169 investigations of, 619–620, 619f–620f management of, 975–976 anticoagulants, 621 caval filters, 621 thrombolytic therapy, 621 pregnancy and, 620b, 1285 prognosis, 621 prophylaxis of, 976–977, 977b retinal vein, 509f stroke, 1151f Wells score, 187b Ventilation airway pressure release, 204 continuous positive pressure, 202 intermittent positive pressure, 203–204 mechanical ARDS, 198 asthma, 573b COPD, 578 critically ill patients, 202 envenomation, 160 setting, 203, 203f non-invasive, 202, 578 ‘open lung’, 204 pressure support, progressive reduction in, 210 respiratory failure, 567 in respiratory system, 549–550 Ventilation-perfusion matching, 549–550 hypoxaemia and, 192 in old age, 550b Ventricles, of heart, 449f Ventricular aneurysm, in acute coronary syndrome, 496, 496f Ventricular assist devices, 468 Ventricular contractility, reduced, 462b Ventricular ectopic beats, 474, 475f Ventricular fibrillation, 456f cardiac arrest, 456 myocardial infarction, 495 Ventricular inflow obstruction, 462b Ventricular outflow obstruction, 462b Ventricular premature beats, 474–475, 475f Ventricular remodelling, in acute coronary syndrome, 496, 496f Ventricular rupture, in acute coronary syndrome, 496 Ventricular septal defect, 535–536, 536f heart murmur, 460b incidence, 531b tetralogy of Fallot, 536–537 Ventricular septum rupture, in acute coronary syndrome, 496 Ventricular tachyarrhythmias, 480b, 483 Ventricular tachycardia, 475–476, 475b, 475f–476f poisoning, 137b pulseless, 457 Ventricular volume overload, 462b Ventriculitis, 1122 Ventriculography, left, 453–454 Verapamil angina, 490–491, 491b, 500 aortic dissection, 508 arrhythmias, 471–472, 480b, 481 for cluster headache, 1096 hypertension, 513 tachyarrhythmias atrial fibrillation, 471–472 atrial flutter, 470 Verocytotoxigenic Escherichia coli, 263, 263f Verotoxin, 408–409 Verrucae, 1238 Verruga peruana, 272, 272b Vertebral fracture, 995b Vertebroplasty, 1002b for osteoporosis, 1049 Vertical gaze palsy, 1072b Vertigo, 1086 benign paroxysmal positional, 1104, 1104f in older people, 1309 Very low-density lipoproteins, 371–372 Vesicle, definition of, 1211f Vesico-ureteric reflux, 430–431, 431f Vesicovaginal fistula, 437 Vessel wall abnormalities, 970 Vestibular disorders, 1104–1105 Vestibular failure, acute, 1104 Vestibular neuronitis, 780f, 1104 Vestibulitis, 336b Vestibulocochlear (8th cranial) nerve, tests of, 1063b Vibration-controlled transient elastography (Fibroscan), 855 Vibrio cholerae, 104b, 264–265 Vibrio parahaemolyticus, 265 Vibrio vulnificus, 227 Vildagliptin, 747 Villous atrophy, 806 Vinblastine, Hodgkin lymphoma, 963 Vinca alkaloids, 936b Vincristine bronchial carcinoma, 602 leukaemia, 957b non-Hodgkin lymphoma, 966 polyneuropathy, 1139b VIP see Vasoactive intestinal peptide VIPoma, 678b Viral arthritis, 1020–1021 Viral encephalitis, 1121–1123 Viral haemorrhagic fevers, 231f, 245–247, 245b Viral hepatitis, 871–878 acute clinical features of, 871–872 complications of, 872b causes of, 871b chronic, HIV-related, 317–318 features of, 872b icteric, 878 immunisation, 876b investigations for, 872 management of, 872 non-A, non-B, 877 non-A, non-B, non-C (NANBNC), 878 pregnancy and, 1284 sexual, 343–344 transmission, 873b blood donation, 930–931 sexual, 343–344 treatment, 126–127, 127b see also under individual hepatitis viruses Viral infections, 236–250 antiviral agents, 126–128, 127b,

arthritis, 1020–1021 cancer and, 1320b diabetes type 1, 729 gastrointestinal, 249 haemorrhagic fevers, 245–247, 245b immune deficiencies and, 73b nervous system encephalitis, 1121–1123 meningitis, 1118 with neurological involvement, 249–250 respiratory tract, 249 pneumonia, 241, 605b upper, 581–587 with rheumatological involvement, 250 sexually transmitted, 341–344 of skin, 247–249, 1238–1239 HIV/AIDS, 1238–1239 systemic with exanthem, 236–240 without exanthem, 240–247 TSEs, 250, 1126–1127 see also specific infections/infectious diseases Viral load hepatitis B, 875, 875f HIV, 875 Viral meningitis, 1118 Viral warts, 1238–1239, 1239f Virchow’s gland, 764f Virilisation, 657, 1242 Virions, HIV, 309–310 Virology of hepatitis C, 877 skin, 1215 Viruses, 100 bioterrorism, 111 incubation period, 232b life cycle, 101f oncogenic HPV, 343 Visceral leishmaniasis, 282–284, 282f clinical features of, 282 differential diagnosis of, 283 HIV co-infection, 283–284 investigations of, 282–283, 282f management of, 283 Vision, 1069, 1070f double (diplopia), 1088–1090, 1090f loss diabetes, 757 leprosy, 268 older people, 1302f Vision distortion, of ophthalmic disease,

Visual analogue scale, 1343b Visual deficit, 1152 Visual disorders, 1088–1093 antineutrophil cytoplasmic antibody-associated vasculitis, 1041f giant cell arteritis, 1042 Graves’ disease, 631b, 645–646, 645f investigation of, 1168–1169 electrophysiology, 1169 imaging, 1168–1169 perimetry, 1168 positive visual phenomena, 1088 pregnancy and, 1175b stroke, 1152 Visual disturbance, 1088–1093 Visual electrophysiology, 1169 Visual evoked potential (VEP) recording, 1077f Visual fields confrontation for, 631b loss, 1089b Visual Infusion Phlebitis (VIP) score, 251b Visual loss, 1088 Visual pathways, 1069, 1069f Visual phenomena, 1088 Visuo-spatial dysfunction, 1152 Vital capacity (VC), 554f forced, 550b, 554f, 555 Vitamin A (retinol), 712–713 biochemical assessment of, 712b deficiency, 713, 713f dietary sources of, 711b excess, 713 reference nutrient intake of, 711b supplements, 713 toxicity, 713 Vitamin B1 see Thiamin Vitamin B2 see Riboflavin Vitamin B3 see Niacin Vitamin B6 see Pyridoxine Vitamin B12, 715, 943–944 absorption, 943–944 biochemical assessment of, 712b deficiency, 943, 1138b causes of, 944 management of, 945 neurological consequences of, 715, 944b, 1139b neurological findings in, 944b older people, 712b pregnancy, 941b small bowel disease, 944 dietary sources of, 711b reference nutrient intake of, 711b reference range of, 1362b Vitamin C (ascorbic acid), 715–716 biochemical assessment of, 712b deficiency, 715–716, 716b, 716f,

dietary sources of, 711b reference nutrient intake of, 711b Vitamin D, 713 biochemical assessment of, 712b concentrations, seasonal changes in, 1050f deficiency, 713, 1049–1051 older people, 712b, 1049–1051 reference range of, venous blood, 1360b rickets/osteomalacia management,

dietary sources of, 711b excess, 713 metabolism of, 1051f for osteoporosis, 1048, 1048b reference nutrient intake of, 711b reference range of, venous blood, 1360b Vitamin D analogues, hypoparathyroidism, 665 Vitamin D and calcium supplements, osteoporosis prophylaxis, 1049b Vitamin D-deficient osteomalacia, biochemical abnormalities in, 990b Vitamin D-resistant rickets (VDRR),

Vitamin E, 713–714 biochemical assessment of, 712b deficiency, 714 dietary sources of, 711b for non-alcoholic fatty liver, 885 reference nutrient intake of, 711b Vitamin K, 714 antagonists, 938b anticoagulant poisoning, 714 biochemical assessment of, 712b blood coagulation, 714 deficiency, 714 dietary sources of, 711b reference nutrient intake of, 711b supplements, epilepsy in pregnancy, 1103b Vitamins, 711–716, 711b absorption of, 769 biochemical assessment of, 712b deficiency, 712 in old age, 712b dietary sources, 711b excess, 712 fat-soluble, 711b, 712–714 malabsorption of, gastrointestinal disorders associated with, 712b reference nutrient intake, 711b storage of, liver and, 851 water-soluble, 711b, 714–716 see also specific vitamins Vitiligo, 1257–1258, 1257f, 1326 Vitrectomy, 1174 Vitreous gel, in eye, 1168 VLDL see Very low-density lipoproteins Voiding see Micturition Volatile substance, poisoning from, 144 Volume of distribution (Vd), 18, 18f Vomiting, 227–230, 780 causes of, 777b, 780f cyclical vomiting syndrome, 803 functional causes of, 803 palliative care, 1353–1354, 1353f peptic ulcer, 801–802 psychogenic, 803 Von Gierke disease, 370b von Hippel-Lindau disease, 1132, 1321b von Willebrand disease (vWD), 974, 974b von Willebrand factor, 974 Voriconazole, 125b, 126 acute leukemia and, 957 aspergillosis, 598 candidiasis, 302 fusariosis, 302–303 mycetoma, 301 paracoccidioidomycosis, 304 VT see Ventricular tachycardia Vulva chronic pain of, 336, 336b herpetic ulceration of, 342f

INDEX • 1417 pruritus, 336, 336b schistosomal papilloma, 295–296 Vulvodynia, 336b VUR see Vesico-ureteric reflux W Waddling gait, 1063b Waist circumference, 693b Waldenström macroglobulinaemia, 966 Wallenberg syndrome, 1072b Warfarin, 939 adverse reactions of, 22b for antiphospholipid syndrome, 978 for atrial fibrillation, 472 bleeding in, 940 drug interaction of, 24b indications for, 938b monitoring, 922 for older people, 32b, 472b pharmacodynamic, 24b pharmacokinetic, 24b poisoning, 148b in pregnancy, 620b, 1282 problems with, 939 pulmonary embolism, 620b for stroke prevention, 1161f for systemic lupus erythematosus,

venous thromboembolism, 620b Warfarin-like rodenticides, 148b Warm antibodies, 949 Warm autoimmune haemolysis, 949 Warts anogenital, 342–343 seborrhoeic, 1234 viral, 1238–1239, 1239f Water absorption and secretion of, 769, 769f basic daily requirements of, 353b depletion, 353 see also Dehydration distribution of, 349, 349f excess, 354b homeostasis, 349, 355–360 inhalation, 169–170 investigations, 357–358 presenting problems in, 352–355 reabsorption, 350 renal handling, 356f restriction of, for ascites, 863 safe, for HIV-related exposure, 323 total body (TBW), 349 Water deprivation test, for diabetes insipidus, 688b ‘Waterbrash’, 791–792 Waterhouse-Friderichsen syndrome, 671b Watermelon stomach, 1037–1038 Watery/dry eye, of ophthalmic disease,

Wax baths, 1001 Weakness, 1081–1083, 1082b, 1082f facial, 1082–1083 ICU-acquired, 211–212 muscle, 1000, 1000b stroke and, 1152 Weal, definition of, 1252–1253 Weaning, from respiratory support, 209–210 Weber syndrome, 1072, 1072b Wegener’s granulomatosis, 1171 Weight, and endocrine disease, 630f Weight control, for musculoskeletal disease, 1001–1002 osteoarthritis, 1012 Weight gain history of, 700 reversible causes of, 700, 700b see also Obesity Weight loss, 785–786 after gastric resection, 801 anorexia nervosa and, 1203 cancer patients, 1323 causes of, 786f diabetes and, 729–730, 732 diets, 701–702, 701b HIV-related, 313, 313f investigations, 786 musculoskeletal disease, 1001–1002 obesity, 701 in palliative care, 1354 pancreatitis and, 840 physiological causes of, 785 rheumatoid arthritis, 1023 Weight management, for diabetes,

Weil-Felix test, 108 Weil’s disease, 258 Wells score, 187b Wenckebach phenomenon, 477f Werner’s syndrome, 41, 689b Wernicke-Korsakoff syndrome, 1195 prevention of, 1195 Wernicke’s aphasia, 1088f Wernicke’s area, 1066 Wernicke’s encephalopathy, 714 West Nile encephalitis, 250, 1121–1122 West Nile virus, 250 Western blot, 107 WG see Wegener’s granulomatosis Wheezing, asthma, 568 Whipple’s disease, 809, 809b Whipple’s operation, under-nutrition and, 706 Whipple’s triad, 676–677, 677f Whipworm (Trichuris trichiura), 290 White blood cells, 917 appearance of, 926f count acute fever without localising signs, 232b differential, 1362b high, 926–927 low, 925–926 viral hepatitis and, 872 formation, 917 polymorphonuclear see Neutrophils reference values, 1362b results of, interpreting, 926b White eye, 1170 White spirit, poisoning, 148b Whiteheads, 1242 Whitlow, herpetic, 247f WHO see World Health Organization Whole bowel irrigation, 136 Whole-exome sequencing, 54b Whole-genome sequencing, 54b Whooping cough, 582 antimicrobial prophylaxis, 119b immunisation, 115b incubation period, 111b periods of infectivity, 111b Wickham’s striae, 1252 Williams’ syndrome, 44b Wills, living, 1307 Wilm’s tumour, 1321b Wilson’s disease, 718, 896–897 investigations, 897 Kayser-fleischer rings and, 896–897 liver disease and, 896 liver function test (LFT) abnormality in, 854b neurological aspects of, 1115 Windkessel effect, 447 Winterbottom’s sign, 279 Withdrawal effects, 16, 16b Wnt, in bone remodelling, 986b Wolbachia spp., 291 Wolff-Parkinson-White (WPW) syndrome, 473–474, 474f Wood’s light, 1214 World Health Organization (WHO) analgesic ladder, 1350, 1351f classification of psychiatric disorders, 1180, 1180b ICD-10, 1180 macronutrient recommendations, 698b refeeding diet, 705b Wound dressing, 1226–1227, 1227b Wound infections staphylococcal, 251, 251f tetanus, 1126 WPW syndrome see Wolff-ParkinsonWhite (WPW) syndrome Wrist fracture, 1045f pain, 998 Writer’s cramp, 1086 Wuchereria bancrofti infection, 233b, 290, 291f X X chromosome, 38 abnormalities see individual conditions inactivation, 48–49 see also X-linked X-linked agammaglobulinaemia, 78 X-linked hypophosphataemic rickets (XLH), 1052 X-linked inheritance, 47b, 48–49 X-rays, 164, 164f for acute respiratory distress syndrome, 198, 199f for ankylosing spondylitis, 1030f of body packers, 144f cardiovascular system see Chest radiography/X-ray for Charcot foot, 759f chest see Chest radiography/X-ray for chest pain, 178 for gastrointestinal disease, 772, 773b, 773f achalasia, 795f contrast studies, 773 inflammatory bowel disease, 818f, 819–820 hepatobiliary disease, 164 hyperparathyroidism, 663 for musculoskeletal disease, 988, 988b bone fractures, 994–995, 1045f bony metastases, 662 Charcot joint, 1058f chondrocalcinosis, 1016f complex regional pain syndrome (CRPS) type 1, 1055f CPPD crystal deposition disease,

fracture, 994–995 osteoarthritis, 1009f–1011f osteomalacia, 1052, 1052f osteonecrosis, 1055 osteoporosis, 1045f osteosarcoma, 1056–1057 Paget’s disease, 1054f reactive arthritis, 1032 rheumatoid arthritis, 1025 supraspinatus tendon calcification, 1017f of nervous system, 1073b properties of, 164f respiratory system see Chest radiography/X-ray of skull, 1073 of spine, 1075f Xa inhibitors, 472–473 Xanthelasma cholestatic jaundice and, 861b hyperlipidaemia and, 346f Xanthomas, 1264 biliary cholangitis, 887 cholestatic jaundice and, 861b hyperlipidaemia and, 346f tendon, 375 Xanthomatosis, cerebrotendinous, 375b Xeroderma pigmentosum, 1221b, 1321b Xerophthalmia, 713 Xerostomia, 1038 XLH see X-linked hypophosphataemic rickets Y Y chromosome, 38 microdeletions of, 656 Yaws, 253–254, 254b Yellow Card scheme, 23 Yellow fever, 243f, 244–245, 245b incubation period of, 245b vaccination, 245 Yersinia enterocolitica, 264 in Graves’ thyrotoxicosis, 644 Yersinia pestis, 259 Young adults, diabetes mellitus in, 753–754 Young’s syndrome, 550 Z Zanamivir, 127, 127b, 241 Zero-order kinetics, 19 Zidovudine (ZVD), 324b adverse reactions of anaemia, 322 lipodystrophy, 326f neutropenia, 322, 926b for HIV/AIDS, 324–325, 324b muscle pain/weakness from, 1000b for onychomycosis, 316 Zika virus infection, 247 in pregnancy, 235b Zinc, 717 deficiency, 717 dietary sources of, 717b refeeding diet, 705b reference nutrient intake of, 717b reference range of urine, 1361b venous blood, 1360b supplements, 717 for Wilson’s disease, 897 Zinc phosphide poisoning, 148 Zinc therapy, for Wilson’s disease, 897 Zoledronic acid bone metastases, 1329 for osteoporosis, 1048b for Paget’s disease, 1054, 1054b Zollinger-Ellison syndrome, 802 Zoonoses transmission of, 110 viral haemorrhagic fevers, 245–246 Zoster sine herpete, 239

7KLVSDJHLQWHQWLRQDOO\OHIWEODQN